Most recent edit on 2007-11-23 11:35:21 by KathyFromEngland
Additions:
~*Primary Tumors Can Chose Among (at Least) Three Different Strategies To Spread And Form Metastases
*Cancer Susceptibility May Be Influenced By Tiny Genes, Jefferson Scientists Find
Cancer Susceptibility May Be Influenced By Tiny Genes, Jefferson Scientists Find
Article Date: 29 May 2007 - 14:00 PDT
New evidence indicates that small pieces of noncoding genetic material known as microRNAs (miRNAs) might influence cancer susceptibility. Differences in certain miRNAs may predispose some individuals to develop cancer, say researchers collaborating in a joint study at the Kimmel Cancer Center at Jefferson in Philadelphia, Ohio State University Medical Center in Columbus and Roswell Park Cancer Institute in Buffalo.
MiRNAs play a number of roles in biological regulation, including development and cell differentiation, helping to determine what type a cell ultimately becomes. But when damaged, they can contribute to cancer by either turning on cancer-causing genes or by inhibiting tumor-blocking genes. The ways that
MiRNAs are expressed have been used to profile tumor types in humans.
To see if miRNAs could affect cancer risk, Linda Siracusa, Ph.D., associate professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University, research associate Cinzia Sevignani, Ph.D., and co-workers George Calin, M.D., Ph.D., and Carlo M. Croce, M.D., at Ohio State University in Columbus and Peter Demant, M.D., Ph.D., at Roswell Park Cancer Institute in Buffalo compared the mouse chromosome locations of genes known to affect cancer susceptibility - or "susceptibility loci" - in eight different types of tumors to the locations of mouse miRNAs.
Reporting in the journal Proceedings of the National Academy of Sciences, the team showed that overall, miRNAs were found 1.5 times more likely to be in susceptibility regions than in non-susceptibility regions. "
MiRNAs appear to be frequently located near places in the mouse genome that affect cancer susceptibility," the researchers say, suggesting that miRNAs could be "a new family of cancer tumor susceptibility genes."
Susceptibility loci are forms of the same gene. While one form may give a person a higher risk of developing a cancer, an alternate form may confer resistance to that particular type of cancer.
The researchers identified changes in the DNA sequences surrounding several miRNAs that were located at or near the susceptibility areas in mouse strains with a variety of tumor types. The team also looked at which mouse strains were cancer-resistant and which were susceptible to cancer, uncovering seven miRNAs that had genetic sequence differences between the two groups. Five of these miRNAs had changes within their predicted promoter regions, which turn on and potentially regulate the genes' expression levels.
"We have hypothesized that changes in the promoter regions could affect the levels of miRNAs, which could influence a person's lifetime risk of cancer," Dr. Siracusa notes.
Dr. Siracusa and her collaborators plan to examine miRNA expression levels among inbred mice strains. "Could the level of a particular miRNA affect the expression of other genes and regulate the stability of the RNA transcript" she asks. "Having a slightly lower level of a particular miRNA could make a person more susceptible to a particular cancer or the reverse, or a slightly increased level might protect that person."
http://www.medicalnewstoday.com/articles/71979.php∞
Edited on 2007-11-14 01:41:04 by KathyFromEngland
Additions:
~*UCSD Discovery Raises Questions About Some Therapies Designed To Treat Half Of All Human Cancers
*Primary Tumors Can Chose Among (at Least) Three Different Strategies To Spread And Form Metastases
Primary Tumors Can Chose Among (at Least) Three Different Strategies To Spread And Form Metastases
15 May 2007
Primary tumors can spread towards distant organs as single cells, when they lose a protein called E-cadherin. But they can also move as a cell cluster, if they sense the activity of a protein called podoplanin. Or, in a third scenario, they can sprout lymphatic vessels that facilitate their dissemination when they perceive the presence of two molecules called VEGF-C and VEGF-D. The existence of several different kinds of metastatic mechanisms was advanced today by Gerhard Christofori, head of the Tumor Biology group at the Center of Biomedicine of the University of Basel, during the closing keynote of the Workshop on Cell Migration: From Molecules to Organisms and Diseases promoted by the European School of Molecular Medicine (SEMM) and the University of Milan, in collaboration with IFOM The FIRC Institute for Molecular Oncology of the Italian Foundation for Cancer Research, and IEO European Institute of Oncology. The Workshop was held at the IFOM-IEO Campus (via Adamello, 16, Milan) that was recently opened and represents the biggest area dedicated to the oncological research in Europe.
Until recently, cancer scientists thought that tumors followed a unique pattern of dissemination within the body, being the first step triggered by the detachment of single "riot" cells that were freed from the original tissue and became insensitive towards the surroundings. Now, this scenario has completely changed, as deeper investigations have revealed the existence of at least three distinct mechanisms of spreading, each of them relying on diverse signaling molecules. "When single cells detach from the "mother tissue" explains Christofori we can observe the inhibition of a protein called E-cadherin. Its absence represents a molecular switch able to trigger a cascade of events leading to single cell migration".
This mechanism, however, is not the only one. As Christofori proved, the invasion of surrounding tissues by clusters of malignant cells is promoted by a protein called podoplanin. "We were able to show that podoplanin induces the formation of so-called filopoda, long protrusions stemming from the front line of the tumor that sense the environment and help the cells to make decisions as where to go."
The third process identified by Christofori and colleagues involves the two lymphoangiogenic (i.e. involved in the development of novel lymphatic vessels) growth factors VEGF-C and VEGF-D. Due to upregulated expression of these two molecules, the tumor induces an increase of lymphatic vessel density in its surroundings, which in turns facilitates the dissemination of tumor cells (through the lymphatic system) and the formation of lymph node metastases.
"These results altogether comments Ugo Cavallaro, IFOM scientist and member of the Workshop Scientific Committee could change the way scientists have so far thought about metastases formation, since the three processes do not exclude one another in an individual patient." These findings open then new possibilities for clinical approach, which should be diversified depending on what mechanism(s) is observed in each patient.
IFOM - THE FIRC INSTITUTE OF MOLECULAR ONCOLOGY FOUNDATION
Via Adamello 16
20139 Milano
http://www.ifom-ieo-campus.it∞
http://www.medilexicon.com/medicalnews.php?newsid=70886∞
Edited on 2007-05-08 11:35:08 by KathyFromEngland
Additions:
Using mutant mice that express the most common forms of human p53 mutants, Xu's team found that the mutant proteins affected a multi-protein complex called Mre11complex that attaches to double-stranded breaks in DNA, the key genetic material of the cell, and participates in its repair. This prevented cells in the mice, as well as human cancer cells, from recognizing DNA damage, the scientists discovered, and led to genetic instabilities such as the translocation of chromosomes that can significantly increase genetic mutations in the cells, eventually promoting the growth of cancer cells.
Deletions:
Using mutant mice that express the most common forms of human p53 mutants, Xu's team found that the mutant proteins affected a multi-protein complex called Mre11complex that attaches to double-stranded breaks in DNA, the key genetic material of the cell, and participates in its repair. This prevented cells in the mice, as well as human cancer cells, from recognizing DNA damage, the scientists discovered, and led to genetic instabilities such as the translocation of chromosomes that can significantly increase genetic mutations in the cells, eventually promoting the growth of cancer cells.
Edited on 2007-05-08 11:33:26 by KathyFromEngland
Additions:
~*One Wwox Is Not Enough For Cancer Protection
*UCSD Discovery Raises Questions About Some Therapies Designed To Treat Half Of All Human Cancers
UCSD Discovery Raises Questions About Some Therapies Designed To Treat Half Of All Human Cancers
08 Apr 2007
Biologists at the University of California, San Diego have uncovered a new way by which common mutants of a critical human tumor-suppressing gene can promote tumor progression, a finding which may explain why some cancer treatments targeting human cancers with these mutants have proven ineffective.
Their discovery, detailed in a paper published in this week's early online issue of the journal Nature Cell Biology, also raises questions about the effectiveness of certain cancer therapies that may be unintentionally enhancing rather than retarding the progression of human cancers by expressing the mutated cancer-promoting tumor suppressor.
"Our findings could explain the resistance of human cancer cells expressing the mutants of this important tumor suppressing gene, p53, to current cancer therapies," says Yang Xu, an associate professor of biology at UCSD who headed the research team, which included Hoseok Song, a postdoctoral fellow at UCSD, and Monica Hollstein, a collaborator at England's University of Leeds.
Scientists have long known that the p53 gene is critical in suppressing the formation of tumors in the human body. Over the past 20 years, researchers have also discovered that when the p53 gene is mutated, which occurs in about half of all cancer cases, the p53 mutant protein not only loses its tumor suppressing properties, but can promote the progression of cancer and the resistance of cancer cells to drug therapies.
"The expression of p53 mutants is correlated with the poor prognosis of cancer patients," notes Xu. "Therefore, it is critical to understand the gain of function of p53 mutants in promoting cancer and resistance to current cancer therapy."
Using mutant mice that express the most common forms of human p53 mutants, Xu's team found that the mutant proteins affected a multi-protein complex called
Mre11complex that attaches to double-stranded breaks in DNA, the key genetic material of the cell, and participates in its repair. This prevented cells in the mice, as well as human cancer cells, from recognizing DNA damage, the scientists discovered, and led to genetic instabilities such as the translocation of chromosomes that can significantly increase genetic mutations in the cells, eventually promoting the growth of cancer cells.
"Current cancer treatments, including radiotherapy and many forms of chemotherapy, kill cancer cells by inducing DNA double-stranded break damage in their genomes," says Xu. "Our findings could explain why cancer cells with p53 mutants are resistant to such therapies."
In addition, because such treatments attempt to kill cancer cells by inducing genetic mutations through DNA strand-break damage, the findings suggest they may lead to genetic mutations if the DNA damage is not repaired efficiently and properly. In other words, they may be unintentionally enhancing rather than retarding cancer progression by inducing genetic mutations of the mutant cancer-promoting genes.
"These cancer treatments may be further promoting genetic instability in p53 mutant-expressing cancer cells because they lack the ability to recognize DNA damage," says Xu.
The project was supported by grants from the National Institutes of Health and Department of Defense.
www.ucsd.edu
http://www.medilexicon.com/medicalnews.php?newsid=67328∞
Edited on 2007-05-08 11:30:43 by KathyFromEngland
Additions:
~*Gadd45a Wakes Sleeping Genes
Gadd45a Wakes Sleeping Genes
The cell uses this mechanism of putting genes to sleep and waking them up again when needed for many regulation processes. Scientists have already found out how the methyl groups are attached. The reverse process of demethylation, however, has been poorly understood so far. Researchers from the divisions of Professor Dr. Christof Niehrs and Professor Dr. Frank Lyko at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now been able to identify a protein called Gadd45a as a key player in demethylation. Gadd45a is a long known protein that is involved in many cellular processes.
The researchers showed in a series of experiments that an increase of Gadd45a levels in the cells wakes deactivated genes from their sleep. Control experiments showed that methyl groups are indeed no longer attached to genes thus reactivated. In contrast, if Gadd45a is deliberately switched off, hypermethylation of many DNA areas is the result. When removing the methyl groups, as the investigators have further demonstrated, Gadd45a interacts with enzymes that are involved in DNA repair. The data obtained by Niehrs and Lyko indicate that Gadd45a induces DNA-cutting enzymes of the DNA repair troops to remove the methylated areas, which are subsequently replaced again by unmethylated building blocks.
"The role of Gadd45a for cancer development is shown in mice lacking this protein," Niehrs und Lyko explained. "These animals suffer particularly often from malignant tumors. Now we are able to make sense of this: The knockdown of Gadd45a in these animals causes excessive methylation of tumor suppressor genes so that many of the natural tumor 'brakes' fail to work. Therefore, Gadd45a may also become an interesting target for clinical oncology."
The study appears in PLoS ONE, the international, peer-reviewed, open-access, online publication from the Public Library of Science (PLoS).
Deletions:
~*Gadd45a Wakes Sleeping Genes
Gadd45a Wakes Sleeping Genes
The cell uses this mechanism of putting genes to sleep and waking them up again when needed for many regulation processes. Scientists have already found out how the methyl groups are attached. The reverse process of demethylation, however, has been poorly understood so far. Researchers from the divisions of Professor Dr. Christof Niehrs and Professor Dr. Frank Lyko at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now been able to identify a protein called Gadd45a as a key player in demethylation. Gadd45a is a long known protein that is involved in many cellular processes.
The researchers showed in a series of experiments that an increase of Gadd45a levels in the cells wakes deactivated genes from their sleep. Control experiments showed that methyl groups are indeed no longer attached to genes thus reactivated. In contrast, if Gadd45a is deliberately switched off, hypermethylation of many DNA areas is the result. When removing the methyl groups, as the investigators have further demonstrated, Gadd45a interacts with enzymes that are involved in DNA repair. The data obtained by Niehrs and Lyko indicate that Gadd45a induces DNA-cutting enzymes of the DNA repair troops to remove the methylated areas, which are subsequently replaced again by unmethylated building blocks.
"The role of Gadd45a for cancer development is shown in mice lacking this protein," Niehrs und Lyko explained. "These animals suffer particularly often from malignant tumors. Now we are able to make sense of this: The knockdown of Gadd45a in these animals causes excessive methylation of tumor suppressor genes so that many of the natural tumor 'brakes' fail to work. Therefore, Gadd45a may also become an interesting target for clinical oncology."
The study appears in PLoS ONE, the international, peer-reviewed, open-access, online publication from the Public Library of Science (PLoS).
Edited on 2007-05-02 01:37:04 by KathyFromEngland
Additions:
~*New Cell Type Identified In Cancer Development
*One Wwox Is Not Enough For Cancer Protection
One Wwox Is Not Enough For Cancer Protection
20 Mar 2007
A new study shows that the loss of even one of the two copies of a particular tumor-suppressor gene greatly increases the risk that lung cancer will develop in experimental animals.
The study examined the Wwox gene, a suspected tumor-suppressor gene, and showed that even when mice have one working copy of the gene, they nonetheless develop five times more lung tumors than do mice with both copies of the gene. Tumor-suppressor genes normally keep damaged cells from becoming cancerous.
The findings were published in the Proceedings of the National Academy of Sciences by investigators at the Ohio State University Comprehensive Cancer Center.
"Classic tumor-suppressor genes don't increase cancer risk until cells lose both copies of the gene or when both copies are mutated," says first author Rami I. Aqeilan, research assistant professor of molecular virology, immunology and medical genetics at Ohio State.
"These findings suggest that losing one copy of Wwox can predispose normal cells to become cancerous. This emphasizes the importance that Wwox may have in initiating the disease."
Surprisingly, the research also links loss of the gene and a form of bone cancer called chondroid osteosarcoma. The research may offer the first animal model for the study of this human disease.
Osteosarcoma is rare in humans, but it is the most common form of bone tumor and the second highest cause of cancer-related death in children, after leukemia, he says.
"Osteosarcoma forms at an early age due to the rapid growth of the bones and skeleton," says Aqeilan, who is also a researcher with the Ohio State human cancer genetics program.
"These mice have given us a very interesting clue that loss of both copies of Wwox gene may initiate tumors in the bone."
This study initially set out to prove that Wwox is a bona fide tumor suppressor gene. The gene is missing or altered in 85 percent of lung cancers, 65 percent of breast cancers, and in a high proportion of cancers of the stomach, colon and prostate and some lymphomas.
Wwox is located on chromosome 16, spanning a region called a fragile site, a place where the chromosome often breaks during environmental stress. Breakage at fragile sites results in the loss of pieces of chromosomes and in chromosomal abnormalities. Both can lead to cancer.
"The location of this gene in a fragile site is important," Aqeilan says. "Our findings suggest that if an environmental stress, such as tobacco smoke, causes the loss of one copy of the gene, it might predispose a person to lung cancer."
For this study, Aqeilan and colleagues at Ohio State and the University of Massachusetts Medical School developed strains of mice that were missing one copy of the Wwox gene. The mice were bred to produce animals lacking both Wwox genes and mice having both copies of the gene. Mice with both copies served as controls.
Mice born with no copies of Wwox died by four weeks of age. Thirteen of those animals were studied closely, and four of them (31 percent) showed evidence of early osteosarcoma.
Of 58 animals with only one copy of the gene, 16 percent - or nearly one in six - developed lung cancer compared with only 3 percent of the control mice, a five-fold increase.
The researchers also exposed animals with one copy of the gene to a carcinogen, ethyl nitrosourea, to learn about the kinds of tumors that Wwox might help suppress.
Of 46 animals exposed to the chemical, 80 percent developed tumors vs. just under half of control animals that had both copies of the gene. Most of the animals developed lung cancer or lymphoma. Liver cancer, squamous cell carcinoma and malignant B-cell infiltration into the liver and lungs developed in small numbers.
The researchers are now looking for the loss of Wwox in human osteosarcomas and are generating a mouse model that will allow them to study the ability of the gene to reverse tumor growth after it is restored in adult animals with cancer.
"Wwox-mutant mice are useful in understanding the role of this gene in human cancer, and they provide models for studying the carcinogenecity of compounds, and the development, prevention and treatment of common cancers," Aqeilan says.
http://www.medilexicon.com/medicalnews.php?newsid=65399∞
Edited on 2007-03-19 07:26:37 by KathyFromEngland
Additions:
~*More Gene Mutations Drive Cancer Than Previously Thought
*New Cell Type Identified In Cancer Development
New Cell Type Identified In Cancer Development
19 Mar 2007
Scientists have discovered a new type of cell that appears to play a role in the development of cancer - a highly volatile, precancerous stem cell that can either remain benign or become malignant, depending upon environmental cues. The finding may help define the role of cancer stem cells in the growth and recurrence of the disease as well as offer new options for cancer prevention, detection and treatment.
Current cancer stem cell theory holds that tumors are comprised of a variety of cell types. Among them is a small subset of rather primitive cells that, like other stem cells in the body, are self-sustaining, self-renewing and multipotent, or capable of creating other types of cells and tissues. These cells are different from normal stem cells, however, in that injecting even as few as 100 of them into laboratory animals will cause cancer. Scientists have dubbed these cancer stem cells.
Cancer stem cells were first identified in leukemia, but they have also been found in breast, brain, colon and prostate cancers. Because they are rather unstable, they are notoriously tricky to isolate and describe. They are also resistant to virtually any kind of treatment, and some scientists believe they are the reason cancer recurs. Until now, no one has known how they arise.
But a team of scientists, led by Dr. Jian-Xin Gao, a researcher in the department of pathology at Ohio State University Medical Center, has identified a new set of cells he calls precancerous stem cells (pCSCs).
These cells share some of the characteristics full-fledged cancer stem cells have, but they are different in that they respond to distinct cell signals that determine their ultimate fate - whether they will continue to grow into cancer or cancer stem cells, lie inactive or be eradicated by the body's immune system.
"These hybrid cells are very complex. They have properties of normal and abnormal stem cells, and do not always lead to cancer - only some of the time, and under very specific conditions," says Gao, who is also a member of the Ohio State University Comprehensive Cancer Center. "These cells appear to be a whole new class of cells involved in the development of cancer."
The study appears in
PLoS ONE, the international, peer-reviewed, open-access, online publication from the Public Library of Science (
PLoS).
The findings emerged from a study in which Gao and his colleagues were investigating tumor growth in mice. They discovered that some of the animals had lymphoma, and that several cell lines from those tumors carried a unique and provocative phenotype, or surface protein signature: They carried neither the Sca-1 or c-kit markers, hallmarks of normal bone marrow stem cells, nor the lineage markers most of the cancer cells had, but they did exhibit stem-like structure. The researchers suspected these unusual cells might be precancerous stems cells and designed several tests and experiments to find out more about them.
They selected three pCSC lines and injected them subcutaneously, intraperitoneally or intravenously into three groups of mice. The mice represented different levels of immune function: One group was comprised of severe combined immune deficient mice, a second group was composed of mice whose immune systems had been knocked out by radiation, but had been partially restored by an infusion of bone marrow cells; and the third group was made up of normal, healthy mice.
The results showed that the strength of the immune system affected whether or not the mice got cancer. The scientists found that the pCSCs, like normal stem cells, had the ability to create various types of benign cells in mice with healthy or recovering immune systems. These daughter cells, however, were likely to die, especially when they encountered signals to further differentiate - a strong contrast to the behavior of normal stem cells.
"We thought this was an interesting development," says Gao, "because these precancerous cells were actually stopped from becoming malignant. We are calling this process 'differentiation-induced cell death,' a protective mechanism the body may invoke to prevent pCSCs from maturing into full-blown cancer stem cells."
It was a different story with the mice with impaired immune systems, however. In those animals, the pCSCs developed into solid tumors, developing additional mutations in different cell types as they grew and spread.
Additional experiments revealed that the piwil2 gene may exclusively regulate the process of pCSC development.
Gao says these data suggest some important characteristics of pCSCs.
"First, it appears that pCSCs require some sort of signal, or cue, from their immediate environment that directs them to become benign or malignant. Second, it seems clear that they can be detected and eliminated by a robust immune system when they are actively developing into cancer cells."
Cancer stem cell theory is still in its infancy, but Gao feels these findings, if validated by additional studies, point to a candidate population of precancerous cells that may one day be a valuable target for new drugs and treatments. "To cure cancer, we have to eliminate all potential malignant cells - not just the ones within easy reach."
http://www.medilexicon.com/medicalnews.php?newsid=65223∞
Edited on 2007-03-08 13:08:13 by KathyFromEngland
Additions:
~*Gadd45a Wakes Sleeping Genes
*More Gene Mutations Drive Cancer Than Previously Thought
More Gene Mutations Drive Cancer Than Previously Thought
08 Mar 2007
Scientists surveying the human genome have found that many more gene mutations drive the development of cancer than previously thought.
The survey is reported in the journal Nature.
In the largest survey of its kind, an international team comprising over 60 scientists from the UK, Hong Kong, the Netherlands, Belgium, USA and Australia, working for the Cancer Genome Project, examined more than 500 genes and 200 cancers and sequenced more than 250 million letters of DNA code.
They found about 120 new genes that drive the development of cancer cells.
All cancers are thought to be caused by gene mutations. Genes control the behaviour of cells, for example they tell them when to divide and when to die; thus abnormal genes either issue faulty instructions or the correct instructions at the wrong time or both, which leads to abnormal cell development and cancer.
Michael Stratton from the Wellcome Trust's Sanger Institute in Cambridge, UK, and one of the survey team leaders said "This is a lot more cancer genes than we expected to find."
The survey also discovered that two types of gene mutation are involved in cancer: driver and passenger. The driver mutations are thought to drive the rampant cell growth that causes cancer, while the passenger ones, which exist in much larger numbers, just go along for the ride.
Of the 1,000 cancer-specific mutations found, the team believes that about 150 of them are driver genes.
It is not easy to spot the difference between a driver and passenger gene, something this survey suggests will pose a great challenge for scientists.
Dr Andy Futreal, co-leader of the Cancer Genome Project explained "It turns out that most mutations in cancers are passengers."
"However, buried amongst them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought," he added.
The types of genes that Futreal and his colleagues investigated are known as kinase genes. They have been linked with cancer development before. These protein genes act like relays, switching different types of cell behaviour on and off.
One example of a kinase gene is the BRAF, which an earlier study showed to be mutated in 60 per cent of malignant melanomas. This led to the development of new drugs, now in clinical trials, to treat melanoma.
This broader survey covered a wider range of the more common types of cancer, including breast, lung, colorectal and stomach cancers.
The researchers also found that a particular group of kinase genes "involved in the Fibroblast Growth Factor Receptor signalling pathway was hit much more than we expected, particularly in colorectal cancers," said Dr Futreal.
The survey also showed that buried inside each mutation are important coded messages, and that the type of mutation varied widely between different cancer types. This suggests that in some cases the process of mutation begins decades before the cancer presents itself.
It is as though gene mutations are "archeological sites" where written inside the DNA of each cell is a historical coded pattern that reveals the original cause of the cancer. In some cases the code can be deciphered, for instance damage from UV radiation or sunlight, or carcinogens in tobacco smoke, but in other cases the code is too hard to crack, which means more research effort is needed to unravel their mysteries.
"This study vindicates all of the effort that went into the Human Genome Project," said Dr Mark Walport, Director of the Wellcome Trust, the largest independent charity in the UK and the second largest medical research charity in the world, and the sponsors of the survey.
"Understanding the mutations that cause cancer is crucial in order to develop accurately targeted treatments," added Dr Walport.
http://www.medilexicon.com/medicalnews.php?newsid=64804∞
Edited on 2007-02-11 08:38:52 by KathyFromEngland
Additions:
~*Major Player In Cell Growth Identified By Cancer Biologists
*
Gadd45a Wakes Sleeping Genes
Gadd45a Wakes Sleeping Genes
11 Feb 2007
For several years now, cancer researchers have been studying a mechanism that contributes to the development of malignant tumors: The cell attaches small molecules containing a carbon atom, called methyl groups, to specific building blocks of DNA, thereby individually switching off the genes thus labeled. This silencing also affects the function of many tumor suppressor genes, which, in their unmethylated state, put the brakes on uncontrolled cell growth. In contrast to 'real' mutations, where DNA building blocks are exchanged or lost, these epigenetic changes are reversible. Therefore, this mechanism is considered to be a promising approach in fighting cancer.
The cell uses this mechanism of putting genes to sleep and waking them up again when needed for many regulation processes. Scientists have already found out how the methyl groups are attached. The reverse process of demethylation, however, has been poorly understood so far. Researchers from the divisions of Professor Dr. Christof Niehrs and Professor Dr. Frank Lyko at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now been able to identify a protein called
Gadd45a as a key player in demethylation.
Gadd45a is a long known protein that is involved in many cellular processes.
The researchers showed in a series of experiments that an increase of
Gadd45a levels in the cells wakes deactivated genes from their sleep. Control experiments showed that methyl groups are indeed no longer attached to genes thus reactivated. In contrast, if
Gadd45a is deliberately switched off, hypermethylation of many DNA areas is the result. When removing the methyl groups, as the investigators have further demonstrated,
Gadd45a interacts with enzymes that are involved in DNA repair. The data obtained by Niehrs and Lyko indicate that
Gadd45a induces DNA-cutting enzymes of the DNA repair troops to remove the methylated areas, which are subsequently replaced again by unmethylated building blocks.
"The role of
Gadd45a for cancer development is shown in mice lacking this protein," Niehrs und Lyko explained. "These animals suffer particularly often from malignant tumors. Now we are able to make sense of this: The knockdown of
Gadd45a in these animals causes excessive methylation of tumor suppressor genes so that many of the natural tumor 'brakes' fail to work. Therefore,
Gadd45a may also become an interesting target for clinical oncology."
The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V.).
http://www.medilexicon.com/medicalnews.php?newsid=62792∞
Edited on 2007-02-11 08:36:00 by KathyFromEngland
Additions:
~*Scientists Are Uncovering New Meaning In The Genetic Code
*Major Player In Cell Growth Identified By Cancer Biologists
Major Player In Cell Growth Identified By Cancer Biologists
09 Feb 2007
When cells go about the business of dividing, they can get sidelined. Maybe there aren't enough nutrients. Maybe there aren't the right signals to resume multiplying. Either way, cells go quiet.
What can restart cell division -- the process that drives the development of embryos, the renewal of hair, skin and blood, and the creation of cancer -- is a single transcription factor called GABP, according to new research from The Warren Alpert Medical School of Brown University and Rhode Island Hospital.
The work, published online in Nature Cell Biology, introduces a new pathway that can be manipulated to control cell growth. Since cell growth is a fundamental biological process, the research may shed light on everything from miscarriages to muscular dystrophy. The main application, however, is cancer. Since a key characteristic of cancer cells is unchecked growth, the research identifies potential targets for new treatments.
"As a scientist and a physician, I am tremendously excited," said Alan Rosmarin, M.D., an associate professor in the Department of Medicine and the Department of Molecular Biology, Cell Biology and Biochemistry at Brown and director of clinical oncology research for Lifespan, Rhode Island's largest health care system. "This discovery not only adds to our basic understanding of cell division, it could lead to better cancer drugs. And they're needed. Cancer touches everyone."
During the cell cycle, the four-phase process of cell division, there is a period when the biochemical brakes are put on and cells become inactive. Then the process is kick-started and cells move into the so-called S phase, when DNA is duplicated. This is a critical juncture. If genes are missing or broken, these alterations are passed on to the new cell -- and could result in disability or in diseases such as cancer.
So biologists are keenly interested in identifying the accelerators that rev-up cell division. Ets transcription factors, a family of gene-regulating proteins that are major players in embryonic and cancer development, seemed obvious culprits. Rosmarin, a hematologist-oncologist, studies one member of the Ets family called GABP. This transcription factor helps make a variety of cells, including white blood cells. If those cells develop abnormally, leukemia results.
But the exact function of GABP in the cell cycle wasn't known. Rosmarin wanted to find out. So he and members of his laboratory created mice that carried a mutation -- tiny DNA sequences were inserted into their GABP-making gene. These DNA bits would serve as a time bomb of sorts, deleting a critical piece of the gene when given a chemical signal.
From these mice, Rosmarin and his team grew fibroblasts -- common connective tissue cells -- in a Petri dish with nutrient-rich serum and watched them grow. When they detonated their time bomb, GABP was disrupted, and the fibroblasts' ability to divide was dramatically reduced. At the same time, other genes known to restart cell division were unchanged.
The team confirmed GABP's critical role in cell growth another way. Simply forcing dormant cells to make GABP, they found, was enough to rouse cells from their slumber and get them to grow again.
"So we've found a new pathway to control cell growth," Rosmarin said. "Now that we know a way to disrupt GABP and stop division, there is the possibility that a drug can be made to do the same thing in cancer cells."
http://www.medilexicon.com/medicalnews.php?newsid=62515∞
Edited on 2007-01-26 11:06:24 by KathyFromEngland
Additions:
~*Study Supports A Stem Cell Origin Of Cancer
*Scientists Are Uncovering New Meaning In The Genetic Code
Scientists Are Uncovering New Meaning In The Genetic Code
25 Jan 2007
The genetic code may seem like a recipe for life scripted with cold precision, but scientists are discovering that the code reads more like a poem in which syllables within words can bear hidden and critical meaning, according to an article scheduled for the Jan. 22 issue of Chemical & Engineering News (C&EN), ACS' weekly newsmagazine.
In the article, C&EN senior editor Ivan Amato focuses on synonyms in the genetic code -- very short word-like sequences or codons that translate into exactly the same amino acids during construction of a protein. These so-called synonymous codons can influence the three-dimensional shape of a protein, architecture with critical implications for health and disease. "It's akin to the way the same hand can fold into an affirming thumbs-up conformation or into a shape involving the middle finger that conveys another sentiment altogether," Amato explains.
The article discusses how new research is revealing that this phenomenon -- termed silent polymorphism -- may be quite vocal biologically. It is involved, for instance, in the mechanism that renders about half of human cancers resistant to chemotherapy. Such findings have stirred new interest in understanding silent polymorphism, and determining its precise role in human health, the article points out.
http://www.medilexicon.com/medicalnews.php?newsid=61380∞
Edited on 2007-01-11 04:17:05 by KathyFromEngland
Additions:
~*Profiling Of Cancer Genes May Lead To Better And Earlier Detection
*Study Supports A Stem Cell Origin Of Cancer
Study Supports A Stem Cell Origin Of Cancer
11 Jan 2007
Researchers at the University of Southern California (USC) recently made significant strides toward settling a decades-old debate centering on the role played by stem cells in cancer development. According to the study's findings, which appear in an upcoming issue of Nature Genetics and now available online, genes that are reversibly repressed in embryonic stem cells are over-represented among genes that are permanently silenced in cancers; this link lends support to the increasingly discussed theory that cancer is rooted in small populations of stem cells.
USC researchers uncovered this link after observing that of 177 genes repressed by Polycomb group (
PcG) proteins, fully 77 showed evidence of cancer-associated enzymatic modification of DNA (known as methylation). "Finding that a Polycomb target in an embryonic stem cell is 12 times more likely to become abnormally methylated in cancer is highly significant," says Peter Laird, Ph.D., one of the lead researchers and associate professor of surgery, biochemistry and molecular biology, and director of basic research for surgery at the Keck School of Medicine of USC.
Laird and his colleagues discovered that some genes repressed by Polycomb in embryonic stem cells are essentially pre-marked to become permanently silenced by DNA methylation. "This permanent silencing," Laird explains, "prevents embryonic stem cells from differentiating, and they thus become the seeds of cancer development later in life." USC researchers made these observations in relation to breast, colorectal, lung, and ovarian cancer.
Not only does the USC study provide empirical evidence for a stem cell origin of cancer, but, according to Laird, "It also supports a very early involvement of epigenetics in cancer. We found that cancer arises in cells that have already undergone epigenetic alterations," he adds, "which points to epigenetic events preceding genetic events in cancer development." Laird notes that this theory, while relatively new, is gaining support among scientists.
Findings from the USC study also can be applied to stem cell research funded by the California Institute for Regenerative Medicine (CIRM), which was created through passage of California Proposition 71 in 2004. "One of CIRM's aims," says Laird, "is to culture and differentiate embryonic stems cells �" cells that would then be placed into patients. Since our research shows that cancer is rooted in stem cells, it would be very important to screen for the epigenetic abnormalities that we uncovered, so as to prevent people from receiving potentially cancer-prone cells."
Looking ahead, Laird and his USC colleagues would next like to focus on what causes some genes to transition from temporary repression to permanent silencing. "Once we determine that," Laird explains, "we can turn to the fundamental question: How can we prevent this transition?"
Laird collaborated with colleagues at USC and England's University College London.
http://www.medilexicon.com/medicalnews.php?newsid=60460∞
Edited on 2007-01-02 14:54:39 by KathyFromEngland
Additions:
~*Stem Cells Are The Cells Of Origin For Cancer
*Profiling Of Cancer Genes May Lead To Better And Earlier Detection
Profiling Of Cancer Genes May Lead To Better And Earlier Detection
01 Jan 2007
A research team at UT Southwestern Medical Center has for the first time identified several genes whose expression is lost in four of the most common solid human cancers -
lung, breast,
prostate and
colon cancer.
The findings, which researchers say could form the basis for a new early detection screen for certain cancers, are published today in the online journal Public Library of Science Medicine.
The expression of genes that inhibit cancer development, so-called tumor suppressor genes, is often lost in tumor cells. This can occur through a mutation in the gene's DNA sequence or through deletion of the gene. Loss of tumor suppression function also can occur in a process called methylation, where a chemical called a methyl group is attached to a DNA region near the gene and prevents it from being activated, essentially "silencing" the gene.
"These results show the power of studying tumors on a genome-wide basis, looking at many genes at the same time," said Dr. John Minna, the study's senior author and director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research at UT Southwestern.
In an effort to identify new tumor-suppressor genes that might be important to lung and breast cancer development, the UT Southwestern team examined which genes are active in those kinds of tumors and compared them to gene expression profiles from normal lung epithelial cells. The researchers then examined the gene expression profiles of these various cell types before and after treatment with a drug that inhibits methylation.
The researchers identified approximately 130 genes that may be methylated and thus silenced in lung, breast, prostate and colon cancers. They analyzed 45 of these new genes in both normal and cancerous tissues from the same patients and found that many of the genes were methylated specifically in the tumor samples.
"We ended up with a large number of genes that are involved in the development of lung cancer that, despite years of work in the field, I had never connected to lung cancer before," said Dr. Minna.
Patient samples from UT Southwestern's new Harold C. Simmons Comprehensive Cancer Center tissue repository and previous results from study author Dr. David Euhus allowed the research team to quickly extend its findings to breast, prostate and colon cancer. A Hamon Center postdoctoral researcher and lead study author Dr. David Shames was instrumental in identifying the genes, Dr. Minna said.
"What would have normally taken us several years, David Shames was able to determine in less than a month," Dr. Minna said. "The new genes Dr. Shames discovered are now forming the basis for a new early detection screen that could be mounted against the most common human cancers."
The genes the researchers found to be methylated specifically in the tumor samples might control the conversion of normal cells into cancer cells, Dr. Minna said, but this possibility needs to be tested on a case-by-case basis.
Although it is known that gene expression patterns in tumors vary greatly from tissue to tissue, the researchers hope that the similarities of the methylation patterns found in this study might lead to a better approach to detect cancer early and help identify new promising therapeutic targets to treat some of the most prevalent cancers.
"The findings from our study suggest that it may be possible to develop a methylation profiling platform that could be used to screen patients for common solid tumors, while at the same time identify what type of tumor the patient may have," Dr. Shames said.
The study also illustrates that some of the basic processes that underlie the development of breast and lung cancer are identical, even though the chemicals that initiate those processes - estrogen and tobacco carcinogens, for example - may be different, said Dr. Euhus, associate professor of surgical oncology.
"I was also struck that some of these processes could be detected in benign breast cells from high-risk women, more so than in lower-risk women," said Dr. Euhus, co-director of the Mary L. Brown Breast Cancer Genetics and Risk Assessment Program. "Methylation is potentially a reversible change and there may be some interventions that would effectively reduce the risk of several types of cancer simultaneously."
http://www.medilexicon.com/medicalnews.php?newsid=59834∞
Edited on 2007-01-02 12:45:07 by KathyFromEngland
Additions:
~*Low-Protein, Low-Calorie Dieters Have Reduced Levels Of Hormone Linked To Cancer
*Stem Cells Are The Cells Of Origin For Cancer
Stem Cells Are The Cells Of Origin For Cancer
02 Jan 2007
Evidence that stem cells are the cells of origin for cancer is published online on 31st December 2006 in Nature Genetics.
A key step in the normal development of stem cells is the suppression of genes which when later switched on lead to the differentiation of cells into specific mature cell types (eg breast, ovarian or bowel cells). In normal stem cells, the suppression of these genes is reversible. However in cancer cells these critical genes are modified by a process called DNA methylation, which predisposes to cancer by causing permanent and irreversible gene suppression.
Lead author of the research Dr Martin Widschwendter and his team are based at the Institute for Women's Health (
IfWH), directed by Professor Ian Jacobs at UCL (University College London). Additional work in the field of colorectal cancer was also carried out by Dr Laird's group at the Norris Comprehensive Cancer Centre at the University of Southern California in Los Angeles.
The work involved analysis of 200 different genes in adult stem cells and normal and cancerous tissues of breast, ovary, bowel and lung and was funded by UCL, UCLH (University College London Hospital NHS Foundation) and The Eve Appeal charity .
Dr Marin Widschwendter, of UCL's
IfWH, says: This research has proven for the first time that acquisition of promoter DNA methylation can keep stem cells at an 'undifferentiated' early stage of development which predisposes them to cancer. We have also identified this abnormal DNA methylation in the bone marrow stem cells of women with cancer. These findings open a complete new window of opportunity to identify women at risk of breast or ovarian cancer independently of their family history. 90 per cent of ovarian and breast cancers in the UK occur in women who do not come from a high risk family.
In addition, identification of factors which contribute to the abnormal DNA methylation process in stem cells may provide us with new strategies to prevent these deadly diseases. We have this next stage of the research lined up and ready to go and just need more funding to press ahead. It is possible that in two years' time we could be introducing a whole new way of predicting cancer risk - based on a simple blood test.
Professor Ian Jacobs, Director of UCL's
IfWH, Medical Director of The Eve Appeal and Vice-Dean for Research at UCL, says: Martin Widschwendter is an outstanding doctor and scientist. His work is of great importance and is likely to have a major impact on our ability to identify women most at risk of ovarian or breast cancer. It may enable us to introduce a much more targeted way of early detection and cancer prevention in women. The hope is that it will enable us to focus resources used for screening and prevention on the group of women with these abnormalities rather than the entire population.
The next stage of the research will involve identifying DNA methylation patterns in white blood cells to predict breast and ovarian cancer, and identifying how cancer predisposing conditions contribute to alterations in DNA methylation patterns in the circulation and white blood cells DNA.
The Eve Appeal is fundraising for the next stage of Dr Widschwendter's work. Donations can be made online at
http://www.eveappeal.org.uk∞.
http://www.medilexicon.com/medicalnews.php?newsid=59876∞
Edited on 2006-12-13 10:15:50 by KathyFromEngland
Additions:
~*Cancer Drug Side Effect Caused By Cell Pump' Problem
*Low-Protein, Low-Calorie Dieters Have Reduced Levels Of Hormone Linked To Cancer
Low-Protein, Low-Calorie Dieters Have Reduced Levels Of Hormone Linked To Cancer
12 Dec 2006
A great deal of research connects nutrition with cancer risk. Overweight people are at higher risk of developing post-menopausal breast cancer, endometrial cancer, colon cancer, kidney cancer and a certain type of esophageal cancer. Now preliminary findings from researchers at Washington University School of Medicine in St. Louis suggest that eating less protein may help protect against certain cancers that are not directly associated with obesity.
The research, published in the December issue of the American Journal of Clinical Nutrition, shows that lean people on a long-term, low-protein, low-calorie diet or participating in regular endurance exercise training have lower levels of plasma growth factors and certain hormones linked to cancer risk.
"However, people on a low-protein, low-calorie diet had considerably lower levels of a particular plasma growth factor called IGF-1 than equally lean endurance runners," says the study's first author Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University and an investigator at the Istituto Superiore di Sanita in Rome, Italy. "That suggests to us that a diet lower in protein may have a greater protective effect against cancer than endurance exercise, independently of body fat mass."
The study involved three groups of people. The first ate a low-protein, low-calorie, raw food vegetarian diet and was made up of 21 lean men and women. Another group consisted of 21 lean subjects who did regular endurance running, averaging about 48 miles per week. The runners ate a standard Western diet, consuming more calories and protein than group one. The third group included 21 sedentary people who also consumed a standard Western diet, higher in sugars, processed refined grains and animal products. The subjects were matched for age, sex and other demographic factors, and no one smoked or had diabetes, cardiovascular disease, cancer, lung disease or other chronic illness.
Protein intake was, not surprisingly, lowest in the low-protein group. They averaged a daily intake of 0.73 grams of protein per kilogram of body weight. Endurance runners ate 1.6 grams and sedentary people on the Western diet, 1.23 grams. The recommended daily allowance for protein intake is 0.8 grams. That's about three ounces of protein per day for a 220-pound man.
"It's interesting to us that both the runners and especially the sedentary people consumed about 50 percent more protein than recommended," says Fontana. "We know that if we consume 50 percent more calories than recommended, we will become obese. But there is not a lot of research on whether chronic over-consumption of protein also has harmful effects."
Fontana and colleagues found significantly lower blood levels of plasma insulin-like growth factor 1 (IGF-1) in the low-protein diet group than in either the equally lean runners or the sedentary people eating a standard Western diet. Past research has linked pre-menopausal breast cancer, prostate cancer and certain types of colon cancer to high levels of IGF-1, a powerful growth factor that promotes cell proliferation. Data from animal studies also suggest that lower IGF-1 levels are associated with maximal lifespan.
"Our findings show that in normal weight people IGF-1 levels are related to protein intake, independent of body weight and fat mass," Fontana says. "I believe our findings suggest that protein intake may be very important in regulating cancer risk."
He calls the study a hypothesis-generating paper that suggests connections between dietary protein and epidemiological studies that show associations between IGF-1 levels and the risk of cancer. But he says more research is needed to clarify what that connection is.
The researchers also found that the group of endurance runners in the study consumed the highest number of calories, averaging more than 2,600 per day. Those on a standard Western diet consumed just over 2,300 calories daily, while those in the low-calorie, low-protein group ate just under 2,000 calories a day. Members of the latter group also tended to weigh less than sedentary people but slightly more than the endurance runners. The average body mass index (BMI) in the low-protein, low-calorie group was 21.3. BMI averaged 21.1 among the runners and 26.5 among those who were sedentary. BMI is a measurement of weight divided by height squared. People with a BMI greater than 25 are considered overweight.
Fontana says most of us don't eat nearly enough fruits and vegetables or enough whole-grains, cereals or beans. "Many people are eating too many animal products - such as meat, cheese, eggs and butter - as well as refined grains and free sugars," he says. "Our intake of vegetables and fruits is low, and beans are vastly underconsumed in the U.S. and Europe these days. "
He believes diets would be healthier if we ate more whole grains, beans, fruits and vegetables and far fewer animal products. He recommends mostly fish, low-fat dairy products and, occasionally, some red meat. Such a diet would both cut total calories and reduce the amount of protein we consume to a level closer to the range recommended by the nutrition experts of the Food Nutrition Board of the National Academy of Sciences. It also might result in lower levels of IGF-1.
"Eating too many calories increases our risk of developing obesity, diabetes, cardiovascular disease and of certain types of cancer related to obesity," Fontana says. "We hope to further clarify what happens to cancer risk when we are chronically eating more protein than we need."
http://www.medilexicon.com/medicalnews.php?newsid=58434∞
Edited on 2006-12-10 12:12:15 by KathyFromEngland
Additions:
~*How Diet, Obesity And Even Gum Disease May Affect Immune System And Cancer
*Cancer Drug Side Effect Caused By Cell Pump' Problem
Cancer Drug Side Effect Caused By Cell Pump' Problem
10 Dec 2006
A troublesome side effect caused by some cancer drugs appears to be caused by a broken "pump" in the liver that fails to push these medicines into a "drain," according to investigators at St. Jude Children's Research Hospital. The finding offers clinicians a way to identify patients who are likely to develop diarrhea as a side effect from taking these drugs, the researchers said.
The discovery also has implications for people taking other drugs, since this pump controls the blood levels of many of the prescription drugs on the market. This study is the first to show that a specific gene mutation disables the pump-a protein called ABCG2-preventing it from disposing of these drugs. The mutation, a type of alteration called a single nucleotide polymorphism, is designated 421C>A in reference to the specific change in one of the DNA building blocks of the gene.
ABCG2 pushes drugs out of cells and back into the blood, or in the case of the liver, the pump pushes drugs into a tube-like structure called the bile canaliculum, which eventually leads to the intestine, from which it is excreted, according to the researchers. ABCG2 also pumps drugs out of the cells lining the intestine, preventing drugs taken by mouth from flooding into the body. Once past the intestine, blood vessels pick up the drugs and bring them to the liver and other parts of the body.
However, mutant ABCG2 can be less efficient at pushing gefitinib out of cells in the intestine, the researchers noted. A buildup of drug within these cells can cause diarrhea.
The ABCG2 mutation sets up a tradeoff between high levels of drug in the cancer cells and high levels in the blood, according to Sharyn Baker, Pharm.D., Ph.D, associate member of Pharmaceutical Sciences at St. Jude. Although high levels of a cancer drug in the cell can increase its killing effect, high levels in the blood can cause side effects. "It's a balancing act, and knowing which mutation to look for in people will help clinicians identify patients who should have their treatment modified by reducing the dose of the drug or switching to another one," she said.
The finding was made during a study of patients being treated with gefinitib for non-small cell lung cancer. The results suggest that other cancer drugs handled by the ABCG2 pump pose the threat of side effects to patients as well, according to Baker. She is the senior author of a report on this study that appears in the December 6 issue of the Journal of the National Cancer Institute.
"Gefitinib represents a new type of treatment called targeted therapy, which researchers hoped would avoid causing significant side effects," Baker explained. "Targeted drugs are designed to knock out specific molecules that occur in abnormal cells, while sparing normal cells. But our work showed that people with the ABCG2 mutation are at increased risk for side effects."
Since diarrhea and skin toxicity limit the use of this drug in some patients, the researchers looked for a specific variation in the ABCG2 gene that could disrupt the function of the ABCG2 protein.
Among patients getting this drug, 44 percent of 124 individuals with the mutation in the ABCG2 gene developed diarrhea after receiving gefitinib; only 12 percent of 108 patients without the mutation developed diarrhea. However, this specific mutation did not cause acne, another side of effect of gefitinib. "Our finding also means that as targeted therapies become common in the years ahead it will be important to have a selection of such drugs so clinicians can choose those that are appropriate to the genetic makeup of the patient," Baker said.
Baker was at The Sidney Kimmel comprehensive Cancer Center at Johns Hopkins when she worked on this project.
http://www.medicalnewstoday.com/medicalnews.php?newsid=58307&nfid=30587∞
Edited on 2006-11-21 03:21:41 by KathyFromEngland
Additions:
~*Insights Into How The Immune System Avoids Attacking Itself Provided By Penn Researchers
*How Diet, Obesity And Even Gum Disease May Affect Immune System And Cancer
How Diet, Obesity And Even Gum Disease May Affect Immune System And Cancer
18 Nov 2006
The immune system is fickle, and easily influenced by more than just viruses and bacteria. It can be swayed by the seemingly unexpected, such as by what we eat, for example, and affected by surprising sources. At the American Association for Cancer Research's Frontiers in Cancer Prevention Research meeting, scientists are taking a closer look at the link between increasingly common lifestyle factors, the immune system and cancer, with the ultimate goals of preventing and better understanding cancer development.
A Prospective Study of Periodontal Disease and Pancreatic Cancer
Can diseased gums increase the risk of pancreatic cancer? Epidemiologists at the Harvard School of Public Health in Boston think it could, at least according to the findings of a study analyzing 16 years of health data on more than 52,000 men.
Dominique Michaud, Sc.D., assistant professor of epidemiology in the Harvard School of Public Health in Boston, and colleagues at Dana-Farber Cancer Institute and the University of Puerto Rico wanted to know if inflammation, and specifically, systemic inflammation from periodontal disease, might be related to pancreatic cancer.
According to Michaud, several studies have linked inflammation and cancer, and researchers have found a high risk of developing pancreatic cancer among individuals with pancreatitis, or inflammation of the pancreas. But the ties between periodontal disease and cancer have been more tenuous.
Previous studies have shown associations between tooth loss and cancer, and pancreatic cancer as well. But the validity of such studies was questionable because of confounding factors, including smoking, which contributes to both periodontal disease and cancer. An association with periodontal disease and heart disease has also been examined, with systemic inflammation being a potential mechanism behind the connection. Periodontal disease results in chronic inflammation over many years, both in the mouth and potentially, systemically, as well.
The researchers analyzed the health records of a fairly homogenous group of about 52,000 highly educated, male health professionals between ages 40 and 75 who participated in the Health Professionals Follow-up Study, which was created in 1986 to look at lifestyle factors related to cancer and other chronic diseases. They continue to be followed at present through mailed questionnaires, with a greater than 95 percent follow-up rate, Michaud said.
The researchers recorded 216 cases of pancreatic cancer in the 16 years of follow-up between 1986 and 2002. Men who reported having periodontal disease had a 63 percent higher risk of developing pancreatic cancer compared to those who did not report periodontal disease, after the team adjusted for smoking, diabetes, age, physical activity and diet. Those men who never smoked fared even worse, with a two-fold increase in risk. Men who reported a history of periodontal disease and tooth loss in the last four years showed a more than a 2.5-fold increase in the risk of developing pancreatic cancer compared to those without periodontal disease and recent tooth loss.
In a secondary analysis, the team looked at tooth loss at both the beginning of the study (baseline) and during the follow-up period. While tooth loss at baseline was not associated with a risk of pancreatic cancer, those who lost teeth during follow up showed an increased, albeit lesser, risk for pancreatic cancer. Tooth loss among older individuals is likely due to periodontal disease, Michaud explained, whereas tooth loss at enrollment in the study is more likely to reflect teeth that were lost or removed because of cavities.
"The results confirm our hypothesis that pancreatic cancer is related to periodontal disease, not merely tooth loss," Michaud said.
Other potential mechanisms, she said, include the fact that those with periodontal disease have high amounts of bacteria in the mouth and in the gut, and also tend to have higher amounts of nitrosamines, which have been proposed to increase pancreatic cancer risk.
"The work might provide new insights in understanding the role of systemic inflammation on initiation or promotion of pancreatic cancer," she said. Smoking, she noted, is a risk factor that could be acting as a promoter by causing inflammation.
"Establishing whether periodontal disease increases the risk and understanding the mechanisms behind these associations are important because we know so little about pancreatic cancer."
Pancreatic cancer, the fourth-leading cause of cancer death in this country, takes some 30,000 lives a year.
Diet-Induced Obesity Impairs Both Innate and Adaptive Immune Responses
Obese mice experience a far lower immune response than do normal weight mice to a vaccine typically given to cancer patients, according to studies by National Cancer Institute immunologists.
The diminished immune activity not only may explain the connection between obesity and heightened cancer risk, it also suggests that obesity might reduce the effectiveness of common vaccines, such as flu and tetanus.
According to Connie Rogers, Ph.D., MPH, a research fellow at the Laboratory of Tumor Immunology and Biology at the National Cancer Institute (NCI) in Bethesda, several studies over the years have implicated obesity with diminishing immune function. In the early 1990s, studies showed low antibody levels after vaccination in those who had a high Body Mass Index, or BMI, which is a measure of body fatness.
"We hypothesized that perhaps there are global immune impairments that occur in the face of obesity, and in turn, maybe this is one of several mechanisms that might lead to, or mediate, the relationship between obesity and tumor risk," she said.
Rogers and co-workers at NCI and at the University of Texas compared the immune system function of lean, overweight and obese mice. They created lean mice by slightly restricting their diets and watching carbohydrates. Mice that were given unlimited access to food with a mildly fat content, about 10 percent versus the usual 5 percent to 7 percent fat in their diet, became overweight. Mice that were given unlimited access to a diet made up of about 60 percent in fat, similar to consuming a diet plentiful in fast-foods, became overweight to obese.
"The mice differed in body fat," Rogers noted, "and we wanted to tease out whether it was the weight or body fat that impaired immune function, and if there was a fat threshold in regard to immune function."
The researchers injected mice with a vaccine usually used for cancer patients and which targeted tumor antigens commonly seen in breast, prostate or colon cancers. By stimulating the immune system and measuring a specific response, they could compare the extent of obesity-induced immune function impairment in each animal body type.
"We needed to simulate the immune system and be able to measure a specific response," she said. The study also served "as a tool to probe the immune system and to shed some light on whether obesity might be impacting patients we see who come in for cancer vaccine treatment."
The scientists gave mice a primary vaccination and two booster vaccines to mimic as closely as possible the schedule used in patients. They examined both the broad-based or innate immune responses, and the adaptive immune responses, including T- and B-cell responses to vaccination. While adaptive immune responses require prior exposure to a foreign protein such as a virus or bacterium, innate immunity does not.
"Interestingly, it looks like both innate immune responses such as natural killer cell function and T-cell proliferation to broad-based stimuli were impaired, and importantly, their adaptive immune responses to the vaccine were impaired," Rogers said. The group found that the obese mice failed to develop appropriate antibody levels and "their ability to proliferate in response to the vaccine antigens was impaired." Both are important for generating an adequate immune response to a vaccine.
Neither the lean mice nor the moderately overweight mice showed similar immune system impairments in response to vaccination, suggesting that the response might be a "stepwise decrease" in adaptive immunity, Rogers said.
"I think we now know that this obesity-induced impairment is fairly widespread, and affects many components of the immune system," she said. "The clinical and public health importance of this is that there are probably some significant long-term consequences. We targeted many components of the immune system, and several, such as general response to infection and tumor response to vaccine, for example, could be affected by this obesity-induced impairment in immunity."
"In the long term, we're considering the usual cancer patient who is in his sixties and probably overweight," Rogers said. "But a basic biological question and one with public health significance is that of general immune health of overweight or obese people. That has an impact on long-term health."
Rogers and her team have several questions to explore. "Now that we know about obesity-induced impairments in immune function, we want to know whether these can be reversed by interventions, such as diet and exercise," she said. "Is a person permanently immunologically impaired, or can losing weight, body fat or both, reverse the effects, or is some other mechanism involved?" Such studies involving diet and exercise currently are underway in animals.
The rest of the article discusses Prostate Cancer and can be found here:
A 23-Year Survival Analysis of Prediagnostic BMI and Risk of Lethal Prostate Cancer
http://ostomyland.com/wiki/ProstateCancerResearch∞
Complete article:
http://www.medilexicon.com/medicalnews.php?newsid=56640∞
Edited on 2006-10-16 11:33:45 by KathyFromEngland
Additions:
A finding by University of Pennsylvania School of Medicine researchers about how immune cells "decide" to become active or inactive may have applications in fighting cancerous tumors, autoimmune diseases, and organ transplant rejection. Pathology and Laboratory Medicine Professor Gary A. Koretzky, MD, PhD, director of the Signal Transduction Program at Penn's Abramson Family Cancer Research Institute describes, in the current issue of Nature Immunology, one way in which T cells may develop tolerance to host cells and proteins. Koretzky and colleagues found that small fatty acids called diacylglycerols (DAGs), and the enzymes that metabolize them, are critical players in the molecular pathway that leads to activity versus inactivity.
Deletions:
A finding by University of Pennsylvania School of Medicine researchers about how immune cells "decide" to become active or inactive may have applications in fighting cancerous tumors, autoimmune diseases, and organ transplant rejection. Pathology and Laboratory Medicine Professor Gary A. Koretzky, MD, PhD, director of the Signal Transduction Program at Penn's Abramson Family Cancer Research Institute describes, in the current issue of Nature Immunology, one way in which T cells may develop tolerance to host cells and proteins. Koretzky and colleagues found that small fatty acids called diacylglycerols (DAGs), and the enzymes that metabolize them, are critical players in the molecular pathway that leads to activity versus inactivity.
Edited on 2006-10-16 11:33:14 by KathyFromEngland
Additions:
~*Mechanisms That Shape Cells For Better Or Worse Uncovered By FSU Biologists
*Insights Into How The Immune System Avoids Attacking Itself Provided By Penn Researchers
Insights Into How The Immune System Avoids Attacking Itself Provided By Penn Researchers
15 Oct 2006
A finding by University of Pennsylvania School of Medicine researchers about how immune cells "decide" to become active or inactive may have applications in fighting cancerous tumors, autoimmune diseases, and organ transplant rejection. Pathology and Laboratory Medicine Professor Gary A. Koretzky, MD,
PhD, director of the Signal Transduction Program at Penn's Abramson Family Cancer Research Institute describes, in the current issue of Nature Immunology, one way in which T cells may develop tolerance to host cells and proteins. Koretzky and colleagues found that small fatty acids called diacylglycerols (DAGs), and the enzymes that metabolize them, are critical players in the molecular pathway that leads to activity versus inactivity.
Immune cells called T lymphocytes recognize invaders in the body, such as viruses, bacteria, tumor cells, or allergens. Normally, T cells are activated by a complex series of signals that end with the destruction of the foreign substance. However, some T cells are not activated, in fact they are inactivated by a process called anergy or tolerance. This process helps prevent immune cells from attacking themselves and other normal cells and proteins.
"How T lymphocytes become activated or inactivated has been one of the major questions in the field of immunology," says senior author Koretzky. "Our discovery shows that DAGs are critical for T-cell activation so these cells can respond to foreign invaders. However, when DAGs are chemically modified by enzymes called diacylglycerol kinases, T cells become tolerant or unresponsive to foreign substances and to self."
The discovery was made by studying mice that had been engineered to lack diacylglycerol kinases (DGKs). Although T cells from these knock-out mice were normal in most respects the induction of tolerance was impaired. When DAGs could not be chemically altered because the DGKs were absent, the T cells were hyperreactive to foreign antigens and could not be made tolerant to host cells.
Hyperreactivity was shown when purified T cells from DGK knockout mice were stimulated by antigen in a culture dish. The failure of the T cells to become tolerant was demonstrated in experiments where mice were treated with a toxin from staphylococcal bacteria that should have induced unresponsiveness. Instead, the T cells produced about five times more of an immunity factor than did cells from normal mice.
The hyperreactive state, if controlled, might be beneficial to the body under some circumstances; for example, some T cells might be made more effective at eliminating tumors. The research team is continuing to study DGK knock-out mice to see if they are more resistant to tumors. If the hyper-reactive T cells in these mice recognize the tumor cell as a foreign invader, then the tumor might be eliminated or reduced. Conversely, if the tolerant state could be induced in a controlled manner, it might benefit individuals with autoimmune disease or help prevent rejection of transplants.
Oldest known version of this page was edited on 2006-08-20 03:13:14 by KathyFromEngland []
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Articles which explain aspects of Cancer, why it develops in the first place etc.
Contents
*New Gene That Causes Spread Of Cancer Identified, University Of Liverpool
*Breakthrough In DNA Sequencing For Cancer Research Announced By Dana Farber And 454 Life Sciences
*Stanford Scientists Identify Protein Involved In Fast-spreading Cancers
*Studies Shed New Light On Why Exercise Can Protect Against Skin And Bowel Cancers
*Epidermal Growth Factor Receptor (EGFr)
*Protein's Role In Cancer Spread Pinpointed By Study
*Three-way Signaling Pathway Directly Involved In Tumor Development Identified
*No Cell Walls, No New Cancer Cells
*Mechanisms That Shape Cells For Better Or Worse Uncovered By FSU Biologists
New Gene That Causes Spread Of Cancer Identified, University Of Liverpool
31 Mar 2006
Professor Philip Rudland, Dr Guozheng Wang and Dr Roger Barraclough from the University's Cancer and Polio Research Fund Laboratories have discovered an additional member of the S100 family of protein genes - S100P - that causes the spread of cancerous cells from an original tumour to other parts of the body.
If present in the primary tumour, metastagenes such as S100P trigger the rapid spread of cancerous secondary tumours to other tissues in the body via the bloodstream - a process known as metastasis. Although primary tumours can be removed surgically, secondary tumours are more difficult to control. This research has been funded by the Cancer and Polio Research Fund.
The new discovery builds on several years' work carried out at the University to investigate the genes that cause cancerous tumours to travel to other tissues in the body. To date, three other metastasis-inducing genes have been discovered - S100A4, osteopontin, and more recently, AGR2.
Chemotherapy and
radiotherapy are often the only options available to treat secondary tumours but these procedures can be problematic to the patient as they can damage other healthy tissue and do not always succeed in eradicating the cancer.
S100P is commonly found in ten different types of normal tissue including the placenta, spleen, colon, ovary, prostate, lung and heart. Scientists believe proteins like S100P function in healthy tissue by increasing the movement of white blood cells around the body. If the protein is found in a cancerous tumour however, it causes the tumour to spread to other tissues.
Professor Rudland said: ?It is the spread of cancer from the initial tumour that is the key contributor to death of a cancer patient. Metastagenes are fundamental to this process and can be found in most common cancers, including breast, lung and colon. If these genes are over-expressed in the cancerous tumour, early death of the patient is much more likely.
?The next major step is to develop drugs that will switch off the action of these genes. If we can do this, we can stop the spread of the primary tumour and therefore improve the chances of survival for patients.
?We are grateful for the support given by the Cancer and Polio Research Fund.?
The research is published in the current edition of Cancer Research.
1. The University of Liverpool is one of the UK's leading research institutions. It attracts collaborative and contract research commissions from a wide range of national and international organisations valued at more than ?90 million annually.
2. The Cancer and Polio Research Fund is a charity based on the Wirral that funds research nationwide into cancer and other crippling diseases. In the 43 years of its existence, it has spent more than ?35 million on a wide range of medical research projects and the provision of equipment and facilities. It is entirely dependent on charitable donations for its income. For more information please contact Roger Thornhill on 01948 667 729.
http://www.liv.ac.uk∞
http://www.medilexicon.com/medicalnews.php?newsid=40588∞
Breakthrough In DNA Sequencing For Cancer Research Announced By Dana Farber And 454 Life Sciences
28 Jun 2006
454 Life Sciences Corporation, a majority-owned subsidiary of CuraGen Corporation (Nasdaq: CRGN), in collaboration with scientists at Dana Farber Cancer Center and Broad Institute, today reported a new method for the detection of cancer gene mutations present at extremely low levels. The research, published online (ahead of print) in the journal Nature Medicine, describes how the 454 Sequencing? method identifies rare cancer-associated genetic variations at the molecular level, potentially enabling the personalization of targeted therapies.
454 SequencingTM technology was used to analyze mutations in five exons of the Epidermal Growth Factor Receptor (EGFR) gene in tumor samples from 22 patients with lung cancer. The EGFR gene is the target for several new anti-cancer drugs called EGFR inhibitors. This research proposes that 454 SequencingTM may help to validate the ability of EGFR mutations to predict patient responsiveness to treatment with an EGFR inhibitor.
It has been realized that genetic mutations are responsible for sensitizing some tumor cells to chemotherapy, while other mutations render tumor cells completely resistant to drug treatments. Historically, research progress has been slowed by the complex mix of cells in a tumor sample, compounded by cost-prohibitive, conventional low-resolution sequencing methods that lack sufficient accuracy to characterize the DNA in cancerous cells. 454 SequencingTM is the first advanced sequencing technology that can generate hundreds of thousands of DNA sequences in one run, rapidly and comprehensively conducting high-throughput nucleotide sequencing, with specific application to sequencing of whole genomes and ultra-deep sequencing of target genes. By enabling a method of sequencing that is more comprehensive and less expensive than conventional sequencing methods, 454 SequencingTM may be used in medical research settings to detect cancer-associated genetic mutations.
"Analysis of DNA from tumors is complicated by varying amounts of tumor cells in patient samples. Furthermore, the heterogeneous nature of many tumors makes it difficult to accurately sequence the tumor DNA, which is required in order to personalize treatment," explained senior author of the study, Matthew Meyerson, M.D. Ph.D., of Dana Farber Cancer Center and Broad Institute. "454 Sequencing may facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies," added Meyerson.
The technology is already being explored at other institutions. "We have validated 454 Sequencing for medical sequencing on a gene target of interest," stated Robert Strausberg, Ph.D. Deputy Director and Vice President of Human Genomic Medicine at The J. Craig Venter Institute. "The method is not only very sensitive, but it is also quantitative and provides a digital display of gene variation within tumors. We have already identified a mutation missed by our previous sequencing approach," said Strausberg.
"The publication of this paper demonstrates the versatility of our system and its ability to enable medical research that has been considered impractical until now," stated co-author Michael Egholm, Ph.D., Vice President of Molecular Biology at 454 Life Sciences. "454 Sequencing can open new research opportunities through its low cost, high throughput, and superior sensitivity. The ability to sequence entire exons in a single read is unique to 454 Sequencing among the commercially available, next generation sequencing technologies. Ultimately, we hope our system will enable personalized medicine, such as identifying the early stages of drug resistance and facilitating a change in treatment that is tailored to a patient's unique genetic response," added Egholm.
http://www.medilexicon.com/medicalnews.php?newsid=45959∞
Stanford Scientists Identify Protein Involved In Fast-spreading Cancers
30 Apr 2006
Researchers at the Stanford University School of Medicine have found a protein that may explain why tumors in a low-oxygen environment are more deadly.
The findings, to be published in April in the journal Nature, reveal that tumors that are hypoxic - low in oxygen - make a protein called lysyl oxidase that helps the tumor spread to other organs. Lysyl oxidase, or LOX, could be a good target for future cancer therapies, the researchers say.
"All tumors have the potential to spread," said lead author Amato Giaccia, MD, professor of radiation oncology. "A low-oxygen environment dials up that potential, and now we know why."
Hypoxia is caused when the supply of oxygen from the bloodstream fails to meet demand from body tissues, such tumors. Hypoxic tumors can be found in many parts of the body. For this study, the researchers examined both breast tumors and head and neck tumors. In each case, patients whose tumors made high levels of LOX were more likely to have cancers that spread and to die of the disease.
The question is whether blocking LOX could also slow the cancer's spread. To find out, the researchers grew human cancers making high levels of LOX in mice. Using three different methods of shutting down LOX production, they found that the tumors were less likely to spread than tumors producing LOX unchecked.
Giaccia said blocking LOX in patients with hypoxic tumors has promise as a new therapy. He added that there are several ways of telling whether a tumor is hypoxic and therefore likely to be producing LOX. What's more, one of the methods used to block LOX in mice was an antibody, the same type of protein as HER2/Neu, which has dramatically improved outcomes in people with some types of breast tumors.
A therapy that specifically treats tumors producing LOX would be particularly exciting given that these are often among the deadliest cancers. Giaccia said trials in people could start as soon as three years from now.
The group is now looking at the relationship between LOX-production and hypoxia in other types of tumors including lung and
Colon.
http://www.medilexicon.com/medicalnews.php?newsid=42337∞
Studies Shed New Light On Why Exercise Can Protect Against Skin And Bowel Cancers
15 May 2006
Two studies published today (Saturday 13 May) have shown that exercise can protect against skin and bowel cancer, and they have identified new mechanisms that could be responsible for this effect.
Published in the journal ?Carcinogenesis?, one study found that female mice that had 24-hour access to running wheels and were exposed to ultraviolet B light (UVB) took longer to develop skin tumours, developed fewer and smaller tumours, and had decreased amounts of body fat compared to mice that did not have access to running wheels. The second study looked at the development of pre-cancerous polyps in the intestines of male mice and discovered that voluntary exercise and a restricted diet reduced the number and size of polyps and improved survival.
Dr Allan Conney, Garbe Professor of Cancer and Leukemia Research and Director of the Susan Lehman Cullman Laboratory for Cancer Research at Rutgers University, New Jersey, USA, is one of the authors of the skin cancer study. He said that programmed cell death (apoptosis), triggered by exercise, might explain why the running wheel mice did better.
?Preliminary indications from follow-up work in the laboratory suggest that voluntary exercise enhances UVB-induced apoptosis in the skin, and that it also enhances apoptosis in UVB-induced tumours. So, although UVB is triggering the development of tumours, exercise is counteracting the effect by stimulating the death of the developing cancer cells.
?Our studies may be the first to suggest an apoptotic mechanism for the effect of voluntary exercise in the development of cancer. In addition, we found that voluntary exercise decreased body fat and that the number of tumours decreased with decreasing amounts of fat. This effect may also play an important role in the mechanism and warrants further investigation, bearing in mind the growing rates of obesity in the Western world, particularly in the USA and UK,? he said.
Dr Lisa Colbert, Assistant Professor at the University of Wisconsin-Madison, USA, lead author of the bowel cancer study, said that her study was the first to suggest that a negative energy balance, produced by increasing the mice's energy output (by use of a running wheel) while maintaining a restricted calorie intake, appeared to be the important factor in inhibiting the growth of polyps (the fore-runners of bowel tumours).
?Negative energy balance was indicated by a lower body weight among the exercising mice, although they retained more body fat at the end of the study than the non-exercising mice - an observation that might be due to the fact that the exercising mice were healthier, while the health of the non-exercising mice was beginning to decline due to higher numbers of polyps. There were higher levels of hormones known to be associated with the onset of cancer - insulin-like growth factor-1 (IGF-1) and corticosterone - amongst the exercising mice, but this did not correlate with higher total polyp numbers. These data suggest that voluntary exercise that induces a negative energy balance protects against the onset of cancer in these mice, but that the mechanism is unlikely to be related to body composition, IGF-1 or corticosterone.?
Dr Conney emphasised that it was not known yet whether exercise decreased the risk of sunlight-induced skin cancer in humans, and clinical trials were needed to investigate this further. However, in bowel cancer, evidence from population studies already suggests that physically active people have a reduced risk of developing the disease, but the mechanisms remain unclear.
The skin cancer study involved two experiments. In a ?high risk? model, mice were exposed to UVB three times a week for 16 weeks, and then for the subsequent 14 weeks, in the absence of further UVB treatment, half the mice had access to running wheels in their cages while the other half did not. In a second, ?complete carcinogenesis? model, mice were exposed to UVB twice a week for 33 weeks and, from the beginning, half had access to a running wheel and half did not. Mice not exposed to UVB acted as controls for the study. In both models, the exercising mice increased their food intake and maintained their normal body weight.
The exercising mice in the high risk model had an average of seven weeks without tumours after the UVB exposure ceased, while the non-exercising mice only had an average of 3.5 tumour-free weeks.
Dr Conney said: ?In both the no running wheel and running wheel groups, the number of tumours per mouse increased with time, but throughout the 14 weeks of tumour development, animals with access to running wheels had a decreased number of tumours per mouse compared to animals with no running wheels. At all times, the tumour size in the no running wheel group was greater than in the running wheel group; on average, the tumour size per mouse for the no wheel group was just over three times more than for the exercise group.?
In the complete carcinogenesis model, mice with no running wheel started to develop tumours 20 weeks after the start of UVB exposure, while tumours in the running wheel group started after 23 weeks. The average tumour-free time was 25 weeks for the no running wheel group and 27 weeks for the running wheel group.
Dr Conney said: ?The rate of increase in tumour numbers per mouse for the no running wheel group was significantly greater than that for the running wheel group. On average, the tumour size per mouse for the no running wheel group was about 3.5 times more than in the exercise group.
?In both models, voluntary running decreased the number of non-malignant tumours per mouse by 34%. Exercise substantially decreased the size of non-malignant tumours and malignant tumours: in the high risk model, the non-malignant tumour size per mouse was decreased by 54% and the malignant tumour size per mouse by 73%, and in the complete carcinogenesis model, tumour size per mouse was decreased by 75% and 69% respectively.?
For the bowel cancer study, Dr Colbert and her co-authors used mice (APC Min mice) that had a genetic mutation that predisposed them to develop intestinal polyps. ?Our studies are relevant for humans in that these Min mice have a mutation in one of the same genes, APC, that is also mutated in human colon cancer,? she explained. ?The protective effect of exercise and lower body weight in our mice is consistent with epidemiological evidence in humans that suggests higher levels of activity and lower body weight reduces the risk of colon cancer.?
Mutations in the APC gene in humans are responsible for an inherited condition called familial adenomatous polyposis (FAP). FAP affects about one in 10,000-15,000 people worldwide, 95% of whom will develop numerous polyps in the bowel which eventually develop into colon cancer, usually before the age of 40. The gene is mutated in sporadic forms of colon cancer as well.
The researchers randomly assigned seven-week-old male mice to either voluntary wheel running or to no exercise for 10 weeks. For the first three weeks both groups had the same amount of food and water, but after that the exercising mice were fed the amount that the non-exercising mice had eaten the week before so that their food consumption was unable to rise with their increased activity, thereby producing a negative energy balance.
By the end of the ten weeks, six of the 23 control mice had died due to the number of polyps that had grown and the resulting anaemia, while all the 24 exercising mice were still alive.
?The exercising mice ran an average of 3.8 km a day, and the further they ran the fewer polyps they had. Exercise significantly reduced total polyp number and polyp size, as well as prolonging survival,? said Dr Colbert. ?On average there were 16 polyps per mouse in the exercising mice compared to 22 polyps in the control mice - a decrease of 25%.?
?Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice? and ?Negative energy balance induced by voluntary wheel running inhibits polyp development in APC Min Mice?. Carcinogenesis journal, published online 13 May 2006.
http://www.medilexicon.com/medicalnews.php?newsid=43305∞
Epidermal Growth Factor Receptor (EGFr)
Although EGFr normally helps regulate the growth of many different cells in the body, EGFr also can stimulate cancer cells to grow. In fact, many cancer cells actually require signals mediated by EGFr for their survival. Residing on the surface of these tumor cells, EGFr is activated when naturally occurring proteins in the body, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha), bind to it. This binding changes the shape of EGFr, which, in turn, triggers internal cellular signals that stimulate tumor cell growth. Panitumumab binds to EGFr, preventing the natural ligands such as EGF and TGF-alpha from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.
http://www.medilexicon.com/medicalnews.php?newsid=40763∞
Protein's Role In Cancer Spread Pinpointed By Study
26 Jul 2006
Edinburgh scientists have identified the way a specific cell protein can trigger the spread of cancer. The study by researchers in the Cell Signalling Unit, University of Edinburgh Cancer Research Centre could pave the way for new drugs which limit the protein's ability to turn a normal cell cancerous.
The protein, MDM2, normally functions to control the activity of a key cancer preventing protein called p53. In some of the body's cells, the biochemical ratio between MDM2 and p53 can become unbalanced causing MDM2 to act as a cancer-promoting agent.
The project's lead investigator, Dr Kathryn Ball, a researcher at the University, explains: "One way in which MDM2 controls the p53 protein is by activating its destruction and we are interested in understanding how this happens at a biochemical level.
"In the current study, funded by Cancer Research UK, we have identified protein fragments which can bind to MDM2, inhibiting its activity. These fragments could be a good template for drugs designed to hinder the role of MDM2 in the p53 destruction pathway. We hope our findings may lead to improved treatments for a broad range of cancer types."
Welcoming the findings, Professor John Toy, medical director at Cancer Research UK, said: "p53 is a crucial protein that acts as a guardian of the normal cell. Its failure to do its job properly is associated with many types of cancer. If p53 is being destroyed by another protein in a cancer cell, then it offers an excellent target when designing new anti-cancer drugs. This research suggests MDM2 is just such a target."
http://www.medilexicon.com/medicalnews.php?newsid=47996∞
Three-way Signaling Pathway Directly Involved In Tumor Development Identified
02 Aug 2006
Studying mice with skin cancer, researchers at the Swiss Institute for Experimental Cancer Research (ISREC) and EPFL (Ecole Polytechnique Federale de Lausanne) have identified a three-way signaling pathway directly involved in tumor development. Their research, published in the August, 2006 issue of Genes and Development, pins down a process that could potentially be manipulated to inhibit the growth of existing carcinomas.
Genetic mutations in our cells accumulate as we age, and carcinomas are associated with alterations in certain key genes, known as tumor suppressor genes and oncogenes. The overexpression of oncogenes disrupts complex cellular signaling pathways and leads to tumor development. However, most oncogenes also play a variety of essential roles in the normal function of a cell. It is extremely difficult to pinpoint the interplay of genetic and cellular events that goes awry when a cell becomes cancerous.
To better understand the intertwined roles of three genes known to be implicated in skin cancer, Professor Andreas Trumpp and
PhD student Thordur Oskarsson studied mice that carried a mutated form of one of them, the oncogene Ras. They then genetically engineered mice whose skin cells also lacked another oncogene, c-myc. The c-myc gene is known to be a master regulator in the cell, responsible for controlling several hundred other genes.
Their first surprise was that the mice without the c-myc gene in their skin cells didn't suffer any adverse effects. Unexpectedly, epidermal cells do not require c-myc for survival, normal differentiation or cellular division. However, even more surprising was that these same mice were completely resistant to developing skin cancer, even though they carried the mutated Ras gene, known to drive tumor development. As expected, mice in the control group carrying a normal copy of the c-myc gene developed cancer.
A piece of the puzzle was clearly missing. The researchers found this in a tumor-suppressing gene known as p21. Mutated Ras drastically increases the level of p21 in the cell, and in this way the tumor-causing effects of Ras are held in check, because p21 inhibits uncontrolled proliferation. However, mutated Ras is a vicious oncogene and has found a way to remove the tumor-suppressing effect of p21. It does this by simultaneously driving increased c-myc activity, which in turn eliminates p21. Thus, epidermis with mutated Ras but no c-myc cannot form tumors as p21 remains highly expressed. Trumpp and his colleagues proved the newly uncovered relationship of this cancer threesome by engineering mice lacking both the c-myc and the p21 genes. As predicted, these mice became sensitive to mutated Ras again and developed extensive skin tumors.
"This work is in vivo proof-of-concept of a key pathway in epithelial tumors," remarks Trumpp. "The gene that is truly critical and protects the cells from oncogenic activity is p21. Inhibiting the c-myc pathway was always thought to be unreasonable because this gene is thought to be implicated in so many cellular functions. However, this might prove to be promising avenue for treating existing carcinomas, because it would only affect tumors and not normal skin cells."
http://www.medilexicon.com/medicalnews.php?newsid=48446∞
No Cell Walls, No New Cancer Cells
05 Aug 2006
Cancer cells, like houses, need building materials for their walls. And as with a house, the cell wall needs to be built at just the right moment to protect and allow the construction of internal components. A team from the Uppsala Branch of the global Ludwig Institute for Cancer Research (LICR) has not only shown how the cell gets this timing right, but has also conducted proof-of-principle studies that indicate taking away the cell's bricks and mortar is a potential strategy for cancer control.
"New cells are created by the duplication of existing cells through a highly-organized process known as the cell cycle," explains lead author, Dr. Maite Bengoechea Alonso. "Last year we discovered that a protein called SREBP1 that regulates the synthesis of lipids needed for new cell walls was regulated during the cell cycle. Now we show that the SREBP1 protein actually controls the cell cycle."
Senior author, LICR's Dr. Johan Ericsson, realized that disrupting the function of SREBP1 might prevent the lipid synthesis required for new cell walls. "In fact, we literally stopped the cell cycle in its tracks by removing SREBP1 from cells. It seems that if you don't have SREBP1 activity, you can't make lipids, and if you don't have lipids, you can't make new cells."
According to Dr. Ericsson, who is also a Research Fellow of the Royal Swedish Academy of Sciences, this approach might one day form the basis of a new strategy for the long-term control of cancer. "Cancer cells divide uncontrollably, so their need for lipids is more urgent and continuous than normal cells. Treatment with an inhibitor of SREBP1 might reduce the rate of cancer cell proliferation to slow down tumor growth, or might enhance the effect of targeted therapies that aim to actually kill cancer cells."
http://www.medilexicon.com/medicalnews.php?newsid=48605∞
Mechanisms That Shape Cells For Better Or Worse Uncovered By FSU Biologists
18 Aug 2006
In a landmark study, biologists at Florida State University have uncovered a specific genetic and molecular mechanism that causes cell polarity -- the asymmetric shape or composition critical to a cell's proper functioning. Their findings in fruit fly eggs may help to clarify how muscular dystrophy and some cancers develop in humans.
That's because many of the genes involved in the cell-to-cell communication that triggers the development of cell polarity in Drosophila oocytes (unfertilized fruit fly eggs) also are known players in the pathogenesis of those diseases.
The research performed by FSU Assistant Professor Wu-Min Deng and doctoral student John S. Poulton in the department of biological science could foster a better overall understanding of polarity and how it develops -- and why it doesn't, sometimes with dire consequences -- in other types of cells and organisms.
Results from the FSU study are described in the Aug. 14 online edition of the journal PNAS (Proceedings of the National Academy of Sciences).
"We have identified a novel component in the polarization of the fruit fly egg and the signals that determine the anterior-posterior positioning of its head and abdomen," said Deng.
"Such a discovery in the biological model provided by Drosophila oocytes has broad implications in humans, where, for example, neurons in the brain are designed, or polarized, to interpret information from the sense organs, and intestinal cells are polarized to take up nutrients and move them into the bloodstream," he said.
Poulton explained that in order to ensure cell polarity in the Drosophila oocyte, the cells surrounding it activate a classic signaling pathway known as the Epidermal Growth Factor Receptor (EGFR) in a process that is also essential to development in humans and a wide range of other organisms.
"Our study shows that EGFR activation in the cells surrounding the fruit fly oocyte acts to turn off a gene known as Dystroglycan, halting production of its protein. EGFR must shut down Dystroglycan in order for the oocyte to properly polarize," Poulton said.
"We proved this by observing that mutated forms of genes in the EGFR pathway of cells surrounding the oocyte led to abnormally high levels of Dystroglycan protein, which in turn disrupted oocyte polarity. However, even with the mutated EGFR pathway gene, we were able to restore normal polarity by turning Dystroglycan off artificially," he said.
"While much remains unknown, our research confirms that EGFR regulation of Dystroglycan plays a key role in the polarization of the oocyte," Deng said. "That knowledge adds a pivotal link to our understanding of precisely how cell-to-cell communication occurs in this model system."
In recognition of groundbreaking work to-date by the FSU scientists -- and to further the understanding of the mechanisms involved in cell-cell communication leading to oocyte polarity -- the National Institutes of Health have awarded Deng a highly competitive "R01" (Research Project Grant) for health-related research and development.
Just after joining the FSU faculty in 2004, Deng led a Drosophila oogenesis study that revealed mechanisms of cell-to-cell signaling along other key pathways. Those findings were published in the 2005 editions of the journal Development.
The current study -- "Dystroglycan down-regulation links EGFR signaling and anterior-posterior polarity formation in the Drosophila oocyte" -- relied heavily on the state-of-the-art laser confocal microscope in FSU's Biological Science Imaging Resource facility. Funding for the research came in part from the American Heart Association.
http://www.medilexicon.com/medicalnews.php?newsid=49866∞
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