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Science teams at Cold Spring Harbor Laboratory identify 13 new tumor-suppressor genes in liver cancer
November 19, 2008Cold Spring Harbor, N.Y. - Over the years, hunting for cancer-related genes and understanding how they work has been an important, although time-consuming, exercise. At Cold Spring Harbor Laboratory (CSHL), five different research groups have now combined their expertise to speed up the rate of discovering cancer-related genes and validating their function in living animals.
The result of the collaborative effort is a large-scale, rapid, cost-effective genetic screen that in a preliminary test succeeded in uncovering 13 new tumor suppressors - genes that inhibit the activity of cancer genes. Tumor suppressors are important in cancer development generally, and specifically in liver cancer, where they frequently have been found to be missing in people who develop the illness.
These discoveries, published online ahead of print on Nov.17 and scheduled to appear in the November 26 issue of Cell, "are a huge step forward in understanding the genetics of cancer and open up a host of new strategies to improve its diagnosis and treatment," according to CSHL Professor Scott W. Lowe, Ph.D., the corresponding author of the study. Other authors include Scott Powers, Ph.D., Director of the Human Cancer Genome Center at CSHL, and CSHL Professors Gregory J. Hannon, Ph.D., W. Richard McCombie, Ph.D., and Michael Wigler, Ph.D.
Pinpointing Tumor Suppressor Genes
Tumor suppressors are a crucial component of intracellular signaling networks that protect against uncontrolled cell proliferation. The benefits of such genes can be lost when DNA undergoes alterations, including mutations or deletions of entire stretches of chromosomes. A highly efficient genome-sequencing technique developed several years ago in the Wigler laboratory has made it possible to scan the genome of cancerous cells for, among other things, deleted portions of chromosomes where tumor suppressors are likely to reside.
Dr. Powers performed a genomic analysis of human liver cancer samples that provided a basis for the work of the combined teams. Powers' lab scanned the genomes of liver cancers from more than 100 patients to compile a list of deletions of chromosomal regions. These regions were hypothesized to be the location of most of the missing tumor suppressor genes. A comparison of this list with the genome sequence of a normal human cell revealed the identity of approximately 300 genes within the deleted chromosomal segments.
Chromosomal deletions aren't limited to cancer-related genes alone; any number of "passenger" or unrelated neighboring genes can inadvertently also be lost. The team therefore had to pinpoint the tumor suppressors among the 300 genes. "Genomic analysis of human tumors is important," Powers observed," but combining it with functional screening in mouse models is a notable step forward."
The usual route of characterizing a gene's function is to mutate it in mouse embryos and then create lines of mice that can then be examined for the mutation's effects. Lowe's group bypassed this step, which is time-consuming, by engineering mutations into the genome of adult mouse cells and then re-injecting these cells into adult mice. The team used a method honed by Dr. Hannon of introducing stable mutations into mouse cells via RNA interference, or RNAi, a technique in which small RNA molecules are introduced into cells to shut off specific genes.
RNA sequences that corresponded to all the 300 or so deleted genes were obtained from an RNAi "library" compiled by the Hannon lab. Lowe's team introduced these RNAi tools (known as "short-hairpin RNAs, or shRNAs) into progenitor cells that develop into mature liver cells, albeit ones engineered to over-produce a cancer gene product called Myc.
In cells with these Myc mutations, an additional "trigger" such as the shutting off of a tumor suppressor gene via RNAi would be sufficient to cause cancer. The engineered cells that carried a Myc mutation and an shRNA were injected into mice. Dramatically, those that received cells in which a tumor suppressor gene had been "silenced" by an shRNA developed tumors within a month.
The scientists homed in on the identity of the silenced tumor suppressors by simply isolating and analyzing the genetic material from the tumors. Their strategy identified 13 new tumor suppressor genes, most of which had not been linked to cancer before.
A rich and unexpected payoff
"The nature of these new genes is not obvious and we wouldn't have guessed their relationship to cancer if we hadn't followed this approach," says Lowe. "They may now allow us to make headway into poorly understood areas of cancer."
The newly identified tumor suppressor genes affect a wide array of cellular activities, including maintenance of cell structure, cellular metabolism, cell proliferation, and control of the levels of various tumor growth-enhancing proteins in the cell's nucleus. In one instance, the team's strategy also uncovered not genes in isolation but an entire network of genes that go awry in liver cancer. "Given that the cancer puzzle involves multiple genes in various combinations, we need to find all the hits that make the cell tip over the edge," says Lowe, explaining one advantage of his team's broad strategy.
Some of the genes identified might also lead to new strategies for cancer therapy. For example, some of the newly discovered tumor suppressor genes "code" for proteins that are secreted, which indicates that their ability to prevent cancer is dependent on their presence outside the cell. Reversing the loss of such proteins - by replenishing their levels via injections - is an easier fix than having to correct a defect in the genome via gene therapy.
In other words, the CSHL team's new strategy now makes it possible to rapidly filter from genomic information those genes that specifically impact cancer development in living animals, and thus focus follow-up studies on those that might be most clinically useful.
"An oncogenomics-based in vivo RNAi screen identifies new tumor suppressors in liver cancer" will appear in Cell on November 26. The complete citation is: Lars Zender, Wen Xue, Johannes Zuber, Camile P. Semighini, Alexander Krasnitz, Beicong Ma, Peggy Zender, Stefan Kubicka, John M. Luk, Peter Schirmacher, Richard W. McCombie, Michael Wigler, James Hicks, Gregory J. Hannon, Scott Powers, and Scott W. Lowe. The paper is available online at: doi:10.1016/j.cell.2008.09.061
Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding of and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
Cold Spring Harbor Laboratory
Pinpointing Tumor Suppressor Genes
Tumor suppressors are a crucial component of intracellular signaling networks that protect against uncontrolled cell proliferation. The benefits of such genes can be lost when DNA undergoes alterations, including mutations or deletions of entire stretches of chromosomes. A highly efficient genome-sequencing technique developed several years ago in the Wigler laboratory has made it possible to scan the genome of cancerous cells for, among other things, deleted portions of chromosomes where tumor suppressors are likely to reside.
Dr. Powers performed a genomic analysis of human liver cancer samples that provided a basis for the work of the combined teams. Powers' lab scanned the genomes of liver cancers from more than 100 patients to compile a list of deletions of chromosomal regions. These regions were hypothesized to be the location of most of the missing tumor suppressor genes. A comparison of this list with the genome sequence of a normal human cell revealed the identity of approximately 300 genes within the deleted chromosomal segments.
Chromosomal deletions aren't limited to cancer-related genes alone; any number of "passenger" or unrelated neighboring genes can inadvertently also be lost. The team therefore had to pinpoint the tumor suppressors among the 300 genes. "Genomic analysis of human tumors is important," Powers observed," but combining it with functional screening in mouse models is a notable step forward."
The usual route of characterizing a gene's function is to mutate it in mouse embryos and then create lines of mice that can then be examined for the mutation's effects. Lowe's group bypassed this step, which is time-consuming, by engineering mutations into the genome of adult mouse cells and then re-injecting these cells into adult mice. The team used a method honed by Dr. Hannon of introducing stable mutations into mouse cells via RNA interference, or RNAi, a technique in which small RNA molecules are introduced into cells to shut off specific genes.
RNA sequences that corresponded to all the 300 or so deleted genes were obtained from an RNAi "library" compiled by the Hannon lab. Lowe's team introduced these RNAi tools (known as "short-hairpin RNAs, or shRNAs) into progenitor cells that develop into mature liver cells, albeit ones engineered to over-produce a cancer gene product called Myc.
In cells with these Myc mutations, an additional "trigger" such as the shutting off of a tumor suppressor gene via RNAi would be sufficient to cause cancer. The engineered cells that carried a Myc mutation and an shRNA were injected into mice. Dramatically, those that received cells in which a tumor suppressor gene had been "silenced" by an shRNA developed tumors within a month.
The scientists homed in on the identity of the silenced tumor suppressors by simply isolating and analyzing the genetic material from the tumors. Their strategy identified 13 new tumor suppressor genes, most of which had not been linked to cancer before.
A rich and unexpected payoff
"The nature of these new genes is not obvious and we wouldn't have guessed their relationship to cancer if we hadn't followed this approach," says Lowe. "They may now allow us to make headway into poorly understood areas of cancer."
The newly identified tumor suppressor genes affect a wide array of cellular activities, including maintenance of cell structure, cellular metabolism, cell proliferation, and control of the levels of various tumor growth-enhancing proteins in the cell's nucleus. In one instance, the team's strategy also uncovered not genes in isolation but an entire network of genes that go awry in liver cancer. "Given that the cancer puzzle involves multiple genes in various combinations, we need to find all the hits that make the cell tip over the edge," says Lowe, explaining one advantage of his team's broad strategy.
Some of the genes identified might also lead to new strategies for cancer therapy. For example, some of the newly discovered tumor suppressor genes "code" for proteins that are secreted, which indicates that their ability to prevent cancer is dependent on their presence outside the cell. Reversing the loss of such proteins - by replenishing their levels via injections - is an easier fix than having to correct a defect in the genome via gene therapy.
In other words, the CSHL team's new strategy now makes it possible to rapidly filter from genomic information those genes that specifically impact cancer development in living animals, and thus focus follow-up studies on those that might be most clinically useful.
"An oncogenomics-based in vivo RNAi screen identifies new tumor suppressors in liver cancer" will appear in Cell on November 26. The complete citation is: Lars Zender, Wen Xue, Johannes Zuber, Camile P. Semighini, Alexander Krasnitz, Beicong Ma, Peggy Zender, Stefan Kubicka, John M. Luk, Peter Schirmacher, Richard W. McCombie, Michael Wigler, James Hicks, Gregory J. Hannon, Scott Powers, and Scott W. Lowe. The paper is available online at: doi:10.1016/j.cell.2008.09.061
Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding of and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
Cold Spring Harbor Laboratory
Tumor Suppressors Current Events and Tumor Suppressors News RSSKEAP1 Keeps major cancer-promoting protein at bay
A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.
Mayo Clinic Researchers Find That Protein Believed to Protect Against Cancer Has a Mr. Hyde Side
In a biological rendition of fiction's Strange Case of Dr. Jekyll and Mr. Hyde, researchers from the Mayo Clinic campus in Florida and Harvard Medical School have found that a protein thought to protect against cancer development can actually spur the spread of tumors.
Carbohydrate acts as tumor suppressor
Scientists at Burnham Institute for Medical Research (Burnham) have discovered that specialized complex sugar molecules (glycans) that anchor cells into place act as tumor suppressors in breast and prostate cancers.
Tumor suppressor gene in flies may provide insights for human brain tumors
In the fruit fly's developing brain, stem cells called neuroblasts normally divide to create one self-renewing neuroblast and one cell that has a different fate. But neuroblast growth can sometimes spin out of control and become a brain tumor.
DKK-3 and WIF-1: Proteins related to liver cancer development?
Liver cancer is one of the most fatal human malignancies and the third most frequent cause of tumor-related death, about half a million people globally each year.
NYU Langone Medical Center researchers find micro RNA plays a key role in melanoma metastasis
Scientists have long wondered how melanoma cells travel from primary tumors on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly.
Genetic breakdown in Fanconi anemia may have link to HPV-associated cancer
A genetic malfunction that causes DNA instability in people with the blood disorder Fanconi anemia may put them at high risk for squamous cell carcinomas linked to human papillomavirus (HPV), according to a study posted online ahead of print by Oncogene.
Study links nicotine with breast cancer growth and spread
A study published in Cancer Research, a journal of the American Association for Cancer Research, suggests a possible role for nicotine in breast tumor development and metastases.
New insights into the regulation of PTEN tumor suppression function
The PTEN tumor suppressor gene controls numerous biological processes including cell proliferation, cell growth and death. But PTEN is frequently lost or mutated; in fact, alteration of the gene is so common among various types of human cancer that PTEN has become one of the most frequently mutated of all tumor suppressors.
CSHL scientists trace causal link between a tumor suppressor gene and liver cancer
Scientists at Cold Spring Harbor Laboratory (CSHL) have taken the search for cancer-causing genes an important step forward. In a newly published paper, they confirm that a gene called DLC1 is a tumor suppressor. They have demonstrated in living mice that its deletion, inactivation or loss precipitates events culminating in an aggressive type of liver cancer closely related to common human epithelial cancers of the liver (also known as hepatocellular carcinoma, or HCC).
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The p53 Tumor Suppressor Pathway and Cancer (Protein Reviews, Vol. 2) by Gerard P. Zambetti (Editor) The p53 tumor suppressor gene is mutated in approximately half of all human malignancies, including colon, lung, and breast cancers. It is well recognized that these mutations directly inactivate p53 tumor suppressor function. Furthermore, the p53 protein operates within a pathway and this pathway, including the mutations in p53, is likely inactivated by nearly every human tumor. In support of this hypothesis, 100% of mice that have been engineered such that they do not express p53 protein (knockout animals), develop highly malignant tumors by only 3-6 months of age. The importance of p53 in preventing human cancer is also evident by families in which a mutated p53 gene is inherited from a parent. Individuals who carry an inherited germline p53 mutation are associated with Li-Fraumeni... |
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Benign Prostatic Hyperplasia AHCPR Clinical Practice Guideline/Tumor Suppressor Genes in Human Cancer (NCME Video 658) Also With: Network For Continuing Medical Education (Primary Contributor), John Wasson (Primary Contributor), Daniel A Haber (Primary Contributor) In February, 1994, the Agency for Health Care Policy and Research (AHCPR) released a clinical practice guideline dealing with the diagnosis and treatment of benign prostatic hyperplasia. This telecourse presents highlights of that guideline. In the 1980's, the study of positive oncogenes was a major focus in the quest to understand the molecular origins of cancer. Today, tumor suppressor genes are sharing the spotlight and may exemplify an untapped resource for anticancer therapy. Dr. Haber demonstrates how recessive oncogenes, which normally control cell growth, allows cells to progress to malignancy when lost or inactivated. |
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Tumor Suppressor Genes by Katherine R. Polinsky (Editor) A tumour suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor. Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive... |
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Tumor Suppressor Genes: An entry from Macmillan Reference USA's Macmillan Reference USA Science Library: Genetics by Giles Watts (Author) This digital document is an article from Macmillan Reference USA Science Library: Genetics, brought to you by Gale®, a part of Cengage Learning, a world leader in e-research and educational publishing for libraries, schools and businesses. The length of the article is 1047 words. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. A comprehensive collection of articles on all aspects of genetics, from Mendel to the decoding of the human genome. Explains the workings of genes and chromosomes, genetic diseases, and biotechnology. Covers the ethical, legal, and social issues connected to genetic science and includes coverage of careers in the field. | |
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Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA ... from: Environmental Health Perspectives by Lamia Benbrahim-Tallaa (Author), Robert A. Waterland (Author), Anna L. Dill (Author), Mukta M. Webber (Author), Michael P. Waalkes (Author) This digital document is an article from Environmental Health Perspectives, published by Thomson Gale on October 1, 2007. The length of the article is 4339 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase.(Research)(deoxyribonucleic acid)(Clinical report) Author: Lamia Benbrahim-Tallaa Publication: Environmental Health Perspectives (Magazine/Journal) Date: October 1, 2007 Publisher: Thomson... | |
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Oncogenes and Tumor Suppressor Genes in Human Malignancies (Cancer Treatment and Research) by C.C. Benz (Editor), E.T. Liu (Editor) This volume begins by reviewing selected malignancies in which the search for clinically relevant oncogenes has led to more focused studies on gain-of-function and loss-of-function genetic abnormalities, as well as autocrine and paracrine growth factor loops known to regulate tumor physiology and malignant cell behavior. Many of these genetic and functional abnormalities are shared by several different tumor types and are not uniformly present in all tumors of the same type. This observation brings up molecular questions about the tissue-specific determinants that underlie individual cancers and also gives added impetus to the suggestion that molecular abnormalities (referred to as tumor markers) be included among the histopathologic features used for clinical diagnosis and... | |
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Tumor Suppressor Genes (Immunology Series) by George Klein (Editor) | |
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Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: Deduction from structural analysis ... for deletions [An article from: DNA Repair] by T. Kohno (Author), J. Yokota (Author) This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Chromosome interstitial deletion (i.e., deletion of a chromosome segment in a chromosome arm) is a critical genetic event for the inactivation of tumor suppressor genes and activation of oncogenes leading to the carcinogenic conversion of human cells. The deletion at chromosome 9p21 removing the p16 tumor suppressor gene is a genetic alteration frequently observed in a variety of human cancers. Thus, structural analyses of breakpoints for p16 deletions in several kinds of human cancers have been performed to elucidate the... |
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Tumor Suppressor Genes and Cell Proliferation Control in the Carcinogenesis of the Oral Mucosa by Sabine Christiane Girod (Author) This text is aimed at those involved with cancer research, particularly those interested in epithelial cancers of the aerodigestive tract accounting for one third of all cancer deaths each year. The recent discovery of two groups of genes, oncogenes and tumour suppresor genes has thrown doubt on the possibility of a genetic predisposition in all cases. The current knowledge and recent results concerning the role of tumour suppressor genes in oral carcinogenesis are described, as is the importance of understanding the basic principles and the application of molecular biology techniques. | |
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Tumor Suppressor Genes: Volume 1: Pathways and Isolation Strategies (Methods in Molecular Biology) by Wafik S. El-Deiry (Editor) Univ. of Pennsylvania, PA. Text covers all the known tumor suppressor pathways and provides key information on their discoveries, analysis, and their uses in cancer therapeutics. Focuses on TSGs and the relevance of the biochemical pathways they regulate to human cancer. For researchers. DNLM: Genes, Tumor Suppressor--physiology. |
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