Oncogene Researchers Are Churning Out Highly Cited Papers

Scientists studying the genetic switches that turn cancer on and off are producing some of the most widely cited papers in medical research today. In a January report, the Philadelphia-based Institute for Scientific Information found that six of the 10 most cited papers in medicine in 1991 examined oncogenes or tumor suppressor genes. Researchers in this burgeoning field are excited because the recent advances in oncogene studies--such as identification of tumor suppressor genes and the potential for a gene-based test for cancer--are providing the best hope for ultimately bringing the "War on Cancer" to a close. "The excitement is that for the very first time, the precise genes are being defined, and so we begin to see what's happening at the level of the genetic material of cancer," says Bernard Weinstein, director of the Columbia University Comprehensive Cancer Center. "We hope, therefore, that this will provide clinically useful information." Six of the 10 most cited papers in medicine--based on citation data for papers published since 1989 and cited between September and October 1991--are in the field of oncogenes and their role in signal transduction. As reported in the Institute for Scientific Information publication Science Watch (3:5, January 1992), the papers are: * E.R. Fearon, B. Vogelstein, "A genetic model for colorectal tumorigenesis," Cell, 61(5):759-67, 1990. * J.M. Nigro, S.J. Baker, A.C. Preisinger, J.M. Jessup, et al., "Mutations in the p53 gene occur in diverse human tumor types," Nature, 342:705-8, 1989. * E.R. Fearon, K.R. Cho, J.M. Nigro, S.E. Kern, et al., "Identification of a chromosome-18q gene that is altered in colorectal cancers," Science, 247:49-56, 1990. * L.C. Cantley, K.R. Auger, C. Carpenter, B. Duckworth, et al., "Oncogenes and signal transduction," Cell, 64:281-302, 1991. * J.L. Bos, "ras oncogenes in human cancer: a review," Cancer Research, 49:4682-9, 1989. * D.P. Lane, S. Benchimol, "p53: Oncogene or anti-oncogene?" Genes and Development, 4:1-8, 1990. --L.J. Evidence suggests that this hope is being fulfilled. One of the top research teams in the field, led by oncologist Bert Vogelstein at Johns Hopkins University Oncology Center, reported this spring on a gene-based diagnostic test for colon cancer and premalignant polyps (Science, 256:102-4, 1992). The new test detects mutations of the ras onco-gene in tumor cells found in stools. This method may prove more specific and precise in detecting colon cancer than is the current test, which detects hidden blood in the stool, a symptom not only of colon cancer but also of several other conditions. Although they're far from a cure, such detection methods still represent thrilling advances. "If you took apart your TV set and you couldn't see anything wrong, you wouldn't have a chance of fixing it," says oncologist Ken Kinzler, a colleague of Vogelstein's at the Hopkins Oncology Center. "In colon cancer, now we've got the equivalent of seeing one of those transistors being burned up. We may not know how to fix it now, but at least we have an idea of what the problem is. In the future we may be able to fix it." "At the present time, cancer treatment is sort of empirical," Weinstein says. "One looks for drugs that maybe attack DNA randomly or block cell division. But we hope that soon drugs can be designed based on knowing exactly what's wrong with the tumor. So, for example, if a tumor is missing a suppressor gene, maybe a drug can be given which, in a sense, replaces that function." This transfer of laboratory-based research into tangible patient applications is fueling the interest in the study of the genetics of cancer. When he started training in the M.D./Ph.D. program at Johns Hopkins 12 years ago, molecular oncologist James Sherley was attracted to cancer research for just that reason: "I wanted to be a basic scientist, as I am now, but I wanted to work in a way that allowed me to think constantly about how the things we're working on could be applied to human disease." Sherley is one of many researchers studying p53, one of the most intriguing genes in cancer research today. Originally thought to be an oncogene, p53 actually turned out to be a tumor suppressor gene. "It's clear that p53 is a little bit different because it can act as an oncogene if it's mutated, but in its wild type form it's a suppressor. It's kind of a dual-function protein," he says. "The problem that people interested in cancer biology always had before them is the simple question: `How does a normal cell become a transformed cell, a cancer cell?' " says Sherley, now at Fox Chase Cancer Center in Philadelphia. "So when oncogenes were discovered, almost 20 years ago, a whole new area of research opened up in terms of understanding that process." An oncogene is a normal gene in a cell that has some role in telling the cell when to grow. In cancers, this normal gene either becomes overexpressed, so the cell makes too much of it, or is somehow mutated so that it's activated, allowing excessive growth of the cells. "So it does its job 10 times or 100 times better," explains Sherley. Oncogenes provided a great explanation for cancers in which scientists were seeing genetic mutations, but the model didn't fit situations in which tumors seemed to be caused by genetic deletions. Then in 1987, the first tumor suppressor gene was cloned, with its role in the normal cell being to put the brakes on cell division. Originally identified in the lab of Arnold Levine at Princeton University and first linked to human cancer in Vogelstein's lab, p53 has turned out to be the most commonly altered gene yet indentified in tumors of many different types. Altered p53 is found in 70 percent of colon cancers, in up to 50 percent of breast cancers, and in 50 percent of lung cancers. And, as a reflection of this widespread linkage, the literature is full of papers on p53. "If I see another mutational p53 in some cancer I will literally throw up, because every day I receive five or six or seven or 10 such papers," quips cancer geneticist Carlo Croce, editor-in-chief of Cancer Research and director of the cancer center at Jefferson Medical College in Philadelphia. Croce explains that "p53 is a gene that is mutated in a large variety of cancers, so it is not a marker for a specific type of cancer. But mutation in p53 occurs, in some cases, in very high frequency in a variety of human tumors." Even though many people are tracking down cancer-associated p53 mutations, it is "an antioncogene in want of a function," according to Sherley. Signal transduction is the popular way of explaining how oncogenes transform a cell, but the mechanisms by which p53 and many other oncogenes can also function as antioncogenes are being studied to better understand their roles in cells. Basically, the critical mechanisms involved in the conversion of a cell from normal to cancerous require a signal to travel along a pathway from the surface of the cell to the nucleus. The signal's path begins outside the cell, since in adult animals, cells don't have an internal clock or an internal signal to tell them to grow. There are receptors on cell membranes to which growth factors can bind. "When the receptor isn't bound, you can think of it as just kind of not doing much of anything," Sherley says. "When a growth factor binds to that receptor, it changes chemically or conformationally, and the result is the initiation of a signal that involves the transfer of chemical information from one protein to another. "And so there's a cascade of information that goes from that initial event to the cell nucleus." On the way to the nucleus the signal passes through two general classes of intermediary proteins. Signal amplifiers work as catalysts to amplify the signal many orders of magnitude, and transmitters take the amplified signal and physically transfer that information into the nucleus. Finally, the transmitters give the signal to transcription factors in the nucleus, which initiate the transcription of genes that are required for cell division. A better understanding of what's happening at each step along the signal transduction pathway would have broad appeal across many life science disciplines. "I think the reason this area is so widely read is because it touches on everyone's interests," says cell biologist Lewis Cantley of Tufts University in Boston, who wrote a highly cited review on oncogenes and signal transduction (Cell, 64:281-302, 1991). "If you're working in endocrinology, if you're working in smooth muscle contraction and arteriosclerosis, nerve regeneration, development, or lymphocyte activation and autoimmune diseases--people in all these fields are looking for the signals that control cell growth and development." Oncogenes can be activated by mutations of genes controlling just about any step in the signal transduction pathway. For example, "a cell will make an altered growth factor or it will make too much of the growth factor and basically stimulate itself or its neighbors to grow too much," says Sherley. "Many oncogenes are altered receptors. They are receptors that don't require the binding of a growth factor to send a signal--they just signal all the time, whether or not the growth factor is present. "So basically, if you're studying oncogenesis, you're studying signal transduction. And if you're studying signal transduction, you are studying molecules which have the potential to become oncogenes." Although controversies occasionally arise among the many researchers in this field, the disagreements tend to be short-lived. "If one is really interested in whether a gene does what one proposes it does, then any number of experiments can be done, including knocking out the gene, overexpressing the gene, mutating the gene, and even making transgenic animals where the gene is homozygously deleted," says Cantley. "You can stand on a soap box and say, `My gene is the most important gene for this, that, and the other thing' until the guy down the street makes a homozygous deletion and the mouse develops without any defects. Then you have to get down from your soap box and carry it away." Sherley has intentionally stayed off his soapbox when espousing his "heretical" theory of p53's function. "Most of the field right now thinks that p53 is primarily involved in transcription, except for people like myself," he says. "I think p53 is ultimately going to be involved in regulating amplifiers." Preliminary studies from his lab indicate that p53 regulates how much guanosine triphosphate is in the cell, an important mechanism for regulating cell growth (Journal of Biological Chemistry, 266:24815-28,1991). In any case, answers to the questions of how to stimulate or block cell growth and differentiation are converging on the same or overlapping specifics in signaling apparatus. "Things that are oncogenes in some cells are actually differentiating genes in other cells," says Cantley. "Some of these pathways are very ancient, so people doing genetics in yeast are coming up with the same genes as people looking for differentiation or development or growth regulation in mammalian cells." The field of oncogenes is extremely diverse. "Now you never know what field your competitor may be in. He may be working in yeast genetics and solve your problem for you in arteriosclerosis," says Cantley. "It's a time when the laboratories that are most successful are the ones that form collaborations and take advantage of people's expertise to advance things as quickly as possible," he explains. "Also, if you do win a race you can't decide, 'Now I've made it,' because having won you are ahead for maybe three months. It's running a marathon, not a short race, where you can stop and say, "Now I'll take a breather." The next question is always more important than the one that you just answered." With so many questions to an answer, the field will continue to grow. Researchers are finding new oncogenes, and the younger field of anti-oncogenes is still considered fairly virgin territory. And, as is often the case, learning the function of these genes has lagged behind the molecular biology used to find them. Says Sherley: "In the future, I think we're going to see that people are going to back up and ask the really hard questions about what these genes really do in normal cells, what they really do in tumor cells, and what, exactly, are tumor suppressor genes." Laurel Joyce is a freelance science writer based in Palo Alto, California

Oncogene Researchers Are Churning Out Highly Cited Papers

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