The current dogma of cancer research is that the accumulation of gene mutations in a single cell is responsible for the development and progression of human cancers. "Almost everybody believes that cancer requires certain gene mutations," noted Christoph Lengauer, Ph.D., associate professor of oncology at Johns Hopkins University, Baltimore. "Several genes have to be affected in order to generate cancer, and genetic instability [caused by gene mutations] allows for the accumulation of [these] mistakes."
But this theory is open to debate. Robert Weinberg, Ph.D., professor of cancer research at the Massachusetts Institute of Technology, Cambridge, agrees with Lengauer and believes that tumor cells arise from disruptions in critical signaling pathways as a result of mutations in various oncogenes and tumor suppressor genes. However, Peter Duesberg, Ph.D., professor of molecular and cellular biology at the University of California at Berkeley, believes that aneuploidy, an abnormal number or complement of chromosomes, is the critical mutation responsible for all solid human cancers, independent of specific gene mutations. Both theories have plenty of researchand unanswered questionsbehind them.
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As codiscoverer of viral oncogenes in the 1970s, Duesberg spent 10 years testing the hypothesis that cellular oncogenes cause cancer, but was unsuccessful. "I had my own interests at stake," said Duesberg. "I realized that the fundamental difference that set apart human oncogenes from viral oncogenes was that viral oncogenes have very strong promoters and express [the gene product] 1000-fold higher. We cannot find such a dominant human oncogene." Because of this, he criticizes the widespread use of viral promoters in already aneuploid cells, such as NIH3T3, to prove that an oncogene causes cancer.
Duesberg began to explore alternative cancer theories. "All of a sudden you see a forest when you were looking for trees," said Duesberg on aneuploidy, predicted to be the cause of cancer almost a century ago. "Aneuploidy is a very solid correlation." It is present in nearly all nonviral, solid cancers, and it explains the growing list of nonmutagenic carcinogens and why human oncogenes cannot turn human cells into cancer cells. In addition, "aneuploidy changes thousands of cellular pathways," he noted, explaining the unique properties of cancer cells. He said he believes that aneuploidy is the only somatic mutation that explains all of the characteristics of a cancer cell.
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However, Brinkley believes that aneuploidy "must be preceded by additional mutations or altered gene expression that results in defective mitosis." He is examining the role of a specific mitosis gene that he believes is involved in this process.
Duesberg believes that carcinogens generate defects in the mitotic apparatus by directly targeting the spindle apparatus or fragmenting the chromosomes. In addition to causing cancer, Duesberg predicts that aneuploidy, by reassortment of the chromosomes, is responsible for tumor recurrence and multidrug resistance observed in cancer patients.
"Most people believe that aneuploidy is important for cancer development," said Lengauer, who supports Duesbergs work. "But [Duesberg] goes a little too far in his belief that cancer can occur independent of gene mutations." Lengauer agrees that carcinogens may be able to induce aneuploidy in the absence of gene mutations, but he does not believe that this by itself can cause cancer.
One of Many Changes?
Weinberg believes that aneuploidy is only a consequence of the cancer process, and may not even be a requirement.
"Over the last 25 years, no one had ever succeeded in taking a normal human cell and transforming it into a tumor cell through the introduction of mutant genes," said Weinberg. However, Weinberg and colleagues did just that. In Nature last year, they described the first genetically defined human tumor cells, by adding three mutant genes to two normal human cell lines, embryonic kidney and fibroblasts.
In this study, four cellular pathways were important. An oncoprotein of SV40 virus (large T antigen) simultaneously knocked out two tumor suppressor proteins, p53 and Rb. "And both of them must be inactivated, we believe, in order to create a human tumor cell. At the same time, hTERT [telomerase] must be upregulated [to enable cells to grow indefinitely], and finally the mitogenic growth-promoting pathway indicated by ras must also be upregulated."
The resulting cells were anaplastic, highly angiogenic, minimally invasive, and nonmetastatic. "They set the stage for the long process of trying to relate the genes that are damaged in a human genome with the complex behavioral phenotype of the cancer cell," noted Weinberg. "Of course, theres much that lies ahead because the genes that weve introduced are hardly representative of those that are found mutated in spontaneously arising human tumors."
In response to Weinbergs publication, Duesberg analyzed the cells and published his observations in Proceedings of the National Academy of Sciences, arguing that what was important about the tumor cells was their aneuploidy, not the introduced genes. "And in fact," noted Weinberg, "he argued that this was a troubled hypothesis [gene mutation], and these genes were really an epiphenomenon of the whole process of cancer formation, rather than being at the center of the process."
Weinberg recently had the cells re-examined at the National Cancer Institute, and mentioned that one of the cell lines was found to be diploid, in complete contradiction to Duesbergs observation. Weinberg believes this is proof that "aneuploidy is not an essential prerequisite to the creation of a transformed human malignant cell."
Exclusive Theories or Cooperation?
"If present at the scene of a crime, you are a suspect. If not present, you are excused," noted Duesberg, an analogy to the observation that "not one gene [mutation] has been identified that is consistently found in a highly specific cancer." Weinberg and others believe that many of the identified oncogenes/tumor suppressor genes lie in the same critical pathways that need to be disrupted for cancer development. Lengauer pointed out that 88% of nonhereditary colon cancers have a mutation in the APC gene, and a nonoverlapping 10% have a mutated -catenin gene. Both of these genes lie in the same cellular pathway.
But can gene mutations and aneuploidy really work independently to cause cancer? Can they work together? "Currently, I believe both may be involved in some cancers," said Baylor College of Medicines Brinkley. "Carcinogens that are mutagens may target oncogenes that ultimately destabilize mitosis, setting conditions for errors that lead to aneuploidy. In the case of nongenotoxic carcinogens such as asbestos, aneuploidy appears to be sufficient to cause cancer. The fact that non-mutagenic agents can cause cancer, and the fact that it has been impossible to isolate cellular genes from cancer cells that transform normal human cells, leads me to seriously question whether gene mutation alone (without aneuploidy) can cause cancer."
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