Research on Early-Stage Carcinogenesis: Are We Approaching Paradigm Instability?

Abstract

In a recent article in the New York Times, Gina Kolata reported that a major change is occurring in the way researchers view early-stage carcinogenesis. We offer a more detailed perspective on this change and discuss implications for research funding. The prevailing paradigm for early-stage carcinogenesis is the somatic mutation theory, which states that “cancer results from an accumulation of mutations and other heritable changes in susceptible cells.” The somatic mutation theory has changed over time, and multiple variations have occurred in recent years. In the early 1900s, Theodor Boveri postulated that imperfect or irregular division of the chromosome leads to cancer, and Ernest Tyzzer first used the term somatic mutation in connection with cancer. The discovery of DNA as the genetic material and the observation that cancerous changes are transmitted from one generation of cells to the next pointed to DNA as the critical target of carcinogens. This viewpoint was so ingrained in the research community that, by 1959, future Nobel Laureate Peyton Rous wrote that “numerous workers on cancer are now content to think it [cancer] results from somatic mutations. Hence they see no other reason to seek in other directions to learn its nature.’’ Not surprisingly, in light of the comment of Peyton Rous, the seminal discovery in 1981 that DNA from human cancers introduced into mouse cells resulted in tumors and later experiments that induced human tumors in transgenic mice carrying an oncogene were widely viewed as supporting the somatic mutation theory, and there was little serious consideration of alternative explanations. Since then, an ever-growing list of somatic mutations has been associated with cancer; these are now frequently classified as either driver mutations that confer growth advantage or passenger mutations that do not. Recently, researchers have proposed variations on the somatic mutation theory that share the assumption that carcinogens directly alter the DNA structure or function in cells in the tissue from which cancer arises. These variations, which include epigenetic, chromosomal, and cancer stem-cell theories, differ in how the alteration occurs and in what types of cells are involved. Under the epigenetic theory, heritable changes in gene expression that are not caused by an alteration in the DNA sequence are postulated to contribute to carcinogenesis by increasing chromosomal instability, by reactivating transposons (sequences of DNA that move around the genome), or by loss of imprinting (ie, loss of a silenced genetic locus that leads to monoallelic gene expression). The link between epigenetics and cancer began with the observation of hypomethylation of human tumors and was followed by the identification of hypermethylated tumor-suppressor genes and inactivation of microRNA genes by DNA methylation. However, the epigenetic theory cannot explain unpredictable effects, such as an experiment in which hypomethylation led to fewer tumors than expected. According to the chromosomal theory, a carcinogen induces random aneuploidy, which slowly leads to chromosomal variations and eventual expansion of the most adaptable cells. The chromosomal theory offers an explanation for nonmutagenic carcinogens, the strong association between aneuploidy and cancer, and long latency periods. The more-or-less repeatable patterns of chromosomal changes seen particularly in hematologic cancers is consistent with this theory. According to the stem-cell theory, carcinogens induce cancers by altering those cells that possess characteristics associated with normal stem cells, such as self-renewal and generation of mature cells through differentiation. The stem-cell theory explains experimental results that only a small fraction of injected leukemia cells produce spleen colonies. Support for the stem-cell theory also comes from the apparent identification of stem cells in solid tumors; however, this conclusion was later challenged by findings of substantial genetic differences between the purported stem cells and their descendents. A common feature of the somatic mutation theory and the related epigenetic, chromosomal, and stem-cell theories of cancer is the underlying notion that cancer originates at the cellular level of biologic organization. A central problem for the somatic mutation theory and its variations derives from experiments in which various observations remain unexplained. For example, tumors arise when filters with small holes are inserted subcutaneously in mice but not when filters composed of the same material, but with large holes, are similarly inserted. Equally paradoxical is the observation that tumors arise in epithelial cells at a much higher rate than in controls when normal rat mammary epithelial cells are transplanted adjacent to stroma that had previously been exposed to a chemical carcinogen after clearing out the local epithelial cells. It has been observed that just transplanting normal cells into another (untreated but inappropriate) stromal environment (eg, testis cells to kidney capsule) is enough to induce carcinoma predictably and that, despite the abnormal phenotype of the subsequent cancer JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 20 JULY 1