Cellular Brake Pad Inspection

Tumor Suppressor Genes in Human Cancer Edited by D.E. Fisher Totowa, NJ: Humana Press (2001). 386 pp. $125.00The research field that focuses its attention on tumor suppressor genes (TSGs) is now about two decades old. At present, it is in a period of consolidation, most of the major breakthroughs having been made in the late 1980s and early 1990s. Despite age and the pretenses of maturity, there is still little consensus as to what a TSG is.Taking the broadest view, some would propose that it is a gene whose product militates in some fashion against the appearance of a tumor. Others propose that these cancer-antagonizing genes really fall into two major categories that are determined by function: genes that negatively regulate cell proliferation (including proapoptotic genes) and those that act positively to maintain the integrity of the genome. In one nomenclature, the negative growth regulators have been termed “gatekeepers” while those involved in DNA and chromosome maintenance have been called “caretakers” (Kinzler and Vogelstein, Science 280, 1036–1037, 1998); loss of either type of gene favors cancer. Are both types of genes real TSGs? No nomenclature czar has appeared on the scene to sweep away the fog.The narrowest reading of the term TSG says that these genes act negatively to regulate cell proliferation and that their expression, readily detectable in a normal tissue, is lost when cancer cells arise from that tissue. At one time, it seemed that the only way to lose expression of a TSG was to inactivate it genetically in the genome of the developing cancer cell. But over the past five years, it has become evident that TSG inactivation is achieved equally effectively through methylation and resulting transcriptional repression.Because the criteria governing inclusion in the TSG class are so poorly established, many “candidate TSGs” have been proposed over the past decade, most of whose candidacies remain tentative. One favored route to validate a candidate TSG gene is to test it functionally by introducing it into a tumor cell. Reexpression of bona fide TSGs in a tumor cell lacking the gene is known in many cases to stop the proliferation of this cell, even to induce its entrance into apoptosis. With this in mind, many have introduced their favorite candidate TSGs into tumor cells and observed the same outcome. The pitfall here is an obvious one: most genes, independent of their normal mode of functioning, make cells unhappy whenever they are expressed ectopically and at nonphysiologic levels.Yet another criterion for proving TSG status is the observed progressive downregulation of expression of a gene as a tissue evolves toward a neoplastic growth state. Here the researcher skates on even thinner ice. Some genes may be expressed by only a subset of the cell types present in a normal tissue (e.g., a stromal cell in an epithelial tissue). As a tumor develops in this tissue, the representation of the different cell types in the histologically complex tumor mass changes dramatically, and the level of certain gene products may plummet because the expressing cell type is underrepresented in the overall tumor mass.Downregulation of gene expression can be equally misleading because of confusion between cause and effect. If a bona fide TSG, operating as a master controller, activates expression of dozens of downstream effectors to achieve its ends, do all of these effectors also rise to the level of being TSGs? In the same vein, if a growth-promoting oncogene acts in part by shutting down dozens of normally expressed genes, are all these TSGs?Even the ostensibly rigorous criteria offered by molecular genetics create traps. Because the second, still-wild-type gene copy of a TSG is often discarded during tumor progression through the process of loss of heterozygosity (LOH), some TSGs have risen to prominence simply because their chromosomal region suffers repeated LOH in a series of tumors. But what if a neighboring gene, closely linked to the candidate TSG, happens to be the real target of elimination by LOH? The gold standard here has been a finding that the surviving, now-duplicated allele harbors an inactivating mutation or suffers methylation that shuts down its expression.With all this said, it remains that TSGs are vitally important to understanding the molecular mechanics of cancer cells. Extensive research makes it abundantly clear that the loss of TSG function is as important to the process of cancer pathogenesis as is the gain of oncogene function.David Fischer's anthology of reviews Tumor Suppressor Genes in Human Cancer provides an up-to-date view of this very active research field. By now we know of a rather short list of TSGs whose candidacy is no longer in doubt—genes like p53, Rb, p16, PTEN, NF1, WT-1, and 2, VHL. There are other genes whose inactivation, either in the germline or somatically, accelerates tumorigenesis because the loss of their functions leads to hypermutable genomes; included here are BRCA1 and 2, the mismatch repair genes, the Fanconi anemia genes, the ataxia telangiectasia gene ATM, and those associated with xeroderma pigmentosum (XP). Yet others still wait in a no-man's land, promoted by some, doubted by others for one or another of the reasons cited above. Included here are nm-23, DCC, KA1, and TSP1.Most of these genes are addressed in this volume, written by authorities in these fields, and to a very great extent presented in highly readable, well-organized chapters. These chapters provide the vital information that nonspecialists would need to enter into this complex field. One chapter, a bit out of place in this TSG anthology, has been written by Alex Matter of Novartis; it provides a very good overview of how the research into the molecular biology of cancer pathogenesis is currently being used to identify novel drug targets and, in turn, the development of a new generation of rationally designed anticancer therapeutics. His agenda, after all, represents the most important end-goal of all of this research—exploiting insights into cancer's molecular causes to generate new ways of treating the disease.