MECHANISMS OF DISEASE N Engl J Med, Vol. 347, No. 20 · November 14, 2002 · www.nejm.org · 1593 Review Article Mechanisms of Disease R ULES FOR M AKING H UMAN T UMOR C ELLS W ILLIAM C. H AHN , M.D., P H .D., AND R OBERT A. W EINBERG , P H .D. From the Department of Medical Oncology, Dana–Farber Cancer Insti-tute, and the Department of Medicine, Brigham and Women’s Hospital,Boston (W.C.H.); and the Whitehead Institute for Biomedical Researchand the Department of Biology, Massachusetts Institute of Technology,Cambridge (R.A.W.). Address reprint requests to Dr. Hahn at the Depart-ment of Medical Oncology, Dana–Farber Cancer Institute, 44 Binney St.,Boston, MA 02115, or at [email protected]. HE development of cancer in humans involvesa complex succession of events that usually oc-cur over many decades. During this multistepprocess, the genomes of incipient cancer cells acquiremutant alleles of proto-oncogenes, tumor-suppressorgenes, and other genes that control, directly or indi-rectly, cell proliferation. Different combinations ofthese mutant alleles are found in the genomes of themany distinct types of human cancer as well as in dif-ferent cancers from the same tissue. An ever-increas-ing number of these genes have been shown to makecontributions to the distinct steps involved in neo-plastic transformation. The complexity of these obser-vations provokes the question of whether these genesand the more than 100 distinct types of human cancercan ever be rationalized in terms of a small numberof underlying biologic and biochemical principles.Recent successes in the experimental transformationof human cells indicate that the disruption of a limit-ed number of cellular regulatory pathways is sufficientto impart a tumorigenic phenotype to a wide varietyof normal cells. These results, in turn, suggest a seriesof genetic and cellular principles that may govern theformation of most, if not all, types of human cancers. MULTIPLE ALTERATIONSIN THE GENOMES OF CELLS During the past 25 years, cancer researchers haveenumerated a bewildering array of phenotypes andhave catalogued thousands of molecular alterations as-sociated with the malignant state. The rate at whichthese molecular markers are being identified continuesT to increase rapidly. Indeed, the recent use of transcrip-tional profiling to analyze human cancer cells has ac-celerated the tempo at which descriptions of cancer-related genes appear in the literature. 1-6 Many of these studies have been motivated by thenotion that the complex phenotypes of cancer cellswill ultimately be explained by discovering associatedchanges in the genomes of these cells. There is also thehope of understanding the complex process of neo-plastic transformation at the cellular level in terms ofa small number of underlying genetic changes. Iden-tification of the genetic changes in cancer cells and ofthe proteins that these changes affect promises to pro-vide diagnostic and prognostic markers as well as mo-lecular targets for therapeutic intervention. Simple Transforming Systems For those who believe in the simplification and ra-tionalization of the cancer process, the actual courseof research on the molecular basis of cancer has beenlargely disappointing. Rather than revealing a smallnumber of genetic and biochemical determinants op-erating within cancer cells, molecular analyses of hu-man cancers have revealed a bewilderingly complexarray of such factors. 7, 8 In the early 1970s, research ontransforming retroviruses indicated that the neoplasticphenotype could be conferred on virus-infected cellsby the actions of a limited number of genes. For exam-ple, the actions of a single virus-borne gene allowedRous sarcoma virus to transform the chicken cells thatit infected. 9 An independent line of research, whichinvolved the transfer of genes from tumor cells intoestablished rodent cells, identified specific oncogenesin the genomes of the tumor cells that could trans-form these recipient cells. 10-17 In these cases, the can-cer-causing genes were found to be mutant versionsof normal growth-controlling genes, which came tobe called proto-oncogenes. 18 Collaborating Oncogenes in Rodent Cells In fact, the rodent cells used as recipients in thesegene-transfer studies were not completely normal,since they had previously undergone immortalizationin culture and thus had acquired the ability to prolif-erate indefinitely. 19-21 When truly normal rodent cells— specifically, those recently prepared from rat em-bryos (primary cells) — were tested, single oncogenesfailed to induce transformation. Ultimately, these ex-periments revealed that at least two oncogenes neededto be introduced into the recipient cells to promptthem to enter a tumorigenic state. 22-24 In a general1594 · N Engl J Med, Vol. 347, No. 20 · November 14, 2002 · www.nejm.org The New England Journal of Medicine sense, these observations indicated that under mostconditions, the conversion of normal cells into tumorcells requires multiple mutant genes.The transformation of cultured primary cells fromrodents involved the introduction of two collaborat-ing oncogenes, such as ras and myc . 22,23 These exper-iments were subsequently extended in studies withtransgenic mice, in which these two oncogenes wereplaced under the control of a transcriptional promot-er that ensured their expression in certain tissues. 25,26 In mice carrying in their germ line either a ras or a myc transgene under the control of mammary- or prostate-specific promoters, dysplasia of mammary or prostatetissues developed at high rates. However, when micecarrying ras transgenes were bred with carriers of myc transgenes, cancers developed in the resulting double-transgenic mice; this synergy of the actions of myc and ras in vivo provided strong support for the oncogenecollaboration that had been observed earlier in cul-tured cells. However, the kinetics of tumor develop-ment in these doubly transgenic mice indicated thatthe two oncogenes, expressed together in specific tis-sues of the mice, were still not sufficient to effect fulltumorigenic transformation of the cells in these tis-sues. Indeed, further alterations — ostensibly, the mu-tation of additional genes — appeared to be requiredfor neoplastic transformation in these animal models. Further Complexity in the Transformation of Human Cells Indications that the neoplastic transformation
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