M EC H A NIS MS OF D IS EASE Review Article Mechanisms of Disease R ULES FOR M AKING H UMAN T UMOR C ELLS WILLIAM C HAHN M D PH D ROBERT A WEINBERG PH D AND T HE development of cancer in humans involves a complex succession of events that usually occur over many decades During this multistep process the genomes of incipient cancer cells acquire mutant alleles of proto oncogenes tumor suppressor genes and other genes that control directly or indirectly cell proliferation Different combinations of these mutant alleles are found in the genomes of the many distinct types of human cancer as well as in different cancers from the same tissue An ever increasing number of these genes have been shown to make contributions to the distinct steps involved in neoplastic transformation The complexity of these observations provokes the question of whether these genes and the more than 100 distinct types of human cancer can ever be rationalized in terms of a small number of underlying biologic and biochemical principles Recent successes in the experimental transformation of human cells indicate that the disruption of a limited number of cellular regulatory pathways is sufficient to impart a tumorigenic phenotype to a wide variety of normal cells These results in turn suggest a series of genetic and cellular principles that may govern the formation of most if not all types of human cancers MULTIPLE ALTERATIONS IN THE GENOMES OF CELLS During the past 25 years cancer researchers have enumerated a bewildering array of phenotypes and have catalogued thousands of molecular alterations associated with the malignant state The rate at which these molecular markers are being identified continues From the Department of Medical Oncology Dana Farber Cancer Institute and the Department of Medicine Brigham and Women s Hospital Boston W C H and the Whitehead Institute for Biomedical Research and the Department of Biology Massachusetts Institute of Technology Cambridge R A W Address reprint requests to Dr Hahn at the Department of Medical Oncology Dana Farber Cancer Institute 44 Binney St Boston MA 02115 or at william hahn dfci harvard edu to increase rapidly Indeed the recent use of transcriptional profiling to analyze human cancer cells has accelerated the tempo at which descriptions of cancerrelated genes appear in the literature 1 6 Many of these studies have been motivated by the notion that the complex phenotypes of cancer cells will ultimately be explained by discovering associated changes in the genomes of these cells There is also the hope of understanding the complex process of neoplastic transformation at the cellular level in terms of a small number of underlying genetic changes Identification of the genetic changes in cancer cells and of the proteins that these changes affect promises to provide diagnostic and prognostic markers as well as molecular targets for therapeutic intervention Simple Transforming Systems For those who believe in the simplification and rationalization of the cancer process the actual course of research on the molecular basis of cancer has been largely disappointing Rather than revealing a small number of genetic and biochemical determinants operating within cancer cells molecular analyses of human cancers have revealed a bewilderingly complex array of such factors 7 8 In the early 1970s research on transforming retroviruses indicated that the neoplastic phenotype could be conferred on virus infected cells by the actions of a limited number of genes For example the actions of a single virus borne gene allowed Rous sarcoma virus to transform the chicken cells that it infected 9 An independent line of research which involved the transfer of genes from tumor cells into established rodent cells identified specific oncogenes in the genomes of the tumor cells that could transform these recipient cells 10 17 In these cases the cancer causing genes were found to be mutant versions of normal growth controlling genes which came to be called proto oncogenes 18 Collaborating Oncogenes in Rodent Cells In fact the rodent cells used as recipients in these gene transfer studies were not completely normal since they had previously undergone immortalization in culture and thus had acquired the ability to proliferate indefinitely 19 21 When truly normal rodent cells specifically those recently prepared from rat embryos primary cells were tested single oncogenes failed to induce transformation Ultimately these experiments revealed that at least two oncogenes needed to be introduced into the recipient cells to prompt them to enter a tumorigenic state 22 24 In a general N Engl J Med Vol 347 No 20 November 14 2002 www nejm org 1593 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne sense these observations indicated that under most conditions the conversion of normal cells into tumor cells requires multiple mutant genes The transformation of cultured primary cells from rodents involved the introduction of two collaborating oncogenes such as ras and myc 22 23 These experiments were subsequently extended in studies with transgenic mice in which these two oncogenes were placed under the control of a transcriptional promoter 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 prostatespecific promoters dysplasia of mammary or prostate tissues developed at high rates However when mice carrying ras transgenes were bred with carriers of myc transgenes cancers developed in the resulting doubletransgenic mice this synergy of the actions of myc and ras in vivo provided strong support for the oncogene collaboration that had been observed earlier in cultured cells However the kinetics of tumor development in these doubly transgenic mice indicated that the two oncogenes expressed together in specific tissues of the mice were still not sufficient to effect full tumorigenic transformation of the cells in these tissues Indeed further alterations ostensibly the mutation of additional genes appeared to be required for neoplastic transformation in these animal models Further Complexity in the Transformation of Human Cells Indications that the neoplastic transformation of human cells is even more complex than that of animal cells came from numerous attempts to transform cultured normal human cells into tumor cells by introducing ras myc and other oncogenes Invariably such attempts failed whereas identical
View Full Document
Unlocking...