Tumor Suppressor Genes and Human Cancer

Melissa A. Brown    Somatic Cell Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, England

I INTRODUCTION

Ideas contributing to our understanding of tumorigenic mechanisms date from the 1700s, when early records of cancer families suggested that cancer was a genetic disease. Most of our present knowledge, however, is built on the contributions of researchers in this century (reviewed in Witkowski, 1990). In 1911 Peyton Rous demonstrated that cell-free extracts from chickens could transmit tumors, suggesting the existence of tumor viruses. Subsequent studies on these viruses ultimately led to identification of the first dominantly acting oncogene, src, in 1976. The notion that abnormalities in chromosomes may cause cancer, suggested by Boveri in 1914, together with observations in the 1960s and 1970s that tumorigenicity could be suppressed by fusing malignant cells with either normal cells or specific chromosomes, led to the hypothesis that loss of genetic material may also be a critical event in tumorigenesis. This was later confirmed cytogenetically in 1983, subsequently leading to the isolation of the first tumor suppressor gene, RB, in 1986. Intensive research over the last 20 years has culminated in the isolation and characterization of over 50 dominantly acting oncogenes and the realization that the products of these genes are involved in the regulation of normal cell growth and development; the identification and isolation of many tumor suppressor genes, the products of which have been shown to be negative regulators of cell growth and development; and the demonstration that tumorigenesis is a multistep process requiring mutations in at least two of these cancer genes (reviewed in Fearon and Vogelstein, 1990; Vogelstein and Kinzler, 1993).

It has been only a decade since the isolation of the first tumor suppressor gene, yet a phenomenal amount of information has been generated in this area. Several themes have emerged. Tumor suppressor genes encode a diverse group of proteins which, through a variety of mechanisms, function to negatively regulate cell growth and development (Table 2.1). Perhaps due to the intensive interest in the factors controlling the cell cycle, many of the tumor suppressors isolated so far are directly involved in regulating this process, commonly binding and blocking the function of cyclin-dependent kinases (CDKs) (Fig. 2.1; Table 2.1). The importance of tumor suppressors in the control of other pathways has also been demonstrated: for example, upstream signal transduction pathways in the case of NF1; cell–cell communication in the case of DCC and possibly APC, and the mechanics of transcription in the case of VHL (Table 2.1).