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The Origins of Human Cancer: Molecular Mechanisms of Carcinogenesis and Their Implications for Cancer Prevention and Treatment—Twenty-seventh G. H. A. Clowes Memorial Award Lecture¹

Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine, and School of Public Health, Columbia University, New York, New York 10032

Epidemiological studies provide evidence that environmental factors (external agents such as chemicals, radiation, and viruses) play a major role in the causation of the majority of human tumors. This is a highly optimistic message, since it implies that cancer is largely a preventable disease. To meet this challenge we must, however, understand the mechanisms of cancer causation at the cellular and molecular levels and, in a parallel effort, develop new laboratory methods that can be used to identify specific causative agents in humans. The approach must be comprehensive since it is likely that human cancers are due to complex interactions between multiple factors, including the combined actions of chemical and viral agents. This paper reviews recent studies from our laboratory and studies by other investigators related to these themes.

A major principle in studies on mechanisms of carcinogenesis is that the process proceeds through multiple discernible stages, including initiation, promotion, and progression. It is likely that the transition between these stages is driven by different environmental and endogenous factors and involves different biochemical mechanisms and genetic elements. Several types of chemicals initiate the carcinogenic process by yielding highly reactive species that bind covalently to cellular DNA. Our group has elucidated the details of this process with two groups of compounds, aromatic amines and polycyclic aromatic hydrocarbons, emphasizing how these agents distort the conformation of DNA and its functions during DNA replication and transcription. The implications of these findings with respect to oncogene activation, DNA amplification, gene transposition, and chromosome translocations are discussed. Our studies on tumor promotion have concentrated on the mechanisms of action of the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Studies from several laboratories indicate that this agent and related compounds produce their effects by activating a specific cellular enzyme, protein kinase C (PKC). This produces a cascade of events which include alterations in the function of membrane-associated ion channels and receptors, alterations in gene expression and, ultimately, changes in cellular differentiation and proliferation. Recent studies on the isolation and stable overexpression of a cloned DNA sequence that encodes PKC are described. The results obtained provide direct evidence that PKC plays a critical role in growth control. The possible role of PKC, and other mediators of signal transduction pathways, in the origin of certain human cancers is also discussed.

Finally, this paper discusses how insights into molecular mechanisms of carcinogenesis provide new approaches to the detection of specific causes of human cancer, using an approach termed "molecular cancer epidemiology," and also new strategies for cancer prevention and treatment.

¹ Financial support of this research was provided by the National Cancer Institute, the American Cancer Society, the Alma Toorock Memorial for Cancer Research, and the National Foundation for Cancer Research. Presented at the Seventy-eighth Annual Meeting of the American Association for Cancer Research, May 21, 1987, in Atlanta, GA.

Received 4/11/88. Accepted 5/ 3/88.

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