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Multiple Etiologic Factors in Neoplastic Development

Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, Fulham Road, London S.W. 3, England

This discussion is concerned with the multiplicity of factors that influence the initiation of neoplasia and its subsequent course. Factors that are not strictly "carcinogenic" may, nevertheless, affect the ultimate result decisively. Both genetic and nongenetic factors are implicated in the delivery of a carcinogen to the target tissue in an effective form and amount, and others govern the responsiveness of the tissue. Several factors may operate concurrently or consecutively. The cooperative action of genetic and hormonal factors together with a milk-borne virus is ordinarily most effective in producing a high yield of mammary tumors in mice. Epidermal carcinogenesis provides evidence of successive stages differently controlled. the first stage of initiation establishes a persistent region of incipient neoplasia whence tumors of varied kinds emerge at a later time. When the carcinogenic stimulus is optimal and the genetic sensitivity high, the early lesions are multiple, benign, or "imperfect" neoplasms of the kind usually described as "precancerous"; they are important because progression to malignant neoplasia may take place in one or more of them and because they disclose a region of incipient neoplasia within which malignant tumors may emerge later without spatial relationship to the early lesions.

Effective management of neoplastic disease is likely to depend on better knowledge than is yet available of the successive stages of neoplastic development and of the diverse factors operating at each of them. Different forms of neoplasia will probably call for different kinds of management. Initiation by known carcinogenic agents should be minimized. If the initiating agent is unknown, progression may still be controlled effectively, as in neoplasia of the uterine cervix, by treatment at the "precancer" stage of carcinoma in situ. Even at later stages, some control is practicable, as evidenced by the substantial, if limited, benefits of endocrine therapy for carcinoma of the breast and prostate.

Initiation, the crucial event in experimental carcinogenesis, probably entails persistent replicable change in the affected cells, not necessarily of the kind described as mutation. Recent developments in the theory of genetic structure and genetic action will predictably become increasingly important in the study of neoplasia and are discussed here in a preliminary way.

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