The Multistage Concept of Carcinogenesis

  • Carl Peraino
  • Carol A. Jones


The recognition of carcinogenesis as a complex multievent process has developed from evidence gained over the past 50 years of research in experimental oncology demonstrating that tumors can be induced in high yield by the combined administration of agents that may have little or no carcinogenic activity when given singly. Three major types of tumorigenic enhancement may be defined on the basis of the types of inducing agents used and of the temporal relationships of their administration:
  1. 1.

    Syncarcinogenesis: Synergistic enhancement of tumor formation by simultaneous1 or sequential treatment2 with two carcinogens that separately may have relatively little carcinogenic activity

  2. 2.

    Cocarcinogenesis: Enhancement of tumor formation by simultaneous administration of a carcinogen and an additional agent (cocarcinogen) that has no intrinsic carcinogenic activity but facilitates carcinogen action3–8

  3. 3.

    Two-stage, or initiation-promotion carcinogenesis: Enhancement of tumor formation by the sequential administration of a carcinogen (initiator) and an additional agent (promoter) that has no intrinsic carcinogenic activity but facilitates expression of prior carcinogen-induced cryptic cellular changes.3 In this context, an initiating agent is exemplified by a subcarcinogenic dose of carcinogen, i.e., one that will not elicit neoplasms within the life span of an animal but that will produce an irreversible fundamental change (i.e., mutation) in the cells of a target organ or tissue so as to predispose them to neoplastic transformation when they are further subjected to an appropriate tumor promoting stimulus. A tumor promoter, exemplified by certain plant products, hormones, and xenobiotics acts to affect gene expression and to stimulate a hyperplastic expansion of the initiated cell population. This process ultimately results in the development of persistent precancerous nodules, papillomas, or polyps within the target tissue or organ. Some of these lesions can then undergo progression to malignant neoplasms (see Chapter 10).



Phorbol Ester Tumor Promotion Mouse Skin Metabolic Cooperation Human Endometrial Stromal Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations used in this chapter




butylated hydroxytoluene








hypoxanthineguanine phosphoribosyltransferase




polychlorinated bi-phenyls


protein kinase C




12-O-tetradecanoylphorbol 13-acetate


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Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Carl Peraino
    • 1
  • Carol A. Jones
    • 1
  1. 1.Biological, Environmental, and Medical Research DivisionArgonne National LaboratoryArgonneUSA

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