Vladimir N. Anisimov, MD


Cancer Control. 2007;14(1):23-31. 

In This Article

Multistage Model of Aging and Carcinogenesis

There are two paths of development of the stem cell that can be realized in an organism. One is cellular differentiation and aging and lastly, its individual death (apoptotic or necrotic).[85] When antiaging factors reach some limit in their compensatory ability to support tissue and functional homeostasis in life-important organs, the death of an organism as a whole takes place. Another possibilty is that the influence of harmful exogenous or endogenous factors could lead to cell dedifferentiation, immortalization, and formation of a clone of neoplastic cells.[85,86] Both strategies are multistage processes, many steps of which are well characterized in relation to the process of carcinogenesis.[1,2,8,87] However, the multistage pattern of aging needs serious studies and formalization.[8,28] Multistage models of cellular aging and immortalization have been developed in an attempt to explain delayed genomic instability, in which initiation of carcinogenesis is linked not only to a direct increase in chromosomal aberrations and mutation of oncogenes and tumor suppressor genes, but also to enhanced levels of aberrations and mutation in distant progeny of initiated cells and is a factor of predisposition to immortalization.[28] Carcinogenesis is a multistage process: neoplastic transformation implies the engagement of a cell through sequential stages, and different agents may affect the transition between contiguous stages.[88,89]

The process of neoplastic development is often divided into three operationally defined stages: initiation, promotion, and progression. During the first stage of carcinogenesis (initiation), irreversible changes occur in the genotype of the normal target stem cell, leading to its immortality. During the initiation, the carcinogen or its active metabolites (derived by simple degradation or by active enzymatic process) interact with nucleic acids leading to mutations in oncogenes and in antioncogenes. During the second stage of carcinogenesis (promotion), an initiated (latent, immortalized) cell acquires phenotypic features of transformed (malignant) cell, and under microenvironmental factors can evolve to tumor progression. A carcinogen not only affects the target cell but also influences many factors in the microenvironment of the target cell, creating conditions for the promotion of the immortalized cell (eg, growth factors, cytokines, immunodepression, biogenic amines, hormonal and metabolic imbalance). A complete carcinogen affects both stages of carcinogenesis (initiation and promotion) whereas tumor promoters affect only the second stage.

Unlike initiation, promotion requires prolonged exposure to the carcinogen and may be reversible to a large extent. A carcinogen that is able to act as both initiator and promoter is referred to as a full carcinogen. The dissection of carcinogenesis into initiation, promotion, and progression is useful as a frame of reference. It should not be assumed, however, that only three carcinogenic stages exist; each stage can be subdivided into multiple substages. Promotion may involve the activation of several enzymes (such as protein kinase C and ornithine decarboxylase), enhancement of hexose transport, increase in polyamine production, prevention of cell differentiation, and inhibition of cell-to-cell communication.[88] TPA, a well-known skin tumor promoter, was found to cause free-radical–mediated DNA alterations such as sister chromatid exchanges and expression of proviruses and retroviruses.[88]

The discovery of oncogenes and their function has provided new insights into the carcinogenic process. Carcinogenesis can be viewed as a "cascade" phenomenon, resulting in serial activation of multiple cellular oncogenes and/or inactivation of tumor-suppressing genes (eg, p53).[90]

Both experimental and epidemiologic studies illustrate the interaction of aging and carcinogenesis. The malignant transformation of normal cells involves both quantitative and qualitative changes. The Figure shows an integrated scheme of multistage carcinogenesis. Carcinogenic agents not only cause genomic transformation of the cell, but also create the conditions that facilitate proliferation and clonal selection in the cell microenvironment.[2,8]

Figure 1.

Integral scheme of multistage carcinogenesis. From Anisimov VN. The relationship between aging and carcinogenesis: a critical appraisal. Crit Rev Oncol Hematol. 2003;45:277-304. Reprinted with permission from Elsevier.

The Table summarizes the data available in the literature and obtained in our experiments on some hormonal metabolic shifts in the organism and disturbances at tissue and cellular levels observed in natural aging and in different types of carcinogenesis in vivo. Despite incomplete data, it can be seen that there is a similarity between the shifts in aging and carcinogenesis. On one hand, carcinogens could be thought to initiate a normal cell, interacting with its elements on the molecular level, while on the other hand, they could be thought to produce diverse changes in the organism facilitating promotion and progression of tumor growth.

Thus, three major mechanisms, not mutually exclusive, might explain the association of cancer and age:

Carcinogenesis is a time-consuming process in which the final product -- cancer -- is more likely to occur in persons of advanced age, depending on cumulative exposure to environmental carcinogens.

  • Aging tissues undergo molecular changes that parallel early carcinogenic changes and prime these tissues to the effects of carcinogens.

  • Age-related changes in body microenvironment, including proliferative and immune senescence, may favor cancer development and growth.

We believe that age-related changes in an organism developing at all levels of integration -- molecular, cellular, tissue, organ, and physiologic/systemic -- contribute to the mechanism of age-related increase in cancer incidence.

CME Information

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