Vladimir N. Anisimov, MD


Cancer Control. 2007;14(1):23-31. 

In This Article

Interaction of Aging and Carcinogenesis: Cellular Level

The term "cellular senescence," originally defined as a series of cellular changes associated with aging, now refers more commonly to a signal transduction program leading to irreversible arrest of cell growth, accompanied by a distinct set of changes in the cellular phenotype.[29] Senescence is a potent anticarcinogenic program, and the process of neoplastic transformation involves a series of events that allow cells to bypass senescence.[12,29,30,31] Although the relationships between cellular senescence and aging in vivo is not yet clear, senescent cells were reported to accumulate in aging tissues: in human skin and liver[32,33,34] and in primate retina.[35] Senescent cells were demonstrated capable of stimulating the malignant progression of premalignant keratinocytes and mammary gland epithelial cells.[36] Senescent cells have also been detected at sites of agerelated pathology, including benign hyperplastic prostate[37] and atherosclerotic lesions.[38]

Cellular senescence is controlled by the tumor suppressor proteins p53 and pRb.[12,31] Inactivation of these proteins results in bypass of senescence. Due to its essentially irreveresible growth arrest and the requirement for p53 and pRb function, cellular senescence is considered a potent tumor suppressor mechanism.[12,30,31,39,40] Numerous studies,primarily in human fibroblasts,suggest that telomere shortening is the primary cause of replicative senescence.[12,41]

Cellular senescence can be induced by a variety of extrinsic factors, such as X-ray irradiation, UV-irradiation, H2O2, ectopic expression of certain oncogenes (Ras, Raf, ets2, E2F1) and tumor suppressors (p16, p14, p53, PPML).[41] Recent reports suggest that cellular senescence program controlled by p53 and p16INK4a may be one of the mechanisms by which cancer chemotherapy drugs work in vivo.[29,42]

Some observations failed to support the existence in vivo of a significant number of cells with the phenotype observed during replicative aging.[43] Cristofalo[43] was unable to demonstrate any donor age-specific increase in senescence-associated beta-galactosidase activity staining. He believes that it is likely that this senescent phenotype either does not exist in individuals of any age or quickly dies in vivo.

The natural history of spontaneous tumors in humans (the rate of tumor doubling, the potential for metastasis) and the survival of cancer patients newly diagnosed at different ages provide information on the effects of age on tumor growth in humans. Available data in both experimental animals and humans are contradictory and support different effects of age on tumor development.[44] In general, an "age effect" may be recognized both in experimental and in human malignancies. Mikhnin et al[45] have studied the growth rate and the volume doubling in 150 malignant melanomas of the skin in patients 16 to 85 years of age. Regardless of the pattern of melanoma growth (superficial and/or nodular), there was no influence of age on the kinetics of the tumor growth. This observation contradicts the suggestion that accumulation of senescent cells promotes the tumor growth in humans regardless of target tissue. Rather, tissue origin (histogenesis) and immunogenicity of tumor are the principal factors determining age related differences in tumor growth.

There is increasing evidence, however, that age related changes in tumor microenvironment might also play a significant role. In our experiments, lung-affine cells of rat rhabdomyosarcoma RA-2 were intravenously inoculated into rats of different ages.[46] The number of lung tumor colonies was highest in 1- and 15-month old animals and lowest in 3- and 12-month-old animals. A positive correlation was found between the number of tumor lung colonies and somatomedin activity in the lung. In another experiment, RA-2 cells from a 3- month-old donor were inoculated into 2- to 3- or 21- to 23-month-old recipients and 3 weeks later were separately taken from "young" and "old" hosts and transplanted into 3-month-old recipients. The number of lung colonies was significantly decreased in 3-month old recipients injected with RA-2 cell passed via "old" hosts.[47] The results suggest the critical role of host and donor microenvironment in lung colony forming potential of RA-2 cells.

McCullough et al[48] observed that transformed rat hepatocytic cells lines were only weakly tumorigenic following transplantation into the livers of young adult rats. The tumorigenicity of these cell lines increased progressively with the age of the tumor recipients. These results strongly suggest that the tissue microenvironment is an important determinant in the age-related tumorigenic potential of transformed cells.

Thus, the data available show that some changes in structure and function of DNA are evolving with natural aging. The character of these changes could vary in different tissues and might cause uneven tissue aging. Cellular senescence is suggested to be an important mechanism protecting the organism from cancer at a young age, but it could be a factor of tumor promotion in old age.[12] Thus, cellular senescence may lead to both age-related increases in spontaneous tumor incidence and age-related changes in susceptibility to carcinogens in various organs.[8]


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