Mammalian cells can respond to damage or stress by entering a state of arrested growth and altered function termed cellular senescence.
Several lines of evidence suggest that the senescence response suppresses tumorigenesis.
Cellular senescence is also thought to contribute to aging, but the mechanism is not well understood.
Senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice.
In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14ARF, or hydrogen peroxide.
Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells.
In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors.
It could be suggested that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy.
Multicellular organisms have evolved mechanisms to prevent the unregulated growth and malignant transformation of proliferating cells.
One such mechanism is cellular senescence, which arrests proliferation - essentially irreversibly - in response to potentially oncogenic events.
Cellular senescence appears to be a major barrier that cells must overcome to progress to full-blown malignancy.
Cellular senescence was first described as a process that limits the proliferation of cultured human fibroblasts (replicative senescence).
Proliferating cells progressively lose telomeric DNA, and short telomeres, which are potentially oncogenic, elicit a senescence response.
In addition, DNA damage, oncogene expression, and supraphysiological mitogenic signals cause cellular senescence.
Cellular senescence is controlled by tumor suppressor genes and seems to be a checkpoint that prevents the growth of cells at risk for neoplastic transformation.
In this regard, cellular senescence is similar to apoptosis.
However, whereas apoptosis kills and eliminates damaged or potential cancer cells, cellular senescence stably arrests their growth.
Cellular senescence is also thought to contribute to aging, although how it does so is poorly understood.
In addition to arresting growth, senescent cells show changes in function.
Because senescent cells accumulate with age, they may contribute to age-related declines in tissue function.
If so, cellular senescence may be an example of antagonistic pleiotropy.
Aging phenotypes are thought to result from the declining force of natural selection with age.
Consequently, traits selected to maintain early life fitness can have unselected deleterious effects late in life, a phenomenon termed antagonistic pleiotropy.
The senescence-induced growth arrest may suppress the development of cancer in young organisms.
The functional changes, by contrast, may be unselected consequences of the growth arrest and thus compromise tissue function as senescent cells accumulate.
Cellular senescence has been extensively studied in stromal fibroblasts from humans and mice.
Upon senescence, such cells show striking changes in gene expression, some of which relate to the growth arrest and senescent morphology.
Other changes, however, relate to fibroblast function.
Senescent fibroblasts secrete growth factors, cytokines, extracellular matrix, and degradative enzymes, all of which can alter tissue microenvironments and affect nearby epithelial cells.
Interestingly, this secretory phenotype resembles that of fibroblasts adjacent to some carcinomas, although senescent and tumor-associated fibroblasts differ in growth potential, morphology, and other traits.
Tumor-associated fibroblasts can stimulate epithelial tumorigenesis (Fig. 1).
Fig. 1. Tumor growth stimulated by fibroblasts. Nude mice were injected with epithelial cells alone (Control) or presenescent (Presn), senescent (Sen), or hTERT-immortalized (Telom) fibroblasts. At the indicated intervals (Days), tumor size was measured. The number of animals per group (n) is indicated. The last point on each line indicates when tumors were excised for histology. HaCAT, SCp2, Ha(Pk) and MDA231 - four epithelial cell lines.
Because senescent cells can alter the tissue microenvironment, scientists proposed that senescent cells may contribute to the exponential rise in cancer that occurs with age.
It is now clear that nonmutational events, such as telomere dysfunction or epigenetic changes in gene regulation or the stromal milieu, are important for the development of late-life cancers.
Changes in the stroma, which supports and maintains epithelial functions, may be particularly important in humans, where most age-related cancers arise from epithelial cells.
Thus, senescent human fibroblasts promote the proliferation and tumorigenesis of mutant epithelial cells.
These data suggest that cellular senescence is antagonistically pleiotropic, protecting from cancer early in life, but promoting carcinogenesis in aged organisms.
Several lines of evidence indicate that cellular senescence suppresses tumorigenesis in vivo.
First, many tumors contain cells that have partially or completely overcome senescence.
Second, several oncogenes act at least partly by disabling the senescence checkpoint.
Third, the senescence response requires p53 and pRB, the two most commonly lost tumor suppressors in malignant tumors.
Finally, germ-line inactivation of the p53 or pRB pathways results in senescence-defective cells and cancer prone organisms.
Despite species differences in whether and how cells respond to specific senescence-inducing stimuli, cellular senescence very likely protects mammals from cancer, at least early in life.
It is known that senescent human fibroblasts stimulated hyperproliferation and progression of preneoplastic epithelial cells and accelerated tumorigenesis by neoplastic epithelial cells.
These results may seem at odds with the tumor suppression function of cellular senescence.
They are, however, consistent with the evolutionary theory of antagonistic pleiotropy, which predicts that some genes, selected to enhance the fitness of young organisms, can have unselected deleterious effects in aged organisms.
These findings suggest that cellular senescence, despite protecting from cancer in young adults, may promote cancer progression in aged organisms.
Scientists speculate that the growth arrest was selected to ensure that damaged, mutant, or inappropriately stimulated cells - cells at risk for neoplastic transformation - do not proliferate.
By contrast, the functional changes may be unselected consequences of the growth arrest, having little impact on young organisms where senescent cells are rare.
However, as damage, telomere attrition, or errors cause senescent cells to accumulate with age, their influence, particularly their secretory phenotype, may become significant and deleterious.
Senescent fibroblasts had little impact on the growth of normal epithelial cells, although they can disrupt tissue architecture and function.
However, they clearly stimulated preneoplastic and neoplastic cell growth, largely because of the secretion of both soluble and insoluble factors.
These results suggest that senescent cells produce multiple factors, which act together, to stimulate epithelial cells with oncogenic mutations.
Somatic mutations increase with age, and some are potentially oncogenic.
For example, loss of heterozygosity and mutations in p53 and RAS-Ha accumulate in normal adult tissue.
Scientists suggest that, with age, there is an increasing probability that senescent cells and cells with oncogenic mutations occur in close proximity.
Senescent cells, then, may create a microenvironment that facilitates the growth and progression of the mutant cells.
Although tumors in older organisms tend to be more indolent, neoplastic cells were more likely to form tumors in older animals.
The senescent microenvironment may synergize with multiple factors to contribute to late-life cancers.
In addition to mutations, these include telomere dysfunction, hormonal and immune status, and angiogenic potential of the tissue.
It is still not clear why most late-life cancers are epithelial.
Sarcomas may be less prone to stimulation by senescent fibroblasts, but other factors (e.g., a greater need for mutations or a young hormonal or angiogenic milieu) may explain the relative paucity of sarcomas.
In summary, these results suggest a link between cancer and aging and a plausible mechanism by which genetic (oncogenic mutations) and epigenetic (accumulation of senescent cells) events synergize to generate the exponential rise in cancer that occurs with aging.