The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

Abstract

Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development. In current cancer therapy, cellular senescence is, on the one hand, intended to occur in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, organismic aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by de- or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors. These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. We are presenting an overview of well-documented stress situations and signals, which induce senescence. Among them, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology are critically reviewed with respect to new suggestions for cancer therapy leveraging genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis

“…It is a state of irreversible growth arrest, and is in certain sense a tumor suppressor. Senescence and carcinogenesis are mutually exclusive in most cases, although they can be induced by the same factors (54,55).…”

Role of p53 in the Regulation of Cellular Senescence

“…Moreover, persistent exposure to a damaging environment leads the cells to the next stage of senescence, known as "developing senescence", where cells are poised to demonstrate full-featured senescence [62]. Nevertheless, if senescent conditions continue for extended periods of time, as it happens, for instance, in the aging process, the cells enter a third phase of senescence, known as "late senescence", in which they may be characterized by heterogeneous phenotypes [63]. Many studies described phenotypical and transcriptional heterogeneity of senescent cells in both in vitro and in vivo models.…”

Fibronectin in Cancer: Friend or Foe

“…Indeed, HSP90s are deemed as an essential chaperon family to prevent senescence of normal epithelial cells [134]. The HSP90 deficiency-induced senescence may be evaded if endogenous FN synthesis is prohibited, rationalizing why, in order to allow transformed tumor cells to continue proliferating, they must downregulate their endogenous FN synthesis to foster the regrowth of senescent cells to become transformed tumor cells when the genome instability reaches the degree to which cellular senescence can be evaded and the regrown senescent cells become tumorigenic [20,107,135,136].…”