Senescence and cancer: An evolving inflammatory paradox

Abstract

The senescent phenotype was first described in 1961 as a phenomenon characterized by the cessation of cellular division. After years of debate as to whether it represented a tissue culture artifact or an important biological process, it is now appreciated that senescence plays an important role in tumorigenesis. Further, senescence is integral to normal biological processes such as embryogenesis and the maintenance of tissue homeostasis. Now with defined roles in development, wound healing, tumor promotion and tumor suppression, it is not surprising that attention has turned to refining our understanding of the mechanisms behind, and consequences of, the induction of senescence. One emerging role for senescence lies in the ability of senescence to orchestrate an inflammatory response: factors secreted by senescent cells have been identified in multiple contexts to modulate various aspects of the immune response. As with many of the previously described roles for senescence, the type of inflammation established by the senescence phenotype is varied and dependent on context. In this review, we discuss the current state of the field with a focus on the paradoxical outcomes of the senescence-induced inflammatory responses in the context of cancer. A more complete understanding of senescence and an appreciation for its complexities will be important for eventual development of senescence-targeted therapies.

Keywords: Cancer; Immune cell; Inflammation; Senescence.

Figure 1. Senescence-inflammatory response in epithelium

A. Oncogene-induced senescence (OIS) in hepatic tumor cells, through secretion of SASP-factor CCL2, stimulates natural killer (NK) cell-mediated anti-tumor immune responses. B. Using a model of Nras^G12V-driven, OIS, senescent premalignant hepatocytes stimulate immune surveillance by secretion of SASP factors. SASP factors results in the activation of CD4⁺, T_H1 cells, which subsequently limit liver cancer development via macrophage/monocyte mediate clearance. C. PTEN-loss induced senescent prostate tumor cells promote cancer progression by the SASP factor-mediated establishment of immunosuppressive inflammation. In this model, Jak2/Stat3 dependent SASP factor expression results in recruitment of CD11b⁺Gr-1⁺ myeloid cells which limit cytotoxic T cell (CTL) function and thus tumor growth is unrestrained. D. In a model of colorectal cancer, a SASP related secretory profile, termed the senescence-associated inflammatory response (SIR), is secreted by stressed epithelial cells. The SIR promotes tumorigenesis following the loss of p53 expression. Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can reverse the tumor promoting effects of the SIR.

Figure 2. Senescence-inflammatory response in tumor stroma

A. In a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) model, p53-dependent, senescent hepatic stellate cells promote the enrichment of M1-polarized macrophages. M1 macrophages limit the proliferation of initiated epithelial cells and consequently restrict HCC development. B. A DMBA (7,12-dimethylbenz(a)anthracene)-initiated model of HCC demonstrated that livers of obese mice were predisposed to tumor development via DCA (deoxycholic acid)-induced senescent hepatic stellate cells. DCA was produced by the gut microbiota and resulted in increased senescence in the liver. The senescent stellate cells promoted tumorigenesis by the secretion of SASP factors.

Figure 3. A role for senescence in age-related tumor development

Senescent cells accumulate in tissues with age but little is known regarding the impact of this phenomenon on inflammation and cancer development. SASP factors can both promote and restrict tumor development through modulation of immune cells. The types of inflammation elicited by senescence in aging microenvironments as well as the consequence of this inflammation on tumorigenesis remain open questions.