Senescence and cancer - role and therapeutic opportunities

Abstract

Cellular senescence is a state of stable, terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory, pro-inflammatory phenotype. Entry of cells into senescence can act as a barrier to tumorigenesis and, thus, could in principle constitute a desired outcome for any anticancer therapy. Paradoxically, studies published in the past decade have demonstrated that, in certain conditions and contexts, malignant and non-malignant cells with lastingly persistent senescence can acquire pro-tumorigenic properties. In this Review, we first discuss the major mechanisms involved in the antitumorigenic functions of senescent cells and then consider the cell-intrinsic and cell-extrinsic factors that participate in their switch towards a tumour-promoting role, providing an overview of major translational and emerging clinical findings. Finally, we comprehensively describe various senolytic and senomorphic therapies and their potential to benefit patients with cancer.

Fig. 1. Cell-intrinsic and cell-extrinsic roles of oncogene-induced senescence in tumour suppression.

Oncogene-induced senescence (OIS) is a senescence programme driven by activated oncogenes (for example, NRAS^G12V and BRAF^V600E). OIS forms a natural barrier to tumorigenesis by inducing stable growth arrest of premalignant cells, reinforced by cyclin-dependent kinase inhibitors (such as p16^INK4a and p21). Thus, OIS operates as a cell-intrinsic tumour-suppressive mechanism. Cells undergoing senescence (including OIS) acquire metabolic changes and the senescence-associated secretory phenotype (SASP), both of which mediate tumour suppression in a cell-extrinsic manner. SASP factors, including chemokines, cytokines, growth factors and enzymes, can induce paracrine senescence or a stable proliferation arrest in neighbouring cancer cells. Some SASP factors also enhance immune surveillance, which, in turn, accounts for the clearance of senescent cells. Moreover, SASP factors can induce secondary cell death in the cancer cell population. NK, natural killer; SA-β-gal, senescence-associated β-galactosidase.

Fig. 2. Roles of cellular senescence in tumour promotion.

Following induction of senescence by intrinsic or therapeutic stresses, non-malignant or cancer cells can secrete senescence-associated factors that mediate secondary effects on tumour progression (Supplementary Table 1). Different SASP factors contribute to cancer stemness, proliferation, migration, invasion and metastasis, thus enhancing the malignant potential of the cancer cell population. Moreover, senescence-associated factors also modulate the tumour microenvironment by promoting tumour angiogenesis and preventing the antitumour roles of immune cells. MMP, matrix metalloproteinase; SASP, senescence-associated secretory phenotype.

Fig. 3. Role of senescent cells in treatment-related adverse events.

Endogenous senescent cells in different tissues of older individuals (>65 years) reduce tolerance to cancer therapy and contribute to cancer progression. By contrast, cancer therapies can also induce senescence in different tissues and organs, thereby mimicking accelerated ageing. These senescent cells and associated detrimental SASP factors contribute to treatment-related adverse events, such as fatigue, frailty, cardiac dysfunction, hepatic failure, renal failure, general inflammation, bone loss and muscle weakness. SASP, senescence-associated secretory phenotype.

Fig. 4. Senolytic and senomorphic therapies in cancer.

Three strategies are summarized. a | Senolytic therapies selectively kill senescent cells that have detrimental pro-tumorigenic effects (see Supplementary Table 2). b | Senomorphic therapy inhibits the signalling pathways that regulate the senescence-associated secretory phenotype (SASP), such as NF-κB, mTOR and p38, or individual SASP factors that promote tumour progression (see Supplementary Table 3). c | Alternatively, pro-senescent cancer therapies can promote secretion of less-detrimental SASP factors and, thus, a non-deleterious senescence phenotype.