Effects of senescence on the tumour microenvironment and response to therapy

Abstract

Cellular senescence is a state of durable cell arrest that has been identified both in vitro and in vivo. It is associated with profound changes in gene expression and a specific secretory profile that includes pro‐inflammatory cytokines, growth factors and matrix‐remodelling enzymes, referred to as the senescence‐associated secretory phenotype (SASP). In cancer, senescence can have anti‐ or pro‐tumour effects. On one hand, it can inhibit tumour progression in a cell autonomous manner. On the other hand, senescence can also promote tumour initiation, progression, metastatic dissemination and resistance to therapy in a paracrine manner. Therefore, despite efforts to target senescence as a potential strategy to inhibit tumour growth, senescent cancer and microenvironmental cells can eventually lead to uncontrolled proliferation and aggressive tumour phenotypes. This can happen either through overcoming senescence growth arrest or through SASP‐mediated effects in adjacent tumour cells. This review will discuss how senescence affects the tumour microenvironment, including extracellular matrix remodelling, the immune system and the vascular compartment, to promote tumourigenesis, metastasis and resistance to DNA‐damaging therapies. It will also discuss current approaches used in the field to target senescence: senolytics, improving the immune clearance of senescent cells and targeting the SASP.