Effects of senescence on the tumour microenvironment and response to therapy

• Published in: The FEBS journal 2024-06, Vol.291 (11), p.2306-2319
• Main Authors: Reynolds, Louise E., Maallin, Seynab, Haston, Scott, Martinez‐Barbera, Juan Pedro, Hodivala‐Dilke, Kairbaan M., Pedrosa, Ana‐Rita
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell proliferation; Cellular Senescence - drug effects; DNA damage; Drug Resistance, Neoplasm; endothelial cells; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Gene expression; Growth factors; Humans; Immune clearance; Immune system; Inflammation; Metastases; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Paracrine signalling; Phenotypes; SASP; Senescence; Senescence-Associated Secretory Phenotype - genetics; senolytics; therapy‐induced senescence; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumorigenesis; Tumors; tumour microenvironment
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.16984

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. This review discusses how senescent cells, through the senescent‐associated secretory phenotype (SASP—cytokines, chemokines, growth factors and extracellular remodelling proteins) promote cancer by altering the tumour microenvironment, with a focus on fibroblasts, extracellular matrix, immune cells and the vasculature. Senescent cells accumulate in the tumour bed upon anti‐cancer treatments, such as chemo‐ and radiotherapy. Finally, we discuss approaches that are being tested to eliminate senescent cells, such as senolytics drugs.