Senescence and SASP in the Stromal Microenvironment of Breast Cancer: Dual Role in Progression and Therapeutic Options.

Abstract

Cellular senescence, a process characterized by the typically persistent cell-cycle arrest that occurs in response to DNA damage, plays a dual role in carcinogenesis. This complexity is predominantly influenced by the presence of senescent cancer-associated fibroblasts within the tumor microenvironment. While the induction of cellular senescence in early-stage tumor cells has been shown to inhibit proliferation, the action of senCAFs has been demonstrated to result in adverse consequences. It has been demonstrated that senescent cells are significant producers of the senescence-associated secretory phenotype. The SASP creates an immunosuppressive, therapy-resistant tumor microenvironment (TME) that promotes cancer progression. The current review is dedicated to the analysis of the contradictory role of senescence with focus on senCAFs in breast cancer progression. The review is devoted to the possible mechanisms of senescence induction in CAFs, their functional heterogeneity, and the key effector molecules of SASP (TGF-β, IL-6, MMPs, CXCL12, OPN) that trigger epithelial-mesenchymal transition and suppress antitumor immunity, including NK cell functionality. A particular focus has been placed on paracrine and autocrine regulatory loops, such as the OPN and CXCL12 axis, which have been shown to enhance the aggressive phenotype of both tumor cells and cancer-associated fibroblasts. The ensuing discourse will delve into the innovative strategies of the "one-two punch approach," which are designed to target senCAFs with the objective of counteracting BC progression and enhancing the prognosis for breast cancer patients.