多种生物学过程参与转化生长因子 β 介导的肿瘤耐药

Therapy resistance is a major obstacle to cancer treatment, and transforming growth factor-beta (TGF- ) signaling has emerged as a major instigator across many cancer types and therapeutic regimens. Solid tumors overexpress TGF- ligands, and canonical and non-canonical TGF- signaling pathways drive molecular changes in most cell types within the tumor to hijack therapeutic responses. Cancer therapies further stimulate TGF- release to potentiate this problem. Molecular mechanisms of TGF- action supporting resistance include upregulation of drug efflux pumps, enhanced DNA Damage Repair, elaboration of stiffened extracellular matrix, and decreased neoantigen presentation. TGF- also activates pro-survival pathways, such as epidermal growth factor receptor, B-cell lymphoma-2 expression, and AKT-mTOR signaling.

TGF- -induced epithelial-to-mesenchymal transformation leads to tumor heterogeneity and acquisition of stem-like states. In the tumor microenvironment, TGF- induces extracellular matrix production, contractility, and secretion of immunosuppressive cytokines by cancer-associated fibroblasts that contribute to drug resistance.

TGF- also blunts cytotoxic T and NK cell activities and stimulates recruitment and differentiation of immunosuppressive cells, including T-regulatory cells, M2 macrophages, and myeloid-derived suppressor cells. The importance of TGF- signaling in development of drug resistance cannot be understated and should be further explored mechanistically to identify novel molecular approaches and combinatorial drug dosing strategies to prevent drug-resistance.