During the early stages of carcinogenesis, TGF-β exerts tumor-suppressive effects by inhibiting tumorigenic inflammation (1 in the graphic) or triggering EMT-coupled apoptosis in pre-malignant progenitors harboring RAS mutations (2). To escape TGF-β dependent apoptosis (3), RAS-mutant cells must acquire TGF-β pathway inactivating mutations or alterations that decouple TGF-β signaling from apoptosis. This enables carcinoma progression and turns TGF-β into a tumor-promoting agonist as the disease progresses. The tumor-promoting effects of TGF-β include (4) generation of an immune evasive TME by excluding or suppressing cytotoxic T cells and NK cells and turning macrophages into TAMs and neutrophils into TANs; (5) activation of CAF fibrogenic and paracrine activities, which favor cancer cell growth, invasion, immune evasion, and angiogenesis; (6) induction of cancer cell EMTs that increase tumor invasion, entry into, and exit from the circulation for tumor dissemination; (7) induction of immune evasive dormancy in disseminated metastatic progenitors; (8) downregulation of mediators of immune clearance in dormant cancer cells; (9 and 10) repeated generation of an immune evasive TME, activation of CAFs, and induction of fibrogenic EMTs in disseminated progenitors that resumed proliferation and survived elimination by the immune system; (11) promotion of metastatic outgrowth by stimulating organ-specific cancer cell-stroma interactions. The cancer cell-intrinsic tumorigenic effects of TGF-β (effects 6, 7, 8, 10, and, partly, 11) are available to carcinoma cells that retain an active TGF-β pathway decoupled from apoptosis. The effects of TGF-β on the TME (effects 4, 5, 9, and, partly, 11) are available to carcinoma cells regardless of how the tumor-suppressive effects of TGF-β are canceled.
