Figure 6.

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-dependent EMT 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 which 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, 10) repeated generation of an immune evasive TME, activation of CAFs, and induction of fibrogenic EMT in dormant metastatic progenitors that resume proliferative and survive 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 (though decoupled from apoptosis). The TME effects of TGF-β (effects 4, 5, 9 and, partly, 11) are available to carcinoma cells regardless of how the tumor suppressive effects of TGF-β are cancelled.