(A) TGFβ and BMP suppress the progression of premalignant states in mouse models. Genetic ablation of TGFβ or BMP receptor genes (TGFBRII and BMPR1A, respectively) or SMAD4 alone does not normally lead to carcinoma formation. However, inactivation of these pathways allows carcinoma progression in transitional epithelia and in premalignant lesions caused by oncogene (KRAS) activation or tumor-suppressor gene (APC) inactivation.
(B) Influence of the context on choice of TGFβ tumor-suppressor response. Cells under normal conditions are generally wired for cytostatic or differentiation responses to TGFβ; a loss of TGFβ signaling in this context causes elevated but still regulated cell proliferation (hyperplasia). In contrast, premalignant cells and other hyperproliferative cell states are wired for apoptotic and senescence responses; a loss of TGFβ signaling in this context enables tumor progression (neoplasia).