Overexpression of TGFβ1 enhanced the invasiveness of PCC cells, while inhibition of TGFβ1 decreased the invasiveness of PCC cells, which appeared to be conducted by activated TGFβ receptor signaling-induced upregulation of ZEB1, ZEB2, Snail1, and Snail2, suggesting a process of epithelial-mesenchymal transition (EMT).
Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatinib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis.