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Abstract
Mutational inactivation of TGFβ receptors and Smad signal transducers in gastrointestinal and pancreatic cancers leads to a loss of TGFβ growth inhibitory effects. These mutations established the tumor suppressor role of the TGFβ pathway in human cancer. In animal models, TGFβ can also promote tumor invasion and metastasis, but the clinical relevance of this tumor-promoting role and the identity of TGFβ target genes that mediate metastasis remain largely unknown. Using a gene expression signature, the TGFβ response signature (TBRS), that defines the TGFβ response in epithelial cells, we show that TGFβ activity in primary ER-breast tumors is associated with a high risk of lung metastasis. Experimental evidence suggests that TGFβ activity within primary breast tumors empowers disseminating cells with specific activities to efficiently metastasize to the lungs. To identify a mediator of this effect I focused on angiopoietin-like 4 ( ANGPTL4) as this TBRS gene is shared with the LMS, a previously defined lung metastasis gene-expression signature. ANGPTL4 expression was found to be strongly induced by the canonical TGFβ-Smad pathway in metastatic cells and is required for the promotion of lung metastasis by this pathway. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases.
