ETP stimulates tumor growth and metastasis via fibrosis, angiogenesis, and inflammation.

  • Major finding: ETP stimulates tumor growth and metastasis via fibrosis, angiogenesis, and inflammation.

  • Mechanism: ETP enhances chemotaxis of stromal cells and TGF-β-dependent epithelial-mesenchymal transition.

  • Impact: ETP inhibition blocks remodeling of the tumor microenvironment and suppresses tumor growth.

Adipocytes represent a major stromal component of the mammary gland and secrete numerous protumorigenic chemokines and extracellular matrix proteins, such as collagen type VI (COL6), which has been implicated in mammary tumor growth. COL6 is a glycoprotein that undergoes proteolysis of its α3 chain to generate endotrophin (ETP), a stable cleavage product that is highly expressed in human breast cancer; however, the specific role of ETP in tumor progression is unknown. Park and Scherer observed elevated ETP expression in adipocytes of obese mice, as well as in both cancer and stromal cells within mouse and human breast tumor tissues. ETP expression enhanced mammary tumor growth and pulmonary metastasis in the mouse mammary tumor virus–polyoma middle T antigen (MMTV–PyMT) tumor model. This phenotype was associated with augmented expression of genes involved in epithelial–mesenchymal transition (EMT), angiogenesis, and inflammation and an increase in mesenchymal-like stromal cells, tumor vasculature, and tissue fibrosis, suggesting that ETP promotes tumorigenesis by modulating the tumor microenvironment. The induction of EMT in ETP-expressing tumors was dependent on canonical TGF-β signaling, as TGF-β inhibition reduced fibrosis and diminished lung metastasis. Independent of TGF-β, ETP increased endothelial cell and macrophage recruitment, indicating that ETP functions as a chemokine to stimulate tumor angiogenesis and thus enhance tumor growth. Inhibition of ETP with a monoclonal antibody suppressed this chemokine activity and prevented the ETP-driven induction of angiogenesis and fibrosis; importantly, ETP neutralization also significantly reduced mammary tumor growth. In contrast, ETP expression partially rescued the growth of COL6-deficient cancer cells and was sufficient to induce EMT, fibrosis, and chemoattraction of stromal cells. These findings identify ETP as an important mediator of the protumor effects of COL6 and suggest that targeting ETP may be clinically beneficial.

Park J, Scherer PE. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 2012 October 8 [Epub ahead of print].