Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma.

Abstract

There is growing evidence that antiangiogenic therapy stimulates cancer cell

invasion and metastasis. However, the underlying molecular mechanisms responsible

for these changes have not been fully defined. Here, we report that anti-VEGF

therapy promotes local invasion and metastasis by inducing collagen signaling in

cancer cells. We show that chronic VEGF inhibition in a genetically engineered

mouse model of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less

differentiated mesenchymal-like tumor cell phenotype, TGF-beta expression, and

collagen deposition and signaling. In addition, we show that collagen signaling

is critical for protumorigenic activity of TGF-beta in vitro. To further model

the impact of collagen signaling in tumors, we evaluated PDA in mice lacking

Sparc, a protein that reduces collagen binding to cell surface receptors.

Importantly, we show that loss of Sparc increases collagen signaling and tumor

progression. Together, these findings suggest that collagen actively promotes PDA

spread and that enhanced disease progression associated with anti-VEGF therapy

can arise from elevated extracellular matrix-mediated signaling.