Collagen Signaling Enhances Tumor Progression after Anti-VEGF Therapy in a Murine Model of Pancreatic Ductal Adenocarcinoma

Abstract

There is growing evidence that anti-angiogenic 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 (GEMM) of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less differentiated mesenchymal-like tumor cell phenotype, TGFβ expression, and collagen deposition and signaling. Additionally, we show that collagen signaling is critical for pro-tumorigenic activity of TGFβ 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 ECM-mediated signaling.

CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer

“…Anti-VEGF therapy is in clinical use for the treatment of GC [42,43]. However, anti-angiogenic therapy is often insufficient to control tumor growth especially for increased invasion and metastasis [44]. The novel mechanism in GC that CXCL1 increases VEGF expression through activation of the JAK2-STAT3 signaling suggests that targeting CXCR2 therapy has the potential to improve antiangiogenic therapy and chemotherapy.…”

Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia

“…This is evident in highly desmoplastic tumors where a large fraction of vessels are compressed and may contribute to the failure of AA therapies in these patients (e.g., pancreatic ductal adenocarcinomas, a subset of breast cancers) (Kindler et al, 2010). Moreover, some tumors begin to produce more extracellular matrix in response to VEGF-blockade – partly from increased hypoxia – and become treatment-resistant (Aguilera et al, 2014; Chen et al, 2014). Thus, strategies that can alleviate compressive forces exerted by stromal cells and/or extracellular matrix in desmoplastic tumors should decompress tumor vessels and sensitize these tumors to AA agents.…”

Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

“…Consistent with the role of inflammatory myeloid cells in promoting CAF activation, treatment with dexamethasone reduced desmoplasia and attenuated tumor growth (15). Furthermore, inhibition of collagen binding to its discoidin domain receptor reduced colony formation of primary pancreatic tumor cells (28). Blockade of the HA-CD44 axis inhibited tumor cell proliferation, survival, invasion and epithelial-to-mesenchymal transition (EMT) (29, 30).…”