Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is projected to become the 2nd leading cause of cancer deaths by 2030. PDACs are associated with a high frequency of KRAS mutations (95%) and overexpression of many pro-angiogenic cytokines and growth factors. Using a genetically engineered mouse model (GEMM) that we established in which oncogenic Kras is combined with loss of RB (KRC), we have determined that PDACs arising in these mice (mPDACs) harbor many endothelial cells (ECs) and sinusoidal-like vessels that have blood flow, as determined by intravital confocal microscopy. Array analysis of pancreatic cancer cells (PCCs) derived from KRC tumors revealed gene expression profiles that correlate with active TGF-β signaling pathways, as determined by gene set enrichment analysis (GSEA), and include increased expression of multiple pro-angiogenic genes. In silico analysis indicated that many of these pro-angiogenic genes were TGF-β targets, and inhibition of the type I TGF-β receptor (TβRI) with SB505124 confirmed that TGF-βs drive pro-angiogenic gene expression in KRC PCCs. Moreover, TGF-β increased the levels of pro-angiogenic cytokines in conditioned media (CM) prepared from KRC PCCs, which when added to ECs, activated canonical TGF-β signaling pathways and stimulated EC proliferation and migration. Although SB505124 blocked TGF-β pathway activation in ECs, it failed to suppress CM-enhanced EC proliferation and migration. By contrast, SB505124 attenuated tumor angiogenesis, growth and metastasis in a syngeneic orthotopic mouse model using KRC PCCs. Taken together, these results suggest that TGF-β promotes angiogenesis in an indirect manner, by up-regulating pro-angiogenic factors in PCCs that act on ECs in a paracrine manner. Therefore, targeting TGF-β in PDAC could be a beneficial anti-angiogenic strategy.
Citation Format: Jesse Gore, Kelly E. Craven, Julie L. Wilson, Murray Korc. TGF-beta promotes angiogenesis in an RB-deficient, Kras-driven mouse model of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4180. doi:10.1158/1538-7445.AM2015-4180