Abstract
Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1-2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, with dismal overall 5-year survival rates of 6% [1]
The anti-angiogenic agent TNP-470 reduced neoangiogenesis in tumors formed by MIA-PaCa-2, ASPC-1, and CAPAN-1 pancreatic cancer cells (PCCs), resulting in decreased tumor growth and metastatic spread [11]; targeting vascular endothelial growth factor-A (VEGF-A) expression with a VEGF antisense construct markedly attenuated tumorigenicity in nude mice [10]; VEGF-A fused to diphtheria toxin (DT-VEGF) internalizes in target cells via VEGFRs, inhibits protein synthesis, and directly suppresses the growth of HUVEC endothelial cell (EC), while decreasing tumor volume, tumor spread, and microvessel density in tumors formed by HPAF-2 and ASPC-1 PCCs [12]; adenoviral vectors carrying sequences encoding soluble VEGFR-1 and VEGFR-2 [13, 14], or the VEGFR tyrosine kinase inhibitor PTK 787 [15], inhibit the growth and metastasis of pancreatic tumors in severe combined immune deficient (SCID) mice and athymic mice
To develop a personalized therapeutic approach for PDAC. This is a daunting task given the complexity of the molecular alterations and mutations in PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, with dismal overall 5-year survival rates of 6% [1]. The anti-angiogenic agent TNP-470 reduced neoangiogenesis in tumors formed by MIA-PaCa-2, ASPC-1, and CAPAN-1 PCCs, resulting in decreased tumor growth and metastatic spread [11]; targeting VEGF-A expression with a VEGF antisense construct markedly attenuated tumorigenicity in nude mice [10]; VEGF-A fused to diphtheria toxin (DT-VEGF) internalizes in target cells via VEGFRs, inhibits protein synthesis, and directly suppresses the growth of HUVEC ECs, while decreasing tumor volume, tumor spread, and microvessel density in tumors formed by HPAF-2 and ASPC-1 PCCs [12]; adenoviral vectors carrying sequences encoding soluble VEGFR-1 and VEGFR-2 [13, 14], or the VEGFR tyrosine kinase inhibitor PTK 787 [15], inhibit the growth and metastasis of pancreatic tumors in severe combined immune deficient (SCID) mice and athymic mice
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