TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis

// Jesse Gore 1, 5 , Kelly E. Craven 1, 2 , Julie L. Wilson 1 , Gregory A. Cote 1, 5, 6 , Monica Cheng 1 , Hai V. Nguyen 3 , Harvey M. Cramer 4 , Stuart Sherman 1, 5 , Murray Korc 1, 2, 5 1 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 3 Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 The Melvin and Bren Simon Cancer Center, and the Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA 6 Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA Correspondence to: Murray Korc, e-mail: mkorc@iu.edu Jesse Gore, e-mail: ajgore@iu.edu Keywords: Pancreatic cancer, Angiogenesis, TGF-β, STAT3, mouse model Received: January 24, 2015      Accepted: January 28, 2015      Published: February 25, 2015 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.