title: TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis.
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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Melvin and Bren Simon Cancer Center, and The Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gore
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Craven
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Melvin and Bren Simon Cancer Center, and The Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA.|Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cote
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hai V
authors.initials: HV
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Harvey M
authors.initials: HM
authors.lastname: Cramer
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Melvin and Bren Simon Cancer Center, and The Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Sherman
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Melvin and Bren Simon Cancer Center, and The Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor
keywords: STAT3; TGF-β; angiogenesis; mouse model; pancreatic cancer