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

Jesse Gore, Kelly E. Craven, Julie L. Wilson, Gregory A. Cote, Monica Cheng, Hai V. Nguyen, Harvey M. Cramer, Stuart Sherman, Murray Korc

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7504-7521
Number of pages18
JournalOncotarget
Volume6
Issue number10
DOIs
StatePublished - Jan 1 2015

Keywords

  • Angiogenesis
  • Mouse model
  • Pancreatic cancer
  • STAT3
  • TGF-β

ASJC Scopus subject areas

  • Oncology

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