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 Cramer, Stuart Sherman, Murray Korc

Research output: Contribution to journalArticle

25 Citations (Scopus)

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
Pages (from-to)7504-7521
Number of pages18
JournalOncotarget
Volume6
Issue number10
StatePublished - 2015

Fingerprint

Pancreatic Neoplasms
Heterografts
Conditioned Culture Medium
Adenocarcinoma
Endothelial Cells
Angiogenesis Inducing Agents
Cell Proliferation
Atlases
Cell Movement
Blood Vessels
Neoplasms
Genome
Gene Expression
Survival
Growth
Genes
INCB018424

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Gore, J., Craven, K. E., Wilson, J. L., Cote, G. A., Cheng, M., Nguyen, H. V., ... Korc, M. (2015). TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget, 6(10), 7504-7521.

TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. / Gore, Jesse; Craven, Kelly E.; Wilson, Julie L.; Cote, Gregory A.; Cheng, Monica; Nguyen, Hai V.; Cramer, Harvey; Sherman, Stuart; Korc, Murray.

In: Oncotarget, Vol. 6, No. 10, 2015, p. 7504-7521.

Research output: Contribution to journalArticle

Gore, J, Craven, KE, Wilson, JL, Cote, GA, Cheng, M, Nguyen, HV, Cramer, H, Sherman, S & Korc, M 2015, 'TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis', Oncotarget, vol. 6, no. 10, pp. 7504-7521.
Gore J, Craven KE, Wilson JL, Cote GA, Cheng M, Nguyen HV et al. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget. 2015;6(10):7504-7521.
Gore, Jesse ; Craven, Kelly E. ; Wilson, Julie L. ; Cote, Gregory A. ; Cheng, Monica ; Nguyen, Hai V. ; Cramer, Harvey ; Sherman, Stuart ; Korc, Murray. / TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. In: Oncotarget. 2015 ; Vol. 6, No. 10. pp. 7504-7521.
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