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

Oncotarget
Jesse GoreMurray Korc

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 prolo...Continue Reading

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Citations

Apr 6, 2017·Nucleic Acids Research·Roni RasnicMichal Linial
Jul 28, 2016·Oncotarget·Vito LongoNicola Silvestris
Nov 2, 2017·Journal of Cellular Biochemistry·Fei HouQingsheng Kong
Mar 12, 2021·Cellular Oncology (Dordrecht)·S Mazher HussainEvan S Glazer
Mar 30, 2021·Journal of Inflammation Research·Zeev Elkoshi
May 4, 2021·Gastroenterology·Nancy R GoughLopa Mishra

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
xenograft
xenografts
RNASeq
ELISA
transfection
Fluorescence
biopsies
biopsy

Software Mentioned

Image Pro Plus
Sigma Plot
ImageProPlus
IPA
GSEA
Aperio Imagescope
Ingenuity Pathway Analysis ( IPA
Systat

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