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.

Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

“…S3C) and fibrotic (Supplementary Fig. S3E, arrows), and showed a high heterogeneity of vessel density as in human patients (22), with poorly vascularized regions (arrows in Supplementary Fig. S3D) and regions with a higher vessel density (arrowheads in Supplementary Fig.…”

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model

“…Analysis of TCGA PDAC data was previously described [31, 32]. DESeq was performed for differential expression analysis [33], and genes were identified based on lymphangiogenesis gene ontology (GO) terms and recent reviews on tumor lymphangiogenesis [34, 35].…”

“…Arrays from KRC and KPC tumors was performed by Miltenyi Biotec as described [32]. Briefly, whole genome microarrays were hybridized with RNA from tumors or normal pancreata.…”

Targeting tumor tolerance: A new hope for pancreatic cancer therapy?

“…Conversely, targeting JAK1/2 can also inhibit counterregulatory suppressive mechanisms, such as MDSC function and tumor/stromal cell PDL1 expression (Delitto, et al, 2015b;Yu, et al, 2015). To complicate matters, the development of PC is associated with both activation of JAK receptors and suppression of negative feedback pathways in cancer cells, specifically the suppressor of cytokine signaling-1 (SOCS-1) (Craven, et al, 2016;Fukushima, et al, 2003;Gore, et al, 2015;Mace, et al, 2015;Nagathihalli, et al, 2015). These observations led to a phase II trial of JAK1/2 inhibition in metastatic PC, which demonstrated a therapeutic benefit in a subgroup of patients with elevated serum C-reactive protein levels (Hurwitz, et al, 2015).…”