4.5 Article

XBP-1 regulates angiogenesis in human pancreatic adenocarcinomas

Journal

TRANSLATIONAL ONCOLOGY
Volume 2, Issue 1, Pages 31-U42

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1593/tlo.08211

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Funding

  1. [PO1 CA67166]

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PURPOSE. Tumors encounter endoplasmic reticulum stress during tumor growth and activate an adaptive pathway known as the unfolded protein response (UPR). Because this pathway is induced by the tumor microenvironment, it is a promising target for cancer therapy. We have previously demonstrated that X-box binding protein 1 (XBP-1), a key regulator of the UPR, was required for survival under hypoxia and critical for tumor growth in tumor xenografts In this study, we investigated the role of XBP-1 in regulating tumor angiogenesis METHODS We used an intradermal angiogenesis model to quantify the effect of XBP-1 on angiogenesis We also used a human tumor xenograft model to assay for tumor growth delay. We determined vascular endothelial growth factor (VEGF) expression by quantitative polymerase chain reaction and ELISA. Finally, we stained human pancreatic adenocarcinoma specimens for XBP-1 expression and correlated the expression pattern of XBP-1 with CD31 (endothelial cell marker) expression. RESULTS. We demonstrated that XBP-1 is essential for angiogenesis during early tumor growth. Inhibiting XBP-1 expression by short-hairpin RNA sequence specific for XBP-1 reduced blood vessel formation in tumors from mouse embryonic fibroblast cells and human fibrosarcoma tumor cells (HT1080) Expressing a dominant-negative form of IRE1a also reduced blood vessel formation in tumors. Moreover, expression of spliced XBP-1 (XBP-1s) restored angiogenesis in IRE1a dominant-negative expressing cells. We further demonstrated that XBP-1-mediated angiogenesis does not depend on VEGF. CONCLUSIONS: We propose that the IRE1a-XBP-1 branch of the UPR modulates a complex proangiogenic, VEGF-independent response that depends on signals received from the tumor microenvironment.

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