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Mol. Cell. Biol. 28 (23): 7212-7224

Copyright © 2008 by the American Society for Microbiology. All rights reserved.

Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum Stress{triangledown}

Meletios Verras, Ioanna Papandreou, Ai Lin Lim,, and Nicholas C. Denko*

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305

Received for publication 13 June 2008. Revision received 24 July 2008. Accepted for publication 16 September 2008.

Abstract: Poorly formed tumor blood vessels lead to regions of microenvironmental stress due to depletion of oxygen and glucose and accumulation of waste products (acidosis). These conditions contribute to tumor progression and correlate with poor patient prognosis. Here we show that the microenvironmental stresses found in the solid tumor are able to inhibit the canonical Wnt/β-catenin signaling pathway. However, tumor cells harboring common β-catenin pathway mutations, such as loss of adenomatous polyposis coli, are insensitive to this novel hypoxic effect. The underlying mechanism responsible is hypoxia-induced endoplasmic reticulum (ER) stress that inhibits normal Wnt protein processing and secretion. ER stress causes dissociation between GRP78/BiP and Wnt, an interaction essential for its correct posttranslational processing. Microenvironmental stress can therefore block autocrine and paracrine signaling of the Wnt/β-catenin pathway and negatively affect tumor growth. This study provides a general paradigm relating oxygen status to ER function and growth factor signaling.

* Corresponding author. Mailing address: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Rm. 1245 CCSR South, 269 Campus Dr., Stanford, CA 94305. Phone: (650) 724-5066. Fax: (650) 723-7382. E-mail: ndenko{at}

{triangledown} Published ahead of print on 29 September 2008.

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