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Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum Stress
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 microenvironmentalstress due to depletion of oxygen and glucose and accumulationof waste products (acidosis). These conditions contribute totumor progression and correlate with poor patient prognosis.Here we show that the microenvironmental stresses found in thesolid tumor are able to inhibit the canonical Wnt/β-cateninsignaling pathway. However, tumor cells harboring common β-cateninpathway mutations, such as loss of adenomatous polyposis coli,are insensitive to this novel hypoxic effect. The underlyingmechanism responsible is hypoxia-induced endoplasmic reticulum(ER) stress that inhibits normal Wnt protein processing andsecretion. ER stress causes dissociation between GRP78/BiP andWnt, an interaction essential for its correct posttranslationalprocessing. Microenvironmental stress can therefore block autocrineand paracrine signaling of the Wnt/β-catenin pathway andnegatively affect tumor growth. This study provides a generalparadigm relating oxygen status to ER function and growth factorsignaling.
* 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}stanford.edu
Published ahead of print on 29 September 2008.
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Published ahead of print on 29 September 2008. 
