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PNAS 108 (16): 6561-6566

Copyright © 2011 by the National Academy of Sciences.


Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells

Navin R. Mahadevana, Jeffrey Rodvolda, Homero Sepulvedab, Steven Rossic, Angela F. Drewd, and Maurizio Zanettia,1

aLaboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093-0815; b BD Biosciences, San Diego, CA 92121-1106; cDepartment of Pediatrics, Cancer Symptom Control Program, University of California at San Diego, La Jolla, CA 92093; and dDepartment of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0521

Edited* by Michael G. Rosenfeld, University of California at San Diego, La Jolla, CA, and approved March 3, 2011 (received for review June 22, 2010)

Abstract: Metabolic, infectious, and tumor cell-intrinsic noxae can all evoke the endoplasmic reticulum (ER) stress response in tumor cells, which is critical for tumor cell growth and cancer progression. Evidence exists that the ER stress response can drive a proinflammatory program in tumor cells and macrophages but, to our knowledge, a role for the tumor ER stress response in influencing macrophages and inflammation in the tumor microenvironment has not been suggested. Here we show that macrophages cultured in conditioned medium from ER-stressed tumor cells become activated, and themselves undergo ER stress with the up-regulation of Grp78, Gadd34, Chop, and Xbp-1 splicing, suggesting a general activation of the ER stress-signaling pathways. Furthermore, these macrophages recapitulate, amplify and expand the proinflammatory response of tumor cells. We term this phenomenon "transmissible" ER stress. Although neither Toll-like receptor (TLR)2 nor interleukin 6 receptor (IL6R) signaling is involved, a reduction was observed in the transmission of ER stress to TLR4 KO macrophages, consistent with the fact that a second signal through TLR4 combined with exposure to tumor ER stress-conditioned medium results in a faster ER stress response and an enhancement of proinflammatory cytokine production in macrophages. The injection of tumor ER stress-conditioned medium into WT mice elicited a generalized ER stress response in the liver. We suggest that transmissible ER stress is a mechanism through which tumor cells can control myeloid cells by directing them toward a proinflammatory phenotype, thus facilitating tumor progression.

Author contributions: N.R.M. and M.Z. designed research; N.R.M., J.R., H.S., and S.R. performed research; H.S. and A.F.D. contributed new reagents/analytic tools; N.R.M., J.R., and M.Z. analyzed data; and N.R.M. and M.Z. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: mzanetti{at}

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