Editors' ChoiceCancer

Stressing Out Your Neighbors

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Science Signaling  26 Apr 2011:
Vol. 4, Issue 170, pp. ec114
DOI: 10.1126/scisignal.4170ec114

The endoplasmic reticulum (ER) stress response, which is associated with production of proinflammatory cytokines in tumor cells and macrophages, has been implicated in cancer progression and tumor growth. Noting that inflammation has itself been implicated in malignant transformation and cancer progression, Mahadevan et al. explored the hypothesis that ER stress could provide a mechanistic link whereby tumor cells signal to macrophages to promote an inflammatory microenvironment. Conditioned medium from cancer cell lines experiencing ER stress (in response to thapsigargin treatment or glucose deprivation) stimulated an increase in the abundance of transcripts encoding ER stress response genes in macrophages [J744 cells or bone marrow–derived macrophages (BMDM)] and in Xbp-1 splicing (also indicative of ER stress). Macrophages exposed to such conditioned medium also showed increased abundance of CD86 (indicative of activation) and of transcripts encoding proinflammatory cytokines, and increased secretion of proinflammatory cytokines. The response of BMDM lacking either Toll-like receptor 2 (TLR2), which is up-regulated under ER stress and has been implicated in macrophage activation by tumor-derived versican, or interleukin-6 receptor (IL-6R), which recognizes a proinflammatory cytokine (IL-6) secreted by cancer cells and macrophages, to ER stress–conditioned medium was undiminished. Thus, neither TLR2 nor TL-6R appeared to mediate transmission of the ER stress response. In contrast, the increase in abundance of transcripts encoding proinflammatory cytokines or the ER stress response genes Grp78, Gadd34, and Chop in response to ER stress–conditioned medium was attenuated in BMDM lacking TLR4 and potentiated by concomitant exposure to the TLR4 ligand lipopolysaccharide. Intraperitoneal injection of tumor ER stress–conditioned medium stimulated an increase in Grp78, Chop, Xbp-1, and spliced Xbp-1 in mouse liver. The authors thus conclude that factors released from cancer cells undergoing ER stress allow them to transmit ER stress to macrophages, recruiting them into contributing to an inflammatory microenvironment that promotes tumor progression.

N. R. Mahadevan, J. Rodvold, H. Sepulveda, S. Rossi, A. F. Drew, M. Zanetti, Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc. Natl. Acad. Sci. U.S.A. 108, 6561–6566 (2011). [Abstract] [Full Text]

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