title: Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells.
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.
authors.affiliation: Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093-0815, USA.
authors.forename: Navin R
authors.initials: NR
authors.lastname: Mahadevan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rodvold
authors.forename: Homero
authors.initials: H
authors.lastname: Sepulveda
authors.forename: Steven
authors.initials: S
authors.lastname: Rossi
authors.forename: Angela F
authors.initials: AF
authors.lastname: Drew
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000276:immunology*
chemical_list: D017077:Culture Media, Conditioned; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009363:Neoplasm Proteins