Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis

Crystal Morales, Saleh Rachidi, Feng Hong, Shaoli Sun, Xinshou Ouyang, Caroline Wallace, Yongliang Zhang, Elizabeth Garret-Mayer, Jennifer Wu, Bei Liu, Zihai Li*

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Furthermore, Toll-like receptors have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophagespecific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery, and reduced expression of proinflammatory cytokines, including interleukin (IL)-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.

Original languageEnglish (US)
Pages (from-to)446-459
Number of pages14
JournalCancer Research
Volume74
Issue number2
DOIs
StatePublished - Jan 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis'. Together they form a unique fingerprint.

  • Cite this

    Morales, C., Rachidi, S., Hong, F., Sun, S., Ouyang, X., Wallace, C., Zhang, Y., Garret-Mayer, E., Wu, J., Liu, B., & Li, Z. (2014). Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Research, 74(2), 446-459. https://doi.org/10.1158/0008-5472.CAN-13-1677