Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APC Δ468 mice

Eric C. Cheon, Khashayarsha Khazaie*, Mohammad W. Khan, Matthew J. Strouch, Seth B. Krantz, Joseph Phillips, Nichole R. Blatner, Laura M. Hix, Ming Zhang, Kristen L. Dennis, Mohammed R. Salabat, Michael Heiferman, Paul J. Grippo, Hidayatullah G. Munshi, Elias Gounaris, David J. Bentrem

*Corresponding author for this work

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Abstract

Arachidonic acid metabolism has been implicated in colon carcinogenesis, but the role of hematopoietic 5-lipoxygenase (5LO) that may impact tumor immunity in development of colon cancer has not been explored. Here we show that tissue-specific deletion of the 5LO gene in hematopoietic cells profoundly attenuates polyp development in the APCΔ468 murine model of colon polyposis. In vitro analyses indicated that mast cells in particular utilized 5LO to limit proliferation of intestinal epithelial cells and to mobilize myeloid-derived suppressor cells (MDSCs). Mice lacking hemapoietic expression of 5LO exhibited reduced recruitment of MDSCs to the spleen, mesenteric lymph nodes, and primary tumor site. 5LO deficiency also reduced the activity in MDSCs of arginase-1, which is thought to be critical for MDSC function. Together, our results establish a pro-tumorigenic role of hematopoietic 5LO in the immune microenvironment and suggest 5LO inhibition as an avenue for future investigation in treatment of colorectal polyposis and cancer.

Original languageEnglish (US)
Pages (from-to)1627-1636
Number of pages10
JournalCancer Research
Volume71
Issue number5
DOIs
StatePublished - Mar 1 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cheon, E. C., Khazaie, K., Khan, M. W., Strouch, M. J., Krantz, S. B., Phillips, J., Blatner, N. R., Hix, L. M., Zhang, M., Dennis, K. L., Salabat, M. R., Heiferman, M., Grippo, P. J., Munshi, H. G., Gounaris, E., & Bentrem, D. J. (2011). Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APC Δ468 mice. Cancer Research, 71(5), 1627-1636. https://doi.org/10.1158/0008-5472.CAN-10-1923