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

doi:10.1158/0008-5472.CAN-10-1923

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

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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 APC^Δ468 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 language	English (US)
Pages (from-to)	1627-1636
Number of pages	10
Journal	Cancer Research
Volume	71
Issue number	5
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-1923
State	Published - Mar 1 2011

Funding

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-10-1923

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

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title = "Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APC Δ468 mice",

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.",

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

year = "2011",

month = mar,

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doi = "10.1158/0008-5472.CAN-10-1923",

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Cheon, EC, Khazaie, K, Khan, MW, Strouch, MJ, Krantz, SB, Phillips, J, Blatner, NR, Hix, LM, Zhang, M, Dennis, KL, Salabat, MR, Heiferman, M, Grippo, PJ, Munshi, HG, Gounaris, E & Bentrem, DJ 2011, 'Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APC ^Δ468 mice', Cancer Research, vol. 71, no. 5, pp. 1627-1636. https://doi.org/10.1158/0008-5472.CAN-10-1923

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AU - Krantz, Seth B.

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AU - Blatner, Nichole R.

AU - Hix, Laura M.

AU - Zhang, Ming

AU - Dennis, Kristen L.

AU - Salabat, Mohammed R.

AU - Heiferman, Michael

AU - Grippo, Paul J.

AU - Munshi, Hidayatullah G.

AU - Gounaris, Elias

AU - Bentrem, David J.

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N2 - 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.

AB - 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.

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