Mast cells infiltrating inflamed or transformed gut alternatively sustain mucosal healing or tumor growth

Alice Rigoni, Lucia Bongiovanni, Alessia Burocchi, Sabina Sangaletti, Luca Danelli, Carla Guarnotta, Amy Lewis, Aroldo Rizzo, Andrew R. Silver, Claudio Tripodo, Mario P. Colombo

Research output: Contribution to journalArticlepeer-review

Abstract

Mast cells (MC) are immune cells located next to the intestinal epithelium with regulatory function in maintaining the homeostasis of the mucosal barrier. We have investigated MC activities in colon inflammation and cancer in mice either wildtype (WT) or MC-deficient (KitW-sh) reconstituted or not with bone marrow-derived MCs. Colitis was chemically induced with dextran sodium sulfate (DSS). Tumors were induced by administering azoxymethane (AOM) intraperitoneally before DSS. Following DSS withdrawal, KitW-sh mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or KitW-sh mice reconstituted with bone marrowderived MCs. MCs were localized in areas of mucosal healing rather than damaged areas where they degraded IL33, an alarmin released by epithelial cells during tissue damage. KitW-sh mice reconstituted with MC deficient for mouse mast cell protease 4 did not restore normal mucosal healing or reduce efficiently inflammation after DSS withdrawal. In contrast with MCs recruited during inflammation-associated wound healing, MCs adjacent to transformed epithelial cells acquired a protumorigenic profile. In AOM- and DSS-treated WT mice, high MC density correlated with high-grade carcinomas. In similarly treated KitW-sh mice, tumors were less extended and displayed lower histologic grade. Our results indicate that the interaction of MCs with epithelial cells is dependent on the inflammatory stage, and on the activation of the tissue repair program. Selective targeting of MCs for prevention or treatment of inflammation-associated colon cancer should be timely pondered to allow tissue repair at premalignant stages or to reduce aggressiveness at the tumor stage.

Original languageEnglish
Pages (from-to)3760-3770
Number of pages11
JournalCancer Research
Volume75
Issue number18
DOIs
Publication statusPublished - Sep 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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