title: Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth.
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 wild-type (WT) or MC-deficient (Kit(W-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, Kit(W-sh) mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or Kit(W-sh) mice reconstituted with bone marrow-derived 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. Kit(W-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 Kit(W-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.
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Rigoni
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Bongiovanni
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Burocchi
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sangaletti
authors.affiliation: Inserm UMRS-1149, Paris; Université Paris Diderot, Sorbonne 7 Paris Cite; Laboratoire d'excellence INFLAMEX, Paris, France.
authors.forename: Luca
authors.initials: L
authors.lastname: Danelli
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Whitechapel, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Human Pathology Section, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Aroldo
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Whitechapel, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Silver
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. mario.colombo@istitutotumori.mi.it.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001397:Azoxymethane / Q000633:toxicity; D002277:Carcinoma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D002452:Cell Count; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000502:physiology; D007413:Intestinal Mucosa / Q000502:physiology*; D008407:Mast Cells / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D019009:Proto-Oncogene Proteins c-kit / Q000172:deficiency / Q000235:genetics; D018123:Receptors, Interleukin / Q000502:physiology; D012038:Regeneration / Q000276:immunology*; D012697:Serine Endopeptidases / Q000172:deficiency; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D018123:Receptors, Interleukin; D016264:Dextran Sulfate; D019009:Proto-Oncogene Proteins c-kit; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D001397:Azoxymethane