Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner

Abdulrahman M. Saadalla, Abu Osman, Michael F. Gurish, Kristen L. Dennis, Nichole R. Blatner, Abdulmohammad Pezeshki, Kelly M. McNagny, Hilde Cheroutre, Fotini Gounari, Khashayarsha Khazaie

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Mast cells (MCs) are tissue resident sentinels that mature and orchestrate inflammation in response to infection and allergy. While they are also frequently observed in tumors, the contribution of MCs to carcinogenesis remains unclear. Here, we show that sequential oncogenic events in gut epithelia expand different types of MCs in a temporal-, spatial-, and cytokine-dependent manner. The first wave of MCs expands focally in benign adenomatous polyps, which have elevated levels of IL-10, IL-13, and IL-33, and are rich in type-2 innate lymphoid cells (ILC2s). These vanguard MCs adhere to the transformed epithelial cells and express murine mast cell protease 2 (mMCP2; a typical mucosal MC protease) and, to a lesser extent, the connective tissue mast cell (CTMC) protease mMCP6. Persistence of MCs is strictly dependent on T cell-derived IL-10, and their loss in the absence of IL-10–expressing T cells markedly delays small bowel (SB) polyposis. MCs expand profusely in polyposis-prone mice when T cells over-express IL-10. The frequency of polyp-associated MCs is unaltered in response to broad-spectrum antibiotics, arguing against a microbial component driving their recruitment. Intriguingly, when polyps become invasive, a second wave of mMCP5+/mMCP6+ CTMCs expands in the tumor stroma and at invasive tumor borders. Ablation of mMCP6 expression attenuates polyposis, but invasive properties of the remaining lesions remain intact. Our findings argue for a multistep process in SB carcinogenesis in which distinct MC subsets, and their elaborated proteases, guide disease progression.

Original languageEnglish (US)
Pages (from-to)1588-1592
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
StatePublished - Feb 13 2018

Keywords

  • Cancer
  • ILC2
  • Inflammation
  • Mast cells
  • Small bowel

ASJC Scopus subject areas

  • General

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