Decreased susceptibility of mast cell-deficient Kit/Kit mice to the development of 1, 2-dimethylhydrazine-induced intestinal tumors

Abstract

Administration of 1,2-dimethylhydrazine (DMH) induces intestinal epithelial tumors in mice. Increased numbers of mast cells have been reported to occur both within and near a variety of different neoplasms, including DMHinduced intestinal tumors. We investigated the role of the tyrosine kinase receptor, c-kit, and mast cells, in this model by administering DMH to c-kit mutant mast cell-deficient mice and the congenic normal mice. We attempted to induce colonic tumors by administering DMH (20 mg/kg body weight, s.c., weekly for 20 weeks) tomice and W/ W v mice that had been repaired of their mast cell deficiency by adoptive transfer of bone marrow cells derived from the congenic þ / þ mice. The susceptibility to the development of DMH-induced colonic tumors, and the numbers of mast cells associated with these tumors, was evaluated. Normal ( þ / þ ) mice exhibited significantly higher numbers of mast cells in DMH-induced intestinal tumors than in macroscopically normal colonic mucosa. Treatment with DMH induced development of colonic tumors in 97% of þ / þ mice, but in only 32% of the W/W v mice. W/W v mice that had been repaired of their mast cell deficiency by transfer of þ / þ bone marrow cells expressed susceptibility to the development of colonic tumors that was similar to that of wild-type mice. These results show that genetic impairment of c-kit function reduces the susceptibility of mice to DMH-induced colonic tumors, and that defects in bone marrow-derived cells in the W/W v mice contribute significantly to this result. Our findings also are consistent with the possibility that mast cells promote the development of DMHinduced colonic epithelial tumors in mice.

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

“…7 MC density in CRC tissues is positively associated with poor clinical outcomes in patients 10–13,15,17 and decreased intestinal tumor growth has been observed in MC-deficient mice. 28,29 Our study further provides experimental evidence that primary human MC promote colon cancer growth by stimulating production of pro-tumorigenic mediators in a bidirectional manner. Thus far, most studies in human MC-cancer interaction were using MC cell lines (LAD2 and HMC-1) 30–35 with specific limitations that these cell lines are leukemia-derived (e.g.…”

“…It has been shown that murine MC promote colon cancer growth, as illustrated by MC-deficient mouse models 28,29 and the coculture of primary murine MC and mouse colon cancer CT26. 17 We present for the first time that primary human MC can directly support human colon cancer proliferation.…”

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

“…MCs have been shown to support progression from polyposis to adenocarcinoma in models of chemically induced and oncogene-driven carcinogenesis (13,46,47). However, the transfer of the APC Min/þ mutation onto the Kit W-sh background resulted in increased tumorigenesis, highlighting the antitumor activity of MCs in this setting (14).…”

“…Colons were dissected at different time points during the acute and recovery phase (day [11][12][13][14][15][16][17] and the frequency of c-kit and FceRI double-positive cells in CD45 þ CD11b À infiltrating cells assessed (Fig. 1A).…”

“…The activity of MCs in colon inflammation has been widely studied in mice, but different results have been obtained depending on the model or on the experimental setting chosen for the investigation (13,14). There is also evidence of a pathogenic role for the mouse mast cell protease (mMCP)-6, the mouse homolog of the human tryptase, in dextran sodium sulfate (DSS)-induced colitis (15), but no conclusive data exist about the actual role of mMCP-6 in colon inflammation.…”