The dual role of mast cells in sporadic colorectal tumorigenesis: clinical and experimental evidence

Mast cells (MCs) impact significantly on the development of colorectal cancer (CRC), although their precise activity remains controversial. To this end, we analyzed human samples and performed a comprehensive meta-analysis to show that MC numbers vary in CRC cases, a fact related not only to different cell proliferation rates but also to complex immunological reactions. In carcinogenically exposed mice, deficient MC numbers (KitW/sh mouse model) increased the development of colorectal tumors and showed a significant immunological reaction related to T cell activity. Shortly after the carcinogenic exposure, MC deficiency decreased DNA damage levels but promoted proliferation in colonocytes. Exposing interleukin 33 receptor knockout (KO) mice to the same carcinogenic protocol revealed that increased MC density was related to a decrease in cell proliferation and β-catenin expression levels. Further experimentation with different KO mouse strains demonstrated that the major histocompatibility complex I decreased MCs density while its type II increased their numbers. Interestingly, MCs deficient mice given half of the carcinogenic dosage showed reduced development of preneoplastic lesions. Bone marrow transplantation increased not only stromal MC density but also the expression of CRC biomarkers in KitW/sh mice. Whether pharmacologically inhibiting MCs activity throughout carcinogenic exposure promoted the development of preneoplastic lesions, applying the same treatment following carcinogen injections inhibited such events. Our data suggest that the pro- and anti-tumorigenic effects of MCs are not only related to the intensity of carcinogenic exposure but also other immunological reactions controlling the multi-stepped development of CRC. Colon tumor mRNA profiles of AOM-exposed Kit-B6 and Kit-W/sh mice were generated by RNA sequencing using QIAseq Targeted RNAseq Mouse Immuno-Oncology panel and QIAseq Targeted RNA 96-Index I (#333117) in a in MiSeq Sequencing System (Illumina; Illumina MiSeq Reagent Kit v3 - 150 cycles, #15043894).