Activation of tumor associated mast cells suppresses the growth of breast carcinoma
Ramses Ilarraza1, Ruwani Kalupahana2 And Marianna Kulka1,3
1Dept of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada; 2University of Prince Edward Island, Charlottetown, PE, Canada; 3National Research Council of Canada, Edmonton, AB, Canada
Mast cells (MC) are major players in the immune system, acting as sentinels, responders and modulators of localized immune responses. MC are ubiquitously distributed in tissues and acquire local phenotypes, depending on the microenvironment. Upon activation, MC release a complex array of cytokines, chemokines and other immune modulators. The role of MC in cancer is anything but clear. In breast cancer, evidence indicates that infiltrating stromal MC may help reduce tumor growth, and increased MC numbers are associated with a favorable prognosis (Rajput et al., 2008, Breast Cancer Res Treat 107: 249-57; Dabiri et al., 2004, Mod Pathol 17: 690-5; Aaltomaa et al., 1993, Anticancer Res 13:785-8).
We hypothesized that immune mechanisms associated with the direct activation of tumor-associated MC can cause apoptosis of tumor cells and a reduction in tumor size. To test this, we used an orthotopic 4T1 mammary carcinoma mouse model. MC were activated by injecting the secretagogue compound 48/80 (c48/80; 50µg/kg body weight), or PBS (control group), into two peritumoral sites eight days after tumor implantation. We monitored tumour volumes and collected tumor tissues for histological analysis. Eleven days post-treatment with c48/80, average tumor volume in c48/80 mice (474±65 mm3, n=10) was significantly lower than control (827±49.9 mm3, p<0.001, n=11). Histological analysis of tumor tissues showed a greater number of apoptotic cells per field in the c48/80-treated group (10.95±0.93, p<0.0005, n=5) compared to control (4.79±0.45), 72 hours post-treatment. C48/80 was not toxic to 4T1 cells and it did not affect their production or release of factors such as stem cell factor (SCF), interleukin 3 (IL-3), tumor necrosis factor (TNF) or monocyte chemoattractant protein 1 (MCP-1).
In conclusion, peritumoral MC activation showed significant anti-cancer effects, with decreased tumor size and increased tumor cell apoptosis. However, further studies are needed to elucidate the role of MC in breast cancer.
Funding provided by the Canadian Breast Cancer Foundation (CBCF) and the Canadian Institutes of Health Research (CIHR).