Characterization of mast cells in tumor microenvironment

概要

【Introduction】
The tumor microenvironment consists of several types of cells which resident in or infiltrate to the tumor tissue, such as immune cells, blood vessels, and fibroblasts. These cells have the pro-tumorigenic phenotype by promoting angiogenesis and suppressing antitumor immunity. Mast cells are also present in human and mouse tumor tissues and affect tumor growth. For example, in human breast tumor, mast cells inhibited proliferation of tumor cell and the increased number of mast cells correlated with good patient prognosis. Mast cell inactivator inhibited breast tumor growth implanted on mice. On the other hand, in human lung tumor and melanoma, the increased number of mast cells correlated with poor patient prognosis. In mouse melanoma, mast cell-deficiency showed slower tumor growth than WT mice. These reports suggested that the mast cell have pro- or anti-tumorigenic function in tumor. However, the detail character of infiltrated mast cells in tumor and the mechanism to acquire their phenotypes remain unknown.

From these backgrounds, I hypothesized that the mast cell phenotype is different depending on tumor type. To prove this hypothesis, I investigated the mast cell phenotypes in mouse model transplanted with tumor cell. Furthermore, I clarified the mechanism of their phenotype change in tumors.

【Results】
I transplanted tumor cell on mice and collected tumor tissue. Histological analysis suggested that the dye-affinity of tumor mast cells was similar with normal tissue resident mast cells but detailed morphology in regard to nuclei size and granule component was obviously different with tissue resident mast cell. Since the tumor mast cells have clearly different morphology, I next focused on the functional property. Histological analysis suggested that pro-tumorigenic cytokine expression of tumor mast cells was different with resident mast cell. In vitro study showed that morphology and function of tumor mast cells may changes by tumor cell-derived substances.

To identify the factors which change the property of mast cell function, I measured the mRNA expression of some cytokine, which relate mast cell maturation and differentiation, in normal skin and tumor tissue. Tumor tissue express high level of these cytokine compared to normal skin tissue. The blockade of these cytokine signal abolished the tumor cell cultured supernatant-induced pro-tumorigenic cytokine mRNA increase in bone marrow derived mast cells. These results suggested that tumor-derived substance changed the mast cells to pro-tumorigenic function.

【Conclusion】
The present study showed that mast cells phenotype varies depending on tumor type and it may be controlled by tumor cell-derived substance.