Abstract
Macrophages play a crucial role in tumorigenesis depending upon the phenotype of macrophages found in tumor microenvironments. To date, how the tumor microenvironment affects the phenotypes of macrophages is not yet fully understood. In this study, we constructed a NIH3T3/Src cell line stably overexpresses the Src protein and found that conditioned medium from this cell line was able to induce polarization towards the M2 phenotype in primary bone marrow-derived macrophages (BMDM) and Ana-1 macrophages. Further investigation revealed that IL-6 produced by NIH3T3/Src cells plays a key role in M2 polarization. During the development of colorectal cancer in C57BL/6J-ApcMin/+ mice, increased IL-6 secretion in the interstitial fluid of the colorectal tissues was observed. Furthermore, tumorigenesis in IL-6tm1Kopf mice treated with AOM-DSS, an IL-6 knockout mouse strain, was significantly inhibited compared with the control group, suggesting the important role of IL-6 in promoting tumorigenicity. Our findings identify the target molecules and proinflammatory cytokines responsible for promoting polarization towards the M2 phenotype in macrophages present in tumor microenvironment, which may be useful for the design of novel therapeutic strategies for colorectal cancer.
Highlights
Solid tumors exist in an extremely complicated microenvironment
Our results suggest that unknown molecules present in cultured media from cancer cells are able to induce the polarization of M2 macrophages
We found that tumors grew much faster (Figure 2C and 2D) as the average weight of the tumors formed from NIH-3T3/Src cells mixed with M2 macrophages was nearly double the weight of tumors generated from the NIH-3T3/Src cells alone (Figure 2E)
Summary
Solid tumors exist in an extremely complicated microenvironment. “Tumor microenvironment” refers to the steady-state local environment during tumor growth, which consists of tumor cells and a variety of other cell types including macrophages [1, 2]. It is wellestablished that M1 macrophages are involved in the inflammatory response and antitumor immunity whereas M2 macrophages exert anti-inflammatory and protumorigenic activities. Studies have demonstrated that macrophages play an important role in tumorigenesis because of their dual functions in inhibition and promotion of tumor growth that varies with their phenotype [3]. Upon stimulation by certain cytokines and secretory growth factors in the tumor microenvironment, macrophages can be polarized to the M2 phenotype, which promotes tumor growth. How macrophages are polarized with the tumor microenvironment remains to be fully understood
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