Colony stimulating factor-1 receptor (CSF-1R) 在巨噬細胞的分化以及M1/M2巨噬細胞的極化 (polarization) 扮演了一個相當重要的角色。一般認為，腫瘤相關巨噬細胞 (tumor-associated macrophages, TAMs) 屬於M2的巨噬細胞，而這些M2的巨噬細胞可以促進血管新生、腫瘤細胞的生長、侵犯以及遠端的轉移。我們實驗室發現位於CSF-1R形成二聚體化 (dimerization) 的區域有一個遺傳性基因變異，而我的研究最主要是探討這個CSF1R的遺傳性基因變異是否會和巨噬細胞的極化與功能有關。
我的實驗結果指出：在大腸癌、子宮內膜癌與卵巢癌腫瘤組織中，具有CSF1R變異的腫瘤會有較多的M1巨噬細胞，同時這些腫瘤組織會有較低的血管內皮生長因子 (vascular endothelial growth factor, VEGF) 表現。而分析利用周邊血液中的單核球分化而來的人類巨噬細胞，也發現具有CSF1R基因變異的巨噬細胞會表現比較多的iNOS (M1巨噬細胞的指標) 以及比較低的CD206 (M2巨噬細胞的指標)。進一步利用CSF-1來刺激這些巨噬細胞，結果發現具有CSF1R基因變異的巨噬細胞其細胞表面CSF-1R的胞吞作用變化較慢且磷酸化的程度也較不明顯。當給予巨噬細胞CSF-1R的抑制劑時，具有CSF1R基因變異的巨噬細胞對於CSF-1R抑制劑較敏感。綜合以上結果可得知，CSF1R基因的變異和CSF-1R的胞吞作用以及磷酸化有關，而此項基因變異也在巨噬細胞的極化扮演了一個重要的角色。

Colony stimulating factor 1 receptor (CSF-1R) plays an important role in regulation of macrophage differentiation and M1/M2 polarization. It has been shown that most of tumor-associated macrophages (TAM) are M2 type macrophages, which could promote angiogenesis, tumor growth, invasion and metastasis. Our group analyzed the CSF1R germline genetic variants and I further investigated their impacts on the polarization and functions of macrophages. A non-synonymous CSF1R genetic variant, which was located in the domain of CSF-1R dimerization, was identified for further study. My study showed that this CSF1R genetic variant was associated with more M1 macrophages in the tumor specimen of human colorectal, endometrial, and ovarian cancers. The expression level of vascular endothelial growth factor (VEGF), an M2-related cytokine, was lower in tumors with CSF1R genetic variant. Macrophages differentiated from peripheral blood monocytes were used to study the association between CSF1R genetic variants and polarization of macrophages in vitro. The results showed that macrophages with CSF1R genetic variant had higher expression level of iNOS, a marker of M1 macrophages, and lower expression level of CD206, a marker of M2 macrophages. When CSF-1 was used to stimulate macrophages, the endocytosis of CSF-1R was slower in macrophages with CSF1R genetic variant and the phosphorylation of CSF-1R was lower than that in macrophages without CSF1R genetic variant. By using cell viability assay, my study showed that macrophages with this genetic variant were sensitive to CSF-1R inhibitors. Taken together, this CSF1R genetic variant has a great impact on CSF-1R endocytosis, phosphorylation and polarization of macrophages.

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