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標題: Imiquimod在黑色素瘤與巨噬細胞之腫瘤微環境中所扮演的角色
The role of imiquimod on the interplay of melanoma and macrophage in the tumor microenvironment
作者: 劉建廷
Jain Ting Liou
關鍵字: 腫瘤相關巨噬細胞;黑色素瘤;細胞凋亡;Tumor associated macrophage;M2 macrophage;Imiquimod;Melanoma;Apoptosis
腫瘤相關巨噬細胞(Tumor associated macrophage,TAM)有助於癌細胞的侵襲,轉移和耐藥性。許多的文獻均表明了M2巨噬細胞可以促進惡性腫瘤的增生和血管新生。在臨床數據顯示,高水平的M2巨噬細胞浸潤與治療預後不佳有高度的相關性。Imiquimod(IMQ)為一種合成的類核苷酸小分子化合物並且是Toll-like receptor 7(TLR-7)的配體,在臨床治療中對各種惡性皮膚腫瘤具有良好的抗腫瘤和抗病毒活性的能力。然而在臨床病例中顯示,一些黑色素瘤和非黑色素瘤惡性腫瘤細胞存在著對IMQ抗藥性的潛力。在這項研究中,我們檢視了IMQ在腫瘤微環境中黑素瘤與巨噬細胞之間的交互作用。首先,我們建立了小鼠IMQ後天抗性黑色素瘤細胞。我們證明IMQ後天抗性黑色素瘤細胞可促進巨噬細胞的移行,並且在人類黑素瘤細胞也可以在低濃度的IMQ刺激下吸引巨噬細胞。此外,我們觀察到小鼠IMQ後天抗性黑色素瘤細胞的上清液含有更多的pro-M2細胞因子,如IL-4,IL-10和IL-13,並促進巨噬細胞極化為M2型態。最後,我們觀察到M2巨噬細胞可保護黑色素瘤細胞免於IMQ誘導的細胞凋亡和抑制凋亡相關蛋白的表現。相反,M1巨噬細胞則增強了IMQ誘導的黑素瘤細胞凋亡。綜合本篇研究,我們證明IMQ後天抗性黑色素瘤細胞可以召集巨噬細胞,再進一步促進巨噬細胞偏向極化為M2型態,並且這些不同型態的TAM可調節IMQ所誘導的黑色素瘤細胞凋亡。

Tumor associated macrophages (TAMs) contribute to invasion, metastasis, and drug resistance in cancer cells. Many studies have shown that M2 macrophage can promote malignant tumor proliferation and angiogenesis. In clinical, high level of M2 macrophage infiltration is associated with insufficient treatment outcome of anti-tumor therapy. Imiquimod (IMQ), a synthetic nucleotide-like compound and Toll-like receptor 7 (TLR-7) ligand, contains both anti-tumor and anti-viral activity for various skin malignancies in clinical treatment. However, clinical cases had reported that some melanoma and non-melanoma malignances exist a potentiality of IMQ resistance. In this study, we investigated the role of IMQ on the interplay of melanoma and macrophage in the tumor microenvironment. First, we developed a mouse IMQ-acquired resistant melanoma cell. We demonstrate that mouse IMQ-acquired resistant melanoma cells attract macrophages accumulation and human melanoma cell could also attract macrophages accumulation after low-dose IMQ treatment. Next, we observed that supernatant of mouse IMQ-acquired resistant melanoma cell contain more pro-M2 cytokines, such as IL-4, IL-10 and IL-13, and promoted the macrophage M2-phenotype polarization. Finally, we observed that M2 macrophages protected melanoma cell from IMQ-induced apoptosis and down-regulated apoptosis-associate protein expression. Conversely, M1 macrophages enhanced IMQ-induced apoptosis in melanoma cells. In conclusion, we demonstrated that IMQ-acquired resistant melanoma cells could attract macrophage accumulation, promote the macrophage M2-phenotype polarization, and these TAMs modulate IMQ-induce apoptosis in melanoma cells.
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