腫瘤不僅有不正常增生的腫瘤細胞，還包含多種腫瘤周邊細胞，例如：纖維細胞和巨噬細胞。腫瘤相關巨噬細胞已經被發現會促進腫瘤的進程。而巨噬細胞會依據其腫瘤微環境刺激而從M1型改變成M2型。現今對於腫瘤微環境中刺激巨噬細胞極化的因子還仍有許多未知。因此，了解腫瘤微環境中的刺激因子對於巨噬細胞的極化表現是重要的。在我們先前的研究指出在巨噬細胞中，LPS刺激下，Eps8藉由促進TLR4-MyD88結合而誘導的吞噬作用，Eps8在巨噬細胞朝向M1型極化的過程扮演重要的角色。然而，近年來的研究指出：腫瘤細胞藉由SDF-1α/CXCR4聚集巨噬細胞並促使巨噬細胞朝向M2型極化。因此，在腫瘤相關巨噬細胞中，SDF-1α/CXCR4對於多種的腫瘤進程是相當重要的，而Eps8可能參與調控巨噬細胞極化的進行。在本篇研究中，我們發現在巨噬細胞中SDF-1α會抑制LPS誘導的COX2與iNOS表現，而LPS也會抑制SDF-1α誘導的AKT與ERK活化。再者，SDF-1α也會抑制LPS誘導的tnf-α與il-1β表現。這個結果指出活化CXCR4可以干擾TLR4誘導巨噬細胞朝向M1型極化。另一方面，我們研究AOM/DSS-誘發大腸癌的小鼠模型，我們發現，與野生型小鼠比較，在Eps8轉殖基因小鼠中有較多的腫瘤形成與較多的巨噬細胞聚集在腫瘤之中。此外，我們也在小鼠大腸癌原位模型觀察到Eps8轉殖基因鼠中，有較高比例的腫瘤轉移現象與較多巨噬細胞聚集在腫瘤之中。從以上結果得知，Eps8可能在大腸癌的腫瘤微環境與巨噬細胞中促進腫瘤進展扮演重要的角色。

Tumor contains not only the abnormal growing cancer cells but also the surrounding stromal cells, such as fibroblasts and macrophages. The tumor-associated macrophages (TAMs) have been implicated in the promoting tumor progression. The polarity of macrophages changed from M1- toward M2-type depends on the cue present in the tumor microenvironment (TME). Currently, the cellular component(s) that respond to the stimulation exerted from TME in macrophages remains largely unknown. Our previous study reveals that Eps8 (epidermal growth factor receptor pathway substrate 8) plays a crucial role in LPS-stimulated phagocytosis in macrophages via interacting with TLR4 and facilitating TLR4-MyD88 association, suggesting that Eps8 may plays a role in promoting M1-type macrophages. In recent study, tumor cells may recruit macrophage and promote M2-type polarization via CXCR4/SDF-1α axis. Given that SDF-1α/CXCR4 axis in TAM is important for tumor progression in a variety of cancer cells, Eps8 might be the downstream molecule regulating the polarity of macrophages. In this study, we observed that LPS-induced iNOS and COX2 were suppressed by SDF-1α in an Eps8-dependent manner. Vice versa, LPS inhibits SDF-1α-induced activation of AKT and ERK in macrophages. Furthermore, the LPS-induced mRNA expression of tnf-α and il-1β was also decreased by SDF-1α, suggesting that activated CXCR4 might interfere TLR4-induced M1-type macrophage polarity. In AOM/DSS-induced colon cancer model, we found that there are more tumor nodules and TAMs in Eps8 transgenic mice than in wild type mice. In addition, in mouse orthotropic colorectal cancer model, we found that there are higher percentage of mice with metastasis and higher number of tumor macrophages in Eps8 transgenic mice than in wild type mice. In conclusion, macrophage Eps8 plays a crucial role in promoting cancer progression.

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