肿瘤组织浸润的巨噬细胞（tumor-associated MΦs，TAMs）可通过多种途径促进肿瘤的发生发展，包括分泌多种前炎性因子TNF-α，IL-1β，IL-6，生长因子VEGF和bFGF，基质金属蛋白酶等；同时，M2型巨噬细胞可抑制T细胞的增殖，减弱免疫系统对肿瘤的杀伤作用；此外，TAMs也能使其周边的肿瘤细胞发生上皮间质转化。
近日，研究人员使用胃癌细胞系44As3和CAF共培养肿瘤来源的胞外囊泡（tumor-derived extracellular vesicles，TEVs）处理巨噬细胞，发现TEVs能使TAMs表达更多的炎性因子，基质金属蛋白酶和其他免疫抑制分子。当这种TAMs与成纤维细胞共培养后，TAMs能将内含的EVs组分释放并传递给成纤维细胞。这一过程依赖于TAMs内的Caspase3活化，当使用Caspase抑制剂后，这一现象得到一定程度的缓解。研究人员进一步在体外通过基质胶侵袭实验发现，与对照组巨噬细胞相比，TEVs处理的TAMs（TEVs-MΦs）能更多地穿透基质胶。更有意思的是，TEVs-MΦs和44As3细胞共同培养后的混合细胞，也比对照组具有更强的侵袭能力。体内实验结果显示TEVs-MΦs组皮肤内的TAMs分布很弥散，有明显向肿瘤一侧扩散的趋势，而对照组的巨噬细胞则是规则分布，边缘清晰。此外，在原位胃癌模型中，与对照组混合细胞或者单纯肿瘤细胞相比，TEVs-MΦs和44As3细胞共同培养后的混合细胞能更深地侵入至胃壁内部。这些结果证明TEVs-MΦs本身具有更强的侵袭能力。研究人员认为，这项研究发现并提出了TEVs与巨噬细胞相关肿瘤进展的关联，为肿瘤治疗提供了新的靶点。
推荐阅读原文：
Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment.
Tumor-derived extracellular vesicles (TEVs) secreted into the blood create a pre-metastatic niche in distant organs; however, it is unclear how TEVs are delivered and how they affect stromal cells in the tumor microenvironment. Tumor-associated macrophages (TAMs) have pivotal roles in cancer progression by interacting with cancer cells and other stromal cells. Here, we report a novel function of TAMs: delivery and transmission of TEV contents. TEV-incorporating macrophages (TEV-MΦs) showed increased invasiveness and were disseminated widely. Upon contact with host stromal cells (peritoneal mesothelial cells (PMCs), fibroblasts, and endothelial cells), TEV-MΦs released membrane blebs containing TEVs, a process dependent upon localized activation of caspase-3 in MΦs. Scattered blebs were incorporated into stromal cells, leading to transfer of cancer-derived RNA and proteins such as TGF-β, activated Src, Wnt3, and HIF1α. TEV-MΦ-secreted blebs containing cancer-derived components contributed to myofibroblastic changes in recipient stromal cells. TEVs delivered by MΦs penetrated deep into the parenchyma of the stomach in TEV-injected mice, and transmitted TEVs to PMCs lining the stomach surface; this process induced PMCs to undergo mesothelial-mesenchymal transition. PMCs infiltrated the gastric wall and created a niche, thereby promoting tumor invasion. Depletion of MΦs prevented these events. Moreover, TEV-MΦs created a pro-metastatic niche. Taken together, these results suggest a novel function for TAMs: transfer of cancer-derived components to surrounding stromal cells and induction of a pro-tumor microenvironment via an increase in the number of CAF-like cells.
联系客服
