文章：

骨髓髓系-淋巴祖细胞通过细胞融合促进肿瘤淋巴管扩张

Bone Marrow Myeloid–Lymphatic Progenitors Expand Tumor Lymphatic Vasculature Through Cell Fusion

原文发布日期：28 May 2025

DOI: 10.3390/cancers17111804

类型: Article

开放获取: 是

英文摘要：

Background:Bone marrow (BM)-derived myeloid–lymphatic endothelial cell progenitors (M-LECPs) promote formation of tumor lymphatics that are responsible for metastasis to lymph nodes. The regenerative capacity of BM progenitors to other lineages is mediated through cell fusion, a process that delivers a pro-mitotic message directly to division-restricted cells. This suggested that M-LECPs might use a similar mechanism to induce division of lymphatic endothelial cells (LECs). Methods: To test this hypothesis, we determined expression of fusogenic markers in M-LECP produced in vitro and recruited to human or mouse tumors in vivo as well as quantified their fusion with LECs in both settings. Fusion in vivo was determined in female chimera mice grafted with male BM that have been implanted with MDA-MB-231 or EMT6 breast tumors. Co-staining for Y-chromosome and LEC-specific markers allowed us to quantify tumor lymphatic vessels fused with BM progenitors. Results: We found that both tumor-recruited and in-vitro-produced M-LECPs expressed multiple fusogenic regulators and possessed a significant fusogenic activity towards cultured and vessel-lining LECs. Y-chromosomes, a marker of fusion, were detected in nearly half of tumor lymphatics and were associated with mitotic division, vessel formation, and node metastasis. Both in vitro and in vivo assays showed dependency of fusion on Th2 and Toll-like receptor-4 (TLR4) pathways. Conclusions: This novel mechanism of tumor lymphatic formation triggered by fusion with BM myeloid–lymphatic progenitors suggests a variety of new targets for inhibition of metastatic spread.

摘要翻译： 

背景：骨髓源性髓系-淋巴管内皮祖细胞（M-LECPs）能促进肿瘤淋巴管形成，进而导致淋巴结转移。骨髓祖细胞向其他谱系的再生能力通过细胞融合介导，这一过程直接将促有丝分裂信号传递给分裂受限的细胞。这提示M-LECPs可能通过类似机制诱导淋巴管内皮细胞（LECs）分裂。方法：为验证该假说，我们检测了体外培养及体内招募至人或小鼠肿瘤的M-LECPs中融合标记物的表达情况，并在两种条件下量化其与LECs的融合程度。体内融合实验采用移植雄性骨髓的雌性嵌合小鼠模型，并植入MDA-MB-231或EMT6乳腺癌细胞系。通过Y染色体与LEC特异性标记物共染色，量化与骨髓祖细胞融合的肿瘤淋巴管。结果：研究发现，肿瘤招募与体外培养的M-LECPs均表达多种融合调节因子，并对培养状态及血管内衬的LECs具有显著融合活性。在近半数肿瘤淋巴管中检测到作为融合标记的Y染色体，且该现象与有丝分裂、血管形成及淋巴结转移相关。体外与体内实验均显示融合过程依赖于Th2和Toll样受体4（TLR4）通路。结论：这种由骨髓髓系-淋巴祖细胞融合触发的新型肿瘤淋巴管形成机制，为抑制肿瘤转移提供了多种潜在新靶点。

原文链接：

Bone Marrow Myeloid–Lymphatic Progenitors Expand Tumor Lymphatic Vasculature Through Cell Fusion