Athaiya Shaswati, Volk-Draper Lisa, Cox Emma, Robinson Kathy, Zinkevich Natalya, Ran Sophia
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Simmons Cancer Institute at SIU School of Medicine, Springfield, IL 62702, USA.
Cancers (Basel). 2025 May 28;17(11):1804. doi: 10.3390/cancers17111804.
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).
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.
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.
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.
骨髓（BM）来源的髓样-淋巴内皮细胞祖细胞（M-LECPs）促进肿瘤淋巴管的形成，而肿瘤淋巴管负责向淋巴结转移。BM祖细胞向其他谱系的再生能力是通过细胞融合介导的，这一过程直接将促有丝分裂信息传递给限制分裂的细胞。这表明M-LECPs可能利用类似机制诱导淋巴管内皮细胞（LECs）分裂。
为验证这一假设，我们测定了体外产生并募集到体内人或小鼠肿瘤中的M-LECPs中融合标记物的表达，并在两种情况下对它们与LECs的融合进行了定量。在移植了雄性BM并植入MDA-MB-231或EMT6乳腺肿瘤的雌性嵌合小鼠中测定体内融合情况。对Y染色体和LEC特异性标记物进行共染色，使我们能够对与BM祖细胞融合的肿瘤淋巴管进行定量。
我们发现，肿瘤募集的和体外产生的M-LECPs均表达多种融合调节因子，并对培养的和血管内衬的LECs具有显著的融合活性。在近一半的肿瘤淋巴管中检测到融合标记物Y染色体，其与有丝分裂、血管形成和淋巴结转移相关。体外和体内试验均表明融合依赖于Th2和Toll样受体4（TLR4）途径。
这种与BM髓样-淋巴祖细胞融合引发的肿瘤淋巴管形成新机制提示了多种抑制转移扩散的新靶点。
