Multiple myeloma (MM) induces dysfunctional bone marrow (BM) mesenchymal cells and neoangiogenesis. Pericytes and smooth muscle cells (SMCs) could detach from vessels and become cancer-associated fibroblasts. We found that the pericyte and SMC marker endothelin receptor type A (EDNRA) is overexpressed in whole MM bone biopsies; we sought to characterize its expression. EDNRA expression gradually increased with disease progression. High-risk MM patients had higher EDNRA expression than low-risk MM patients and EDNRA expression was highest in focal lesions. High EDNRA expression was associated with high expression of pericyte markers (e.g., RGS5, POSTN, and CD146) and the angiogenic marker FLT1. A single-cell analysis of unexpanded BM mesenchymal cells detected EDNRA expression in a subset of cells that coexpressed mesenchymal cell markers and had higher expression of proliferation genes. Immunohistochemistry revealed that the number of EDNRA+ cells in the interstitial BM increased as MM progressed; EDNRA+ cells were prevalent in areas near the MM focal growth. EDNRA+ cells were detached from CD34+ angiogenic cells and coexpressed RGS5 and periostin. Therefore, they likely originated from pericytes or SMCs. These findings identify a novel microenvironmental biomarker in MM and suggest that the presence of detached EDNRA+ cells indicates disrupted vasculature and increased angiogenesis.
多发性骨髓瘤（MM）可诱导骨髓间充质细胞功能异常并促进新生血管形成。周细胞和平滑肌细胞可能从血管壁脱离并转化为癌症相关成纤维细胞。本研究发现，周细胞与平滑肌细胞标志物内皮素受体A型（EDNRA）在完整MM骨活检组织中过度表达，我们对其表达特征进行了系统解析。EDNRA表达水平随疾病进展逐步升高，高危MM患者较低危患者呈现更高EDNRA表达，且在局灶性病变区域达到峰值。高EDNRA表达与周细胞标志物（如RGS5、POSTN和CD146）及血管生成标志物FLT1的高表达显著相关。通过对未扩增骨髓间充质细胞进行单细胞分析，发现EDNRA在一组共表达间充质细胞标志物且增殖基因高表达的细胞亚群中特异性表达。免疫组化结果显示，骨髓间质中EDNRA阳性细胞数量随MM进展而增加，这些细胞在MM局灶性生长区域尤为富集。EDNRA阳性细胞已脱离CD34阳性血管生成细胞，并共表达RGS5和骨膜蛋白，提示其可能来源于周细胞或平滑肌细胞。本研究首次鉴定出MM微环境中的新型生物标志物，表明脱离血管的EDNRA阳性细胞的存在标志着血管结构破坏和血管生成活性增强。
肿瘤(癌症)患者之家