Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369 and CB16/12/00489, Pamplona, Spain.
Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic.
Leukemia. 2020 Feb;34(2):589-603. doi: 10.1038/s41375-019-0588-4. Epub 2019 Oct 8.
The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.
少数骨髓瘤细胞从骨髓（BM）逸出到外周血（PB）的原因尚不清楚。在这里，我们研究了循环肿瘤细胞（CTC）的分子特征，以确定导致骨髓瘤进入血流的事件。在使用下一代流式细胞术从 32 名患者中分离匹配的 CTC 和 BM 肿瘤细胞后，我们发现单细胞和批量水平的基因表达高度相关（r≥0.94，P=10），仅 55 个基因在 CTC 和 BM 肿瘤细胞之间表达差异。CTC 过度表达与炎症、缺氧或上皮-间充质转化相关的基因，而与增殖相关的基因在 CTC 中下调。癌症干细胞标记物 CD44 在 CTC 中过表达，其敲低显著降低了 MM 细胞向 SDF1-α的迁移及其对纤维连接蛋白的黏附。在新诊断骨髓瘤患者（n=553；CoMMpass）中，约一半（29/55）在 CTC 中表达差异的基因具有预后意义。在包括 R-ISS 的多变量分析中，CENPF 和 LGALS1 的过表达与较差的生存显著相关。总的来说，这些结果有助于了解 PB 中 CTC 的存在，并表明缺氧的 BM 生态位加上促炎微环境会导致增殖停滞，迫使肿瘤细胞在 PB 中循环，并寻找其他 BM 生态位继续生长。
