Department of Signal Transduction, Research Institute for Microbial Disease, Osaka University, Suita, Osaka, Japan.
Cancer Sci. 2020 Jul;111(7):2400-2412. doi: 10.1111/cas.14452. Epub 2020 Jun 1.
Escape of cancer cells from chemotherapy is a problem in the management of cancer patients. Research on chemotherapy resistance has mainly focused on the heterogeneity of cancer cells, multiple gene mutations, and quiescence of malignant cancer cells. However, some studies have indicated that interactions between cancer cells and vascular cells promote resistance to chemotherapy. Here, we established mouse leukemia models using the cell lines THP-1 or MEG-1. These were derived from acute and chronic myeloid leukemias, respectively, and highly expressed DNA replication factor PSF1, a member of the GINS complex. We found that, after anti-cancer drug administration, surviving GFP-positive leukemia cells in the bone marrow were located adjacent to blood vessels, as previously reported in a subcutaneous solid tumor transplantation model. Treating THP-1 and MEG-1 cells with anti-cancer drugs in vitro revealed that those most strongly expressing PSF1 were most chemoresistant, suggesting that PSF1 induces not only cell cycle progression but also facilitates cell survival. Indeed, when PSF1 expression was suppressed by shRNA, the growth rate was reduced and cell death was enhanced in both cell lines. Furthermore, PSF1 knockdown in leukemia cells led to a change in their location at a distance from the blood vessels in a bone marrow transplantation model. These findings potentially reflect a mechanism of escape of leukemic cells from chemotherapy and suggest that PSF1 may be a possible therapeutic target to enhance the effect of chemotherapy.
癌细胞对化疗的逃逸是癌症患者治疗管理中的一个问题。关于化疗耐药性的研究主要集中在癌细胞的异质性、多个基因突变和恶性癌细胞的静止状态上。然而，一些研究表明，癌细胞与血管细胞之间的相互作用促进了对化疗的耐药性。在这里，我们使用源自急性和慢性髓性白血病的细胞系 THP-1 或 MEG-1 建立了小鼠白血病模型，这些细胞系高度表达 DNA 复制因子 PSF1，PSF1 是 GINS 复合物的成员。我们发现，在用抗癌药物治疗后，骨髓中存活的 GFP 阳性白血病细胞位于血管附近，这与先前在皮下实体肿瘤移植模型中报道的情况一致。在体外用抗癌药物处理 THP-1 和 MEG-1 细胞后发现，PSF1 表达最强的细胞对化疗的耐药性最强，这表明 PSF1 不仅诱导细胞周期进程，还促进细胞存活。事实上，当用 shRNA 抑制 PSF1 表达时，两种细胞系的生长速度都降低，细胞死亡增加。此外，在骨髓移植模型中敲低白血病细胞中的 PSF1 会导致其位置远离血管发生改变。这些发现可能反映了白血病细胞逃避化疗的一种机制，并表明 PSF1 可能是增强化疗效果的一个潜在治疗靶点。
