Saeednejad Zanjani Leili, Madjd Zahra, Rasti Arezoo, Asgari Mojgan, Abolhasani Maryam, Tam Kevin J, Roudi Raheleh, Mælandsmo Gunhild Mari, Fodstad Øystein, Andersson Yvonne
Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
Front Oncol. 2019 Dec 4;9:1302. doi: 10.3389/fonc.2019.01302. eCollection 2019.
Cancer stem cells (CSCs) are a theorized small subpopulation of cells within tumors thought to be responsible for metastasis, tumor development, disease progression, treatment-resistance, and recurrence. The identification, isolation, and biological characterization of CSCs may therefore facilitate the development of efficient therapeutic strategies targeting CSCs. This study aims to compare the biology and telomerase activity of CSCs to parental cells (PCs) in renal cancer. Renal CSCs were enriched from the ACHN cell line using a sphere culture system. Spheroid-derived cells (SDCs) and their adherent counterparts were compared with respect to their colony and sphere formation, expression of putative CSC markers, tumorigenicity in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and invasiveness. The expression of genes associated with CSCs, stemness, EMT, apoptosis, and ABC transporters was also compared between the two populations using quantitative real-time PCR (qRT-PCR). Finally, telomerase activity, hTERT expression, and sensitivity to MST-312, a telomerase inhibitor, was investigated between the two populations. We demonstrated that a subpopulation of ACHN cells was capable of growing as spheroids with many properties similar to CSCs, including higher clonogenicity, superior colony- and sphere-forming ability, and stronger tumorigenicity and invasiveness. In addition, SDCs demonstrated a higher expression of markers for CSCs, stemness, EMT, apoptosis, and ABC transporter genes compared to PCs. The expression of hTERT and telomerase activity in SDCs was significantly lower than PCs; however, the SDC population was more sensitive to MST-312 compared to PCs. These findings indicate that the SDC population exhibits stem-like potential and invasive characteristics. Moreover, the reduced expression of hTERT and telomerase activity in SDCs demonstrated that the expressions of hTERT and telomerase activity are not always higher in CSCs. Our results also showed that MST-312 treatment inhibited SDCs more strongly than PCs and may therefore be useful as a complementary targeted therapy against renal CSCs in the future.
癌症干细胞（CSCs）是肿瘤中理论上存在的一小部分细胞亚群，被认为与转移、肿瘤发展、疾病进展、治疗抵抗及复发有关。因此，对癌症干细胞的识别、分离及生物学特性进行研究，可能有助于开发针对癌症干细胞的有效治疗策略。本研究旨在比较肾癌中癌症干细胞与亲代细胞（PCs）的生物学特性及端粒酶活性。采用球体培养系统从ACHN细胞系中富集肾癌症干细胞。比较了球体衍生细胞（SDCs）及其贴壁对应细胞在集落和球体形成、假定癌症干细胞标志物的表达、在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠中的致瘤性及侵袭性方面的差异。还使用定量实时PCR（qRT-PCR）比较了这两个群体之间与癌症干细胞、干性、上皮-间质转化（EMT）、凋亡及ABC转运蛋白相关基因的表达。最后，研究了这两个群体之间的端粒酶活性、人端粒酶逆转录酶（hTERT）表达及对端粒酶抑制剂MST-312的敏感性。我们证明，ACHN细胞的一个亚群能够形成具有许多与癌症干细胞相似特性的球体，包括更高的克隆形成能力、更强的集落和球体形成能力以及更强的致瘤性和侵袭性。此外，与亲代细胞相比，球体衍生细胞显示出癌症干细胞、干性、EMT、凋亡及ABC转运蛋白基因标志物的更高表达。球体衍生细胞中hTERT的表达和端粒酶活性明显低于亲代细胞；然而，与亲代细胞相比，球体衍生细胞群体对MST-312更敏感。这些发现表明，球体衍生细胞群体具有干细胞样潜能和侵袭特性。此外，球体衍生细胞中hTERT表达和端粒酶活性的降低表明，hTERT表达和端粒酶活性在癌症干细胞中并不总是更高。我们的结果还表明，MST-312处理对球体衍生细胞的抑制作用比对亲代细胞更强，因此未来可能作为一种针对肾癌症干细胞的辅助靶向治疗手段。
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