Division of Pediatric Oncology, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS One. 2010 Nov 11;5(11):e13943. doi: 10.1371/journal.pone.0013943.
Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model - remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal.
METHODOLOGY/PRINCIPAL FINDINGS: We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDH(high)) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDH(high) cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo.
CONCLUSIONS/SIGNIFICANCE: Ewing's sarcoma contains an ALDH(high) stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.
癌症干细胞是一种具有自我更新能力并能再生大部分肿瘤的化疗耐药细胞群体，从而导致肿瘤复发和患者死亡。尤因肉瘤是青少年和年轻人中第二常见的骨肿瘤形式，其临床模式与癌症干细胞模型一致——即使对于转移性疾病患者，缓解也很容易实现，但肿瘤复发仍然很常见，且通常是致命的。
方法/主要发现：我们从人类细胞系和在免疫缺陷小鼠中生长的人类异种移植物中分离出了一种尤因肉瘤细胞亚群，该亚群表达高醛脱氢酶（ALDH(high)）活性，且具有集落形成、球体形成和肿瘤起始能力。ALDH(high)细胞在体外对化疗具有耐药性，但这可以通过三磷酸腺苷结合盒转运蛋白抑制剂维拉帕米克服。重要的是，这些细胞对 YK-4-279 不耐药，YK-4-279 是一种 EWS-FLI1 的小分子抑制剂，对体外和体内的尤因肉瘤细胞均具有选择性毒性。
结论/意义：尤因肉瘤中含有一种 ALDH(high) 样干性化疗耐药细胞群体，其对 EWS-FLI1 抑制仍保持敏感性。抑制 EWS-FLI1 癌蛋白可能通过靶向在标准化疗后存活的尤因肉瘤干细胞，成为改善患者预后的有效手段。
