Marcato Paola, Dean Cheryl A, Giacomantonio Carman A, Lee Patrick W K
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Mol Ther. 2009 Jun;17(6):972-9. doi: 10.1038/mt.2009.58. Epub 2009 Mar 17.
Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.
最近的证据表明，癌症干细胞（CSCs）在癌症中起着重要作用，因为这些细胞具有更强的肿瘤形成能力，并且对当前的抗癌疗法具有抗性。因此，新的癌症疗法需要同时针对肿瘤消退和癌症干细胞进行测试。在此我们表明，溶瘤呼肠孤病毒可诱导移植到免疫缺陷小鼠体内的人乳腺癌原发肿瘤样本消退，并且还能有效靶向并杀死这些肿瘤中的癌症干细胞。基于CD24(-)CD44(+)细胞表面表达和醛脱氢酶的过表达来鉴定癌症干细胞。经呼肠孤病毒治疗后，肿瘤内癌症干细胞群体与非癌症干细胞群体以相同的速率减少。来自经呼肠孤病毒处理和模拟处理的小鼠的乳腺肿瘤组织样本的免疫荧光证实，癌症干细胞和非癌症干细胞均可被呼肠孤病毒感染，末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记（TUNEL）分析表明，这两个群体均通过凋亡死亡。已证明可介导呼肠孤病毒溶瘤作用的Ras在所有细胞类型中的水平相似，这与它们对呼肠孤病毒的敏感性相当是一致的。这些实验表明，溶瘤呼肠孤病毒有潜力在乳腺癌患者中诱导肿瘤消退。更重要的是，癌症干细胞群体同样减少，并且与非癌症干细胞群体一样对呼肠孤病毒治疗敏感。
