Institute of Biochemistry, Biocenter, University of Würzburg, Am hubland, D-97074, Würzburg, Germany.
J Transl Med. 2012 Aug 17;10:167. doi: 10.1186/1479-5876-10-167.
Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy.
Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44(+)CD24(+)ESA(+) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models.
We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44(+)CD24(+)ESA(+) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44(+)CD24(-)ESA(+) cells.
Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.
最近的数据表明，癌症干细胞（CSC）在癌症中起着重要作用，因为这些细胞具有增强的肿瘤形成能力，并负责在明显的治愈性治疗后复发。因此，需要新的癌症疗法来测试肿瘤消退和 CSC 靶向。溶瘤痘苗病毒（VACV）的使用代表了一种有吸引力的抗肿瘤方法，目前正在临床试验中进行评估。本研究的目的是证明 VACV 是否能杀死对辐射和化疗有抵抗力的 CSC。
通过醛脱氢酶 1（ALDH1）活性评估，利用 ALDEFLUOR 测定法，从人乳腺癌细胞系 GI-101A 中鉴定和分离出具有癌症干细胞样特征的癌症干细胞样细胞，如化疗耐药性、辐射耐药性和肿瘤起始能力，并在细胞培养和动物模型中得到证实。VACV 治疗应用于细胞培养中的 ALDEFLUOR 阳性细胞和源自这些细胞的异种移植肿瘤。此外，我们还从 GI-101A 的上皮-间充质转化（EMT）中鉴定和分离出 CD44(+)CD24(+)ESA(+)细胞。这些细胞在细胞培养和动物模型中也具有类似的特征。
我们首次证明，溶瘤痘苗病毒 GLV-1h68 株在具有干细胞样特征的 ALDH1 活性较高的细胞中比在 ALDH1 活性较低的细胞中更有效地复制。GLV-1h68 选择性地定植并最终根除源自具有较高 ALDH1 活性的细胞的异种移植肿瘤。此外，GLV-1h68 还在 GI-101A 发生 EMT 诱导后衍生的 CD44(+)CD24(+)ESA(+)细胞以及源自这些细胞的异种移植肿瘤中优先复制，这些肿瘤比 CD44(+)CD24(-)ESA(+)细胞具有更强的致瘤性。
综上所述，我们的研究结果表明，GLV-1h68 能够有效地复制和杀死癌症干细胞样细胞。因此，GLV-1h68 可能成为一种有前途的根除原发性和转移性肿瘤的药物，特别是那些含有对化疗和/或放疗有抵抗力的癌症干细胞样细胞的肿瘤，这些细胞可能是肿瘤复发的原因。
