Ontario Cancer Institute, Campbell Family Cancer Research Institute, Toronto, ON, Canada M5G 1L7.
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6468-73. doi: 10.1073/pnas.1005529108. Epub 2011 Mar 30.
The cancer stem cell (CSC) model proposes that tumors have a hierarchical organization in which only some cells indefinitely self-renew and thereby sustain tumor growth. In addition, the CSC model requires that tumor-initiating cells (TICs) be prospectively isolatable on the basis of their phenotype. Previous studies have suggested that serous ovarian cancer (SOC) conforms to the CSC model, but these used arguably nonfidelitous immortalized cell lines, cultured primary cells, or passaged xenografts as the source of tumor cells. We developed a robust assay for quantifying TICs from primary SOC. Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ(-/-) (NSG) mice. TIC frequency (TICf) varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TICf is an intrinsic property of ovarian tumors. CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133(+) and CD133(-) fractions, whereas still other cases have exclusively CD133(-) TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133(+) can give rise to xenografts that contain substantial numbers of CD133(-) TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application.
癌症干细胞（CSC）模型提出，肿瘤具有层次结构，只有一些细胞能够无限自我更新，从而维持肿瘤生长。此外，CSC 模型还要求肿瘤起始细胞（TIC）能够根据其表型进行前瞻性分离。先前的研究表明，浆液性卵巢癌（SOC）符合 CSC 模型，但这些研究使用的是有争议的非忠实永生化细胞系、培养的原代细胞或传代异种移植作为肿瘤细胞的来源。我们开发了一种从原发性 SOC 中定量 TIC 的稳健测定方法。使用该测定方法，我们发现当在 NOD/SCID 或 NOD/SCID/IL2Rγ（-/-）（NSG）小鼠中进行检测时，TIC 非常罕见。尽管原发性卵巢肿块和大网膜转移中的 TICf 相似，但 TICf 在患者之间存在很大差异，这表明 TICf 是卵巢肿瘤的固有特性。CD133 标记了来自几个原发性 SOC 病例的所有 TIC。然而，在其他情况下，在 CD133（+）和 CD133（-）部分都发现了大量的 TIC 活性，而其他情况下则只有 CD133（-）TIC。此外，TIC 表型可以在异种移植中发生变化：所有 TIC 均为 CD133（+）的原发性肿瘤可能会产生含有大量 CD133（-）TIC 的异种移植物。我们的结果强调了在评估 TIC 时需要定量严谨性，并在进行此类研究时谨慎使用传代异种移植。此外，尽管我们的数据表明 SOC 符合 CSC 假设，但 TIC 表型的异质性可能使其临床应用复杂化。
