CXC Chemokine Receptor 4 is Essential for Maintenance of Renal Cell Carcinoma-Initiating Cells and Predicts Metastasis
CXC Chemokine Receptor 4 is Essential for Maintenance of Renal Cell Carcinoma-Initiating Cells and Predicts Metastasis
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DOI：
10.1002/stem.1407
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发表时间：
2013-08-01
期刊：
影响因子：
5.2
通讯作者：
Pohla, Heike
中科院分区：
文献类型：
--
作者：
Gassenmaier, Maximilian;Chen, Dong;Pohla, Heike
在许多实体肿瘤中，癌症干细胞（CSC）代表了一个具有肿瘤启动、自我更新和分化潜力的群体，可以通过表面蛋白标记物来识别。目前还没有普遍适用于肾细胞癌（RCC）的标志物。两种RCC细胞系（RCC-26, RCC-53）在体外形成球的能力和在小鼠体内形成肿瘤的能力存在很大差异，这可能反映了CSC含量的差异。表达CXC趋化因子受体4 （CXCR4）的亚群仅存在于更致瘤性的细胞系RCC-53中。当培养成球形时，大多数RCC-53细胞呈cxcr4阳性，表达干细胞相关转录因子基因水平升高，并且对酪氨酸激酶抑制剂舒尼替尼、索拉非尼和帕唑帕尼更具抗性。筛选后的cxcr4阳性细胞在体内比cxcr4阴性细胞表现出更大的成球能力和肿瘤诱导潜能。值得注意的是，来自局部而非弥散性疾病患者的原发性RCC肿瘤中较高的CXCR4 mRNA水平预示着更短的生存期。通过小干扰RNA （siRNA）或AMD3100的药理抑制下调CXCR4的表达会损害肿瘤球的形成、CXCR4阳性细胞的活力，并增加它们对酪氨酸激酶抑制剂的反应性。综上所述，CXCR4在RCC细胞系中识别了一个肿瘤启动细胞亚群，并在其维持中发挥作用。这些细胞对酪氨酸激酶抑制剂的相对不敏感可能有助于RCC患者治疗耐药的发展。因此，未来的治疗方法可能将阻断CXCR4信号通路与标准治疗相结合，以更有效地治疗转移性RCC。
In many solid tumors, cancer stem cells (CSC) represent a population with tumor-initiating, self-renewal, and differentiation potential, which can be identified by surface protein markers. No generally applicable markers are yet known for renal cell carcinoma (RCC). Two RCC cell lines (RCC-26, RCC-53) were found to differ widely in their capacity to form spheres in vitro and to establish tumors in mice, potentially reflecting differences in CSC content. A subpopulation expressing the CXC chemokine receptor 4 (CXCR4) was present only in the more tumorigenic cell line RCC-53. When grown as spheres, most of the RCC-53 cells were CXCR4-positive, expressed stem cell-associated transcription factor genes at elevated levels, and were more resistant toward the tyrosine kinase inhibitors sunitinib, sorafenib, and pazopanib. Sorted CXCR4-positive cells exhibited greater capacity for sphere formation and tumor growth-inducing potential in vivo than CXCR4-negative cells. Significantly, higher CXCR4 mRNA levels in primary RCC tumors from patients with localized but not disseminated disease predicted shorter survival. Downregulation of CXCR4 expression by small interfering RNA (siRNA) or pharmacological inhibition by AMD3100 compromised tumor sphere formation, viability of CXCR4-positive cells, and increased their responsiveness toward tyrosine kinase inhibitors. In conclusion, CXCR4 identifies a subpopulation of tumor-initiating cells in RCC cell lines and plays a role in their maintenance. The relative insensitivity of such cells to tyrosine kinase inhibitors might contribute to the development of therapy resistance in RCC patients. Future therapies therefore could combine blockade of the CXCR4 signaling pathway with standard therapies for more effective treatments of metastatic RCC.