Identification and characterization of ovarian cancer-initiating cells from primary human tumors
Identification and characterization of ovarian cancer-initiating cells from primary human tumors
复制标题
来自原发性人类肿瘤的卵巢癌起始细胞的鉴定和表征
DOI：
10.1158/0008-5472.can-08-0364
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Nephew, Kenneth P.
中科院分区：
文献类型：
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作者：
Zhang, Shu;Balch, Curt;Nephew, Kenneth P.
本研究的目的是鉴定和鉴定完全能够在动物体内连续繁殖其原始肿瘤表型的人卵巢肿瘤细胞亚群(卵巢癌启动细胞，OCICs)。卵巢浆液性腺癌被分解，并接受生长条件的选择，以自我更新，以前被证明是来自组织干细胞的非粘附性球体。为了确认OCICs的存在，只有100个分离的球形细胞进行异种移植，可以完全重现原始肿瘤(2级/3级浆液性腺癌)，而>；10(5)未选择的细胞保持非致瘤性。通过细胞增殖分析和逆转录-聚合酶链式反应进一步确定OCICs的干细胞特性，表明在分化条件下与亲代肿瘤细胞或OCICs相比，OCICs对卵巢癌化疗药物顺铂或紫杉醇的耐药性增强，干细胞标志物(BMI-1、干细胞因子、Notch-1、Nanog、Nestin、ABCG2和Oct-4)上调。球体免疫染色显示透明质酸受体CD44和干细胞因子受体CD117(c-kit)显著上调，以确定OCIC细胞的表面表型。与球体形成的OCICs相似，仅注射100个CD44(+)CD117(+)细胞也可以连续生长其原始肿瘤，而10(5)CD44(-)CD117(-)细胞保持无致瘤性。基于这些发现，我们断言上皮性卵巢癌起源于CD44(+)CD117(+)细胞亚群，因此代表了这种毁灭性疾病的可能治疗靶点。
The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas > 10(5) unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell-selective conditions) were further established by cell proliferation assays and reverse transcription-PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44(+)CD117(+) cells could also serially propagate their original tumors, whereas 10(5) CD44(-)CD117(-) cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44(+)CD117(+) cells, thus representing a possible therapeutic target for this devastating disease.