CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis.
CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis.
复制标题
DOI：
10.1158/1535-7163.mct-14-0607
复制
发表时间：
2015-07
影响因子：
5.7
通讯作者：
Buckanovich RJ
中科院分区：
文献类型：
--
作者：
Burgos-Ojeda D;Wu R;McLean K;Chen YC;Talpaz M;Yoon E;Cho KR;Buckanovich RJ
众所周知，卵巢癌由不同的癌细胞群组成，其中一些癌细胞表现出更强的癌症起始和/或转移能力。由于对肿瘤生长的长期需求、患者之间的变异性以及免疫缺陷小鼠肿瘤生长的需要，对人类癌细胞群体的研究是困难的。因此，我们在卵巢癌转基因小鼠模型中表征了不同癌细胞群体的致癌能力。在该模型中，卵巢表面上皮(OSE)中APC、Pten和Trp53的条件性缺失导致高级别转移性卵巢癌的产生。来源于这些小鼠肿瘤的细胞系表达许多可能的干细胞标志物，包括CD24、CD44、CD90、CD117、CD133和ALDH。我们发现CD24+和CD133+细胞增加了肿瘤球体的形成能力。CD2 4+细胞较CD2 4−细胞具有更强的起瘤能力和肿瘤生长能力。CD44+、CD90+、CD117+或ALDH+与阴性对照相比，无明显的肿瘤启动或生长优势。我们发现，与CD24−细胞相比，CD24+细胞中STAT3的磷酸化水平和靶基因Nanog和c-myc的表达水平都有所增加。JAK2抑制STAT3的磷酸化优先诱导CD24+细胞的细胞毒作用。在体内，JAK2抑制剂治疗显著减少了肿瘤转移，延长了总生存期。这些发现表明CD24+细胞在肿瘤的迁移和转移中发挥作用，并支持JAK2作为卵巢癌的治疗靶点。
Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, inter-patient variability and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers including CD24, CD44, CD90, CD117, CD133 and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells vs CD24− cells, had significantly greater tumor initiation and tumor growth capacity. No preferential tumor initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared to CD24− cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.