Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production
Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production
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DOI：
10.1172/jci45273
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Buckanovich, Ronald J.
中科院分区：
文献类型：
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作者：
McLean, Karen;Gong, Yusong;Buckanovich, Ronald J.
越来越多的证据表明，间充质干细胞(MSCs)被招募到肿瘤微环境中；然而，关于它们在实体瘤中的作用仍存在争议。在这项研究中，我们鉴定并证实了我们分析的大多数人卵巢肿瘤标本中存在肿瘤相关MSCs(CA-MSCs)。这些CA-MSCs形态正常，核型正常，无致瘤性。CA-MSCs具有多向脂肪、软骨和骨分化的能力。当在体内与肿瘤细胞结合时，CA-MSCs比对照MSCs更有效地促进肿瘤生长。体外和体内研究表明，CA-MSCs通过增加肿瘤干细胞的数量促进肿瘤生长。尽管CA-MSCs表达传统的MSCs标志物，但它们的表达谱不同于健康人的MSCs，包括BMP2、BMP4和Bmp6的表达增加。重要的是，BMP2的体外治疗模仿了CA-MSCs对肿瘤干细胞的作用，而在体外和体内抑制BMP信号，部分地阻断了MSC促进的肿瘤生长。综上所述，我们的数据表明，卵巢肿瘤微环境中的MSCs具有促进肿瘤形成的表达谱，抑制BMP可能是治疗卵巢癌的有效方法。
Accumulating evidence suggests that mesenchymal stem cells (MSCs) are recruited to the tumor microenvironment; however, controversy exists regarding their role in solid tumors. In this study, we identified and confirmed the presence of carcinoma-associated MSCs (CA-MSCs) in the majority of human ovarian tumor samples that we analyzed. These CA-MSCs had a normal morphologic appearance, a normal karyotype, and were nontumorigenic. CA-MSCs were multipotent with capacity for differentiating into adipose, cartilage, and bone. When combined with tumor cells in vivo, CA-MSCs promoted tumor growth more effectively than did control MSCs. In vitro and in vivo studies suggested that CA-MSCs promoted tumor growth by increasing the number of cancer stem cells. Although CA-MSCs expressed traditional MSCs markers, they had an expression profile distinct from that of MSCs from healthy individuals, including increased expression of BMP2, BMP4, and BMP6. Importantly, BMP2 treatment in vitro mimicked the effects of CA-MSCs on cancer stem cells, while inhibiting BMP signaling in vitro and in vivo partly abrogated MSC-promoted tumor growth. Taken together, our data suggest that MSCs in the ovarian tumor microenvironment have an expression profile that promotes tumorigenesis and that BMP inhibition may be an effective therapeutic approach for ovarian cancer.