Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
J Clin Invest. 2011 Aug;121(8):3206-19. doi: 10.1172/JCI45273.
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.
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，它们在实体瘤中的作用仍存在争议。在这项研究中，我们在分析的大多数人类卵巢肿瘤样本中鉴定并证实了癌相关间充质干细胞（CA-MSCs）的存在。这些 CA-MSCs 具有正常的形态外观、正常的核型，并且是非致瘤性的。CA-MSCs 具有多能性，能够分化为脂肪、软骨和骨骼。当与肿瘤细胞在体内结合时，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 通过增加癌症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，但它们的表达谱与来自健康个体的 MSCs 不同，包括 BMP2、BMP4 和 BMP6 的表达增加。重要的是，体外 BMP2 处理模拟了 CA-MSCs 对癌症干细胞的作用，而体外和体内抑制 BMP 信号通路部分阻断了 MSC 促进的肿瘤生长。总之，我们的数据表明，卵巢肿瘤微环境中的 MSCs 具有促进肿瘤发生的表达谱，抑制 BMP 可能是治疗卵巢癌的有效方法。
