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Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production
Karen McLean, … , Kathleen R. Cho, Ronald J. Buckanovich
Karen McLean, … , Kathleen R. Cho, Ronald J. Buckanovich
Published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3206-3219. https://doi.org/10.1172/JCI45273.
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Research Article Oncology

Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production

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Abstract

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.

Authors

Karen McLean, Yusong Gong, Yunjung Choi, Ning Deng, Kun Yang, Shoumei Bai, Lourdes Cabrera, Evan Keller, Laurie McCauley, Kathleen R. Cho, Ronald J. Buckanovich

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Figure 5

CA-MSCs have a gene expression profile distinct from that of control MSCs.

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CA-MSCs have a gene expression profile distinct from that of control MSC...
(A) Heat map of gene expression of MSC-associated gene expression in CA-MSCs, adipose control MSCs (lot 1, 2, 3), and control MSCs cultured with tumor-conditioned media from either SKOV3 or Hey1 ovarian tumor cells. The blue line indicates genes differentially expressed in CA-MSCs and MSCs treated with tumor-conditioned media. The orange bar indicates genes that appear to be uniquely expressed in CA-MSCs. Avg, average; max, maximum. (B) qRT-PCR using independently derived gene-specific primers performed to confirm differential expression of the indicated genes in control versus 4 CA-MSC–derived cell isolates (top), pooled analysis of qRT-PCR results (middle), and BMP2 expression in controls, cultured CA-MSCs, and FACS-isolated CA-MSCs (bottom). Tum cond media, tumor-conditioned media. (C) Western blot demonstrating increased BMP2 protein expression in adipose control MSCs and CA-MSCs. Quantification of BMP2 band intensity from immunoblotting is shown with average and standard deviation indicated. **P = 0.03. (D) Western blot detection of p-SMAD 1/5 before and after treatment with BMP2 in the presence or absence of the BMP inhibitor Noggin.

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