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

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 3

CA-MSCs promote ovarian tumorigenesis more than control MSCs.

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CA-MSCs promote ovarian tumorigenesis more than control MSCs. (A) Tumor ...
(A) Tumor weights of SKOV3 tumors grown alone or with the indicated MSCs (SKOV3 plus control MSCs, n = 10; SKOV3 plus CA-MSCs, n = 20; pooled results, n = 5 for 4 CA-MSC cell lines). Results are representative of 2 independent experiments. (B and C) Bioluminescent-based tumor growth curve of SKOV3-luciferase tumors alone or in combination with the indicated MSCs (control MSCs, n = 10 and Pt 134 MSCs, n = 8, in 2 independent experiments). Signal intensity mapping for tumors is shown (p/s/cm2). (D) Ki67 immunohistochemistry and quantification from SKOV3+adipose MSC and SKOV3+CA-MSC tumors. Original magnification, ×100. Cont, control. (E) Hematoxylin and eosin stains of paraffin-embedded tumor specimens grown with MSCs or CA-MSCs, demonstrating tumor adipocytes (top right and bottom left). Tumors with CA-MSCs demonstrated areas of early bone formation (bottom right). Original magnification, ×40. All results represent means with standard deviations. *P < 0.01; **P < 0.001.