Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production
Karen McLean, Yusong Gong, Yunjung Choi, Ning Deng, Kun Yang, Shoumei Bai, Lourdes Cabrera, Evan Keller, Laurie McCauley, Kathleen R. Cho, Ronald J. Buckanovich
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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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 1

Isolation of ovarian CA-MSCs.

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Isolation of ovarian CA-MSCs. (A) Photograph of mixed primary ovarian tu...
(A) Photograph of mixed primary ovarian tumor culture (top left) and the resultant, distinct purified colonies of epithelial tumors cells or CA-MSCs. Original magnification, ×100. (B) FACS analysis of primary ovarian tumor ascites, demonstrating CD44+CD73+CD90+ cells. (C) qRT-PCR to confirm CA-MSC purity. CA-MSC lines have no significant expression of the indicated endothelial or epithelial cell markers. Whole primary tumor mRNA (tumor) was used as a positive control. Expression levels were relative to the sample with maximal expression defined as 1. Nml, normal. (D) CA-MSCs demonstrate multipotent differentiation capacity in differential culture conditions. Specific cell stains used were Alizarin Red-S for bone, alcian blue for cartilage, and Oil Red O for adipose. Original magnification, ×100. Pt, patient.