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

• Published in: The Journal of clinical investigation Vol. 121; no. 8; pp. 3206 - 3219
• Main Authors: McLean, Karen, Gong, Yusong, Choi, Yunjung, Deng, Ning, Yang, Kun, Bai, Shoumei, Cabrera, Lourdes, Keller, Evan, McCauley, Laurie, Cho, Kathleen R, Buckanovich, Ronald J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2011
• Subjects: Biomedical research; Bone marrow; Bone morphogenetic proteins; Bone Morphogenetic Proteins - metabolism; Breast cancer; Cell Differentiation; Cell growth; Cell Line, Tumor; Cell Separation; Cloning; Development and progression; Female; Gastric cancer; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Lung cancer; Mesenchymal Stromal Cells - cytology; Models, Biological; Multiple myeloma; Neoplastic Stem Cells - cytology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Phenotype; Physiological aspects; Signal Transduction; Stem cells; Tumor Microenvironment; Tumorigenesis; Tumors; United States
• ISSN: 0021-9738; 1558-8238
• 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.