Abstract
Purpose
We have previously shown that BMP-2 induces bone formation and inhibits tumorigenicity of cancer stem cells (CSCs) in a human osteosarcoma OS99-1 cell line. In this study, we sought to determine whether BMP-2 can similarly induce bone formation and inhibit the tumorigenicity of renal CSCs identified based on aldehyde dehydrogenase (ALDH) activity in renal cell carcinoma (RCC) cell lines and primary tumors.
Methods
Using a xenograft model in which cells from human RCC cell lines ACHN, Caki-2, and primary tumors were grown in NOD/SCID mice, renal CSCs were identified as a subset of ALDHbr cells. The ALDHbr cells possessed a greater colony-forming efficiency, higher proliferative output, increased expression of stem cell marker genes Oct3/4A, Nanog, renal embryonic marker Pax-2, and greater tumorigenicity compared to cells with low ALDH activity (ALDHlo cells), generating new tumors with as few as 25 cells in mice.
Results
In vitro, BMP-2 was found to inhibit the ALDHbr cell growth, down-regulate the expression of embryonic stem cell markers, and up-regulate the transcription of osteogenic markers. In vivo, all animals receiving a low number of ALDHbr cells (5 × 103) from ACHN, Caki-2, and primary tumor xenografts treated with 30 µg BMP-2 per animal showed limited tumor growth with significant bone formation, while untreated cells developed large tumor masses without bone formation.
Conclusions
These results suggest that BMP-2 inhibits the tumor-initiating ability of renal CSCs and induces osseous bone formation. BMP-2 may therefore provide a beneficial strategy for human RCC treatment by targeting the CSC-enriched population.
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Acknowledgments
The authors gratefully acknowledge funding support provided by National Institutes of Health Grant R01 AR 056649 and the pilot research fund of the Department of Neurosurgery, University of Michigan. The authors also thank Mrs. Holly Wagner for assistance in the preparation of the manuscript and Mr. Martin J. White for flow cytometry.
Conflict of interest
The authors have no conflicts of interest to report pertaining to the materials or methods used in this study or the findings specified in this paper.
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Wang, L., Park, P., La Marca, F. et al. BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation. J Cancer Res Clin Oncol 141, 1013–1024 (2015). https://doi.org/10.1007/s00432-014-1883-0
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DOI: https://doi.org/10.1007/s00432-014-1883-0