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Abstract
Purpose
Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations.
Experimental Design
Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis.
Results
Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density.
Conclusions
Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed by the authors.
Authors’ Contributions
Conception and design: N.M. Reusser, A.K. Sood.
Development of methodology: N.B. Jennings, S. Pradeep, R. Rupaimoole, K. Gharpure, A. Nagaraja, Y. Wen, W. Hu, C. Pecot, T. Miyake, J. Huang.
Acquisition of data (provided animals, provided cells, performed experiments, provided facilities, etc.): N.M. Reusser, H.J. Dalton, H.G. Vasquez, K. Gharpure, S. Pradeep, G. Lopez-Berestein, A.K. Sood.
Analysis and interpretation of data (e.q., statistical analysis, computational analysis): N.M. Reusser, H.J. Dalton, H.G. Vasquez, A.K. Sood.
Writing, review, and/or revision of the manuscript: N.M. Reusser, H.J. Dalton, R. Rupaimoole, A.K. Sood.
Administrative, technical, or material support (i.e., reporting or organizing data): H.J. Dalton, N.B. Jennings, S. Pradeep, H.G. Vasquez, C. Pecot, A. Nagaraja, K. Gharpure, R. Rupaimoole.
Study supervision: A.K. Sood.
Acknowledgments
The authors thank D. Hackett and A. Scholtz in the Department of Scientific Publications at MD Anderson Cancer Center for editing our manuscript.
Grant Support
Financial support was provided by the National Institutes of Health (P50 CA098258, CA 109298, P50 CA 083639, CA016672, CA 128797, U54 CA151668), the CPRIT (RP110595), the Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), the US. Department of Defense (OC073399, OC093146), the Chapman Foundation, the Meyer and Ida Gordon Foundation #2, the Betty Anne Asche Murray Distinguished Professorship, and National Cancer Institute institutional Core Grant CA16672. H.J.D. is supported by a T32 Training Grant (T32 CA101642).