Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms
Zhi Gang Li, … , Sankar Maity, Nora M. Navone
Zhi Gang Li, … , Sankar Maity, Nora M. Navone
Published July 10, 2008
Citation Information: J Clin Invest. 2008;118(8):2697-2710. https://doi.org/10.1172/JCI33093.
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Research Article Oncology

Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

Abstract

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor–negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer–induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor–null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

Authors

Zhi Gang Li, Paul Mathew, Jun Yang, Michael W. Starbuck, Amado J. Zurita, Jie Liu, Charles Sikes, Asha S. Multani, Eleni Efstathiou, Adriana Lopez, Jing Wang, Tina V. Fanning, Victor G. Prieto, Vikas Kundra, Elba S. Vazquez, Patricia Troncoso, Austin K. Raymond, Christopher J. Logothetis, Sue-Hwa Lin, Sankar Maity, Nora M. Navone

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Figure 8

Effects of FGF9 blockade on MDA PCa 118b bone growth and osteoblastic reaction in vivo.

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Effects of FGF9 blockade on MDA PCa 118b bone growth and osteoblastic re...
(A) Tumor volume. MDA PCa 118b tumor visualized and quantified by T2-weighted, fat-suppressed MR. Left and middle: Representative axial MR images of mice injected with MDA PCa 118b cells in the femur and obtained after 5 weeks of treatment with FGF9-neutralizing Ab or IgG isotype. Arrows indicate tumor. Tumors were confined to the bone, spreading throughout the femur area in the IgG-treated mice (control) and scattered in the bone area in the mice treated with FGF9-neutralizing Ab. Right: Volumes of regions of increased signal in the MDA PCa 118b–injected femur measured by MR after 5 weeks of treatment were significantly higher in the control than in the treated mice (P = 0.011). (B) Bone mass. X-ray: Radiographs show mouse pelvis and rear limbs of mice 7 weeks after intrafemoral injection of MDA PCa 118b cells in the control and treatment groups. Arrows indicate area illustrated in the lower panels. H&E: H&E-stained sections of MDA PCa 118b–bearing femurs. Note that the marrow cavity is filled with new bone (NB) in the femurs of the control but not the treated mice. B, bone matrix; NB, new bone. μCT: Effect of FGF9 blockade on bone volume fraction. Bottom right: Cross-sectional μCT images of both control treated (IgG) and neutralizing Ab–treated (FGF9 Ab) tumor-bearing bones. Error bars indicate SEM.