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 2

Androgen receptor expression in the human tissue biopsy samples and MDA PCa 118 variants and the in vivo growth of MDA PCa 118b cells in sham-operated male, female, or castrated male mice.

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Androgen receptor expression in the human tissue biopsy samples and MDA ...
(A) Western blot of androgen receptor (AR) expression in the MDA PCa 118a and MDA PCa 118b prostate cancer xenografts probed with mAb against human androgen receptor. Positive controls were the human prostate cancer cell lines VCaP and MDA PCa 2b, and the negative control was the human prostate cancer cell line PC3. β-Actin was used as a loading control. (B) Immunohistochemical staining of biopsy samples from the pubic metastasis (the source of MDA PCa 118a) and iliac metastasis (source of MDA PCa 118b) and of the MDA PCa 118a and MDA PCa 118b xenografts with an Ab against human androgen receptor. Normal prostate and MDA PCa 2b cells grown subcutaneously in SCID mice were used as positive controls (ctrl). Original magnification, ×200. (C) Volume of tumors formed 2–5 weeks after subcutaneous injection of MDA PCa 118b cells in sham-operated (intact) male, female, and castrated male mice (5 per group). Tumor volumes (in mm3) were calculated using the formula for volume of an ellipsoid [4/3π (length/2 × width/2 × height/2)]. Error bars indicate SEM.