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.
View: Text | PDF
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

×

Figure 1

The origin of MDA PCa 118 xenografts; histopathologic and immunohistochemical stains of human tissue biopsy specimens and the derived MDA PCa 118 variant; and the karyotype of MDA PCa 118b cells.

Options: View larger image (or click on image) Download as PowerPoint
The origin of MDA PCa 118 xenografts; histopathologic and immunohistoche...
(A) Top: Contrast-enhanced CT scans of the pelvis of a 49-year-old man of mixed European descent with androgen-independent prostate cancer show the expansile ossified lesion involving the left pubis (arrow, left panel) that was the source of MDA PCa 18a cells and the left ilium (arrow, right panel) that was the source of the MDA PCa 118b cells. Bottom: H&E-stained tissue sections of biopsy specimens from the lesions in the pubic (arrow, top left panel) and iliac (arrow, top right panel) metastases. Original magnification, ×200. T, prostate cancer cells; asterisks indicate stroma. (B) Top row: H&E-stained biopsy specimens of the pubic and iliac metastases and the MDA PCa 118a and 118b variants. Middle row: Cytokeratin-stained sections. Bottom row: Vimentin-stained sections. The mouse stroma in the xenografts did not stain for vimentin because the Ab (clone V9) reacts with human, not mouse, vimentin. Original magnification, ×200. T, prostate cancer cells; asterisks indicate stroma. (C) Giemsa-banded karyotype of MDA PCa 118b human prostate cancer cells showing marker chromosomes (M1–M10) and various anomalies. The tentative identification of the markers is as follows: M1, iso(1p); M2, t(3q;6p); M3, t(3q;?); M4, del(3p); M5, 15p+; M6, 17p+; M7 and M8, markers containing an abnormally banded region (ABR); M9, t(11q;18q); M10, unidentified marker.