Osteomimetic properties of prostate cancer cells: A hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment

• Published in: The Prostate 1999-06, Vol.39 (4), p.246-261
• Main Authors: Koeneman, Kenneth S., Yeung, Fan, Chung, Leland W.K.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; bone morphogenetic protein; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Bone Neoplasms - therapy; bone sialoprotein; bone stroma; Cell Division; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; growth factors; Growth Substances - metabolism; Humans; insulin growth factor; Male; Medical sciences; Neoplasm Proteins - metabolism; Nephrology. Urinary tract diseases; osteoblast differentiation; Osteoblasts - metabolism; Osteoblasts - pathology; osteocalcin; osteoclast differentiation; osteopontin; Phenotype; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; PTHrP; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/(SICI)1097-0045(19990601)39:4<246::AID-PROS5>3.0.CO;2-U

BACKGROUND Unlike most other malignancies, prostate cancer metastasizes preferentially to the skeleton and elicits osteoblastic reactions. METHODS We present a hypothesis, based upon results obtained from our laboratory and others, on the nature of progression of prostate cancer cells and their predilection to growth and metastasis in the bone microenvironment. We propose the hypothesis that osseous metastatic prostate cancer cells must be osteomimetic in order to metastasize, grow, and survive in the skeleton. The reciprocal interaction between prostate cancer and bone stromal growth factors, including basic fibroblast growth factor (bFGF), hepatocyte growth factor/scatter factor (HGF/SF), and especially the insulin growth factor (IGF) axis initiates bone tropism, and is enhanced by prostate secreted endothelin‐1 (ET‐1) and urokinase‐type plasminogen activator (uPA). Growth factors and peptides that have differentiating activity, such as transforming growth factor beta (TGF‐β), parathyroid hormone‐related protein (PTH‐rp), and the bone morphogenetic proteins (BMPs), can shift local homeostasis to produce the characteristic blastic phenotype, via interaction with prostate‐secreted human kalikrein 2 (hK2), and prostate‐specific antigen (PSA). This proposal asserts that altering the expression of certain critical transcription factors, such as Cbfa and MSX in prostate cancer cells, which presumably are under the inductive influences of prostate or bone stromal cells, can confer profiles of gene expression, such as osteopontin (OPN), osteocalcin (OC), and bone sialoprotein (BSP), that mimic that of osteoblasts. RESULTS AND CONCLUSIONS Elucidation of common proteins, presumably driven by the same promoters, expressed by both prostate cancer and bone stromal cells, could result in the development of novel preventive and therapeutic strategies for the treatment of prostate cancer skeletal metastasis. Agents developed using these strategies could have the potential advantage of interfering with growth and enhancing apoptosis in both prostate cancer and bone stromal compartments. The selective application of gene therapy strategy, driven by tissue‐specific and tumor‐restricted promoters for the safe delivery and expression of therapeutic genes in experimental models of prostate cancer metastasis, is discussed. Prostate 39:246–261, 1999. © 1999 Wiley‐Liss, Inc.