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

BACKGROUND. Unlike most other malignancies, prostate cancer metastasizes pr eferentially to the skeleton and elicits osteoblastic reactions. METHODS. We present a hypothesis, based upon results obtained from our labo ratory and others, on the nature of progression of prostate cancer cells an d their predilection to growth and metastasis in the bone microenvironment. We propose the hypothesis that osseous meta-static prostate cancer cells m ust be osteomimetic in order to metastasize, grow, and survive in the skele ton. The reciprocal interaction between prostate cancer and bone stromal gr owth factors, including basic fibroblast growth factor (bFGF), hepatocyte g rowth factor/scatter factor (HGF/SF), and especially the insulin growth fac tor (IGF) axis initiates bone tropism, and is enhanced by prostate secreted endothelin-l (ET-1) and urokinase-type plasminogen activator (uPA). Growth factors and peptides that have differentiating activity, such as transform ing growth factor beta (TGF-beta), parathyroid hormone-related protein (PTH -rp), and the bone morphogenetic proteins (BMPs), can shift local homeostas is to produce the characteristic blastic phenotype, via interaction with pr ostate-secreted human kalikrein 2 (hK2), and prostate-specific antigen (PSA ). This proposal asserts that altering the expression of certain critical t ranscription factors, such as Cbfa and MSX in prostate cancer cells, which presumably are under the inductive influences of prostate or bone stromal c ells, can confer profiles of gene expression, such as osteopontin (OPN), os teocalcin (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 c ells, could result in the development of novel preventive and therapeutic s trategies for the treatment of prostate cancer skeletal metastasis agents d eveloped using these strategies could have the potential advantage of inter fering 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 deliv ery and expression of therapeutic genes in experimental models of prostate cancer metastasis, is discussed. (C) 1999 Wiley-Liss, Inc.