Abstract
Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer. Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies. OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM. Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.
Highlights
Localized carcinoma of the prostate (CaP) can potentially be cured by surgery or radiation therapy
Neutralizing antibodies to IL-6 blocked proliferation and expression of prostate-specific antigen (PSA) by OCM. Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the androgen receptor (AR)
Osteoblastic lesions are the major cause of CaP-related morbidity, and mortality and even small, bone-limited tumor burden in patients are strongly correlated to cachexia and death
Summary
Localized carcinoma of the prostate (CaP) can potentially be cured by surgery or radiation therapy. In vitro studies have shown increased proliferation of prostate cancer cells stimulated by conditioned media from or cocultured with osteoblasts, growth factor extracts, and individual growth factors derived from bone, such as interleukin-6 (IL-6), insulin-like growth factor I (IGF-I) and IGF-II, epidermal growth factor, keratinocyte growth factor, bone morphogenic proteins, fibroblast growth factors, transforming growth factor-, cytokines, plateletderived growth factor, vascular endothelial growth factor, and endothelin-1 [5,6,7,8,9,10,11,12,13] Many of these growth factors may be involved in circumventing the need for androgen in advanced disease by a mechanism involving ligand-independent activation of the androgen receptor Many of these growth factors may be involved in circumventing the need for androgen in advanced disease by a mechanism involving ligand-independent activation of the androgen receptor (AR; Refs. 6 and 14 –17)
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