Osteoblasts stimulate the osteogenic and metastatic progression of castration-resistant prostate cancer in a novel model for in vitro and in vivo studies

Abstract

Castration-resistant prostate cancer (CRPC) is strongly associated with sclerotic bone metastases and poor prognosis. Models that mimic human CRPC are needed to identify the mechanisms for prostate cancer (PC) growth in bone and to develop new therapeutic strategies. We characterize a new model, LNCaP-19, and investigate the interaction between tumor cells and osteoblasts in the sclerotic tumor response of CRPC. Osteogenic profiling of PC cell lines (LNCaP-19, LNCaP, C4-2B4, and PC-3) was performed by gene expression arrays and mineral staining. Conditioned medium from MC3T3-E1 was used for osteoblast stimulation of CRPC cells. The capacity of LNCaP-19 cells to induce sclerotic lesions was assessed in intratibial xenografts and verified by serum markers, histological analysis and bone mineral density (BMD) measurements. The CRPC cell line LNCaP-19 expresses a pronounced osteogenic profile compared to its parental androgen-dependent cell line LNCaP. Osteoblast-derived factors further increase the expression of genes known to enhance metastatic progression of PC. LNCaP-19 forms sclerotic tumors in tibia of castrated mice as evident by increased total BMD (P < 0.01). There was a strong correlation between serum osteocalcin and BMD (total: R2 0.811, P < 0.01, trabecular: R2 0.673, P < 0.05). For the first time we demonstrate that a CRPC cell line generated in vitro has osteogenic capacity and that osteomimicry can be an inherent feature of these cells. Osteoblast-derived factors further promote the osteogenic and metastatic phenotype in CRPC cells. Altogether, our model demonstrates that both tumor cells and osteoblasts are mediators of the bone forming process of CRPC.

Tasquinimod inhibits prostate cancer growth in bone through alterations in the bone microenvironment

“…Osteoblasts are the cells responsible for the formation and mineralization of new bone. We and others have previously shown that osteoblasts are stimulated by PC tumor cells . In addition, we demonstrated that osteoblasts induce a more aggressive phenotype along with osteomimicry in osteoblastic CRPC cells .…”

“…We and others have previously shown that osteoblasts are stimulated by PC tumor cells . In addition, we demonstrated that osteoblasts induce a more aggressive phenotype along with osteomimicry in osteoblastic CRPC cells . Together with their role in the pre‐metastatic niche, this makes osteoblasts important players in both establishment and growth of sclerotic bone metastases.…”

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

“…Bone microtumors were established by intratibial (i.t.) injections (right leg tibiae) with PC3-PSCA cells under anesthesia, as previously described [20]. After implantation, the animals received analgesics (Rimadyl; 5 mg/kg) for 5 days.…”

Prostatic calculi cause osteoblastic immunophenotype of prostate cancer

“…PGC cells are able to synthesize substances with a significant osteostimulatory effect, in particular, prostate specific antigen, endothelin-1, insulin-like growth factor 1 and others. These compounds have a direct effect on the osteogenesis in metastasis foci of PGC and possibly PC development in PGC tissue [8]. Similar substances, other than prostate specific antigen, also have been found in bone tissue [9,10].…”