Prostate-derived soluble factors block osteoblast differentiation in culture

Abstract

Bone metastasis is a common event and a major cause of morbidity in prostate cancer patients. After colonization of bone, prostate cells induce an osteoblastic reaction which is not associated with marrow fibrosis (i.e., osteoblast but not fibroblast proliferation). In the present study we test the hypothesis that the tumoral prostatic cell line (PC-3) secretes factors that block the osteoblast differentiation process, resulting in an increase of the relative size of the proliferative cell pool. Our results, using fetal rat calvaria cells in culture, show that conditioned medium from PC-3 cells (PC-3 CM) stimulates osteoblast proliferation and inhibits both alkaline phosphatase (AP) activity (an early differentiation marker) and the mineralization process, measured as calcium accumulation (late differentiation marker). The inhibition of the expression of AP and mineralization depends on the presence of PC-3 CM during the proliferative phase of culture and suggests that both processes occur in a nonsimultaneous fashion. The inhibitory effect of PC-3 CM was not reverted by dexamethasone, which would indicate that prostatic-derived factors and the glucocorticoid do not share a common site of action. Measurement of the proliferative capacity of subcultures from control and treated cells demonstrates that PC-3 CM treatment induces the maintenance of the proliferative potential that characterizes undifferentiated precursor cells.

Kallikrein 4 is a potential mediator of cellular interactions between cancer cells and osteoblasts in metastatic prostate cancer

“…As expected, the SaOs2 cells had high levels of ALP activity which declined when co-cultured either directly or indirectly with PC3 or LNCaP cells suggesting that secreted factors from the prostate cancer cells inhibit osteoblast activity. Similarly, previous studies demonstrated that mouse osteoblasts or rat fetal calvaria co-cultured with PC3 cells exhibited a decrease in both ALP activity and the mineralization process, suggesting that PC3 cells secrete molecules that inhibit osteoblast differentiation [35,41], thus supporting the more osteolytic phenotype observed in bone metastasis induced by PC3 cells [27,35,37].…”

Human Osteocalcin and Bone Sialoprotein Mediating Osteomimicry of Prostate Cancer Cells: Role of cAMP-Dependent Protein Kinase A Signaling Pathway

“…Despite the prevalence of prostate cancer metastasis to the skeleton, the molecular mechanisms of bone tropism are poorly understood. Previous studies suggest that prostate cancer cell adhesion, extravasation, migration, and interaction with bone cells are critical determinants that govern prostate cancer bone colonization (2)(3)(4). Reports using clinical prostate cancer metastasis specimens (5-7) and experimental cell and animal models (8)(9)(10) found the bone-specific proteins osteocalcin and bone sialoprotein to be expressed in a heterogeneous manner by human prostate cancer specimens.…”

A Proteome Study of Secreted Prostatic Factors Affecting Osteoblastic Activity: Galectin-1 Is Involved in Differentiation of Human Bone Marrow Stromal Cells

“…An explanation could be that PC3 cells produce parathyroid hormone‐related peptide (PTHrP) and transforming growth factor α (TGF‐α), both stimulators of the osteolytic response (12, 13) . However, it has been shown that PC3 cells secrete a factor or factors that stimulates the mitogenic activity of osteoblast‐like cells (14–16) . The PC3 derived mitogens were found to be proteins with molecular weights ranging from 20 to 30 kDa (14, 15) .…”