Osteoclasts Are Active in Bone Forming Metastases of Prostate Cancer Patients

Abstract

BackgroundBone forming metastases are a common and disabling consequence of prostate cancer (CaP). The potential role of osteoclast activity in CaP bone metastases is not completely explained. In this study, we investigated ex vivo whether the osteolytic activity is present and how it is ruled in CaP patients with bone forming metastases.MethodologyForty-six patients affected by newly diagnosed CaP and healthy controls were enrolled. At diagnosis, 37 patients had a primary tumour only, while 9 had primary tumour and concomitant bone forming metastases. In all patients there was no evidence of metastasis to other non-bone sites. For all patients and controls we collected blood and urinary samples. We evaluated patients' bone homeostasis; we made peripheral blood mononuclear cell (PBMC) cultures to detect in vitro osteoclastogenesis; we dosed serum expression of molecules involved in cancer induced osteoclatogenesis, such as RANKL, OPG, TNF-alpha, DKK-1 and IL-7. By Real-Time PCR, we quantified DKK-1 and IL-7 gene expression on micro-dissected tumour and healthy tissue sections.Principal FindingsCaP bone metastatic patients showed bone metabolism disruption with increased bone resorption and formation compared to non-bone metastatic patients and healthy controls. The CaP PBMC cultures showed an enhanced osteoclastogenesis in bone metastatic patients, due to an increase of RANKL/OPG ratio. We detected increased DKK-1 serum levels and tissue gene expression in patients compared to controls. IL-7 resulted high in patients' sera, but its tissue gene expression was comparable in patients and controls.ConclusionsWe demonstrated ex vivo that osteoclastogenesis is an active mechanism in tumour nesting of bone forming metastatic cancer and that serum DKK-1 levels are increased in CaP patients, suggesting to deeply investigate its role as tumour marker.

The PCa Tumor Microenvironment

“…[ [151][152][153] Fibroblasts Fibroblasts produce the support structures, including the bulk of extracellular matrix, for the prostate. In cancer, they may differentiate into a myofibroblast (a cell with characteristics of both fibroblasts and smooth muscle cells).…”

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

“…Increased osteoclast activity is seen in many osteopenic disorders, including postmenopausal osteoporosis [1,2], Paget's disease [3,4], bone metastases [5,6], periodontitis [7,8], and rheumatoid arthritis [9,10]. Mature osteoclasts are giant, multinucleated cells that synthesize and directionally secrete bone matrix-degrading enzymes, including cathepsin K, matrix metalloproteinase-9 (MMP9), and tartrate-resistant acid phosphatase (TRAP).…”

Orthopaedic Research in Italy: State of the Art

“…This has been documented in patients with metastatic neuroblastoma and poor responders to chemotherapy (56), in nonsmall cell lung cancer, where spontaneous increase in osteoclastogenesis from peripheral blood mononuclear cells, higher serum interleukin-7 levels and urinary crosslinks were observed in patients with bone metastases (57), or in patients with bone met~tases from prostate carcinoma, which showed an enhanced osteoclastogenesis, and increased Dkk-l serum levelst issue gene expression (58).…”