Osteoclasts are active in bone forming metastases of prostate cancer patients.
BACKGROUND
Bone 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.


METHODS
Forty-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.


RESULTS
CaP 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.


CONCLUSIONS
We 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.
Roato
Ilaria
I
CeRMS (Center for Experimental Research and Medical Studies) University and A.O.U. San Giovanni Battista, Turin, Italy. roato78@libero.it
D'Amelio
Patrizia
P
Gorassini
Eva
E
Grimaldi
Anastasia
A
Bonello
Lisa
L
Fiori
Cristian
C
Delsedime
Luisa
L
Tizzani
Alessandro
A
De Libero
Alfredo
A
Isaia
Giancarlo
G
Ferracini
Riccardo
R
D000368:Aged; D001859:Bone Neoplasms / Q000097:blood / Q000209:etiology* / Q000503:physiopathology / Q000556:secondary*; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D001862:Bone Resorption / Q000235:genetics / Q000503:physiopathology; D002277:Carcinoma / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015851:Interleukin-7 / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D053244:Osteoprotegerin / Q000097:blood / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D053245:RANK Ligand / Q000097:blood / Q000235:genetics
C501126:DKK1 protein, human; C508605:IL7 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015851:Interleukin-7; D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human