Alterations of the RANKL pathway in blood and bone marrow samples of prostate cancer patients without bone metastases.
OBJECTIVE
The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow-mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases.


METHODS
We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry.


RESULTS
PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC.


CONCLUSIONS
The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre-metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC.
Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
Tilman
T
Todenhöfer
Jörg
J
Hennenlotter
Benjamin Joachim
BJ
Schmiedel
Andrea
A
Hohneder
Sabrina
S
Grimm
Ursula
U
Kühs
Helmut Rainer
HR
Salih
Hans-Jörg
HJ
Bühring
Tanja
T
Fehm
Georgios
G
Gakis
Gunnar
G
Blumenstock
Stefan
S
Aufderklamm
David
D
Schilling
Arnulf
A
Stenzl
Christian
C
Schwentner
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001859:Bone Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000556:secondary; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D053245:RANK Ligand / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D014408:Biomarkers, Tumor; D053245:RANK Ligand; C505688:TNFSF11 protein, human