Prostate carcinoma cells that have resided in bone have an upregulated IGF-I axis.
BACKGROUND
Prostate cancer (PC) has a propensity to metastasize to the skeleton, inducing an osteoblastic response in the host. Recent epidemiological studies have suggested that circulating IGF-I may be important for both the pathogenesis and dissemination of PC. We have postulated that tumor secreted IGF-I in conjunction with endogenous IGF-I contributes to the osteoblastic phenotype characteristic of metastatic PC.


METHODS
To test this thesis we studied the established LNCaP PC progression model consisting of three genetically related human PC cell lines.


RESULTS
Using RIA, we found serum-free conditioned media (CM) of LNCaP and C4-2 had no measurable IGF-I, whereas IGF-I was easily detected in CM from C4-2B cells at 24 hr (i.e., 1.8 +/- 0.53 ng/mg cell protein). Real-time PCR of IGF-I mRNA showed that C4-2B expressed 100-fold more IGF-I mRNA than LNCaP cells. In addition, C4-2B expression of IGF-I mRNA was substantially increased in the presence of exogenous IGF-I to nearly twofold. While IGFBP-3 and IGFBP-1 were not detectable in the CM of any PC line, all cells secreted IGFBP-2. C4-2B cells produced 40% more IGFBP-2 than LNCaP or C4-2 cells (C4-2B at 167 +/- 43 ng/mg cell protein). RANKL, a product of bone stromal cells, was also differentially expressed: LNCaP had threefold higher RANKL mRNA compared to C4-2 and C4-2B and at least equivalent protein expression.


CONCLUSIONS
Our results suggest that PC cells that have metastasized to bone have an upregulated IGF-I regulatory system. This suggests an activated IGF-I axis contributes to the host-PC interaction in promoting osteoblastic metastases.
Rubin
J
J
Department of Medicine, VAMC and Emory University, Atlanta, Georgia 30033, USA. jrubin02@emory.edu
Chung
L W K
LW
Fan
X
X
Zhu
L
L
Murphy
T C
TC
Nanes
M S
MS
Rosen
C J
CJ
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D018969:Insulin-Like Growth Factor Binding Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D007334:Insulin-Like Growth Factor I