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2015 ; 10
(11
): e0142058
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SOST Inhibits Prostate Cancer Invasion
#MMPMID26545120
Hudson BD
; Hum NR
; Thomas CB
; Kohlgruber A
; Sebastian A
; Collette NM
; Coleman MA
; Christiansen BA
; Loots GG
PLoS One
2015[]; 10
(11
): e0142058
PMID26545120
show ga
Inhibitors of Wnt signaling have been shown to be involved in prostate cancer
(PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored.
Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts
promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1
promotes PC elongation and filopodia formation, morphological changes
characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to
activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have
opposing roles on Wnt signaling in this context. Gene expression analysis of PC3
cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified
CRIM1 as one of the transcripts upregulated under highly invasive conditions. We
found CRIM1 overexpression to also promote cell-invasion. These findings suggest
that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1
expression and facilitating cancer cell invasion and adhesion to bone. We
concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that
bone-derived Wnt signaling positively contributes to the invasive phenotypes of
PC3 cells by activating CRIM1 expression and facilitating PC-OB physical
interaction. As such, we investigated the effects of high concentrations of SOST
in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein
in NSG mice did not readily metastasize, and those injected intrafemorally had
significantly reduced osteolysis, suggesting that targeting the molecular bone
environment may influence bone metastatic prognosis in clinical settings.
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