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SOST Inhibits Prostate Cancer Invasion.

Hudson BD, Hum NR, Thomas CB, Kohlgruber A, Sebastian A, Collette NM, Coleman MA, Christiansen BA, Loots GG - PLoS ONE (2015)

Bottom Line: We found CRIM1 overexpression to also promote cell-invasion.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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Morphological changes in PC3 cells.A-C, Representative SEM images (1500x) of PC3 cells treated with rhDKK1 (B, b), or rhSOST (C, c). D-H, Immunofluorescence staining of PC3 cells treated with rhDKK1 (E), rhSOST (F), rhCRIM1 (G) and rhWNT3A (H); anti–CRIM1 (green) and rhodamine-conjugated phalloidin (blue).
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pone.0142058.g005: Morphological changes in PC3 cells.A-C, Representative SEM images (1500x) of PC3 cells treated with rhDKK1 (B, b), or rhSOST (C, c). D-H, Immunofluorescence staining of PC3 cells treated with rhDKK1 (E), rhSOST (F), rhCRIM1 (G) and rhWNT3A (H); anti–CRIM1 (green) and rhodamine-conjugated phalloidin (blue).

Mentions: To investigate whether the effects of DKK1 and CRIM1 on cancer cell invasion and metastasis are associated with actin filaments, we examined morphological changes in PC3 cells treated with rhDKK1 and rhSOST. PC3 cells treated with DKK1 were elongated, displaying fibroblast-like morphology with many more filopodia projections as compared to either untreated or rhSOST treated PC3 cells (Fig 5A–5C), which were more rounded and had fewer filopodia. Moreover, both untreated and rhSOST treated PC3 cells adhered less strongly to the plastic surface and tended to be more clumped together forming aggregates. Morphological appearance was consistent with the underlying cytoskeletal organization; phalloidin staining showed enhanced actin organization in rhDKK1 and rhWNT3A treated PC3 cells, relative to PC3 and rhSOST treated cells (Fig 5D–5H). Similarly, the exogenous addition of a secreted form of CRIM1 also promoted the formation of lamellipodia and filopodia, as visualized by phalloidin–stained actin in PC3 cells treated with CRIM1. Collectively, these findings indicate that both DKK1 and CRIM1 promote filopodia formation in highly invasive PC3 cells and that this process is associated with the reorganization of actin filaments.


SOST Inhibits Prostate Cancer Invasion.

Hudson BD, Hum NR, Thomas CB, Kohlgruber A, Sebastian A, Collette NM, Coleman MA, Christiansen BA, Loots GG - PLoS ONE (2015)

Morphological changes in PC3 cells.A-C, Representative SEM images (1500x) of PC3 cells treated with rhDKK1 (B, b), or rhSOST (C, c). D-H, Immunofluorescence staining of PC3 cells treated with rhDKK1 (E), rhSOST (F), rhCRIM1 (G) and rhWNT3A (H); anti–CRIM1 (green) and rhodamine-conjugated phalloidin (blue).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4636315&req=5

pone.0142058.g005: Morphological changes in PC3 cells.A-C, Representative SEM images (1500x) of PC3 cells treated with rhDKK1 (B, b), or rhSOST (C, c). D-H, Immunofluorescence staining of PC3 cells treated with rhDKK1 (E), rhSOST (F), rhCRIM1 (G) and rhWNT3A (H); anti–CRIM1 (green) and rhodamine-conjugated phalloidin (blue).
Mentions: To investigate whether the effects of DKK1 and CRIM1 on cancer cell invasion and metastasis are associated with actin filaments, we examined morphological changes in PC3 cells treated with rhDKK1 and rhSOST. PC3 cells treated with DKK1 were elongated, displaying fibroblast-like morphology with many more filopodia projections as compared to either untreated or rhSOST treated PC3 cells (Fig 5A–5C), which were more rounded and had fewer filopodia. Moreover, both untreated and rhSOST treated PC3 cells adhered less strongly to the plastic surface and tended to be more clumped together forming aggregates. Morphological appearance was consistent with the underlying cytoskeletal organization; phalloidin staining showed enhanced actin organization in rhDKK1 and rhWNT3A treated PC3 cells, relative to PC3 and rhSOST treated cells (Fig 5D–5H). Similarly, the exogenous addition of a secreted form of CRIM1 also promoted the formation of lamellipodia and filopodia, as visualized by phalloidin–stained actin in PC3 cells treated with CRIM1. Collectively, these findings indicate that both DKK1 and CRIM1 promote filopodia formation in highly invasive PC3 cells and that this process is associated with the reorganization of actin filaments.

Bottom Line: We found CRIM1 overexpression to also promote cell-invasion.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.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.

View Article: PubMed Central - PubMed

Affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus