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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.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 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

SOST reduces PC3-mediated osteolysis in xenograft derived tumor lesions.Representative femur micro-CT scans from PC3 (A), PC3DKK1 (B) and PC3SOST (C) injected NSG mice (N = 6/group). Bone volume was quantified for both PC injected and uninjected contralateral femurs, and relative bone loss due to osteolysis was calculated for each group by subtracting the injected (L) from the uninjected (R) values (D). PCSOST injected femurs experienced significantly less bone loss due to advanced osteolytic lesions (*p<0.05).
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pone.0142058.g006: SOST reduces PC3-mediated osteolysis in xenograft derived tumor lesions.Representative femur micro-CT scans from PC3 (A), PC3DKK1 (B) and PC3SOST (C) injected NSG mice (N = 6/group). Bone volume was quantified for both PC injected and uninjected contralateral femurs, and relative bone loss due to osteolysis was calculated for each group by subtracting the injected (L) from the uninjected (R) values (D). PCSOST injected femurs experienced significantly less bone loss due to advanced osteolytic lesions (*p<0.05).

Mentions: To determine whether SOST impacts metastasis, NSG mice we injected intravenously with PC3, PC3DKK1 or PC3SOST and tissues were examined for the presence of tumors 10 weeks post injection. Intravenous delivery of PC3 cells resulted in an 80% tumor rate (8/10 mice) with lung and kidney being the most frequent sites of metastasis. PC3DKK1 cells behaved highly similar to PC3 cells, while PC3SOST-injected mice had significantly lower rates of metastasis, with only 1/9 mice (spleen) showing visible macroscopic metastasis at 10-weeks post-injection (Table 1). These data suggested that SOST-induced inhibition of Wnt signaling significantly reduces PC3 invasion and metastasis, in vivo. Next we examined whether overexpression of SOST in PC3 cells reduces osteolytic tumor formation. Ten NSG mice per group received 5x105 PC3, PC3DKK1 or PC3SOST cells intrafemorally. Four weeks post injections bone volume was quantified using micro-CT. While all three groups showed bone loss and damage at the distal site where the needle was inserted to deliver the cancer cells, the scans showed dramatic loss of bone in the proximal femur of PC3 and PC3DKK1, but significantly less bone loss in PC3SOST injected femurs (Fig 6A–6C). To assess bone loss differences due to osteolysis we subtracted the bone volume of the PC injected femur from the contralateral uninjected femur and found PC3SOST cells to induce significantly less bone loss than PC3 or PC3DKK1. These findings suggest that the overexpression of SOST in PC3 cells blunts osteolysis and reduces the tumor formation rate.


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)

SOST reduces PC3-mediated osteolysis in xenograft derived tumor lesions.Representative femur micro-CT scans from PC3 (A), PC3DKK1 (B) and PC3SOST (C) injected NSG mice (N = 6/group). Bone volume was quantified for both PC injected and uninjected contralateral femurs, and relative bone loss due to osteolysis was calculated for each group by subtracting the injected (L) from the uninjected (R) values (D). PCSOST injected femurs experienced significantly less bone loss due to advanced osteolytic lesions (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4636315&req=5

pone.0142058.g006: SOST reduces PC3-mediated osteolysis in xenograft derived tumor lesions.Representative femur micro-CT scans from PC3 (A), PC3DKK1 (B) and PC3SOST (C) injected NSG mice (N = 6/group). Bone volume was quantified for both PC injected and uninjected contralateral femurs, and relative bone loss due to osteolysis was calculated for each group by subtracting the injected (L) from the uninjected (R) values (D). PCSOST injected femurs experienced significantly less bone loss due to advanced osteolytic lesions (*p<0.05).
Mentions: To determine whether SOST impacts metastasis, NSG mice we injected intravenously with PC3, PC3DKK1 or PC3SOST and tissues were examined for the presence of tumors 10 weeks post injection. Intravenous delivery of PC3 cells resulted in an 80% tumor rate (8/10 mice) with lung and kidney being the most frequent sites of metastasis. PC3DKK1 cells behaved highly similar to PC3 cells, while PC3SOST-injected mice had significantly lower rates of metastasis, with only 1/9 mice (spleen) showing visible macroscopic metastasis at 10-weeks post-injection (Table 1). These data suggested that SOST-induced inhibition of Wnt signaling significantly reduces PC3 invasion and metastasis, in vivo. Next we examined whether overexpression of SOST in PC3 cells reduces osteolytic tumor formation. Ten NSG mice per group received 5x105 PC3, PC3DKK1 or PC3SOST cells intrafemorally. Four weeks post injections bone volume was quantified using micro-CT. While all three groups showed bone loss and damage at the distal site where the needle was inserted to deliver the cancer cells, the scans showed dramatic loss of bone in the proximal femur of PC3 and PC3DKK1, but significantly less bone loss in PC3SOST injected femurs (Fig 6A–6C). To assess bone loss differences due to osteolysis we subtracted the bone volume of the PC injected femur from the contralateral uninjected femur and found PC3SOST cells to induce significantly less bone loss than PC3 or PC3DKK1. These findings suggest that the overexpression of SOST in PC3 cells blunts osteolysis and reduces the tumor formation rate.

Bottom Line: 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 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