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SOST Inhibits Prostate Cancer Invasion

Journal Article · · PLoS ONE
 [1];  [1];  [1];  [1];  [2];  [1];  [3];  [4];  [2]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Merced, Merced, CA (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Davis Medical Center, Sacramento, CA (United States)
  4. Univ. of California Davis Medical Center, Sacramento, CA (United States)
+ Show Author Affiliations
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. In conclusion, 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.
Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
National Institute of Health (NIH); USDOE
OSTI ID:
1259524
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 11 Vol. 10; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (5)

Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment journal April 2019
Tracking Tumor Colonization in Xenograft Mouse Models Using Accelerator Mass Spectrometry journal October 2018
Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts journal November 2017
Bone Marrow Adipocyte: An Intimate Partner With Tumor Cells in Bone Metastasis journal June 2018
Bone-Targeted Therapies in Cancer-Induced Bone Disease journal October 2017

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