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Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion()
Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilectio...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109463/ https://www.ncbi.nlm.nih.gov/pubmed/32217460 http://dx.doi.org/10.1016/j.tranon.2020.100747 |
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author | Wang, Yugang Singhal, Udit Qiao, Yuanyuan Kasputis, Tadas Chung, Jae-Seung Zhao, Huiru Chammaa, Farah Belardo, Jacob A. Roth, Therese M. Zhang, Hao Zaslavsky, Alexander B. Palapattu, Ganesh S. Pienta, Kenneth J. Chinnaiyan, Arul M. Taichman, Russell S. Cackowski, Frank C. Morgan, Todd M. |
author_facet | Wang, Yugang Singhal, Udit Qiao, Yuanyuan Kasputis, Tadas Chung, Jae-Seung Zhao, Huiru Chammaa, Farah Belardo, Jacob A. Roth, Therese M. Zhang, Hao Zaslavsky, Alexander B. Palapattu, Ganesh S. Pienta, Kenneth J. Chinnaiyan, Arul M. Taichman, Russell S. Cackowski, Frank C. Morgan, Todd M. |
author_sort | Wang, Yugang |
collection | PubMed |
description | Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non–tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P < .05; 7-fold increase in LNCaP cells, P < .05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P < .05) and LNCaP (60%, P < .05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P < .05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P < .05; 63% shFZD8, P < .05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion. |
format | Online Article Text |
id | pubmed-7109463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-71094632020-04-03 Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() Wang, Yugang Singhal, Udit Qiao, Yuanyuan Kasputis, Tadas Chung, Jae-Seung Zhao, Huiru Chammaa, Farah Belardo, Jacob A. Roth, Therese M. Zhang, Hao Zaslavsky, Alexander B. Palapattu, Ganesh S. Pienta, Kenneth J. Chinnaiyan, Arul M. Taichman, Russell S. Cackowski, Frank C. Morgan, Todd M. Transl Oncol Original article Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non–tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P < .05; 7-fold increase in LNCaP cells, P < .05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P < .05) and LNCaP (60%, P < .05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P < .05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P < .05; 63% shFZD8, P < .05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion. Neoplasia Press 2020-03-25 /pmc/articles/PMC7109463/ /pubmed/32217460 http://dx.doi.org/10.1016/j.tranon.2020.100747 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Wang, Yugang Singhal, Udit Qiao, Yuanyuan Kasputis, Tadas Chung, Jae-Seung Zhao, Huiru Chammaa, Farah Belardo, Jacob A. Roth, Therese M. Zhang, Hao Zaslavsky, Alexander B. Palapattu, Ganesh S. Pienta, Kenneth J. Chinnaiyan, Arul M. Taichman, Russell S. Cackowski, Frank C. Morgan, Todd M. Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title | Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title_full | Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title_fullStr | Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title_full_unstemmed | Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title_short | Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion() |
title_sort | wnt signaling drives prostate cancer bone metastatic tropism and invasion() |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109463/ https://www.ncbi.nlm.nih.gov/pubmed/32217460 http://dx.doi.org/10.1016/j.tranon.2020.100747 |
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