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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-04-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523319306291 |
| _version_ | 1818942583703863296 |
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| author | Yugang Wang Udit Singhal Yuanyuan Qiao Tadas Kasputis Jae-Seung Chung Huiru Zhao Farah Chammaa Jacob A. Belardo Therese M. Roth Hao Zhang Alexander B. Zaslavsky Ganesh S. Palapattu Kenneth J. Pienta Arul M. Chinnaiyan Russell S. Taichman Frank C. Cackowski Todd M. Morgan |
| author_facet | Yugang Wang Udit Singhal Yuanyuan Qiao Tadas Kasputis Jae-Seung Chung Huiru Zhao Farah Chammaa Jacob A. Belardo Therese M. Roth Hao Zhang Alexander B. Zaslavsky Ganesh S. Palapattu Kenneth J. Pienta Arul M. Chinnaiyan Russell S. Taichman Frank C. Cackowski Todd M. Morgan |
| author_sort | Yugang Wang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T07:13:45Z |
| format | Article |
| id | doaj.art-6e608decd127484f99fae140df2265b0 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-20T07:13:45Z |
| publishDate | 2020-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-6e608decd127484f99fae140df2265b02022-12-21T19:48:50ZengElsevierTranslational Oncology1936-52332020-04-01134Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and InvasionYugang Wang0Udit Singhal1Yuanyuan Qiao2Tadas Kasputis3Jae-Seung Chung4Huiru Zhao5Farah Chammaa6Jacob A. Belardo7Therese M. Roth8Hao Zhang9Alexander B. Zaslavsky10Ganesh S. Palapattu11Kenneth J. Pienta12Arul M. Chinnaiyan13Russell S. Taichman14Frank C. Cackowski15Todd M. Morgan16Department of Urology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109; Department of Urology, Inje University, Haeundae Paik Hospital, Busan, Republic of KoreaDepartment of Urology, University of Michigan, Ann Arbor, MI 48109; Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, People's Republic of ChinaCollege of Literature, Science, and Arts, University of Michigan, Ann Arbor, MI 48104College of Literature, Science, and Arts, University of Michigan, Ann Arbor, MI 48104Department of Urology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109Departments of Urology and Medical Oncology, Johns Hopkins University School of Medicine and James Buchanan Brady Urological Institute, Baltimore, MD 21287Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, Department of Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109Department of Periodontics, University of Alabama at Birmingham School of Dentistry, Birmingham, AL 35233Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Address all correspondence to: Todd M. Morgan, M.D., Department of Urology, University of Michigan Health System, 1500 E. Medical Center Drive, 7308 Rogel Cancer Center, Ann Arbor, MI 48109.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.http://www.sciencedirect.com/science/article/pii/S1936523319306291 |
| spellingShingle | Yugang Wang Udit Singhal Yuanyuan Qiao Tadas Kasputis Jae-Seung Chung Huiru Zhao Farah Chammaa Jacob A. Belardo Therese M. Roth Hao Zhang Alexander B. Zaslavsky Ganesh S. Palapattu Kenneth J. Pienta Arul M. Chinnaiyan Russell S. Taichman Frank C. Cackowski Todd M. Morgan Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion Translational Oncology |
| 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 |
| url | http://www.sciencedirect.com/science/article/pii/S1936523319306291 |
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