Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion.,Translational Oncology

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Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion.
Translational Oncology ( IF 5 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.tranon.2020.100747
Yugang Wang ₁ , Udit Singhal ₁ , Yuanyuan Qiao ₂ , Tadas Kasputis ₁ , Jae-Seung Chung ₃ , Huiru Zhao ₄ , Farah Chammaa ₅ , Jacob A Belardo ₅ , Therese M Roth ₁ , Hao Zhang ₁ , Alexander B Zaslavsky ₆ , Ganesh S Palapattu ₆ , Kenneth J Pienta ₇ , Arul M Chinnaiyan ₈ , Russell S Taichman ₉ , Frank C Cackowski ₁₀ , Todd M Morgan ₆

Affiliation

Department of Urology, University of Michigan, Ann Arbor, MI 48109.
Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
Department of Urology, University of Michigan, Ann Arbor, MI 48109; Department of Urology, Inje University, Haeundae Paik Hospital, Busan, Republic of Korea.
Department 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 China.
College of Literature, Science, and Arts, University of Michigan, Ann Arbor, MI 48104.
Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
Departments of Urology and Medical Oncology, Johns Hopkins University School of Medicine and James Buchanan Brady Urological Institute, Baltimore, MD 21287.
Rogel 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 48109.
Department of Periodontics, University of Alabama at Birmingham School of Dentistry, Birmingham, AL 35233.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, 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.

中文翻译：

Wnt信号驱动前列腺癌的骨转移和侵袭。

Wnt信号传导已被认为是前列腺癌相关成骨细胞分化的驱动力，并且先前的研究已经将Wnt功能的改变与诱导肿瘤转移联系起来。小鼠模型中前列腺癌骨转移的一个独特方面是与前肢（肱骨）相比，它们相对于后肢（股骨）的相对偏爱。在非荷瘤小鼠的肱骨和股骨中进行了比较基因表达谱分析，以评估这些部位的微环境差异。这表明与股骨相比，Wnt信号抑制剂WIF1和SOST在肱骨中相对过表达，且WNT5A升高表达在股骨骨髓中，提示与肱骨相比，股骨内Wnt信号的协同上调。来自骨髓基质细胞（HS-5细胞）的条件培养基（CM）用于模拟骨髓微环境，该环境强烈促进前列腺癌细胞的侵袭（PC3细胞增加3.3倍，P  <.05；增加7倍）在LNCaP细胞中，P  <.05）。产生CM的HS-5细胞内的WNT5A shRNA敲低显着降低了PC3（56％，P  <.05）和LNCaP（60％，P  <.05）细胞侵袭。同样，CM与WIF1的预温育可显着阻止LNCaP细胞侵袭（40％，P <.05）。shRNA介导的Wnt受体FZD4和FZD8的敲低也强烈抑制肿瘤细胞的侵袭（shFZD4抑制率为60％，P  <.05；shFZD8抑制率为63％，P  <.05）。此外，小分子抑制JNK是非经典Wnt信号通路的重要组成部分，可显着抑制CM介导的肿瘤浸润。总体而言，这项研究揭示了Wnt信号作为前列腺癌骨转移性和侵袭性的驱动因素。

更新日期：2020-03-25

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