ORIGINAL ARTICLE
Crosstalk between OPG/RANKL/RANK in bone marrow mesenchymal stem cells and Wnt/b-catenin pathway in prostate cancer cells regulates bone metastasis of prostate cancer
1
Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan City, Ninde, Fujian, 355000, China
These authors had equal contribution to this work
Submission date: 2025-01-08
Acceptance date: 2025-03-05
Publication date: 2025-04-28
Corresponding author
Guangbing Chen
Department of Urology, Mindong Hospital Affiliated to Fujian Medical University. Fuan City, Ninde, Fujian, 355000, China
Department of Urology, Mindong Hospital Affiliated to Fujian Medical University. Fuan City, Ninde, Fujian, 355000, China
Pol J Pathol 2025;76(1):25-37
KEYWORDS
TOPICS
ABSTRACT
This study aimed to investigate whether the crosstalk between the osteoprotegerin (OPG)/receptor activator of nuclear factor-kB (RANK)/receptor activator of nuclear factor-kB ligand (RANKL) in bone marrow mesenchymal stem cells (BMSCs) and Wnt/b-catenin pathways in Pca cells regulates bone metastasis of PCa.
Our study showed that there was increased OPG/RANKL/RANK and b-catenin expression in the tissue of PCa and its bone metastasis. This study further showed that RANKL knockdown in BMSCs or b-catenin knockdown in PC-3s blocked the proliferation and migration of BMSCs and the proliferation, migration, and invasion of PC-3s in vitro. Conversely, RANKL overexpression in BMSCs and b-catenin overexpression in PC-3s promoted the proliferation and migration of BMSCs and the proliferation, migration, and invasion of PC-3s in vitro. These data indicate that the RANKL pathway in BMSCs promoted the PC-3s invasion and the catenin pathway in PC-3s activated BMSCs with expression of cancer-associated fibroblast markers, which promoted the bone metastasis.
This suggests that the interaction and crosstalk between BMSCs in bone microenvironment and PCa play a critical role in the exquisite tropism for Pca bone metastasis. Cancer therapies classically target tumour cells; however, based on this study, targeting BMSCs in bone microenvironment is a reasonable option for PCa therapy strategy.
Our study showed that there was increased OPG/RANKL/RANK and b-catenin expression in the tissue of PCa and its bone metastasis. This study further showed that RANKL knockdown in BMSCs or b-catenin knockdown in PC-3s blocked the proliferation and migration of BMSCs and the proliferation, migration, and invasion of PC-3s in vitro. Conversely, RANKL overexpression in BMSCs and b-catenin overexpression in PC-3s promoted the proliferation and migration of BMSCs and the proliferation, migration, and invasion of PC-3s in vitro. These data indicate that the RANKL pathway in BMSCs promoted the PC-3s invasion and the catenin pathway in PC-3s activated BMSCs with expression of cancer-associated fibroblast markers, which promoted the bone metastasis.
This suggests that the interaction and crosstalk between BMSCs in bone microenvironment and PCa play a critical role in the exquisite tropism for Pca bone metastasis. Cancer therapies classically target tumour cells; however, based on this study, targeting BMSCs in bone microenvironment is a reasonable option for PCa therapy strategy.
REFERENCES (25)
1.
Pernar CH, Ebot EM, Wilson KM, Mucci LA. The epidemiology of prostate cancer. Cold Spring Harb Perspect Med 2018; 8: a030361.
2.
Sayyid RK, Benton JZ, Reed WC, et al. Prostate cancer mortality rates in low- and favorable intermediate-risk active surveillance patients: a population-based competing risks analysis. World J Urol 2023; 41: 93-99.
3.
Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31: 578-583.
4.
Mazzone E, Preisser F, Nazzani S, et al. Location of metastases in contemporary prostate cancer patients affects cancer-specific mortality. Clin Genitourin Cancer 2018; 16: 376-384 e1.
5.
Baldessari C, Pipitone S, Molinaro E, et al. Bone metastases and health in prostate cancer: from pathophysiology to clinical implications. Cancers (Basel) 2023; 15: 1518.
6.
Wong SK, Mohamad NV, Giaze TR, Chin KY, Mohamed N, Ima-Nirwana S. Prostate cancer and bone metastases: the underlying mechanisms. Int J Mol Sci 2019; 20: 2587.
7.
Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert Rev Cardiovasc Ther 2006; 4: 801-811.
8.
Zhang Y, Liang J, Liu P, Wang Q, Liu L, Zhao H. The RANK/RANKL/OPG system and tumor bone metastasis: potential mechanisms and therapeutic strategies. Front Endocrinol (Lausanne) 2022; 13: 1063815.
9.
Gao Q, Wang L, Wang S, Huang B, Jing Y, Su J. Bone marrow mesenchymal stromal cells: identification, classification, and differentiation. Front Cell Dev Biol 2021; 9: 787118.
10.
Ridge SM, Bhattacharyya D, Dervan E, et al. Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic ‘activated’ state that enhances prostate cancer cell migration. Int J Cancer 2018; 142: 2056-2067.
11.
Borghese C, Casagrande N, Pivetta E, et al. Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells. Oncotarget 2017; 8: 42926-42938.
12.
Bisson I, DM Prowse. WNT signaling regulates self-renewal and differentiation of ,rostate cancer cells with stem cell characteristics. Cell Res 2009; 19: 683-697.
13.
Park M, Cho YJ, Kim B, et al. RANKL immunisation inhibits prostate cancer metastasis by modulating EMT through a RANKL-dependent pathway. Sci Rep 2021; 11: 12186.
14.
Patel S, Alam A, Pant R, Chattopadhyay S. Wnt signaling and its significance within the tumor microenvironment: novel therapeutic insights. Front Immunol 2019; 10: 2872.
15.
Humeniuk R, Mishra PJ, Bertino JR, Banerjee D. Molecular targets for epigenetic therapy of cancer. Curr Pharm Biotechnol 2009; 10: 161-165.
16.
Xu Y, Li W, Lin S, Liu B, Wu P, Li L. Fibroblast diversity and plasticity in the tumor microenvironment: roles in immunity and relevant therapies. Cell Commun Signal 2023; 21: 234.
17.
Prantl L, Muehlberg F, Navone NM, et al. Adipose tissue-derived stem cells promote prostate tumor growth. Prostate 2010; 70: 1709-1715.
18.
Ye H, Cheng J, Tang Y, et al. Human bone marrow-derived mesenchymal stem cells produced TGFbeta contributes to progression and metastasis of prostate cancer. Cancer Invest 2012; 30: 513-518.
19.
Guo Q, Jin Y, Chen X, et al. NF-kappaB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9: 53.
20.
Ming J, Cronin SJF, Penninger JM. Targeting the RANKL/RANK/OPG axis for cancer therapy. Front Oncol 2020; 10: 1283.
21.
Ridge SM, Sullivan FJ, Glynn SA. Mesenchymal stem cells: key players in cancer progression. Mol Cancer 2017; 16: 31.
22.
Lee MA, Park JH, Rhyu SY, et al. Wnt3a expression is associated with MMP-9 expression in primary tumor and metastatic site in recurrent or stage IV colorectal cancer. BMC Cancer 2014; 14: 125.
23.
Huang D, Du X. Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 2008; 14: 1823-1827.
24.
Rao C, Lin SL, Ruan WJ, Wen H, Wu DJ, Deng H. High expression of IGFBP7 in fibroblasts induced by colorectal cancer cells is co-regulated by TGF-beta and Wnt signaling in a Smad2/3-Dvl2/3-dependent manner. PLoS One 2014; 9: e85340.
25.
Jridi I, Canté-Barrett K, Pike-Overzet K, Staal FJT. Inflammation and Wnt signaling: target for immunomodulatory therapy? Front Cell Dev Biol 2020; 8: 615131.
Share
RELATED ARTICLE
| eISSN: | 2084-9869 |
| ISSN: | 1233-9687 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
