Interactions of the WNT and RANKL/OPG pathways in osteomimicry of prostate cancer
Final Report Abstract
Prostate cancer is the most common malignancy in men and the second leading cause of death from cancer in men. It is characterized by a high propensity to home to bone and the development of osteosclerotic bone metastasis. As it is still unclear how prostate cancer cells acquire this osteoblast-like phenotype (osteomimicry) and modulate osteogenesis we aimed to investigate the role of WNT proteins, in particular WNT5A, in promoting tumor development and tumor cell osteomimicry and modulating osteoclast biology through receptor activator of NF-KB ligand (RANKL) and osteoprotegerin (OPG). The main outcome of this research project was the identification of Wnt5a, which was found to be specifically expressed in primary samples of osteotropic prostate cancer cells. Overexpression of Wnt5a led to enhanced apoptosis and inhibition of proliferation in vitro while correspondingly subcutaneous and intratibial tumor growth as well as subsequent bone destruction was inhibited. Consistently, a high tumor expression of Wnt5a was associated with a longer survival in a cohort of 397 prostate cancer patients. To determine, which specific Wnt molecules were differentially expressed between osteotropic and non-osteotropic prostate cancer cell lines, a Wnt array was performed, indicating that Wnt5a was amongst the most differentially expressed genes showing a 10-fold higher expression in osteotropic cells compared to non-osteotropic cells. To gain more insight into the expression of Wnt5a in primary prostate tumor tissue, we analyzed a cDNA array composed of 39 prostate cancer and 9 healthy control tissues. Wnt5a was highly abundant in the cancer tissue as compared to the controls. To validate these findings in a larger cohort we generated a tissue microarray (TMA). Using the clinical database from the Department of Urology, in which follow-up data for all prostate cancer patients treated by radical prostatectomy have been collected since 1995, we created a TMA with 400 samples and their healthy controls. The TMA confirmed the cDNA data and showed increased Wnt5a levels of patients with prostate cancer compared to patients with benign hyperplasia. Furthermore, a high tumor expression of Wnt5a was associated with a longer survival in prostate cancer patients. We also found that overexpression of Wnt5a induced apoptosis and inhibited proliferation in vitro. While Wnt5a induced apoptosis in all studied prostate cancer cell lines, overexpression in breast cancer cells did not affect proliferation or apoptosis, indicating its specificity for prostate cancer. In the next step, we determined whether high levels of Wnt5a also inhibit prostate tumor growth in vivo. Correspondingly to the in vitro results, Wnt5a overexpressing cells inhibited subcutaneous, intratibial, and intracardiac tumor growth and subsequent bone destruction. Collectively, these data - obtained in collaboration with other SKELMET projects - support a crucial role for Wnt5a in the development of prostate cancer by inducing apoptosis and inhibiting proliferation and suggest a prognostic marker function. Whether Wnt5a expression by tumor cells also alters the metastatic characteristics of prostate cancer cells and whether bone marrow-derived Wnt5a can induce prostate cancer cell apoptosis in a paracrine way were follow-up studies.
Publications
- Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett. 2014;346:172-7
Rachner TD, Göbel A, Benad-Mehner P, Hofbauer LC, Rauner M
(See online at https://doi.org/10.1016/j.canlet.2014.01.010) - DKK-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res. 2014;16:R20
Rachner TD, Goebel A, Thiele S, Rauner M, Benad-Mehner P, Hadji P, Ziller V, Muders M, Jakob F, Ebert R, Bornhäuser M, Schem C, Hofbauer LC
(See online at https://doi.org/10.1186/bcr3616) - Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol. 2014;2:500-12
Hofbauer LC, Rachner TD, Coleman RE, Jakob F
(See online at https://doi.org/10.1016/S2213-8587(13)70203-1) - High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer. 2014;14:649
Rachner TD, Thiele S, Göbel A, Browne A, Fuessel S, Erdmann K, Wirth MP, Fröhner M, Todenhöfer T, Muders MH, Kieslinger M, Rauner M, Hofbauer LC
(See online at https://doi.org/10.1186/1471-2407-14-649) - Targeting syndecan-1 in breast cancer inhibits osteoclast function through up-regulation of osteoprotegerin. J Bone Oncol. 2014;3:18-24
Benad-Mehner P, Thiele S, Rachner TD, Goebel A, Rauner M, Hofbauer LC
(See online at https://doi.org/10.1016/j.jbo.2013.11.001) - Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;838202
Todenhöfer T, Stenzl A, Hofbauer LC, Rachner TD
(See online at https://doi.org/10.1155/2015/838202) - WNT5A has anti-prostate cancer effects in vitro and reduces tumor growth in the skeleton in vivo. J Bone Miner Res. 2015;30:471-80
Thiele S, Göbel A, Rachner TD, Fuessel S, Froehner M, Muders MH, Baretton GB, Bernhardt R, Jakob F, Glüer CC, Bornhäuser M, Rauner M, Hofbauer LC
(See online at https://doi.org/10.1002/jbmr.2362) - Bone metastases: New aspects of pathogenesis and systemic therapy. Internist (Berl). 2016;57:666-74
Rachner TD, Jakob F, Hofbauer LC
(See online at https://doi.org/10.1007/s00108-016-0076-0) - WNT5A and its receptors in the bone-cancer dialogue. J Bone Miner Res. 2016;31:1488-96
Thiele S, Rachner TF, Rauner M, Hofbauer LC
(See online at https://doi.org/10.1002/jbmr.2899) - Bone mass is compromised by the chemotherapeutic Trabectedin in association with effects on osteoblasts and macrophage efferocytosis. J Bone Miner Res. 2017;32:2116-27
Sinder BP, Zweifler L, Koh AJ, Michalski MN, Hofbauer LC, Aguirre JI, Roca H, McCauley LK
(See online at https://doi.org/10.1002/jbmr.3196) - Bone health during endocrine therapy for cancer. Lancet Diabetes. Endocrinol. 2018;11:901-10
Rachner TD, Coleman R, Hadji P, Hofbauer LC
(See online at https://doi.org/10.1016/S2213-8587(18)30047-0) - Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget. 2018;9:27293-304
Thiele S, Zimmer A, Göbel A, Rachner TD, Rother S, Fuessel S, Froehner M, Wirth MP, Muders MH, Baretton GB, Jakob F, Rauner M, Hofbauer LC
(See online at https://doi.org/10.18632/oncotarget.25551)
