Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is a gender-biased tumor. Here we report that there is also a gender difference between pulmonary metastasis and lymph node metastasis showing that the androgen receptor (AR)-positive ccRCC may prefer to metastasize to lung rather than to lymph nodes. A higher AR expression increases ccRCC hematogenous metastasis yet decreases ccRCC lymphatic metastases. Mechanism dissection indicates that AR enhances miR-185-5p expression via binding to the androgen response elements located on the promoter of miR-185-5p, which suppresses VEGF-C expression via binding to its 3′ UTR. In contrast, AR-enhanced miR-185-5p also promotes HIF2α/VEGF-A expression via binding to the promoter region of HIF2α. Together, these results provide a unique mechanism by which AR can either increase or decrease ccRCC metastasis at different sites and may help us to develop combined therapies using anti-AR and anti-VEGF-C compounds to better suppress ccRCC progression.

Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR

“…The androgen receptor (AR) can promote progression and hematogenous metastasis in ccRCC through ASS1P3/miR-34a-5p/ASS1 and miR-185-5p/HIF-2a/VEGF signaling, respectively. This is consistent with the higher incidence and more malignant phenotypes in males according to data from the Surveillance Epidemiology and End Results (SEER) database (5)(6)(7). Furthermore, targeting AR with the antiandrogen enzalutamide could restore sunitinib sensitivity in the sunitinib-resistant PDX mouse model, suggesting enhancing TKI efficacy through inhibition of AR to better suppress ccRCC progression (8).…”

A magic drug target: Androgen receptor

“…Currently, enzalutamide is in combination with gemcitabine and cisplatin at phase I clinical trial for the therapy of bladder cancer (NCT02300610). For kidney cancer, AR and AR signaling also play an important role, and the molecular mechanisms have recently been gradually revealed especially by Chang's group . It is proved that an increased AR expression results in higher hematogenous metastasis and lower lymphatic metastasis of clear cell renal cell carcinoma .…”

“…For kidney cancer, AR and AR signaling also play an important role, 141,142 and the molecular mechanisms have recently been gradually revealed especially by Chang's group. [143][144][145][146][147] It is proved that an increased AR expression results in higher hematogenous metastasis and lower lymphatic metastasis of clear cell renal cell carcinoma. 145 At present, an early phase I clinical trial is in process for enzalutamide to treat kidney cancer before surgery (NCT02885649).…”

“…[143][144][145][146][147] It is proved that an increased AR expression results in higher hematogenous metastasis and lower lymphatic metastasis of clear cell renal cell carcinoma. 145 At present, an early phase I clinical trial is in process for enzalutamide to treat kidney cancer before surgery (NCT02885649). And such application has not been found at clinical trial for lung cancer.…”

Recent advances in understanding the complexities of metastasis

“…This process, shown to occur in mammary carcinoma, squamous cell carcinoma, and melanoma model systems, implicates lymph node metastases as a key step for establishing distant metastases of these tumours 69 . Nonetheless, metastatic disease as a whole is likely to consist of a complex interplay between disseminating cancer cells exiting the tumours via a combination of both routes, modulated by local and systemic factors and possibly even by sex in cases such as renal clear cell carcinoma where androgen receptor (AR) has been shown to increase haematogenous metastasis yet decrease lymphatic metastasis 153 .…”