Dual role of the androgen receptor in kidney cancer metastasis

Researchers have identified a dual role of the androgen receptor (AR) in the metastasis of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer.

ccRCC is a gender-biased tumor. Men have a higher risk of developing the cancer than women. Symptoms usually do not appear until the disease has progressed, making it hard to treat. ccRCC often involves alterations in the androgen/AR signaling. AR is a nuclear receptor for the male sex hormone androgen, and functions as a transcription factor.

Prior kidney cancer studies have reported conflicting results concerning the role of AR. Some suggested that AR stimulates ccRCC progression, while others indicated that it correlates with less malignancy.

To better elucidate AR's role in ccRCC, researchers from the University of Rochester Medical Center in the USA teamed up with researchers from Chinese PLA General Hospital and Tianjin Institute of Urology in China.

The team analyzed a survey of 3989 patients with kidney cancer. The results showed that 3613 of the patients had ccRCC, including 2673 male patients and 940 female patients. Importantly, there appeared to be an association between AR expression and metastatic destinations of primary ccRCC cells.  ccRCC cells with higher AR were more likely to spread to the pulmonary tissues, whereas ccRCC cells with lower AR tended to move to the lymph nodes.

Previous studies had shown that inactivation of the tumor suppressor gene VHL is seen in most ccRCC cases, and this inactivation leads to the overexpression of VEGF. Therefore, VEGF is a particularly relevant therapeutic target in ccRCC.

In the further experiments, the team carried out a series of experiments in multiple kidney cancer cell lines, and found that androgen/AR signals appeared to upregulate VEGF-A and downregulate VEGF-C expression in VHL-mutated ccRCC cells. The researchers assumed that "AR plays a dual role in ccRCC metastasis through differential regulation of VEGF-A vs. VEGF-C expression."

Chawnshang Chang, corresponding author of the study, and other researchers have published their findings in a paper (Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma), appearing in the journal Nature Communications.

Dr. Chang has been studying the connections between sex hormones/nuclear receptors and diseases like cancer for about two decades.
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