Park Jee Soo, Lee Myung Eun, Jung Minsun, Kim Jongchan, Jang Won Sik, Ham Won Sik
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
Cancer Cell Int. 2025 Jun 11;25(1):209. doi: 10.1186/s12935-025-03834-7.
β3-adrenergic receptor (β3-AR) agonists, widely used in clinical urology, have recently been implicated in modulating cancer progression. While prior studies have reported both pro- and anti-tumor effects via fat browning and immune modulation, the mechanisms and organ-specific outcomes remain unclear. We aimed to confirm the effects of β3-AR agonists on primary tumors and lung metastasis using metastatic orthotopic murine renal cell carcinoma (RCC) models.
Metastatic orthoptic murine RCC models were developed, and mirabegron, a β3-AR agonist, was orally administered at different dosages and exposure times. The mice were later sacrificed and their kidney and lung tissues harvested. The primary tumor weight and lung nodule number were noted. Perirenal adipose tissue (PAT) browning and tumor immune microenvironment (TIME) remodeling were evaluated and compared between the mirabegron and vehicle treatment groups.
Mirabegron-treated mice showed a significant increase in tumor growth in the early phase; however, tumor growth rates reduced (by > 56%) in the mid and late phases. Mirabegron significantly increased the lung metastatic burden (by > 41%) in all phases. Mirabegron modulated TIME both in primary tumors and lung nodules and increased PAT browning.
The β3-AR agonist increases PAT browning, initially promoting primary tumor progression and possibly contributing to tumor initiation, but eventually inducing immune tolerance, leading to anticancer effects on primary tumors. Effects on lung metastases differed from those on primary tumors.
β3肾上腺素能受体（β3-AR）激动剂在临床泌尿外科中广泛应用，最近被认为与调节癌症进展有关。虽然先前的研究报告了通过脂肪褐变和免疫调节产生的促肿瘤和抗肿瘤作用，但其机制和器官特异性结果仍不清楚。我们旨在使用转移性原位小鼠肾细胞癌（RCC）模型来确认β3-AR激动剂对原发性肿瘤和肺转移的影响。
建立转移性原位小鼠RCC模型，并以不同剂量和暴露时间口服给予β3-AR激动剂米拉贝隆。随后处死小鼠并收集其肾脏和肺组织。记录原发性肿瘤重量和肺结节数量。评估并比较米拉贝隆治疗组和载体治疗组之间的肾周脂肪组织（PAT）褐变和肿瘤免疫微环境（TIME）重塑情况。
米拉贝隆治疗的小鼠在早期肿瘤生长显著增加；然而，在中期和后期肿瘤生长速率降低（超过56%）。米拉贝隆在所有阶段均显著增加肺转移负担（超过41%）。米拉贝隆调节原发性肿瘤和肺结节中的TIME，并增加PAT褐变。
β3-AR激动剂增加PAT褐变，最初促进原发性肿瘤进展并可能促进肿瘤起始，但最终诱导免疫耐受，从而对原发性肿瘤产生抗癌作用。对肺转移的影响与对原发性肿瘤的影响不同。
