Abstract
M2 macrophages in the tumor microenvironment are important drivers of cancer metastasis. Exosomes play a critical role in the crosstalk between different cells by delivering microRNAs or other cargos. Whether exosomes derived from pro-tumorigenic M2 macrophages (M2-Exos) could modulate the metastatic behavior of renal cell carcinoma (RCC) is unclear. This study found that M2-Exos promotes migration and invasion in RCC cells. Inhibiting miR-21-5p in M2-Exos significantly reversed their pro-metastatic effects on RCC cells in vitro and in the avian embryo chorioallantoic membrane in vivo tumor model. We further found that the pro-metastatic mechanism of miR-21-5p in M2-Exos is by targeting PTEN-3′UTR to regulate PTEN/Akt signaling. Taken together, our results demonstrate that M2-Exos carries miR-21-5p promote metastatic features of RCC cells through PTEN/Akt signaling. Reversing this could serve as a novel approach to control RCC metastasis.
Highlights
Renal cell carcinoma (RCC) ranks amongst the top ten most common cancer types, with over 400,000 newly diagnosed cases worldwide in 2018 [1]
We demonstrated that M2-Exos carrying miR-21-5p augmented the migration and invasion of renal cell carcinoma (RCC) cells by downregulating the phosphatase and tensin homolog (PTEN) tumor suppressor, which in turn activated the Akt pathway
We confirmed that RCC tumors contain M2 macrophages by performing immunohistochemistry (IHC) for CD163, a clinically-relevant marker of M2 macrophages [20], in ten consecutive surgical cases of RCC of different subtypes that were excised by one surgeon
Summary
Renal cell carcinoma (RCC) ranks amongst the top ten most common cancer types, with over 400,000 newly diagnosed cases worldwide in 2018 [1]. Clear cell renal cell carcinoma (ccRCC) comprises almost 80% of RCC subtypes [2]. A better understanding of the mechanism of metastasis in RCC could be helpful to devise new therapeutic interventions. Dictated by their front-line innate immune responses, macrophages are highly adaptable cells influenced heavily by environmental stimuli. The classical M1 macrophages display pro-inflammatory activities for clearing foreign pathogens and cancer cells. Tumor-associated macrophages (TAMs) are designated as M2 that provide numerous pro-tumorigenic functions [6,7], such as fostering an immunosuppressive environment and promoting cancer invasion and metastasis [8,9]. The specific mechanism by which M2 macrophages promote RCC metastasis is unknown
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