Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a.

Jung-Hyun Lee,Julio Vera-Gonzales,Christian Ostalecki,Stefani Gross,Stefan Wild,Nina Koliha,Jochen Dindorf,Gerold Schuler,Martin Eberhardt,Xin Lai,Katja Blume,Heiko Bruns,Andreas S Baur

doi:10.26508/lsa.201800205

Jung-Hyun Lee, Julio Vera-Gonzales + Show 11 more

Open Access

https://doi.org/10.26508/lsa.201800205

Copy DOI

Abstract

Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients, exhibiting strong suppressive effects on the proliferation of tumor cells. Plasma vesicle numbers, miRNAs, and protein levels were elevated two- to tenfold and detected many years after tumor resection. The vesicles revealed individual and clinical stage-specific miRNA profiles as well as active ADAM10. However, whereas pEV from patients preventing tumor relapse down-regulated β-catenin and blocked tumor cell proliferation in an miR-34a-dependent manner, pEV from metastatic patients lost this ability and stimulated β-catenin-mediated transcription. Cancer-induced pEV may constitute an innate immune mechanism suppressing tumor cell activity including that of residual cancer cells present after primary surgery.

Highlights

Recent work suggested that most malignant cancers secrete extracellular vesicles (EVs) into the periphery that have tumorigenic properties (Skog et al, 2008; Filipazzi et al, 2012; Peinado et al, 2012; Zomer et al, 2015)
Plasma EV miRNAs were quantified by microarray from 14 melanoma patients with tumor burden, ranging from primary melanomas to skin and/or lymph-node or disseminated organ metastases
We describe two effects, namely, suppression of the β-catenin pathway and inhibition of cell proliferation by miR34a, the wide array of microRNAs in these tumor-induced plasma extracellular vesicles (pEVs) point at a more complex function

Summary

Introduction

Recent work suggested that most malignant cancers secrete extracellular vesicles (EVs) into the periphery that have tumorigenic properties (Skog et al, 2008; Filipazzi et al, 2012; Peinado et al, 2012; Zomer et al, 2015). Cancer EVs, such as other EVs in plasma (pEVs), contain an array of miRNAs, mRNAs, and various cellular factors and are believed to be a rich source of biomarkers (Martins et al, 2013; Properzi et al, 2013; Melo et al, 2015). Their assumed detrimental function makes them an emerging therapeutic target in cancer therapy (Vader et al, 2014). We described an additional type of EV, budding directly from endosomal compartments (Muratori et al, 2009; Ostalecki et al, 2016), characteristically containing numerous cytokines, chemokines, and soluble factors (hereafter termed CCF), ADAM10/17 proteases, and a surface marker set that is different from exosomes (Lee et al, 2013, 2016)

Methods

Results

Conclusion