Organ-Specific Uptake of Extracellular Vesicles Secreted by Urological Cancer Cells.

Johannes Linxweiler,Philip Zeuschner,Anja Kolbinger,Michael Stöckle,Kerstin Junker,Matthias Saar,Dirk Himbert

doi:10.3390/cancers13194937

Abstract

Simple SummaryExtracellular vesicles (EVs) play an important role in the communication of cancer cells with their local microenvironment and distant organ systems, in order to promote a supportive tumor microenvironment, as well as to prepare premetastatic niches. In this study, we aimed to analyze if the EVs secreted by urological cancer cells are taken up by specific organ systems, depending on their origin. After the intravenous injection of fluorescence-labeled EVs from benign and malignant prostate, kidney, and bladder cells in immunodeficient mice, their organs were harvested and analyzed for the presence of fluorescent EVs. We could show that (i) EVs are taken up not entirely organ-specifically but in different amounts, depending on their origin; (ii) EVs from malignant cells are taken up more efficiently than EVs from benign cells; and (iii) EVs are taken up very fast. These observations hint to an organotropism in EV uptake, which needs to be further investigated.Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In this study, we analyzed the organ-specific uptake of EVs secreted by urological cancer cells using an innovative in-vivo approach. EVs from benign and malignant prostate, kidney, and bladder cells were isolated using ultracentrifugation, fluorescence-labeled and injected intravenously in immunodeficient mice. After 12 or 24 h, the animals were sacrificed, their organs were harvested and analyzed for the presence of EVs by high-resolution fluorescence microscopy. Across all entities, EVs were taken up fast (12 h > 24 h), and EVs from malignant cells were taken up more efficiently than EVs from benign cells. Though not entirely organ-specific, EVs were incorporated in different amounts, depending on the entity (prostate: lung > liver > brain; kidney: brain > lung > liver; bladder: lung > liver > brain). EV uptake in other organs than lung, liver, brain, and spleen was not observed. Our results suggest a role of EVs in the formation of premetastatic niches and an organotropism in EV uptake, which have to be examined in more detail in further studies.

Highlights

The observation that malignant tumors preferentially metastasize into specific organ systems is called organotropism—a phenomenon known for a very long time in cancer biology but still incompletely understood at the molecular level
Prostate cancer affects the bone and lymph nodes in more or less all cases of metastatic disease, renal cell carcinoma most often metastasizes into the bone and brain, and urothelial carcinoma of the urinary bladder tends to spread to lymph nodes, bone, and lungs [1,2,3]
We examined, in detail, the organ-specific uptake of intravenously injected extracellular vesicles (EVs) from different urological cell lines but did not analyze what molecular processes these EVs induce in their target organs and whether their uptake leads to the formation of premetastatic niches and a stimulation of metastatic spread

Summary

Introduction

The observation that malignant tumors preferentially metastasize into specific organ systems is called organotropism—a phenomenon known for a very long time in cancer biology but still incompletely understood at the molecular level. One long-standing and famous explanation of organotropism in cancer is the seed-and-soil hypothesis by the British surgeon and oncologist Stephen Paget [4] He compared tumor cells circulating in the bloodstream to seeds that need to find a fertile soil, i.e., a supportive microenvironment in distant organ systems that allows them to extravasate, survive, and establish new metastatic foci. Several elegant studies have been performed, which identified extracellular vesicles (EVs) secreted by primary tumor cells as further important players in the process of organotropic metastasis [9,10,11] They contribute to this process, for example, by inducing vascular leakiness, inhibiting anti-tumor immune response, educating stromal cells, or altering the extracellular matrix in the so-called premetastatic niches in metastatic target organs [12]

Objectives

Methods

Results

Conclusion