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

Abstract

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.

Bidirectional Communication Between the Brain and Other Organs: The Role of Extracellular Vesicles

“…Finally, whether EVs generated in vitro could be used as next-generation therapeutic approaches, such as alternative viruses or synthetic nanovectors, for organ-targeted biotherapies. Addressing the first challenge requires to find organ-specific EVs or craft strategies to use novel technologies to label organ-specific EVs in appropriate animal models (Chand et al 2020 ; Linxweiler et al 2021 ). The next challenge may require the generation of genetic animal models with organ-specific defects in the production of EVs.…”

Prostate cancer-derived small extracellular vesicle proteins: the hope in diagnosis, prognosis, and therapeutics

“…These PCa-derived sEVs may play a significant role in regulating communication between tumor cells, the tumor microenvironment (TME), and distant metastasis sites through both autocrine and paracrine mechanisms [ 74 ]. This promotes signal transduction and the formation of pre-metastasis niches (PMNs), ultimately contributing to tumor development and metastasis [ 75 ]. Notably, cancer cells require sufficient oxygen to grow, and studies indicate that cancer-derived sEVs serve as carriers of various proteins, RNAs and lipids, which re-program the secretion of growth factors and cytokines by endothelial cells, activate signaling pathways, and prompt perivascular cell migration and the formation of new blood vessels [ 76 ].…”

Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context

“…Exosomes secreted by metastatic cancer cells could be preferentially uptaken by specific host organ to organize the pre-metastatic niche via upregulation of proinflammatory gene expression and immunosuppressive cytokine, which leads to organotropic metastasis [ 98 ]. The amount and origin of EVs affect their organ-specific uptake during metastasis as the rate of EV uptake secreted by malignant cancer cells is more than benign cancer cells [ 99 ]. It has also been shown that targeting the integrins α6β4 and αvβ5 of exosomes reduced their uptake and metastasis to lung and liver, respectively [ 83 ].…”