Prostate cancer exosomes as modulators of the tumor microenvironment

Shephard, Alex P.; Yeung, Vincent; Clayton, Aled; Webber, Jason P.

doi:10.20517/2394-4722.2017.32

Cited by 16 publications

(13 citation statements)

References 124 publications

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“…The importance of cellular crosstalk between PCa cells and to their tumor microenvironment (TME) to promote progression and metastasis has been documented in cancer research. Although a number of studies suggested the role of soluble factors in modulating TME, the potential role of exosomes in altering TME to induce tumor aggressiveness is gaining momentum [30,31]. Understanding the underlying mechanisms and cargo contents of exosomes-mediated transfer to and from PCa cells and TME at advanced stages of the disease will constitute a strong foundation on which novel and more specific therapeutic targets may be evolved.…”

Section: Discussionmentioning

confidence: 99%

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Gaballa

Ali

Mahmoud

et al. 2020

Cancers

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Although integrin alpha 2 subunit (ITGA2) mediates cancer progression and metastasis, its transfer by exosomes has not been investigated in prostate cancer (PCa). We aimed to determine the role of exosomal ITGA2 derived from castration-resistant PCa (CRPC) cells in promoting aggressive phenotypes in androgen receptor (AR)-positive cells. Exosomes were co-incubated with recipient cells and tested for different cellular assays. ITGA2 was enriched in exosomes derived from CRPC cells. Co-culture of AR-positive cells with CRPC-derived exosomes increased their proliferation, migration, and invasion by promoting epithelial-mesenchymal transition, which was reversed via ITGA2 knockdown or inhibition of exosomal uptake by methyl-β-cyclodextrin (MβCD). Ectopic expression of ITGA2 reproduced the effect of exosomal ITGA2 in PCa cells. ITGA2 transferred by exosomes exerted its effect within a shorter time compared to that triggered by its endogenous expression. The difference of ITGA2 protein expression in localized tumors and those with lymph node metastatic tissues was indistinguishable. Nevertheless, its abundance was higher in circulating exosomes collected from PCa patients when compared with normal subjects. Our findings indicate the possible role of the exosomal-ITGA2 transfer in altering the phenotype of AR-positive cells towards more aggressive phenotype. Thus, interfering with exosomal cargo transfer may inhibit the development of aggressive phenotype in PCa cells.

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Section: Discussionmentioning

confidence: 99%

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Gaballa

Ali

Mahmoud

et al. 2020

Cancers

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“…The large variety of EV subtypes also highlights the multifaceted nature of EV‐mediated communication, as the EVs vary also in their molecular content [1,4]. For example, EVs from cancerous prostate cells significantly differ in their cargo from those secreted by normal prostate epithelial cells [5], and differences in content and function have also been reported between EVs from prostate cancer cells of varying metastatic potential [6,7]. However, properties and functional effects have mostly been studied with EVs obtained from in vitro cell cultures.…”

Section: Introductionmentioning

confidence: 99%

Metabolic signature of extracellular vesicles depends on the cell culture conditions

Palviainen

Saari

Kärkkäinen

et al. 2019

J of Extracellular Vesicle

103

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One of the greatest bottlenecks in extracellular vesicle (EV) research is the production of sufficient material in a consistent and effective way using in vitro cell models. Although the production of EVs in bioreactors maximizes EV yield in comparison to conventional cell cultures, the impact of their cell growth conditions on EVs has not yet been established. In this study, we grew two prostate cancer cell lines, PC-3 and VCaP, in conventional cell culture dishes and in two-chamber bioreactors to elucidate how the growth environment affects the EV characteristics. Specifically, we wanted to investigate the growth condition-dependent differences by non-targeted metabolite profiling using liquid chromatography-mass spectrometry (LC-MS) analysis. EVs were also characterized by their morphology, size distribution, and EV protein marker expression, and the EV yields were quantified by NTA. The use of bioreactor increased the EV yield >100 times compared to the conventional cell culture system. Regarding morphology, size distribution and surface markers, only minor differences were observed between the bioreactor-derived EVs (BR-EVs) and the EVs obtained from cells grown in conventional cell cultures (C-EVs). In contrast, metabolomic analysis revealed statistically significant differences in both polar and non-polar metabolites when the BR-EVs were compared to the C-EVs. The results show that the growth conditions markedly affected the EV metabolite profiles and that metabolomics was a sensitive tool to study molecular differences of EVs. We conclude that the cell culture conditions of EV production should be standardized and carefully detailed in publications and care should be taken when EVs from different production platforms are compared with each other for systemic effects.

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“…The TME includes the diverse cells in the vicinity of the tumor, such as fibroblast, endothelial, immune, fat, neural, epithelial, and mesenchymal stem cells [29], as well as the soluble and insoluble factors, extracellular matrix and exosomes [30]. Although multiple studies have focused on the modulating role of soluble factors on the TME, new evidence for the potential role of exosomes in altering the TME and promoting aggressive tumor behavior has now been documented [31].…”

Section: The Soil/seed Analogy: Tumor Microenvironment (Tme) and Tumomentioning

confidence: 99%

Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

Saber

Ali

Gaballa

et al. 2020

Cells

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Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.

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Prostate cancer exosomes as modulators of the tumor microenvironment

Cited by 16 publications

References 124 publications

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Metabolic signature of extracellular vesicles depends on the cell culture conditions

Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

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