Extracellular vesicle interactions with the external and internal exposome in mediating carcinogenesis

The influence of environmental factors on an individual, from conception onwards, is defined as the exposome. It can be categorized into the external exposome, which includes external factors such as air pollution, chemical contaminants, and diet, and the internal exposome, which is unique to an individual, and involves age, physiology, and their genetic profile. The effect of external exposures on the internal exposome, or genetic profile, can be determined through omics analyses. However, this is often compromised due to low sample quantity and cost. Therefore, identification of other factors that can provide an insight into the cellular profile of an individual, provides an exciting avenue, and an emerging field is that of extracellular vesicles (EVs). Recently, our understanding of how cells can communicate with each other has shifted to recognise the role of EVs. EVs are secreted by all living cells, and have been identified in all biological fluids studied so far. They transport bioactive molecules (e.g., proteins, miRNAs, and DNA), and their release can be regulated by the cellular microenvironment. Analysis of EVs in respond to environmental factors might provide novel insights into the role of tumour EVs in carcinogenesis. Not only will EVs give some insight into the tumour cells themselves but they will also provide a better understanding of how cells communicate with one another, contributing to cancer progression. Moreover, characterising the content and functions of tumour-derived EVs has the potential to overcome the current challenges to improve cancer patient outcomes. For example, the identification of EVs targets for therapeutic interventions and tumour EVs biomarkers could facilitate the development of early screening for several cancers. The aim of this review, thus, is to discuss the overall role of EVs in response to the various external and internal signals in cancer. We will specifically highlight the biogenesis, secretion, and content of EVs in response to oncogenic transformation and metabolic regulators in cancer

Cross‐Talk Between Hypoxia and the Tumour via Exosomes

Cancer is one of the leading causes of death worldwide, and this is often attributed to the nonspecific symptoms. Additionally, delayed diagnosis and a lack of treatment options negatively impact prognosis. Recently, the role of extracellular vesicles in cancer progression, specifically, in metastasis and in the capacity of several tumours to invade and colonise specific organs has been established. Reduced oxygen tension due to imbalanced oxygen supply and consumption is termed hypoxia and is one of the most commonly observed features in solid tumours. This is often correlated with poor cancer prognosis. Several reports have established that low oxygen tension (i.e. hypoxia) is a common feature of the tumour microenvironment often enhancing the process of epithelial‐to‐mesenchymal transition (EMT) in cancer cells, thus promoting tumourigenesis and metastasis. Furthermore, hypoxia increases the number of extracellular vesicles released from cancer cells and also modifies their bioactivity and function. The aim of this chapter is to review the association between the tumour microenvironment and extracellular vesicles (EVs), focusing on a specific subpopulation of EVs of endocytic origin, termed exosomes

Extracellular Vesicle-Associated miRNAs and Chemoresistance: A Systematic Review

Cancer is a leading public health issue globally, and diagnosis is often associated with poor outcomes and reduced patient survival. One of the major contributors to the fatality resultant of cancer is the development of resistance to chemotherapy, known as chemoresistance. Furthermore, there are limitations in our ability to identify patients that will respond to therapy, versus patients that will develop relapse, and display limited or no response to treatment. This often leads to patients being subjected to multiple futile treatment cycles, and results in a reduction in their quality of life. Therefore, there is an urgent clinical need to develop tools to identify patients at risk of chemoresistance, and recent literature has suggested that small extracellular vesicles, known as exosomes, may be a vital source of information. Extracellular vesicles (EV) are membrane bound vesicles, involved in cell-cell communication, through the transfer of their cargo, which includes proteins, lipids, and miRNAs. A defined exploration strategy was performed in this systematic review in order to provide a compilation of key EV miRNAs which may be predictive of chemoresistance. We searched the PubMed, Science Direct, and Scopus databases using the following keywords: Extracellular vesicles OR exosomes OR EVs AND miRNA AND Chemotherapy OR Chemoresistance OR Cancer Recurrence from 2010 to 2020. We found 31 articles that reported key EV-associated miRNAs involved in cancer recurrence related to chemoresistance. Interestingly, multiple studies of the same tumor type identified different microRNAs, and few studies identified the same ones. Specifically, miR-21, miR-222, and miR-155 displayed roles in response to chemotherapy, and were found to be common in colorectal cancer, ovarian cancer, breast cancer, and diffuse large B cell lymphoma patients (DLBCL). miR-21 and miR-222 were found to favour the development of chemoresistance, whereas miR-155 exhibited a contrasting role, depending on the type of primary tumor. Whilst high levels of miR-155 were found to correlate with chemotherapy resistance in DLBCL, it was found to be predictive of an effective response towards chemotherapy in breast cancer. Thus, further research regarding the roles of these miRNAs would be beneficial in terms of designing novel tools to counteract the progression of cancer in a not-to-distant future

Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression

Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a 'fingerprint' of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression

Ovarian-Cancer-Associated Extracellular Vesicles: Microenvironmental Regulation and Potential Clinical Applications

Ovarian cancer (OC) is one of the most diagnosed gynecological cancers in women. Due to the lack of effective early stage screening, women are more often diagnosed at an advanced stage; therefore, it is associated with poor patient outcomes. There are a lack of tools to identify patients at the highest risk of developing this cancer. Moreover, early detection strategies, therapeutic approaches, and real-time monitoring of responses to treatment to improve survival and quality of life are also inadequate. Tumor development and progression are dependent upon cell-to-cell communication, allowing cancer cells to re-program cells not only within the surrounding tumor microenvironment, but also at distant sites. Recent studies established that extracellular vesicles (EVs) mediate bi-directional communication between normal and cancerous cells. EVs are highly stable membrane vesicles that are released from a wide range of cells, including healthy and cancer cells. They contain tissue-specific signaling molecules (e.g., proteins and miRNA) and, once released, regulate target cell phenotypes, inducing a pro-tumorigenic and immunosuppressive phenotype to contribute to tumor growth and metastasis as well as proximal and distal cell function. Thus, EVs are a “fingerprint” of their cell of origin and reflect the metabolic status. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, EVs can be potent therapeutic agents. This review examines the potential role of EVs in the different aspects of the tumor microenvironment in OC, as well as their application in diagnosis, delivery of therapeutic agents, and disease monitoring

Extracellular vesicles and preeclampsia : current knowledge and future research directions

Preeclampsia (PE) is associated with long-term morbidity in mothers and lifelong morbidities for their children, ranging from cerebral palsy and cognitive delay in preterm infants, to hypertension, diabetes and obesity in adolescents and young adults. There are several processes that are critical for development of materno-fetal exchange, including establishing adequate perfusion of the placenta by maternal blood, and the formation of the placental villous vascular tree. Recent studies provide persuasive evidence that placenta-derived extracellular vesicles (EVs) represent a significant intercellular communication pathway, and that they may play an important role in placental and endothelial cell (both fetal and maternal) function. These functions are known to be altered in PE. EVs can carry and transport a wide range of bioactive molescules that have potential to be used as biomarkers and therapeutic delivery tools for PE. EV content is often parent cell specific, thus providing an insight or “thumbprint” of the intracellular environment of the originating cell (e.g., human placenta). EV have been identified in plasma under both normal and pathological conditions, including PE. The concentration of EVs and their content in plasma has been reported to increase in association with disease severity and/or progression. Placenta-derived EVs have been identified in maternal plasma during normal pregnancy and PE pregnancies. They contain placenta-specific proteins and miRNAs and, as such, may be differentiated from maternally-derived EVs. The aim of this review, thus, is to describe the potential roles of EVs in preecmpatic pregnancies, focussing on EVs secreted from placental cells. The biogenesis, specificity of placental EVs, and methods used to characterise EVs in the context of PE pregnancies will be also discussed

Trophoblast Dependent Secretion of Stannocalcin-1 and Interleukin-8 by Endothelial Cells and Their Role as Possible Mediators of Spiral Artery Remodeling

Around 50% of endometriosis risk is due to genetic factors. Ten genome-wide significant loci have been associated with endometriosis, but most are located in intergenic regions of the genome. To understand how transcriptomic profiles are perturbed by genetic variants, we conducted a transcriptome-wide study of endometrium, fat and endometrial disease tissue from 190 endometriosis cases and 90 controls