The itinerary of circulating miRNAs – implications for cancer progression and diagnosis

microRNAs (miRNAs) are non-coding RNAs that regulate gene expression and protect cells from foreign nucleic acids. miRNA is produced in the nucleus and processed in the cytoplasm. These small nucleic acid molecules are released from cells to the extracellular matrix (extracellular miRNA, ex-miRNA) and reach blood plasma (circulating miRNA). Circulating miRNA can also be detected in other biological fluids, such as saliva, cerebrospinal fluid or urine, and it is usually carried by proteins or extracellular vesicles. Argonaute-miRNA, or miRNA-lipoprotein complex, protect miRNA from being degraded. The entrance of extracellular miRNA into a target cell is mediated by endocytosis and membrane fusion of extracellular vesicles. Additionally, miRNA can also be delivered in high-density lipoproteins by means of interactions with scavenger receptors. miRNAs absorbed into a cell can act as tumour promoters (oncomirs), or suppressors by inhibiting the translation process of the target mRNAs, thus, affecting cells in the tumour microenvironment. miRNA can impact other cells by supporting tumour growth, promoting angiogenesis and modulating the immune system. Molecular high-throughput methods are employed to detect circulating miRNA, and a potentially helpful diagnostic test has been designed to characterise the cancer type. In this review, we aim to summarise the itinerary of miRNAs from a source cell to a target cell, as well as to show how this class of small nucleic acids participates in intercellular communication. Finally, we highlight examples of miRNAs usage as potential molecular markers and discuss treatment approaches in clinical trials.

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Role for extracellular vesicles in the tumour microenvironment

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0488 ◽

2017 ◽

Vol 373 (1737) ◽

pp. 20160488 ◽

Cited By ~ 20

Author(s):

Ana O'Loghlen

Keyword(s):

Cardiovascular Diseases ◽

Nucleic Acids ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Intercellular Communication ◽

Membrane Vesicles ◽

Tumour Microenvironment ◽

Cellular Behaviour ◽

Almost All ◽

Behaviour Changes

Extracellular vesicles (EVs) are small-membrane vesicles secreted by most cells types with the role to provide intercellular communication both locally and systemically. The transfer of their content between cells, which includes nucleic acids, proteins and lipids, confers the means for these interactions and induces significant cellular behaviour changes in the receiving cell. EVs are implicated in the regulation of numerous physiological and pathological processes, including development and neurological and cardiovascular diseases. Importantly, it has been shown that EV signalling is essential in almost all the steps necessary for the progress of carcinomas, from primary tumours to metastasis. In this review, we will focus on the latest findings for EV biology in relation to cancer progression and the tumour microenvironment. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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Detection of Prostate Cancer via IR Spectroscopic Analysis of Urinary Extracellular Vesicles: A Pilot Study

Membranes ◽

10.3390/membranes11080591 ◽

2021 ◽

Vol 11 (8) ◽

pp. 591

Author(s):

Xin-Le Yap ◽

Bayden Wood ◽

Teng-Aik Ong ◽

Jasmine Lim ◽

Bey-Hing Goh ◽

...

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Prostate Cancer Screening ◽

Principal Component ◽

Urine Samples ◽

Cancer Type ◽

Marker Proteins ◽

Novel Strategy ◽

Ir Spectroscopic

Extracellular vesicles (EVs) are membranous nanoparticles naturally released from living cells which can be found in all types of body fluids. Recent studies found that cancer cells secreted EVs containing the unique set of biomolecules, which give rise to a distinctive absorbance spectrum representing its cancer type. In this study, we aimed to detect the medium EVs (200–300 nm) from the urine of prostate cancer patients using Fourier transform infrared (FTIR) spectroscopy and determine their association with cancer progression. EVs extracted from 53 urine samples from patients suspected of prostate cancer were analyzed and their FTIR spectra were preprocessed for analysis. Characterization of morphology, particle size and marker proteins confirmed that EVs were successfully isolated from urine samples. Principal component analysis (PCA) of the EV’s spectra showed the model could discriminate prostate cancer with a sensitivity of 59% and a specificity of 81%. The area under curve (AUC) of FTIR PCA model for prostate cancer detection in the cases with 4–20 ng/mL PSA was 0.7, while the AUC for PSA alone was 0.437, suggesting the analysis of urinary EVs described in this study may offer a novel strategy for the development of a noninvasive additional test for prostate cancer screening.

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Extracellular vesicles in pancreatic cancer progression and therapies

Cell Death and Disease ◽

10.1038/s41419-021-04258-7 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Chao-Hui Chang ◽

Siim Pauklin

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Delayed Diagnosis ◽

Cell Types ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Cancer Hallmarks ◽

Pancreatic Cancers

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

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Current Applications and Discoveries Related to the Membrane Components of Circulating Tumor Cells and Extracellular Vesicles

Cells ◽

10.3390/cells10092221 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2221

Author(s):

Luis Enrique Cortés-Hernández ◽

Zahra Eslami-S ◽

Bruno Costa-Silva ◽

Catherine Alix-Panabières

Keyword(s):

Nucleic Acids ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Liquid Biopsy ◽

Clinical Information ◽

Phospholipid Membrane ◽

Membrane Composition ◽

Metastatic Cascade

In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.

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Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Cancers ◽

10.3390/cancers12030692 ◽

2020 ◽

Vol 12 (3) ◽

pp. 692 ◽

Cited By ~ 5

Author(s):

Geoffroy Walbrecq ◽

Odile Lecha ◽

Anthoula Gaigneaux ◽

Miriam R. Fougeras ◽

Demetra Philippidou ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Expression Patterns ◽

Tumour Microenvironment ◽

Extracellular Vesicle ◽

Growth Conditions ◽

Melanoma Cells ◽

Metabolic Reprogramming ◽

Mesenchymal Transition

Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted target IPO11 were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers.

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Proteomic Approach for Searching for Universal, Tissue-Specific, and Line-Specific Markers of Extracellular Vesicles in Lung and Colorectal Adenocarcinoma Cell Lines

International Journal of Molecular Sciences ◽

10.3390/ijms21186601 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6601

Author(s):

Svetlana Novikova ◽

Natalia Shushkova ◽

Tatiana Farafonova ◽

Olga Tikhonova ◽

Roman Kamyshinsky ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Biological Fluids ◽

Cancer Cell Lines ◽

Label Free ◽

Human Colon Cancer ◽

Tissue Specific ◽

Proteomic Approach

Tumor-derived extracellular vesicles (EVs), including exosomes, contain proteins that mirror the molecular landscape of producer cells. Being potentially detectible in biological fluids, EVs are of great interest for the screening of cancer biomarkers. To reveal universal, tissue-specific, and line-specific markers, we performed label-free mass spectrometric profiling of EVs originating from the human colon cancer cell lines Caco-2, HT29, and HCT-116, as well as from the lung cancer cell lines NCI-H23 and A549. A total of 651 proteins was identified in the EV samples using at least two peptides. These proteins were highly enriched in exosome markers. We found 11 universal, eight tissue-specific, and 29 line-specific markers, the levels of which were increased in EVs compared to the whole lysates. The EV proteins were involved in the EGFR, Rap1, integrin, and microRNA signaling associated with metastasis and cancer progression. An EV protein-based assay could be developed as a liquid biopsy tool.

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Tumour–adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0485 ◽

2017 ◽

Vol 373 (1737) ◽

pp. 20160485 ◽

Cited By ~ 22

Author(s):

Lucía Robado de Lope ◽

Olwen Leaman Alcíbar ◽

Ana Amor López ◽

Marta Hergueta-Redondo ◽

Héctor Peinado

Keyword(s):

Adipose Tissue ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Cell Types ◽

Tumour Microenvironment ◽

Tumour Cells ◽

Breast And Ovarian Cancer ◽

Tumour Metastasis ◽

Bone Marrow Derived Cells

During metastasis, tumour cells must communicate with their microenvironment by secreted soluble factors and extracellular vesicles. Different stromal cell types (e.g. bone marrow–derived cells, endothelial cells and fibroblasts) influence the growth and progression of tumours. In recent years, interest has extended to other cell types in the tumour microenvironment such as adipocytes and adipose tissue–derived mesenchymal stem cells. Indeed, obesity is becoming pandemic in some developing countries and it is now considered to be a risk factor for cancer progression. However, the true impact of obesity on the metastatic behaviour of tumours is still not yet fully understood. In this ‘Perspective’ article, we will discuss the potential influence of obesity on tumour metastasis, mainly in melanoma, breast and ovarian cancer. We summarize the main mechanisms involved with special attention to the role of extracellular vesicles in this process. We envisage that besides having a direct impact on tumour cells, obesity systemically preconditions the tumour microenvironment for future metastasis by favouring the formation of pro-inflammatory niches. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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Novel Aspects of Extracellular Vesicles as Mediators of Cancer-Associated Thrombosis

Cells ◽

10.3390/cells8070716 ◽

2019 ◽

Vol 8 (7) ◽

pp. 716 ◽

Cited By ~ 8

Author(s):

Vitor H. Almeida ◽

Araci M. R. Rondon ◽

Tainá Gomes ◽

Robson Q. Monteiro

Keyword(s):

Platelet Aggregation ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Neutrophil Extracellular Traps ◽

Cancer Type ◽

Initiator Protein ◽

Extracellular Traps ◽

Cancer Types ◽

Cancer Associated Thrombosis

The establishment of prothrombotic states during cancer progression is well reported but the precise mechanisms underlying this process remain elusive. A number of studies have implicated the presence of the clotting initiator protein, tissue factor (TF), in circulating tumor-derived extracellular vesicles (EVs) with thrombotic manifestations in certain cancer types. Tumor cells, as well as tumor-derived EVs, may activate and promote platelet aggregation by TF-dependent and independent pathways. Cancer cells and their secreted EVs may also facilitate the formation of neutrophil extracellular traps (NETs), which may contribute to thrombus development. Alternatively, the presence of polyphosphate (polyP) in tumor-derived EVs may promote thrombosis through a TF-independent route. We conclude that the contribution of EVs to cancer coagulopathy is quite complex, in which one or more mechanisms may take place in a certain cancer type. In this context, strategies that could attenuate the crosstalk between the proposed pro-hemostatic routes could potentially reduce cancer-associated thrombosis.

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Molecular Profile Study of Extracellular Vesicles for the Identification of Useful Small “Hit” in Cancer Diagnosis

Applied Sciences ◽

10.3390/app112210787 ◽

2021 ◽

Vol 11 (22) ◽

pp. 10787

Author(s):

Giusi Alberti ◽

Christian M. Sánchez-López ◽

Alexia Andres ◽

Radha Santonocito ◽

Claudia Campanella ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Cancer Metastasis ◽

Biological Fluids ◽

Cell Communication ◽

Response To Treatment ◽

Molecular Profile ◽

Cell Of Origin ◽

Liquid Biopsies ◽

Precision Therapy

Tumor-secreted extracellular vesicles (EVs) are the main mediators of cell-cell communication, permitting cells to exchange proteins, lipids, and metabolites in varying physiological and pathological conditions. They contain signature tumor-derived molecules that reflect the intracellular status of their cell of origin. Recent studies have shown that tumor cell-derived EVs can aid in cancer metastasis through the modulation of the tumor microenvironment, suppression of the immune system, pre-metastatic niche formation, and subsequent metastasis. EVs can easily be isolated from a variety of biological fluids, and their content makes them useful biomarkers for the diagnosis, prognosis, monitorization of cancer progression, and response to treatment. This review aims to explore the biomarkers of cancer cell-derived EVs obtained from liquid biopsies, in order to understand cancer progression and metastatic evolution for early diagnosis and precision therapy.

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Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2017.0066 ◽

2017 ◽

Vol 373 (1737) ◽

pp. 20170066 ◽

Cited By ~ 7

Author(s):

Ryan Charles Pink ◽

Areeg A. Elmusrati ◽

Daniel Lambert ◽

David Raul Francisco Carter

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Stromal Cells ◽

Royal Society ◽

Therapeutic Potential ◽

Tumour Microenvironment ◽

Therapeutic Benefit ◽

Scientific Meeting ◽

Biological Molecules

Cancer cells do not grow as an isolated homogeneous mass; tumours are, in fact, complex and heterogeneous collections of cancer and surrounding stromal cells, collectively termed the tumour microenvironment. The interaction between cancer cells and stromal cells in the tumour microenvironment has emerged as a key concept in the regulation of cancer progression. Understanding the intercellular dialogue in the tumour microenvironment is therefore an important goal. One aspect of this dialogue that has not been appreciated until recently is the role of extracellular vesicles (EVs). EVs are small vesicles released by cells under both normal and pathological conditions; they can transfer biological molecules between cells leading to changes in phenotype. EVs have emerged as important regulators of biological processes and can be dysregulated in diseases such as cancer; rapidly growing interest in their biology and therapeutic potential led to the Royal Society hosting a Scientific Meeting to explore the roles of EVs in the tumour microenvironment. This cross-disciplinary meeting explored examples of how aberrant crosstalk between tumour and stromal cells can promote cancer progression, and how such signalling can be targeted for diagnostic, prognostic and therapeutic benefit. In this review, and the special edition of Philosophical Transactions of the Royal Society B that follows, we will provide an overview of the content and outcomes of this exciting meeting. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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