Extracellular Vesicles (EVs) and Pancreatic Cancer: From the Role of EVs to the Interference with EV-Mediated Reciprocal Communication

Pancreatic cancer is malignant and the seventh leading cause of cancer-related deaths worldwide. However, chemotherapy and radiotherapy are—at most—moderately effective, indicating the need for new and different kinds of therapies to manage this disease. It has been proposed that the biologic properties of pancreatic cancer cells are finely tuned by the dynamic microenvironment, which includes extracellular matrix, cancer-associated cells, and diverse immune cells. Accumulating evidence has demonstrated that extracellular vesicles (EVs) play an essential role in communication between heterogeneous subpopulations of cells by transmitting multiplex biomolecules. EV-mediated cell–cell communication ultimately contributes to several aspects of pancreatic cancer, such as growth, angiogenesis, metastasis and therapeutic resistance. In this review, we discuss the role of extracellular vesicles and their cargo molecules in pancreatic cancer. We also present the feasibility of the inhibition of extracellular biosynthesis and their itinerary (release and uptake) for a new attractive therapeutic strategy against pancreatic cancer.

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Small extracellular vesicles: from mediating cancer cell metastasis to therapeutic value in pancreatic cancer

Cell Communication and Signaling ◽

10.1186/s12964-021-00806-y ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Wenjie Zhang ◽

Juan Xing ◽

Tian Liu ◽

Jie Zhang ◽

Zhujiang Dai ◽

...

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Extracellular Vesicles ◽

Cell Communication ◽

Bioactive Substances ◽

Early Biomarkers ◽

Pancreatic Cancer Cells ◽

Cell Metastasis ◽

Therapeutic Value ◽

Distant Organ

AbstractPancreatic cancer is a highly malignant tumor and, is extremely difficult to diagnose and treat. Metastasis is one of the critical steps in the development of cancer and uses cell to cell communication to mediate changes in the microenvironment. Small extracellular vesicles (sEVs)-carry proteins, nucleic acids and other bioactive substances, and are important medium for communication between cells. There are two primary steps in sVEs-mediated metastasis: communication between pancreatic cancer cells and their surrounding microenvironment; and the communication between primary tumor cells and distant organ cells in distant organs that promotes angiogenesis, reshaping extracellular matrix, forming immunosuppressive environment and other ways to form appropriate pre-metastasis niche. Here, we explore the mechanism of localization and metastasis of pancreatic cancer and use sEVs as early biomarkers for the detection and treatment of pancreatic cancer. Graphical Abstract

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Comparative Evaluation of Methods for Isolating Small Extracellular Vesicles Derived from Pancreatic Cells

10.21203/rs.3.rs-110539/v1 ◽

2020 ◽

Author(s):

Jie-Min Wang ◽

Yong-Jiang Li ◽

Jun-Yong Wu ◽

Jia-Xin Cai ◽

Jing Wen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Density Gradient ◽

Extracellular Vesicles ◽

Cell Communication ◽

Size Exclusion ◽

Density Gradient Ultracentrifugation ◽

Pancreatic Cancer Cells ◽

Co Precipitation ◽

Therapeutic Study

Abstract Background: Small extracellular vesicles (sEVs) are nanosized vesicles involved in cell-to-cell communication. sEVs have been widely studied for clinical applications such as early detection of diseases and as therapeutics. Various methods for sEVs isolation have been using, but different methods may result in different qualities of sEVs and impact downstream analysis and applications. Here, we compared current isolation methods and performed a comparative analysis of sEVs derived from pancreatic cancer cells.Results: Ultracentrifugation, ultrafiltration and co-precipitation as concentration methods were firstly evaluated for yield, size, morphology and protein level of pellets. Then, isolate sEVs obtained by four different purification methods: size exclusion chromatography, density gradient ultracentrifugation, ultracentrifugation, and immunoaffinity capturing, were analysed and compared. For the concentration process, ultracentrifugation method obtained high quality and concentration pellets. For the purification process, immunoaffinity capturing method obtained the purest sEVs with less contaminants, while density gradient ultracentrifugation-based method obtained sEVs with the smallest size. Proteomic analysis revealed distinct protein contents of purified sEVs. Conclusions: For isolating sEVs derived from pancreatic cancer cells, ultracentrifugation-based method is recommended for concentration of sEVs, density gradient ultracentrifugation-based method may be suitable for isolation of sEVs for therapeutic study, immunoaffinity capturing may be applied for studies exploring sEVs as biomarkers.

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Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors

Cells ◽

10.3390/cells9122719 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2719

Author(s):

Nunzia Novizio ◽

Raffaella Belvedere ◽

Emanuela Pessolano ◽

Alessandra Tosco ◽

Amalia Porta ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Soluble Form ◽

Annexin A1 ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Pancreatic Cancer Cells ◽

Formyl Peptide

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC.

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Cell‑to‑cell communication via extracellular vesicles among human pancreatic cancer cells derived from the same patient

Molecular Medicine Reports ◽

10.3892/mmr.2018.9376 ◽

2018 ◽

Cited By ~ 1

Author(s):

Mitsuru Chiba ◽

Shiori Kubota ◽

Ayaka Sakai ◽

Satoru Monzen

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

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The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer

Cancers ◽

10.3390/cancers13123040 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3040

Author(s):

Zainab Hussain ◽

Jeremy Nigri ◽

Richard Tomasini

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Pancreatic Tumors ◽

Mediated Communication ◽

Biological Impact ◽

Physiological Relevance ◽

Cellular Components ◽

Tumoral Cells

Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.

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Exosomes: the key of sophisticated cell–cell communication and targeted metastasis in pancreatic cancer

Cell Communication and Signaling ◽

10.1186/s12964-021-00808-w ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Huan Zhang ◽

Juan Xing ◽

Zhujiang Dai ◽

Daorong Wang ◽

Dong Tang

Keyword(s):

Pancreatic Cancer ◽

Cell Communication ◽

Ecological Niches ◽

Clinical Value ◽

Growth And Survival ◽

Pancreatic Cancer Cells ◽

Intercellular Communications ◽

Multiple Signaling ◽

Treatment And Diagnosis ◽

Methods Of Treatment

AbstractPancreatic cancer is one of the most common malignancies. Unfortunately, the lack of effective methods of treatment and diagnosis has led to poor prognosis coupled with a very high mortality rate. So far, the pathogenesis and progression mechanisms of pancreatic cancer have been poorly characterized. Exosomes are small vesicles secreted by most cells, contain lipids, proteins, and nucleic acids, and are involved in diverse functions such as intercellular communications, biological processes, and cell signaling. In pancreatic cancer, exosomes are enriched with multiple signaling molecules that mediate intercellular communication with control of immune suppression, mutual promotion between pancreas stellate cells and pancreatic cancer cells, and reprogramming of normal cells. In addition, exosomes can regulate the pancreatic cancer microenvironment and promote the growth and survival of pancreatic cancer. Exosomes can also build pre-metastatic micro-ecological niches and facilitate the targeting of pancreatic cancer. The ability of exosomes to load cargo and target allows them to be of great clinical value as a biomarker mediator for targeted drugs in pancreatic cancer.

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The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

Cells ◽

10.3390/cells10092316 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2316

Author(s):

Lucia Catani ◽

Michele Cavo ◽

Francesca Palandri

Keyword(s):

Extracellular Vesicles ◽

Immune Escape ◽

Myeloproliferative Neoplasms ◽

Cell Communication ◽

Bioactive Molecules ◽

Driver Genes ◽

Hematopoietic Stem ◽

Increased Risk ◽

Patients Experience

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.

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Platelet Extracellular Vesicles

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314644 ◽

2020 ◽

Author(s):

Florian Puhm ◽

Eric Boilard ◽

Kellie R. Machlus

Keyword(s):

Bone Marrow ◽

Synovial Fluid ◽

Nucleic Acids ◽

Extracellular Vesicles ◽

Cell Communication ◽

Biological Processes ◽

Vascular Integrity ◽

Pathological Conditions ◽

Broad Array

Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.

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Emerging role of extracellular vesicles in liver diseases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00183.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. G739-G749 ◽

Cited By ~ 10

Author(s):

Harmeet Malhi

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Cell Types ◽

Cell Responses ◽

Therapeutic Delivery ◽

Disease States ◽

Therapeutic Uses ◽

Potential Biomarker ◽

Secretion Pathways

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

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