International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Exosomes in Cancer Diagnosis and Therapy

by Aamir Ahmad

Int. J. Mol. Sci. 2022, 23(17), 9930; https://doi.org/10.3390/ijms23179930 - 1 Sep 2022

Cited by 2 | Viewed by 1684

Abstract

Cancer affects millions of people worldwide every year [...] Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

Research

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17 pages, 4406 KiB

Open AccessArticle

Delivery of miR-424-5p via Extracellular Vesicles Promotes the Apoptosis of MDA-MB-231 TNBC Cells in the Tumor Microenvironment

by Yueyuan Zhou, Yusuke Yamamoto, Fumitaka Takeshita, Tomofumi Yamamoto, Zhongdang Xiao and Takahiro Ochiya

Int. J. Mol. Sci. 2021, 22(2), 844; https://doi.org/10.3390/ijms22020844 - 15 Jan 2021

Cited by 53 | Viewed by 3912

Abstract

Programmed cell death ligand-1 (PD-L1) overexpressed on cancer cells has emerged as a key inhibitor that maintains the immunosuppressive microenvironment through its interaction with the PD-1 receptor in cancer. Here, we demonstrated that miR-424-5p delivery via extracellular vesicles (EVs) derived from adipose tissue-mesenchymal [...] Read more.

Programmed cell death ligand-1 (PD-L1) overexpressed on cancer cells has emerged as a key inhibitor that maintains the immunosuppressive microenvironment through its interaction with the PD-1 receptor in cancer. Here, we demonstrated that miR-424-5p delivery via extracellular vesicles (EVs) derived from adipose tissue-mesenchymal stromal cells (AT-MSCs) partly promotes proinflammation and enhances antitumor cytotoxicity in vitro and in vivo. Triple negative breast cancer (TNBC) exhibits increased expression of PD-L1, and PD-L1 is positively correlated with the overall survival of patients with TNBC. PD-L1 shows relatively higher expression in MDA-MB-231 (MM231) cells and can be downregulated by miR-424-5p. Furthermore, miR-424-5p transported by EVs can increase the secretion of proinflammatory cytokines, decrease the secretion of anti-inflammatory cytokines and promote the apoptosis of tumor cells. The intratumoral administration of miR-424-5p-EVs significantly slowed tumor growth. In conclusion, these results demonstrate that EVs may serve as a delivery system for novel immunotherapies for TNBC through the miR-424-5p/PD-L1 pathway. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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18 pages, 1769 KiB

Open AccessArticle

Impact of Extracellular Vesicle Isolation Methods on Downstream miRNA Analysis in Semen: A Comparative Study

by Marina Mercadal, Carolina Herrero, Olga López-Rodrigo, Manel Castells, Alexandre de la Fuente, Francesc Vigués, Lluís Bassas and Sara Larriba

Int. J. Mol. Sci. 2020, 21(17), 5949; https://doi.org/10.3390/ijms21175949 - 19 Aug 2020

Cited by 28 | Viewed by 5026

Abstract

Seminal plasma (SP) contains a unique concentration of miRNA, mostly contained in small extracellular vesicles (sEVs) such as exosomes, some of which could be clinically useful for diagnosis and/or prognosis of urogenital diseases such as prostate cancer (PCa). We optimized several exosome-EV isolation [...] Read more.

Seminal plasma (SP) contains a unique concentration of miRNA, mostly contained in small extracellular vesicles (sEVs) such as exosomes, some of which could be clinically useful for diagnosis and/or prognosis of urogenital diseases such as prostate cancer (PCa). We optimized several exosome-EV isolation technologies for their use in semen, evaluating EV purifying effectiveness and impact on the downstream analysis of miRNAs against results from the standard ultracentrifugation (UC) method to implement the use of SP sEV_miRNAs as noninvasive biomarkers for PCa. Our results evidenced that commercial kits designed to isolate exosomes/EVs from blood or urine are mostly applicable to SP, but showed quantitative and qualitative variability between them. ExoGAG 3500× g and the miRCURY Cell/Urine/CSF 1500× g methods resulted as equivalent alternative procedures to UC for isolating exosomes/sEVs from semen for nanoparticle characteristics and quality of RNA contained in vesicles. Additionally, the expression profile of the altered semen sEV-miRNAs in PCa varies depending on the EV isolation method applied. This is possibly due to different extraction techniques yielding different proportions of sEV subtypes. This is evidence that the exosome-EV isolation method has a significant impact on the analysis of the miRNAs contained within, with important consequences for their use as clinical biomarkers. Therefore, miRNA analysis results for EVs cannot be directly extrapolated between different EV isolation methods until clear markers for delineation between microvesicles and exosomes are established. However, EV extraction methodology affects combined models (semen exosome miRNA signatures plus blood Prostate specific antigen (PSA) concentration for PCa diagnosis) less; specifically our previously described (miR-142-3p + miR-142-5p + miR-223-3p + PSA) model functions as molecular marker from EVs from any of the three isolation methods, potentially improving the efficiency of PSA PCa diagnosis. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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16 pages, 1937 KiB

Open AccessArticle

Exosomal MicroRNAs in Pregnancy Provides Insight into a Possible Cure for Cancer

by Preenan Pillay, Kogi Moodley, Manu Vatish and Jagidesa Moodley

Int. J. Mol. Sci. 2020, 21(15), 5384; https://doi.org/10.3390/ijms21155384 - 29 Jul 2020

Cited by 13 | Viewed by 3680

Abstract

The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding “cancer-like” mechanisms in pregnancy could lead to the development of novel cancer therapeutics, however, little is understood [...] Read more.

The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding “cancer-like” mechanisms in pregnancy could lead to the development of novel cancer therapeutics, however, little is understood on how tumour and trophoblast cells recapitulate similar molecular mechanisms. Based on our observations from a previous study, it was not only evident that exosomal miRNAs are involved in the pathophysiology of preeclampsia but also contained cancer-specific miRNAs, which suggested that “pseudo-malignant-like” exosomal-mediated mechanisms exist in pregnancy. The presented study therefore aimed to identify exosomal miRNAs (exomiR) in pregnancy which can be repurposed towards preventing tumour metastasis and immunosuppression. It was identified that exomiR-302d-3p, exomiR-223-3p and exomiR-451a, commonly associated with cancer metastasis, were found to be highly expressed in pregnancy. Furthermore, computational merging and meta-analytical pathway analysis (DIANA miRPath) of significantly expressed exomiRs between 38 ± 1.9 vs. 30 ± 1.11 weeks of gestation indicated controlled regulation of biological pathways associated with cancer metastasis and immunosuppression. Therefore, the observations made in this study provide the experimental framework for the repurposing of exosomal miRNA molecular mechanisms in pregnancy towards treating and preventing cancer. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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17 pages, 3973 KiB

Open AccessArticle

Induction of Antitumor Immunity by Exosomes Isolated from Cryopreserved Cord Blood Monocyte-Derived Dendritic Cells

by Uyen Thi Trang Than, Huyen Thi Le, Diem Huong Hoang, Xuan-Hung Nguyen, Cuong Thi Pham, Khanh Thi Van Bui, Hue Thi Hong Bui, Phong Van Nguyen, Tu Dac Nguyen, Thu Thi Hoai Do, Thao Thi Chu, Anh Viet Bui, Liem Thanh Nguyen and Nhung Thi My Hoang

Int. J. Mol. Sci. 2020, 21(5), 1834; https://doi.org/10.3390/ijms21051834 - 6 Mar 2020

Cited by 25 | Viewed by 4886

Abstract

(1) Background: Dendritic cell (DC) vaccination has shown outstanding achievements in cancer treatment, although it still has some adverse side effects. Vaccination with DC-derived exosomes has been thought to overcome the side effects of the parental DCs. (2) Method: We performed the experiments [...] Read more.

(1) Background: Dendritic cell (DC) vaccination has shown outstanding achievements in cancer treatment, although it still has some adverse side effects. Vaccination with DC-derived exosomes has been thought to overcome the side effects of the parental DCs. (2) Method: We performed the experiments to check the ability of cryopreserved umbilical cord blood mononuclear cell-derived DCs (cryo CBMDCs) and their exosomes to prime allogeneic T cell proliferation and allogeneic peripheral blood mononuclear cell (alloPBMCs) cytotoxicity against A549 lung cancer cells. (3) Results: We found that both lung tumor cell lysate-pulsed DCs and their exosomes could induce allogeneic T cell proliferation. Moreover, alloPBMCs primed with tumor cell lysate-pulsed DCs and their exosomes have a greater cytotoxic activity against A549 cells compared to unprimed cells and cells primed with unpulsed DCs and their exosomes. (4) Conclusion: Tumor cell lysate-pulsed DCs and their exosomes should be considered to develop into a novel immunotherapeutic strategy—e.g., vaccines—for patients with lung cancer. Our results also suggested that cryo umbilical cord blood mononuclear cells source, which is a readily and available source, is effective for generation of allogeneic DCs and their exosomes will be material for vaccinating against cancer. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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Review

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15 pages, 1164 KiB

Open AccessReview

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

by Takanori Yamaguchi, Eiji Kawamoto, Arong Gaowa, Eun Jeong Park and Motomu Shimaoka

Int. J. Mol. Sci. 2021, 22(4), 1881; https://doi.org/10.3390/ijms22041881 - 13 Feb 2021

Cited by 17 | Viewed by 4669

Abstract

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such [...] Read more.

Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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23 pages, 1343 KiB

Open AccessReview

Exosomes: Cell-Derived Nanoplatforms for the Delivery of Cancer Therapeutics

by Hyosuk Kim, Eun Hye Kim, Gijung Kwak, Sung-Gil Chi, Sun Hwa Kim and Yoosoo Yang

Int. J. Mol. Sci. 2021, 22(1), 14; https://doi.org/10.3390/ijms22010014 - 22 Dec 2020

Cited by 94 | Viewed by 9347

Abstract

Exosomes are cell-secreted nanovesicles that naturally contain biomolecular cargoes such as lipids, proteins, and nucleic acids. Exosomes mediate intercellular communication, enabling the transfer biological signals from the donor cells to the recipient cells. Recently, exosomes are emerging as promising drug delivery vehicles due [...] Read more.

Exosomes are cell-secreted nanovesicles that naturally contain biomolecular cargoes such as lipids, proteins, and nucleic acids. Exosomes mediate intercellular communication, enabling the transfer biological signals from the donor cells to the recipient cells. Recently, exosomes are emerging as promising drug delivery vehicles due to their strong stability in blood circulation, high biocompatibility, low immunogenicity, and natural targeting ability. In particular, exosomes derived from specific types of cells can carry endogenous signaling molecules with therapeutic potential for cancer treatment, thus presenting a significant impact on targeted drug delivery and therapy. Furthermore, exosomes can be engineered to display targeting moieties on their surface or to load additional therapeutic agents. Therefore, a comprehensive understanding of exosome biogenesis and the development of efficient exosome engineering techniques will provide new avenues to establish convincing clinical therapeutic strategies based on exosomes. This review focuses on the therapeutic applications of exosomes derived from various cells and the exosome engineering technologies that enable the accurate delivery of various types of cargoes to target cells for cancer therapy. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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27 pages, 5756 KiB

Open AccessReview

Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases

by Abdul Q. Khan, Sabah Akhtar, Kirti S. Prabhu, Lubna Zarif, Rehan Khan, Majid Alam, Joerg Buddenkotte, Aamir Ahmad, Martin Steinhoff and Shahab Uddin

Int. J. Mol. Sci. 2020, 21(23), 9264; https://doi.org/10.3390/ijms21239264 - 4 Dec 2020

Cited by 27 | Viewed by 5267

Abstract

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been [...] Read more.

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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15 pages, 709 KiB

Open AccessReview

MiRNAs as Noninvasive Biomarkers and Therapeutic Agents of Pituitary Adenomas

by Ozal Beylerli, Narasimha M. Beeraka, Ilgiz Gareev, Valentin Pavlov, Guang Yang, Yanchao Liang and Gjumrakch Aliev

Int. J. Mol. Sci. 2020, 21(19), 7287; https://doi.org/10.3390/ijms21197287 - 2 Oct 2020

Cited by 24 | Viewed by 3108

Abstract

Pituitary adenoma (PA) accounts for 10–15% of all intracranial neoplasms. Even though most pituitary adenomas are benign, it is known that almost 35% of them exhibit an aggressive clinical course, including rapid proliferative activity and invasion of neighboring tissues. MicroRNAs (miRNAs) are short [...] Read more.

Pituitary adenoma (PA) accounts for 10–15% of all intracranial neoplasms. Even though most pituitary adenomas are benign, it is known that almost 35% of them exhibit an aggressive clinical course, including rapid proliferative activity and invasion of neighboring tissues. MicroRNAs (miRNAs) are short single-stranded RNA molecules that can influence post-transcriptional regulation by controlling target genes. Based on research data on miRNAs over the past 20 years, more than 60% of genes encoding human proteins are regulated by miRNAs, which ultimately control basic cellular mechanisms, including cell proliferation, differentiation, and apoptosis. Dysregulation of miRNAs has been observed in a number of diseases, especially tumors like PA. A majority of miRNAs are expressed within the cells themselves. However, the circulating miRNAs can be detected in several biological fluids of the human body. The identification of circulating miRNAs as new molecular markers may increase the ability to detect a tumor, predict the course of a disease, plan to choose suitable treatment, and diagnose at the earliest signs of impending neoplastic transformation. Therapy of PAs with aggressive behavior is a complex task. When surgery and chemotherapy fail, radiotherapy becomes the treatment of choice against PAs. Therefore, the possibility of implementing circulating miRNAs as innovative diagnostic and therapeutic agents for PA is one of the main exciting ideas. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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18 pages, 475 KiB

Open AccessReview

Exosomes: Insights from Retinoblastoma and Other Eye Cancers

by Kashmiri Lande, Jitesh Gupta, Ravi Ranjan, Manjari Kiran, Luis Fernando Torres Solis, Arturo Solís Herrera, Gjumrakch Aliev and Roy Karnati

Int. J. Mol. Sci. 2020, 21(19), 7055; https://doi.org/10.3390/ijms21197055 - 25 Sep 2020

Cited by 26 | Viewed by 6063

Abstract

Exosomes, considered as cell debris or garbage bags, have been later characterized as nanometer-sized extracellular double-membrane lipid bilayer bio-vesicles secreted by the fusion of vesicular bodies with the plasma membrane. The constituents and the rate of exosomes formation differ in different pathophysiological conditions. [...] Read more.

Exosomes, considered as cell debris or garbage bags, have been later characterized as nanometer-sized extracellular double-membrane lipid bilayer bio-vesicles secreted by the fusion of vesicular bodies with the plasma membrane. The constituents and the rate of exosomes formation differ in different pathophysiological conditions. Exosomes are also observed and studied in different parts of the eye, like the retina, cornea, aqueous, and vitreous humor. Tear fluid consists of exosomes that are shown to regulate various cellular processes. The role of exosomes in eye cancers, especially retinoblastoma (RB), is not well explored, although few studies point towards their presence. Retinoblastoma is an intraocular tumor that constitutes 3% of cases of cancer in children. Diagnosis of RB may require invasive procedures, which might lead to the spread of the disease to other parts. Due to this reason, better ways of diagnosis are being explored. Studies on the exosomes in RB tumors and serum might help designing better diagnostic approaches for RB. In this article, we reviewed studies on exosomes in the eye, with a special emphasis on RB. We also reviewed miRNAs expressed in RB tumor, serum, and cell lines and analyzed the targets of these miRNAs from the proteins identified in the RB tumor exosomes. hsa-miR-494 and hsa-miR-9, upregulated and downregulated, respectively in RB, have the maximum number of targets. Although oppositely regulated, they share the same targets in the proteins identified in RB tumor exosomes. Overall this review provides the up-to-date progress in the area of eye exosome research, with an emphasis on RB. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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32 pages, 1816 KiB

Open AccessReview

The Role of Exosomes in Stemness and Neurodegenerative Diseases—Chemoresistant-Cancer Therapeutics and Phytochemicals

by Narasimha M. Beeraka, Shalini H. Doreswamy, Surya P. Sadhu, Asha Srinivasan, Rajeswara Rao Pragada, SubbaRao V. Madhunapantula and Gjumrakch Aliev

Int. J. Mol. Sci. 2020, 21(18), 6818; https://doi.org/10.3390/ijms21186818 - 17 Sep 2020

Cited by 31 | Viewed by 6813

Abstract

Exosomes exhibit a wide range of biological properties and functions in the living organisms. They are nanometric vehicles and used for delivering drugs, as they are biocompatible and minimally immunogenic. Exosomal secretions derived from cancer cells contribute to metastasis, immortality, angiogenesis, tissue invasion, [...] Read more.

Exosomes exhibit a wide range of biological properties and functions in the living organisms. They are nanometric vehicles and used for delivering drugs, as they are biocompatible and minimally immunogenic. Exosomal secretions derived from cancer cells contribute to metastasis, immortality, angiogenesis, tissue invasion, stemness and chemo/radio-resistance. Exosome-derived microRNAs (miRNAs) and long non-coding RNAs (lnc RNAs) are involved in the pathophysiology of cancers and neurodegenerative diseases. For instance, exosomes derived from mesenchymal stromal cells, astrocytes, macrophages, and acute myeloid leukemia (AML) cells are involved in the cancer progression and stemness as they induce chemotherapeutic drug resistance in several cancer cells. This review covered the recent research advances in understanding the role of exosomes in cancer progression, metastasis, angiogenesis, stemness and drug resistance by illustrating the modulatory effects of exosomal cargo (ex. miRNA, lncRNAs, etc.) on cell signaling pathways involved in cancer progression and cancer stem cell growth and development. Recent reports have implicated exosomes even in the treatment of several cancers. For instance, exosomes-loaded with novel anti-cancer drugs such as phytochemicals, tumor-targeting proteins, anticancer peptides, nucleic acids are known to interfere with drug resistance pathways in several cancer cell lines. In addition, this review depicted the need to develop exosome-based novel diagnostic biomarkers for early detection of cancers and neurodegenerative disease. Furthermore, the role of exosomes in stroke and oxidative stress-mediated neurodegenerative diseases including Alzheimer’s disease (AD), and Parkinson’s disease (PD) is also discussed in this article. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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16 pages, 266 KiB

Open AccessReview

Milk Exosomes: Perspective Agents for Anticancer Drug Delivery

by Sergey Sedykh, Anna Kuleshova and Georgy Nevinsky

Int. J. Mol. Sci. 2020, 21(18), 6646; https://doi.org/10.3390/ijms21186646 - 11 Sep 2020

Cited by 62 | Viewed by 6661

Abstract

Exosomes are biological nanovesicles that participate in intercellular communication by transferring biologically active chemical compounds (proteins, microRNA, mRNA, DNA, and others). Due to their small size (diameter 40–100 nm) and high biological compatibility, exosomes are promising delivery tools in personalized therapy. Because artificial [...] Read more.

Exosomes are biological nanovesicles that participate in intercellular communication by transferring biologically active chemical compounds (proteins, microRNA, mRNA, DNA, and others). Due to their small size (diameter 40–100 nm) and high biological compatibility, exosomes are promising delivery tools in personalized therapy. Because artificial exosome synthesis methods are not developed yet, the urgent task is to develop an effective and safe way to obtain exosomes from natural sources. Milk is the only exosome-containing biological fluid that is commercially available. In this regard, milk exosomes are unique and promising candidates for new therapeutic approaches to treating various diseases, including cancer. The appearance of side effects during the use of cytotoxic and cytostatic agents is among the main problems in cancer chemotherapy. According to this, the targeted delivery of chemotherapeutic agents can be a potential solution to the toxic effect of chemotherapy. The ability of milk exosomes to carry out biologically active substances to the cell makes them promising tools for oral delivery of chemotherapeutic agents. This review is devoted to the methods of milk exosome isolation, their biological components, and prospects for their use in cancer treatment. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

21 pages, 856 KiB

Open AccessReview

Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis

by Cristian Muresanu, Siva G. Somasundaram, Sergey V. Vissarionov, Luis Fernando Torres Solis, Arturo Solís Herrera, Cecil E. Kirkland and Gjumrakch Aliev

Int. J. Mol. Sci. 2020, 21(18), 6521; https://doi.org/10.3390/ijms21186521 - 7 Sep 2020

Cited by 7 | Viewed by 5302

Abstract

In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over [...] Read more.

In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time—avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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24 pages, 395 KiB

Open AccessReview

Extracellular Vesicles: New Endogenous Shuttles for miRNAs in Cancer Diagnosis and Therapy?

by Stefano Martellucci, Nicola Salvatore Orefice, Adriano Angelucci, Amalia Luce, Michele Caraglia and Silvia Zappavigna

Int. J. Mol. Sci. 2020, 21(18), 6486; https://doi.org/10.3390/ijms21186486 - 4 Sep 2020

Cited by 42 | Viewed by 7075

Abstract

Extracellular Vesicles (EVs) represent a heterogeneous population of membranous cell-derived structures, including cargo-oriented exosomes and microvesicles. EVs are functionally associated with intercellular communication and play an essential role in multiple physiopathological conditions. Shedding of EVs is frequently increased in malignancies and their content, [...] Read more.

Extracellular Vesicles (EVs) represent a heterogeneous population of membranous cell-derived structures, including cargo-oriented exosomes and microvesicles. EVs are functionally associated with intercellular communication and play an essential role in multiple physiopathological conditions. Shedding of EVs is frequently increased in malignancies and their content, including proteins and nucleic acids, altered during carcinogenesis and cancer progression. EVs-mediated intercellular communication between tumor cells and between tumor and stromal cells can modulate, through cargo miRNA, the survival, progression, and drug resistance in cancer conditions. These consolidated suggestions and EVs’ stability in bodily fluids have led to extensive investigations on the potential employment of circulating EVs-derived miRNAs as tumor biomarkers and potential therapeutic vehicles. In this review, we highlight the current knowledge about circulating EVs-miRNAs in human cancer and the application limits of these tools, discussing their clinical utility and challenges in functions such as in biomarkers and instruments for diagnosis, prognosis, and therapy. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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19 pages, 1292 KiB

Open AccessReview

The Malignant Role of Exosomes as Nanocarriers of Rare RNA Species

by Alina-Andreea Zimta, Olafur Eysteinn Sigurjonsson, Diana Gulei and Ciprian Tomuleasa

Int. J. Mol. Sci. 2020, 21(16), 5866; https://doi.org/10.3390/ijms21165866 - 15 Aug 2020

Cited by 21 | Viewed by 4256

Abstract

Nowadays, advancements in the oncology sector regarding diagnosis methods allow us to specifically detect an increased number of cancer patients, some of them in incipient stages. However, one of the main issues consists of the invasive character of most of the diagnosis protocols [...] Read more.

Nowadays, advancements in the oncology sector regarding diagnosis methods allow us to specifically detect an increased number of cancer patients, some of them in incipient stages. However, one of the main issues consists of the invasive character of most of the diagnosis protocols or complex medical procedures associated with it, that impedes part of the patients to undergo routine checkups. Therefore, in order to increase the number of cancer cases diagnosed in incipient stages, other minimally invasive alternatives must be considered. The current review paper presents the value of rare RNA species isolated from circulatory exosomes as biomarkers of diagnosis, prognosis or even therapeutic intervention. Rare RNAs are most of the time overlooked in current research in favor of the more abundant RNA species like microRNAs. However, their high degree of stability, low variability and, for most of them, conservation across species could shift the interest toward these types of RNAs. Moreover, due to their low abundance, the variation interval in terms of the number of sequences with differential expression between samples from healthy individuals and cancer patients is significantly diminished and probably easier to interpret in a clinical context. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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24 pages, 2304 KiB

Open AccessReview

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

by Yong Weon Yi, Jun Ho Lee, Sang-Yeob Kim, Chan-Gi Pack, Dae Hyun Ha, Sang Rae Park, Jinkwon Youn and Byong Seung Cho

Int. J. Mol. Sci. 2020, 21(2), 665; https://doi.org/10.3390/ijms21020665 - 19 Jan 2020

Cited by 140 | Viewed by 12229

Abstract

Exosomes are nano-sized membranous vesicles produced by nearly all types of cells. Since exosome-like vesicles are produced in an evolutionarily conserved manner for information and function transfer from the originating cells to recipient cells, an increasing number of studies have focused on their [...] Read more.

Exosomes are nano-sized membranous vesicles produced by nearly all types of cells. Since exosome-like vesicles are produced in an evolutionarily conserved manner for information and function transfer from the originating cells to recipient cells, an increasing number of studies have focused on their application as therapeutic agents, drug delivery vehicles, and diagnostic targets. Analysis of the in vivo distribution of exosomes is a prerequisite for the development of exosome-based therapeutics and drug delivery vehicles with accurate prediction of therapeutic dose and potential side effects. Various attempts to evaluate the biodistribution of exosomes obtained from different sources have been reported. In this review, we examined the current trends and the advantages and disadvantages of the methods used to determine the biodistribution of exosomes by molecular imaging. We also reviewed 29 publications to compare the methods employed to isolate, analyze, and label exosomes as well as to determine the biodistribution of labeled exosomes. Full article

(This article belongs to the Special Issue Exosomes in Cancer Diagnosis and Therapy)

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