Faculty Opinions recommendation of The role of extracellular vesicles in the hallmarks of cancer and drug resistance.

Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

Download Full-text

Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21175951 ◽

2020 ◽

Vol 21 (17) ◽

pp. 5951

Author(s):

Laura Patras ◽

Marcel H. A. M. Fens ◽

Pieter Vader ◽

Arjan Barendrecht ◽

Alina Sesarman ◽

...

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles ◽

Hypoxia Inducible Factor ◽

B Cell Lymphoma ◽

Tumour Microenvironment ◽

Hypoxia Inducible Factor 1 ◽

Apoptotic Protein ◽

Donor Cells

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

Download Full-text

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms21072286 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2286 ◽

Cited By ~ 8

Author(s):

Stefania Raimondo ◽

Marzia Pucci ◽

Riccardo Alessandro ◽

Simona Fontana

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Immune Cell ◽

Immune Escape ◽

Immune Checkpoints ◽

Cancer Therapies ◽

Biological Functions ◽

Hallmarks Of Cancer ◽

Tumor Immune Escape

The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

Download Full-text

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

PROTEOMICS ◽

10.1002/pmic.201600375 ◽

2017 ◽

Vol 17 (23-24) ◽

pp. 1600375 ◽

Cited By ~ 25

Author(s):

Priya Samuel ◽

Muller Fabbri ◽

David Raul Francisco Carter

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles

Download Full-text

The Role of Extracellular Vesicles in the Hallmarks of Cancer and Drug Resistance

Cells ◽

10.3390/cells9051141 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1141 ◽

Cited By ~ 6

Author(s):

Cristina P. R. Xavier ◽

Hugo R. Caires ◽

Mélanie A. G. Barbosa ◽

Rui Bergantim ◽

José E. Guimarães ◽

...

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles ◽

Genetic Material ◽

Human Tumor ◽

Current Evidence ◽

Drug Resistant ◽

Intercellular Signaling ◽

Therapeutic Approaches ◽

Intercellular Exchange

Extracellular vesicles (EVs) mediate intercellular signaling and communication, allowing the intercellular exchange of proteins, lipids, and genetic material. Their recognized role in the maintenance of the physiological balance and homeostasis seems to be severely disturbed throughout the carcinogenesis process. Indeed, the modus operandi of cancer implies the highjack of the EV signaling network to support tumor progression in many (if not all) human tumor malignancies. We have reviewed the current evidence for the role of EVs in affecting cancer hallmark traits by: (i) promoting cell proliferation and escape from apoptosis, (ii) sustaining angiogenesis, (iii) contributing to cancer cell invasion and metastasis, (iv) reprogramming energy metabolism, (v) transferring mutations, and (vi) modulating the tumor microenvironment (TME) by evading immune response and promoting inflammation. Special emphasis was given to the role of EVs in the transfer of drug resistant traits and to the EV cargo responsible for this transfer, both between cancer cells or between the microenvironment and tumor cells. Finally, we reviewed evidence for the increased release of EVs by drug resistant cells. A timely and comprehensive understanding of how tumor EVs facilitate tumor initiation, progression, metastasis and drug resistance is instrumental for the development of innovative EV-based therapeutic approaches for cancer.

Download Full-text

Returning to the Hallmarks of Cancer: A Brief Review and Revision

Journal of Clinical Research and Reports ◽

10.31579/2690-1919/200 ◽

2021 ◽

Vol 9 (2) ◽

pp. 01-06

Author(s):

Kaushalendra Mani Tripathi

Keyword(s):

Drug Resistance ◽

Genome Instability ◽

Invasion And Metastasis ◽

Hallmarks Of Cancer ◽

Different Types ◽

Cellular Energetics ◽

Immune Destruction ◽

Near Future ◽

Proliferative Signaling

The hallmarks of cancer represent principals and mechanisms on which, different types of cancers function and proliferate, These principals which also include the revised edition include sustained proliferative signaling, Evading growth suppressors , avoiding immune destruction, enabling replicative immortality, tumor promoting inflammation, activating invasion and metastasis, Inducing angiogenesis, genome instability and mutation, resisting cell death, deregulating cellular energetics. This article reviews these hallmarks and suggests any additional hallmark that can be further investigated and integrated into the revised edition , Hanahan and Weinberg’s hallmark of cancer are great pillars of understanding for modern cancer study and are open to modification , making it easily approachable ,critiqued and adds the possibility of additions in the near future. The role of exosomes are discussed with the potential to categorize drug resistance as a separate hallmark to assist us in developing therapeutics that can counter or bypass these mechanisms that assist cancer cells to proliferate even further.

Download Full-text

Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms221910572 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10572

Author(s):

Maria Giovanna Scioli ◽

Sonia Terriaca ◽

Elena Fiorelli ◽

Gabriele Storti ◽

Giulia Fabbri ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Tumor Growth ◽

Tumor Progression ◽

Extracellular Vesicles ◽

Cross Talk ◽

Cell Populations ◽

Disease Relapse

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.

Download Full-text

The Role of Extracellular Vesicles in Mediating Resistance to Anticancer Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms22084166 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4166

Author(s):

Saeideh Maleki ◽

James Jabalee ◽

Cathie Garnis

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles ◽

Targeted Therapies ◽

Genetic Material ◽

Cell Communication ◽

Genetic Alterations ◽

Damage Repair ◽

Genetic Mechanisms ◽

Lipid Bilayer Vesicles

Although advances in targeted therapies have driven great progress in cancer treatment and outcomes, drug resistance remains a major obstacle to improving patient survival. Several mechanisms are involved in developing resistance to both conventional chemotherapy and molecularly targeted therapies, including drug efflux, secondary mutations, compensatory genetic alterations occurring upstream or downstream of a drug target, oncogenic bypass, drug activation and inactivation, and DNA damage repair. Extracellular vesicles (EVs) are membrane-bound lipid bilayer vesicles that are involved in cell–cell communication and regulating biological processes. EVs derived from cancer cells play critical roles in tumor progression, metastasis, and drug resistance by delivering protein and genetic material to cells of the tumor microenvironment. Understanding the biochemical and genetic mechanisms underlying drug resistance will aid in the development of new therapeutic strategies. Herein, we review the role of EVs as mediators of drug resistance in the context of cancer.

Download Full-text

The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms22083964 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3964

Author(s):

Danilo Marimpietri ◽

Irma Airoldi ◽

Angelo Corso Faini ◽

Fabio Malavasi ◽

Fabio Morandi

Keyword(s):

Immune Response ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Human Neuroblastoma ◽

Response To Chemotherapy ◽

Underlying Mechanisms ◽

Tumor In Childhood ◽

Molecular Components

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.

Download Full-text

Extracellular Vesicles as Mediators of Therapy Resistance in the Breast Cancer Microenvironment

Biomolecules ◽

10.3390/biom12010132 ◽

2022 ◽

Vol 12 (1) ◽

pp. 132

Author(s):

Mark Samuels ◽

Chiara Cilibrasi ◽

Panagiotis Papanastasopoulos ◽

Georgios Giamas

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Breast Cancer Cells ◽

Therapy Resistance ◽

Tumour Microenvironment ◽

Cancer Microenvironment ◽

Bidirectional Communication

Resistance to various therapies, including novel immunotherapies, poses a major challenge in the management of breast cancer and is the leading cause of treatment failure. Bidirectional communication between breast cancer cells and the tumour microenvironment is now known to be an important contributor to therapy resistance. Several studies have demonstrated that crosstalk with the tumour microenvironment through extracellular vesicles is an important mechanism employed by cancer cells that leads to drug resistance via changes in protein, lipid and nucleic acid cargoes. Moreover, the cargo content enables extracellular vesicles to be used as effective biomarkers for predicting response to treatments and as potential therapeutic targets. This review summarises the literature to date regarding the role of extracellular vesicles in promoting therapy resistance in breast cancer through communication with the tumour microenvironment.

Download Full-text