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

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.

scholarly journals Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

2004 ◽  
Vol 24 (7) ◽  
pp. 2875-2889 ◽  
Author(s):  
Janine T. Erler ◽  
Christopher J. Cawthorne ◽  
Kaye J. Williams ◽  
Marianne Koritzinsky ◽  
Bradley G. Wouters ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid Tumors ◽  
Hypoxia Inducible Factor ◽  
Oxygen Deprivation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Drug Induced ◽  
Human Colon Cancer ◽  
Hypoxia Inducible Factor 1

ABSTRACT Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1α to a hypoxia-responsive element (positions −8484 to −8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.

scholarly journals Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology

2021 ◽  
Vol 22 (8) ◽  
pp. 4099
Author(s):  
Ioanna E. Stergiou ◽  
Konstantinos Kambas ◽  
Aikaterini Poulaki ◽  
Stavroula Giannouli ◽  
Theodora Katsila ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hypoxia Inducible Factor ◽  
Aberrant Expression ◽  
Myeloid Lineage ◽  
Hematopoietic Stem ◽  
Transcription Activity ◽  
Hypoxia Inducible Factor 1 ◽  
Abnormal Mitochondria

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target. Therefore, we examine the aberrant HIF-1 stabilization in BMs from MDS patients and controls (CTRLs). Using a nitroimidazole–indocyanine conjugate, we show that HIF-1 aberrant expression and transcription activity is oxygen independent, establishing the phenomenon of pseudohypoxia in MDS BM. Next, we examine mitochondrial quality and quantity along with levels of autophagy in the differentiating myeloid lineage isolated from fresh BM MDS and CTRL aspirates given that both phenomena are HIF-1 dependent. We show that the mitophagy of abnormal mitochondria and autophagic death are prominently featured in the MDS myeloid lineage, their severity increasing with intra-BM blast counts. Finally, we use in vitro cultured CD34+ HSCs isolated from fresh human BM aspirates to manipulate HIF-1 expression and examine its potential as a therapeutic target. We find that despite being cultured under 21% FiO2, HIF-1 remained aberrantly stable in all MDS cultures. Inhibition of the HIF-1α subunit had a variable beneficial effect in all <5%-intra-BM blasts-MDS, while it had no effect in CTRLs or in ≥5%-intra-BM blasts-MDS that uniformly died within 3 days of culture. We conclude that HIF-1 and pseudohypoxia are prominently featured in MDS pathobiology, and their manipulation has some potential in the therapeutics of benign MDS.

scholarly journals Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

2017 ◽  
Vol 373 (1737) ◽  
pp. 20170065 ◽  
Author(s):  
Priya Samuel ◽  
Laura Ann Mulcahy ◽  
Fiona Furlong ◽  
Helen O. McCarthy ◽  
Susan Ann Brooks ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Vesicles ◽  
Bystander Effect ◽  
Tumour Microenvironment ◽  
Ovarian Cancer Cells ◽  
Poor Overall Survival ◽  
Bystander Cells ◽  
Stressed Cells

Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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

Biomolecules ◽  
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.

scholarly journals A role of hypoxia inducible factor 1 alpha in Mouse Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency

2019 ◽  
Author(s):  
Darlah M. López-Rodríguez ◽  
Varvara Kirillov ◽  
Laurie T. Krug ◽  
Enrique A. Mesri ◽  
Samita Andreansky
Keyword(s):  
Oxygen Sensing ◽  
Acute Infection ◽  
Hypoxia Inducible Factor ◽  
Virus Production ◽  
Laboratory Mice ◽  
Hypoxia Inducible Factor 1 ◽  
Lytic Reactivation ◽  
Gammaherpesvirus 68

ABSTRACTThe hypoxia inducible factor 1 alpha (HIFIα) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV) such as Kaposi’ Sarcoma-associated Herpes Virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIFIα during the virus life cycle and its biological relevance in the context of host pathogenesis has been challenging due to the lack of animal models for human γHV. To study the role of HIFIα we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIFIα protein and HIFIα-responsive gene expression in permissive cells. Deletion of HIFIα reduces virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia regulatory element (HRE) such as viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. Intranasal infection of HIF1αLoxP/LoxP mice with MHV68 expressing Cre-recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Moreover, low oxygen conditions accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIFIα plays a critical role to promote virus replication. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.AUTHOR SUMMARYThe host oxygen sensing machinery including the HIF1α pathway is important during the viral life cycle of oncogenic gammaherpesviruses such as KSHV and EBV. However, due to the host specificity, the effects of HIF1α in herpes biology is limited to studies with in vitro systems. Here, we study the role of HIF1α using the mouse gammaherpesvirus 68 (MHV68) that readily infects laboratory mice. We demonstrate that MHV68 infection upregulates HIF1α during replication and inactivation of HIF1α transcriptional activity significantly decreased viral genes expression which results in impaired virus production in vitro. In vivo deletion of HIF1α impaired viral expansion during acute infection and affected reactivation from latency. These results show the importance of the interplay with the oxygen-sensing machinery in gammaherpesvirus infection and pathogenesis, placing the MHV68 mouse model as a unique platform to gain insight into this important aspect of oncogenic gamma-herpesviruses biology and to test HIF1α targeted therapeutics.

scholarly journals The Role of Extracellular Vesicles as Shuttles of RNA and Their Clinical Significance as Biomarkers in Hepatocellular Carcinoma

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 902
Author(s):  
Eva Costanzi ◽  
Carolina Simioni ◽  
Gabriele Varano ◽  
Cinzia Brenna ◽  
Ilaria Conti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Extracellular Vesicles ◽  
Tumor Metastasis ◽  
Biological Processes ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Donor Cells ◽  
Relevant Role

Extracellular vesicles (EVs) have attracted interest as mediators of intercellular communication following the discovery that EVs contain RNA molecules, including non-coding RNA (ncRNA). Growing evidence for the enrichment of peculiar RNA species in specific EV subtypes has been demonstrated. ncRNAs, transferred from donor cells to recipient cells, confer to EVs the feature to regulate the expression of genes involved in differentiation, proliferation, apoptosis, and other biological processes. These multiple actions require accuracy in the isolation of RNA content from EVs and the methodologies used play a relevant role. In liver, EVs play a crucial role in regulating cell–cell communications and several pathophysiological events in the heterogeneous liver class of cells via horizontal transfer of their cargo. This review aims to discuss the rising role of EVs and their ncRNAs content in regulating specific aspects of hepatocellular carcinoma development, including tumorigenesis, angiogenesis, and tumor metastasis. We analyze the progress in EV-ncRNAs’ potential clinical applications as important diagnostic and prognostic biomarkers for liver conditions.

scholarly journals Extracellular Vesicles: Novel Opportunities to Understand and Detect Neoplastic Diseases

2021 ◽  
pp. 030098582199932
Author(s):  
Laura Bongiovanni ◽  
Anneloes Andriessen ◽  
Marca H. M. Wauben ◽  
Esther N. M. Nolte-’t Hoen ◽  
Alain de Bruin
Keyword(s):  
Extracellular Vesicles ◽  
Biologically Active ◽  
Liquid Biopsies ◽  
Donor Cells ◽  
Recent Developments ◽  
Veterinary Pathology ◽  
Cell Components ◽  
Potential Applications ◽  
Intercellular Communications

With a size range from 30 to 1000 nm, extracellular vesicles (EVs) are one of the smallest cell components able to transport biologically active molecules. They mediate intercellular communications and play a fundamental role in the maintenance of tissue homeostasis and pathogenesis in several types of diseases. In particular, EVs actively contribute to cancer initiation and progression, and there is emerging understanding of their role in creation of the metastatic niche. This fact underlies the recent exponential growth in EV research, which has improved our understanding of their specific roles in disease and their potential applications in diagnosis and therapy. EVs and their biomolecular cargo reflect the state of the diseased donor cells, and can be detected in body fluids and exploited as biomarkers in cancer and other diseases. Relatively few studies have been published on EVs in the veterinary field. This review provides an overview of the features and biology of EVs as well as recent developments in EV research including techniques for isolation and analysis, and will address the way in which the EVs released by diseased tissues can be studied and exploited in the field of veterinary pathology. Uniquely, this review emphasizes the important contribution that pathologists can make to the field of EV research: pathologists can help EV scientists in studying and confirming the role of EVs and their molecular cargo in diseased tissues and as biomarkers in liquid biopsies.

scholarly journals Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Fan Zhao ◽  
Tao Zheng ◽  
Wenbin Gong ◽  
Jie Wu ◽  
Haohao Xie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Murine Colitis ◽  
Sting Pathway ◽  
Deficient Mice

AbstractCrohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.

scholarly journals The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

2016 ◽  
Vol 37 (6) ◽  
pp. 969-977 ◽  
Author(s):  
Osigbemhe Iyalomhe ◽  
Sabina Swierczek ◽  
Ngozi Enwerem ◽  
Yuanxiu Chen ◽  
Monica O. Adedeji ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1
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