26 research outputs found
Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance.
The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer
AXL Promotes Metformin-Induced Apoptosis Through Mediation of Autophagy by Activating ROS-AMPK-ULK1 Signaling in Human Esophageal Adenocarcinoma
AXL receptor tyrosine kinase promotes an invasive phenotype and chemotherapy resistance in esophageal adenocarcinoma (EAC). AXL has been implicated in the regulation of autophagy, but the underlying molecular mechanism remains poorly understood. Herein, we investigate the mechanistic role of AXL in autophagy as well as metformin-induced effects on the growth and survival of EAC. We demonstrate that AXL mediates autophagic flux through activation of AMPK-ULK1 signaling in a reactive oxygen species (ROS)-dependent mechanism by glucose starvation. AXL positively regulates basal cellular ROS levels without significantly affecting mitochondrial ROS production in EAC cells. Pharmacological inhibition of cellular ROS using Trolox abrogates glucose starvation-induced AMPK signaling and autophagy. We demonstrate that AXL expression is required for metformin-induced apoptosis in EAC cells in vitro. The apoptosis induction by metformin is markedly attenuated by inhibition of autophagy through genetic silencing of Beclin1 or ATG7 autophagy mediators, thereby confirming the requirement of intact autophagy for enhancing metformin-induced apoptosis in EAC cells. Our data indicate that metformin-induced autophagy displays a pro-apoptotic function in EAC cells. We show that the metformin-induced suppression of tumor growth in vivo is highly dependent on AXL expression in a tumor xenograft mouse model of EAC. We demonstrate that AXL promotes metformin-induced apoptosis through activation of autophagy in EAC. AXL may be a valuable biomarker to identify tumors that are sensitive to metformin. Therefore, AXL expression could inform the selection of patients for future clinical trials to evaluate the therapeutic efficacy of metformin in EAC
Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.Open access publication is supported by Qatar National Library
Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy
Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.This study was supported by a PI grant from Sidra Medicine (5071012001) to Mohammad Haris. Ajaz A. Bhat is supported by Sidra Medicine internal grant (5011041002) and Ramalinga swami (Grant number: D.O.NO.BT/HRD/35/02/2006) Fellowship to Muzafar A. Macha and Nissar A. Wani by Department of Biotechnology (DBT), Govt. of India, New Delhi. Shahab Uddin is supported by Medical Research Centre grants (grant# 16102/6, #16354/16)
Highâtemporal resolution profiling reveals distinct immune trajectories following the first and second doses of COVID-19 mRNA vaccines
Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here, we investigated responses to coronavirus disease 2019 (COVID-19) mRNA vaccination via highâtemporal resolution blood transcriptome profiling. The first vaccine dose elicited modest interferon and adaptive immune responses, which peaked on days 2 and 5, respectively. The second vaccine dose, in contrast, elicited sharp day 1 interferon, inflammation, and erythroid cell responses, followed by a day 5 plasmablast response. Both post-first and post-second dose interferon signatures were associated with the subsequent development of antibody responses. Yet, we observed distinct interferon response patterns after each of the doses that may reflect quantitative or qualitative differences in interferon induction. Distinct interferon response phenotypes were also observed in patients with COVID-19 and were associated with severity and differences in duration of intensive care. Together, this study also highlights the benefits of adopting high-frequency sampling protocols in profiling vaccine-elicited immune responses
Role of PTP4A3 in the aggressiveness of Uveal Melanoma cells
Le mĂ©lanome uvĂ©al constitue le cancer intraoculaire le plus frĂ©quent chez lâadulte. Il sâagit dâun cancer trĂšs agressif puisque plus de 50% des patients dĂ©veloppent des mĂ©tastases principalement localisĂ©es au niveau du foie. Dans le but dâidentifier des gĂšnes pronostiques de dĂ©veloppement mĂ©tastatique, nous avons comparĂ© le transcriptome de 28 tumeurs de mĂ©lanome uvĂ©al issues de patients ayant dĂ©veloppĂ© des mĂ©tastases dans les trois annĂ©es qui ont suivi lâĂ©nuclĂ©ation et 29 tumeurs issues de patients nâayant pas dĂ©veloppĂ© de mĂ©tastases ou ayant dĂ©veloppĂ© des mĂ©tastases aprĂšs 36 mois. Le gĂšne PTP4A3/PRL-3 (protein tyrosine phosphatase type IV member 3/Protein of Regenerating Liver-3) a Ă©tĂ© identifiĂ© comme prĂ©dictif de lâapparition de mĂ©tastases. Il code une phosphatase et sa surexpression dans des cellules de mĂ©lanome uvĂ©al augmente leur migration in vitro et leur invasivitĂ© in vivo. Les Ă©vĂšnements protĂ©olytiques Ă la surface des cellules sont essentiels pour la migration et lâinvasivitĂ© durant plusieurs processus physiologiques ou pathologiques tels que le dĂ©veloppement de mĂ©tastases. Ces Ă©vĂšnements sont assurĂ©s par les mĂ©talloprotĂ©ases (MMPs) qui sont responsables de la dĂ©gradation et du remodelage de la matrice extracellulaire.Dans la premiĂšre partie de cette thĂšse, nous avons observĂ© que la mĂ©talloprotĂ©ase transmembranaire MT1-MMP est enrichie Ă la surface des cellules de mĂ©lanome uvĂ©al OCM-1, des cellules MP41 issues de xĂ©nogreffes de tumeurs de mĂ©lanome uvĂ©al humaines ou dans des tumeurs primaires de mĂ©lanome uvĂ©al, surexprimant PTP4A3. Nous avons aussi observĂ© que cette accumulation de MT1-MMP Ă la surface des cellules de mĂ©lanome uvĂ©al est accompagnĂ©e dâune accumulation de la sĂ©crĂ©tion de MMP2 dans le milieu extracellulaire des cellules exprimant PTP4A3. De plus, nous avons montrĂ© que PTP4A3 et MT1-MMP sâassocient physiquement et que le trafic vĂ©siculaire de MT1-MMP est accĂ©lĂ©rĂ© dans les cellules exprimant PTP4A3 mais pas dans celles exprimant le mutant catalytique inactif PTP4A3(C104S). Enfin, nous avons dĂ©montrĂ© que lâinhibition de lâexpression de MT1-MMP dans les cellules exprimant PTP4A3 diminue leur migration in vitro et leur invasivitĂ© in vivo. Pour conclure, nos rĂ©sultats indiquent que PTP4A3 agit en amont de MT1-MMP Ă travers une accĂ©lĂ©ration de son trafic vĂ©siculaire et son accumulation Ă la surface des cellules afin de promouvoir la migration et lâinvasivitĂ© cellulaires.Dans la deuxiĂšme partie de cette thĂšse, nous nous sommes intĂ©ressĂ©s au rĂŽle de PTP4A3 pendant le dĂ©veloppement embryonnaire. Les mĂ©lanocytes, incluant ceux de lâuvĂ©e, dĂ©rivent de la crĂȘte neurale pendant le dĂ©veloppement embryonnaire. Nous avons alors supposĂ© que la fonction de PTP4A3 pendant la progression mĂ©tastatique pourrait reflĂ©ter un rĂŽle de la phosphatase dans la migration des cellules de crĂȘte neurale pendant le dĂ©veloppement embryonnaire. Dans cette partie de la thĂšse, nous avons montrĂ© que PTP4A3 joue un rĂŽle important dans la migration des cellules de crĂȘte neurale cĂ©phalique pendant le dĂ©veloppement de lâembryon de Xenopus laevis. La perte de fonction de PTP4A3 provoque une rĂ©duction du territoire de la crĂȘte neurale, alors que le gain de fonction de cette phosphatase Ă©largit les faisceaux de migration des cellules de crĂȘte neurale cĂ©phalique. De plus, des expĂ©riences dâisogreffes montrent que les explants de crĂȘte neurale dĂ©pourvus de lâexpression de PTP4A3, sont incapables de migrer dans les embryons greffĂ©s. Plus encore, lâinhibition pharmacologique de PTP4A3 dans des cellules de crĂȘte neurale en culture diminue de façon significative leur vitesse de migration in vitro. Les rĂ©sultats de cette Ă©tude dĂ©montrent que PTP4A3 est requise pour la migration des cellules de crĂȘte neurale cĂ©phalique in vivo pendant le dĂ©veloppement embryonnaire de Xenopus laevis. Donc, les effets pro-migratoire et -invasif reliĂ©s Ă lâexpression de la protĂ©ine PTP4A3 peuvent reflĂ©ter son rĂŽle durant la migration des cellules de crĂȘte neurale.Uveal melanoma (UM) is the most common intraocular malignancy in adults and is an aggressive tumor since about 50% of patients will develop metastases mostly in the liver. In order to identify metastasis prognostic genes, we compared 28 uveal melanoma tumors from patients who developed metastases within three years after enucleation to 29 tumors from patients who did not develop metastases or who developed metastases after 36 months. The PTP4A3/PRL-3 gene (protein tyrosine phosphatase type IV member of Regenerating Liver 3/Protein-3) was identified as a strong predictor of metastasis occurence. PTP4A3 encodes a dual specificity phosphatase and its expression in UM cells increases their in vitro migration and in vivo invasiveness. Proteolytic events at the cell surface are essential for cell migration and invasiveness during many physiological and pathological processes such as tumor metastasis. MMPs are responsible for the degradation and turnover of the extracellular matrix (ECM). In the first part of this thesis, We found that the membrane anchored MT1-MMP is enriched at the cell surface of OCM-1, xenograft MP41 or primary human uveal melanoma tumors expressing PTP4A3. We also found that membrane accumulation of MT1-MMP in presence of PTP4A3 in OCM-1 cells is accompanied by enhanced secretion of MMP2 in the extracellular medium. Moreover, we demonstrated that PTP4A3 and MT1-MMP physically associate and that the vesicular trafficking of MT1-MMP is accelerated in presence of active PTP4A3 but not in presence of the mutant PTP4A3(C104S). Furthermore, we found that inhibition of MT1-MMP expression in PTP4A3 expressing uveal melanoma cells impairs their migration in vitro and invasiveness in vivo. Collectively, our results indicate that PTP4A3 acts upstream of MT1-MMP through acceleration of its vesicular trafficking and accumulation at the cell surface to enhance cell migration and invasiveness of uveal melanoma cells. In the second part of this thesis, we investigated the role of PTP4A3 during embryonic development. Melanocytes, including uveal melanocytes, are derived from the neural crest during embryonic development. We therefore suggested that PTP4A3 function in uveal melanoma metastasis may be related to an embryonic role during neural crest cell migration. We show that PTP4A3 plays a role in cephalic neural crest development in Xenopus laevis. PTP4A3 loss of function resulted in a reduction of neural crest territory, whilst gain of function experiments increased neural crest territory. Isochronic graft experiments demonstrated that PTP4A3-depleted neural crest explants are unable to migrate in host embryos. Pharmacological inhibition of PTP4A3 on dissected neural crest cells significantly reduced their migration velocity in vitro. Our results demonstrate that PTP4A3 is required for cephalic neural crest migration in vivo during embryonic development.Therefore, the pro-invasive and migratory effects related to the expression of PTP4A3 protein may reflect its role during neural crest migration. Thus, understanding the mechanism of action of PTP4A3 during NC migration may provide insight into PTP4A3 related migratory and invasive phenotypes in human uveal melanoma pathology
Transcriptional upregulation of câMYC by AXL confers epirubicin resistance in esophageal adenocarcinoma
AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating câMYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of câMYC markedly sensitizes AXLâdependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of câMYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of câMYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates câMYC expression through activation of the AKT/ÎČâcatenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of câMYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicinâresistant tumors with overexpression of AXL and activation of câMYC
Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis
The role of the mesenchymal stromal cell- (MSC-) derived secretome is becoming increasingly intriguing from a clinical perspective due to its ability to stimulate endogenous tissue repair processes as well as its effective regulation of the immune system, mimicking the therapeutic effects produced by the MSCs. The secretome is a composite product secreted by MSC in vitro (in conditioned medium) and in vivo (in the extracellular milieu), consisting of a protein soluble fraction (mostly growth factors and cytokines) and a vesicular component, extracellular vesicles (EVs), which transfer proteins, lipids, and genetic material. MSC-derived secretome differs based on the tissue from which the MSCs are isolated and under specific conditions (e.g., preconditioning or priming) suggesting that clinical applications should be tailored by choosing the tissue of origin and a priming regimen to specifically correct a given pathology. MSC-derived secretome mediates beneficial angiogenic effects in a variety of tissue injury-related diseases. This supports the current effort to develop cell-free therapeutic products that bring both clinical benefits (reduced immunogenicity, persistence in vivo, and no genotoxicity associated with long-term cell cultures) and manufacturing advantages (reduced costs, availability of large quantities of off-the-shelf products, and lower regulatory burden). In the present review, we aim to give a comprehensive picture of the numerous components of the secretome produced by MSCs derived from the most common tissue sources for clinical use (e.g., AT, BM, and CB). We focus on the factors involved in the complex regulation of angiogenic processes
Protein tyrosine phosphatase 4A3 (PTP4A3) is required for Xenopus laevis cranial neural crest migration in vivo.
Uveal melanoma is the most common intraocular malignancy in adults, representing between about 4% and 5% of all melanomas. High expression levels of Protein Tyrosine Phosphatase 4A3, a dual phosphatase, is highly predictive of metastasis development and PTP4A3 overexpression in uveal melanoma cells increases their in vitro migration and in vivo invasiveness. Melanocytes, including uveal melanocytes, are derived from the neural crest during embryonic development. We therefore suggested that PTP4A3 function in uveal melanoma metastasis may be related to an embryonic role during neural crest cell migration. We show that PTP4A3 plays a role in cephalic neural crest development in Xenopus laevis. PTP4A3 loss of function resulted in a reduction of neural crest territory, whilst gain of function experiments increased neural crest territory. Isochronic graft experiments demonstrated that PTP4A3-depleted neural crest explants are unable to migrate in host embryos. Pharmacological inhibition of PTP4A3 on dissected neural crest cells significantly reduced their migration velocity in vitro. Our results demonstrate that PTP4A3 is required for cephalic neural crest migration in vivo during embryonic development