scholarly journals Pathophysiological Role and Potential Therapeutic Exploitation of Exosomes in Ovarian Cancer

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 814 ◽  
Author(s):  
Aasa Shimizu ◽  
Kenjiro Sawada ◽  
Tadashi Kimura
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Immune Therapy ◽  
Cell Communication ◽  
Target Cells ◽  
Cancer Treatments ◽  
Bioactive Materials ◽  
Advanced Stages ◽  
Application Potential ◽  
Functional Features

Exosomes are extracellular vesicles involved in several biological and pathological molecules and can carry many bioactive materials to target cells. They work as important mediators of cell-cell communication and play essential roles in many diseases, especially in cancer. Ovarian cancer is one of the most common gynecological malignancies. Most patients are diagnosed at advanced stages involving widespread peritoneal dissemination, resulting in poor prognosis. Emerging evidence has shown that exosomes play vital roles throughout the progression of ovarian cancer. Moreover, the development of engineered exosome-based therapeutic applications— including drug delivery systems, biomolecular targets and immune therapy—has increased drastically. Herein, we review the functional features of exosomes in ovarian cancer progression and the therapeutic application potential of exosomes as novel cancer treatments.

scholarly journals Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3388
Author(s):  
Mona Alharbi ◽  
Andrew Lai ◽  
Shayna Sharma ◽  
Priyakshi Kalita-de Croft ◽  
Nihar Godbole ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Multiple Reaction Monitoring ◽  
Metabolic Reprogramming ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Target Cells ◽  
Glycolysis Pathway

Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.

scholarly journals Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1967 ◽  
Author(s):  
Nour Jalaleddine ◽  
Layal El-Hajjar ◽  
Hassan Dakik ◽  
Abdullah Shaito ◽  
Jessica Saliba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Communication ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Genetic Ablation ◽  
Functional Features

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers. In addition, PANX1 inhibition or genetic ablation decreased the invasiveness of MDA-MB-231 cells. Our results suggest PANX1 overexpression in breast cancer is associated with a shift towards an EMT phenotype, in silico and in vitro, attributing to it a tumor-promoting effect, with poorer clinical outcomes in breast cancer patients. This association offers a novel target for breast cancer therapy.

scholarly journals LncRNAs in Ovarian Cancer Progression, Metastasis, and Main Pathways: ceRNA and Alternative Mechanisms

2020 ◽  
Vol 21 (22) ◽  
pp. 8855
Author(s):  
Eleonora A. Braga ◽  
Marina V. Fridman ◽  
Alexey A. Moscovtsev ◽  
Elena A. Filippova ◽  
Alexey A. Dmitriev ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Response To Therapy ◽  
Systematic Analysis ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Advanced Stages ◽  
Competitive Endogenous Rna

Ovarian cancer (OvCa) develops asymptomatically until it reaches the advanced stages with metastasis, chemoresistance, and poor prognosis. Our review focuses on the analysis of regulatory long non-coding RNAs (lncRNAs) competing with protein-coding mRNAs for binding to miRNAs according to the model of competitive endogenous RNA (ceRNA) in OvCa. Analysis of publications showed that most lncRNAs acting as ceRNAs participate in OvCa progression: migration, invasion, epithelial-mesenchymal transition (EMT), and metastasis. More than 30 lncRNAs turned out to be predictors of survival and/or response to therapy in patients with OvCa. For a number of oncogenic (CCAT1, HOTAIR, NEAT1, and TUG1 among others) and some suppressive lncRNAs, several lncRNA/miRNA/mRNA axes were identified, which revealed various functions for each of them. Our review also considers examples of alternative mechanisms of actions for lncRNAs besides being ceRNAs, including binding directly to mRNA or protein, and some of them (DANCR, GAS5, MALAT1, and UCA1 among others) act by both mechanisms depending on the target protein. A systematic analysis based on the data from literature and Panther or KEGG (Kyoto Encyclopedia of Genes and Genomes) databases showed that a significant part of lncRNAs affects the key pathways involved in OvCa metastasis, EMT, and chemoresistance.

scholarly journals Interleukin-1β and Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1791 ◽  
Author(s):  
Cédric Rébé ◽  
François Ghiringhelli
Keyword(s):  
Cancer Progression ◽  
Immune Cells ◽  
Gene Polymorphisms ◽  
Target Genes ◽  
Cell Types ◽  
Target Cells ◽  
Cancer Cell Proliferation ◽  
Cancer Treatments ◽  
Anti Cancer ◽  
Cellular Context

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment.

scholarly journals Role of the Exosome in Ovarian Cancer Progression and Its Potential as a Therapeutic Target

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1147 ◽  
Author(s):  
Koji Nakamura ◽  
Kenjiro Sawada ◽  
Masaki Kobayashi ◽  
Mayuko Miyamoto ◽  
Aasa Shimizu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Peritoneal Dissemination ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Target Cells ◽  
Distinct Form ◽  
Cargo Delivery ◽  
Different Cell Types

Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics.

scholarly journals Glypicans define unique roles for the Hedgehog co-receptors Boi and Ihog in cytoneme-mediated gradient formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Eleanor Simon ◽  
Carlos Jiménez-Jiménez ◽  
Irene Seijo-Barandiarán ◽  
Gustavo Aguilar ◽  
David Sánchez-Hernández ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Direct Contact ◽  
Tissue Repair ◽  
Cell Communication ◽  
Target Cells ◽  
Signaling Proteins ◽  
Long Distance Dispersal ◽  
Long Distance ◽  
Gradient Formation ◽  
Hh Signaling

The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication during development, tissue repair and cancer progression, inducing distinct concentration-dependent responses in target cells located at short and long distances. One simple mechanism for long distance dispersal of the lipid modified Hh is the direct contact between cell membranes through filopodia-like structures known as cytonemes. Here we have analyzed in Drosophila the interaction between the glypicans Dally and Dally-like protein, necessary for Hh signaling, and the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans are required to maintain the levels of Ihog, but not of Boi. We also show that the overexpression of Ihog, but not of Boi, regulates cytoneme dynamics through their interaction with glypicans, the Ihog fibronectin III domains being essential for this interaction. Our data suggest that the regulation of glypicans over Hh signaling is specifically given by their interaction with Ihog in cytonemes. Contrary to previous data, we also show that there is no redundancy of Ihog and Boi functions in Hh gradient formation, being Ihog, but not of Boi, essential for the long-range gradient.

scholarly journals A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 298 ◽  
Author(s):  
Ancuta Jurj ◽  
Oana Zanoaga ◽  
Cornelia Braicu ◽  
Vladimir Lazar ◽  
Ciprian Tomuleasa ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Tumor Development ◽  
Cell Communication ◽  
Cancer Diagnostics ◽  
Target Cells ◽  
Chemotherapeutic Response ◽  
Non Coding Rna ◽  
Comprehensive Picture

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics.

scholarly journals Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

2020 ◽  
Author(s):  
Eléanor Simon ◽  
Carlos Jiménez-Jiménez ◽  
Irene Seijo-Barandiarán ◽  
Gustavo Aguilar ◽  
David Sánchez-Hernández ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Tissue Repair ◽  
Hedgehog Signaling ◽  
Cell Communication ◽  
Target Cells ◽  
Signaling Proteins ◽  
Signaling Mechanism ◽  
Protein Levels ◽  
High Affinity ◽  
Hh Signaling

AbstractThe conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication in development, tissue repair and cancer progression. These proteins can act as morphogens, inducing responses dependent on the ligand concentration in target cells located at a distance. Hh proteins are lipid modified and thereby have high affinity for membranes, which hinders the understanding of their spreading across tissues. Direct contact between cell membranes by filopodia-like structures (also known as cytonemes) could be the simplest explanation for Hh dispersal. To better understand this signaling mechanism, we have analyzed in Drosophila the interaction between the glypicans that, besides for other pathways, are necessary for Hh signaling, plus the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans (Dally and Dally-like protein) are required to maintain Ihog, but not Boi, protein levels. We also show that ectopic Ihog stabilizes cytonemes through its interaction with glypicans, and we determine that two Ihog fibronectin III domains are essential for this interaction. Our data suggest that this interaction with Ihog in cytonemes confers the specificity of glypicans for Hh signaling.

Plant peptide hormone signalling

2015 ◽  
Vol 58 ◽  
pp. 115-131 ◽  
Author(s):  
Ayane Motomitsu ◽  
Shinichiro Sawa ◽  
Takashi Ishida
Keyword(s):  
Communication Systems ◽  
Cell Communication ◽  
Peptide Hormone ◽  
Peptide Hormones ◽  
Target Cells ◽  
Signalling Molecules ◽  
Receptor Complexes ◽  
Environmental Responses ◽  
Plant Life Cycle ◽  
Multicellular Organisms

The ligand–receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone–receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions.

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