Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation

Venturella, Marta; Criscuoli, Mattia; Carraro, Fabio; Naldini, Antonella; Zocco, Davide

doi:10.3390/biology10070606

Cited by 16 publications

(16 citation statements)

References 96 publications

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“…In the tumor microenvironment, EVs are a means of paracrine signalling since the earlier stages, promoting progression, invasiveness and metastasis development [ 57 , 58 ]. It is now well-established that hypoxia affects the number, size, and molecular cargo of EVs in cancer [ 59 ]. Despite differences in cell models and hypoxic treatments, the number of EVs increased upon hypoxic condition in breast cancer, prostate cancer and ovarian cancer [ 60 , 61 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Secretome Analysis of Chemical Hypoxia Treated Cells Identifies Putative Biomarkers of Chondrosarcoma

et al. 2022

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Chondrosarcoma is the second most common bone tumor, accounting for 20% of all cases. Little is known about the pathology and molecular mechanisms involved in the development and in the metastatic process of chondrosarcoma. As a consequence, there are no approved therapies for this tumor and surgical resection is the only treatment currently available. Moreover, there are no available biomarkers for this type of tumor, and chondrosarcoma classification relies on operator-dependent histopathological assessment. Reliable biomarkers of chondrosarcoma are urgently needed, as well as greater understanding of the molecular mechanisms of its development for translational purposes. Hypoxia is a central feature of chondrosarcoma progression. The hypoxic tumor microenvironment of chondrosarcoma triggers a number of cellular events, culminating in increased invasiveness and migratory capability. Herein, we analyzed the effects of chemically-induced hypoxia on the secretome of SW 1353, a human chondrosarcoma cell line, using high-resolution quantitative proteomics. We found that hypoxia induced unconventional protein secretion and the release of proteins associated to exosomes. Among these proteins, which may be used to monitor chondrosarcoma development, we validated the increased secretion in response to hypoxia of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme well-known for its different functional roles in a wide range of tumors. In conclusion, by analyzing the changes induced by hypoxia in the secretome of chondrosarcoma cells, we identified molecular mechanisms that can play a role in chondrosarcoma progression and pinpointed proteins, including GAPDH, that may be developed as potential biomarkers for the diagnosis and therapeutic management of chondrosarcoma.

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Section: Discussionmentioning

confidence: 99%

High-Resolution Secretome Analysis of Chemical Hypoxia Treated Cells Identifies Putative Biomarkers of Chondrosarcoma

et al. 2022

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“…To be able to closely follow OTS patients with those macrophagic and hypoxic features at diagnosis, during treatment and post-therapeutic follow-up, new methods using plasmatic biomarkers can be developed, as in adult cancers [50]. Thus, exosomes have emerged recently as promising non-invasive biomarkers released during hypoxic oncogenesis, which might be quantified in patient plasmas.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, exosomes have emerged recently as promising non-invasive biomarkers released during hypoxic oncogenesis, which might be quantified in patient plasmas. They usually contain a complex cargo of contents derived from the original cancer cell, including proteins, lipids, mRNA, miRNA or DNA that might be specifically measured [50][51][52]. Thus, in the near future, multiple diagnostic assessments measuring or quantifying HIF-1α, CAIX, mTor or CD68/CD163 balance in tumor specimens and/or plasmatic samples might be proposed during the OTS patient journey to evaluate outcome risks.…”

Section: Discussionmentioning

confidence: 99%

Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas

Nazon

Pierrevelcin

Willaume

et al. 2022

Cancers

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Background: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between the tumor-associated macrophages and intra-tumor hypoxia. Methods: Radiological and immunohistochemical (IHC) data were correlated with the outcome in a retrospective and monocentric cohort of 30 pediatric OTS. We studied hypoxic (pS6, phospho-mTor, HIF-1α and carbonic anhydrase IX (CAIX)) and macrophagic (CD68 and CD163) biomarkers. Results: The imaging analyses were based on MRI manual volumetric measures on axial post-contrast T1 weighted images, where, for each tumor, we determined the necrotic volume and its ratio to the entire tumor volume. When they were above 50 cm3 and 20%, respectively, they correlated with a worse overall survival (p = 0.0072 and p = 0.0136, respectively) and event-free survival (p = 0.0059 and p = 0.0143, respectively). IHC assessments enable a significant statistical link between HIF-1α/CAIX hyper-expressions, CD68+ cells and a worse outcome, whereas activation of mTor pathway was linked to a better survival rate and CD163+ cells. Conclusions: This study evidenced the links between hypoxia and immunity in OTS, as their poor outcome may be related to a larger necrotic volume on diagnostic MRI and, in biopsies, to a specific IHC profile.

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“…These can include TME stressors, such as hypoxia, interstitial pressure, and therapy-induced damage [49,50]. These stimuli alter intracellular pathways in ways that are reflected in the molecular content of the cytosol and biomaterials (proteins, RNAs, and miRNAs) that are packaged into multivesicular bodies and their secreted exosomes [51,52]. Therefore, differentially regulated miRNAs can serve as biomarkers for aggressive and even drug-resistant HGSOCs prior to the administration of chemotherapy.…”

Section: Metabolic Reprogramming As a Priming Mechanism In Response T...mentioning

confidence: 99%

Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations

Lee

Pena

Dawson

2022

Cancers

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High-grade serous ovarian cancer (HGSOC) constitutes the majority of all ovarian cancer cases and has staggering rates of both refractory and recurrent disease. While most patients respond to the initial treatment with paclitaxel and platinum-based drugs, up to 25% do not, and of the remaining that do, 75% experience disease recurrence within the subsequent two years. Intrinsic resistance in refractory cases is driven by environmental stressors like tumor hypoxia which alter the tumor microenvironment to promote cancer progression and resistance to anticancer drugs. Recurrent disease describes the acquisition of chemoresistance whereby cancer cells survive the initial exposure to chemotherapy and develop adaptations to enhance their chances of surviving subsequent treatments. Of the environmental stressors cancer cells endure, exposure to hypoxia has been identified as a potent trigger and priming agent for the development of chemoresistance. Both in the presence of the stress of hypoxia or the therapeutic stress of chemotherapy, cancer cells manage to cope and develop adaptations which prime populations to survive in future stress. One adaptation is the modification in the secretome. Chemoresistance is associated with translational reprogramming for increased protein synthesis, ribosome biogenesis, and vesicle trafficking. This leads to increased production of soluble proteins and extracellular vesicles (EVs) involved in autocrine and paracrine signaling processes. Numerous studies have demonstrated that these factors are largely altered between the secretomes of chemosensitive and chemoresistant patients. Such factors include cytokines, growth factors, EVs, and EV-encapsulated microRNAs (miRNAs), which serve to induce invasive molecular, biophysical, and chemoresistant phenotypes in neighboring normal and cancer cells. This review examines the modifications in the secretome of distinct chemoresistant ovarian cancer cell populations and specific secreted factors, which may serve as candidate biomarkers for aggressive and chemoresistant cancers.

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Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation

Cited by 16 publications

References 96 publications

High-Resolution Secretome Analysis of Chemical Hypoxia Treated Cells Identifies Putative Biomarkers of Chondrosarcoma

High-Resolution Secretome Analysis of Chemical Hypoxia Treated Cells Identifies Putative Biomarkers of Chondrosarcoma

Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas

Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations

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