Dataset Information

Blood Circulating CD133+ Extracellular Vesicles Predict Clinical Outcomes in Patients with Metastatic Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most incident and lethal malignancies worldwide. Recent treatment advances prolonged survival in patients with metastatic colorectal cancer (mCRC). However, there are still few biomarkers to guide clinical management and treatment selection in mCRC. In this study, we applied an optimized flow cytometry protocol for EV identification, enumeration, and subtyping in blood samples of 54 patients with mCRC and 48 age and sex-matched healthy controls (HCs). The overall survival (OS) and overall response rate (ORR) were evaluated in mCRC patients enrolled and treated with a first line fluoropyrimidine-based regimen. Our findings show that patients with mCRC presented considerably higher blood concentrations of total EVs, as well as CD133+ and EPCAM+ EVs compared to HCs. Overall survival analysis revealed that increased blood concentrations of total EVs and CD133+ EVs before treatment were significantly associated with shorter OS in mCRC patients (p = 0.001; and p = 0.0001, respectively). In addition, we observed a correlation between high blood levels of CD133+ EVs at baseline and reduced ORR to first-line systemic therapy (p = 0.045). These findings may open exciting perspectives into the application of novel blood-based EV biomarkers for improved risk stratification and optimized treatment strategies in mCRC.

SUBMITTER: Brocco D

PROVIDER: S-EPMC8909146 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Blood Circulating CD133+ Extracellular Vesicles Predict Clinical Outcomes in Patients with Metastatic Colorectal Cancer.

Brocco Davide D Simeone Pasquale P Buca Davide D Marino Pietro Di PD De Tursi Michele M Grassadonia Antonino A De Lellis Laura L Martino Maria Teresa MT Veschi Serena S Iezzi Manuela M De Fabritiis Simone S Marchisio Marco M Miscia Sebastiano S Cama Alessandro A Lanuti Paola P Tinari Nicola N

Cancers 20220307 5

Colorectal cancer (CRC) is one of the most incident and lethal malignancies worldwide. Recent treatment advances prolonged survival in patients with metastatic colorectal cancer (mCRC). However, there are still few biomarkers to guide clinical management and treatment selection in mCRC. In this study, we applied an optimized flow cytometry protocol for EV identification, enumeration, and subtyping in blood samples of 54 patients with mCRC and 48 age and sex-matched healthy controls (HCs). The ov ...[more]

PMID: 35267665

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Project description:IntroductionSepsis is associated with endothelial cell (EC) dysfunction, increased vascular permeability and organ injury, which may lead to mortality, acute respiratory distress syndrome (ARDS) and acute renal failure (ARF). There are no reliable biomarkers to predict these sepsis complications at present. Recent evidence suggests that circulating extracellular vesicles (EVs) and their content caspase-1 and miR-126 may play a critical role in modulating vascular injury in sepsis; however, the association between circulating EVs and sepsis outcomes remains largely unknown.MethodsWe obtained plasma samples from septic patients (n=96) within 24 hours of hospital admission and from healthy controls (n=45). Total, monocyte- or EC-derived EVs were isolated from the plasma samples. Transendothelial electrical resistance (TEER) was used as an indicator of EC dysfunction. Caspase-1 activity in EVs was detected and their association with sepsis outcomes including mortality, ARDS and ARF was analyzed. In another set of experiments, total EVs were isolated from plasma samples of 12 septic patients and 12 non-septic critical illness controls on days 1, and 3 after hospital admission. RNAs were isolated from these EVs and Next-generation sequencing was performed. The association between miR-126 levels and sepsis outcomes such as mortality, ARDS and ARF was analyzed.ResultsSeptic patients with circulating EVs that induced EC injury (lower transendothelial electrical resistance) were more likely to experience ARDS (p<0.05). Higher caspase-1 activity in total EVs, monocyte- or EC-derived EVs was significantly associated with the development of ARDS (p<0.05). MiR-126-3p levels in EC EVs were significantly decreased in ARDS patients compared with healthy controls (p<0.05). Moreover, a decline in miR-126-5p levels from day 1 to day 3 was associated with increased mortality, ARDS and ARF; while decline in miR-126-3p levels from day 1 to day 3 was associated with ARDS development.ConclusionsEnhanced caspase-1 activity and declining miR-126 levels in circulating EVs are associated with sepsis-related organ failure and mortality. Extracellular vesicular contents may serve as novel prognostic biomarkers and/or targets for future therapeutic approaches in sepsis.

Project description:Most cancer-related deaths are caused by distant metastases, which are tumour cells that have escaped from a primary tumour and passed into the bloodstream to colonize a new organ. In this context, communication between tumour and stromal cells is essential. Indeed, tumor cells interact with cells in the tumor microenvironment and are able to modify them to their advantage. Both extracellular vesicles (EVs) and exosomes are heterogeneous populations of small vesicles present in the tumor microenvironment and in body fluids that have recently emerged as powerful mediators involved in this communication and their transport in fluids. Tumor cells release large quantities of exosomes containing tumor markers, which can then spread to distant locations. The exosomes are of endosomal origin. They are composed of proteins, lipids, RNA and DNA, and they circulate in the bloodstream. They can be internalized by specific distant cells and thus deliver a functional message. It has recently been shown that tumor exosomes containing pro-metastatic factors form pre-metastatic niches, before the tumor cells actually arrive, while determining the metastatic organotropism of tumors. These properties are now opening up new avenues of research in tumor biomarkers. In recent years, several studies have highlighted different markers contained specifically in exosomes derived from cancer cells. Consequently, exosomes are considered as potential reservoirs of tumor biomarkers that could be clinically useful for the non-invasive diagnosis of cancer, with the advantage of being performed by liquid biopsy. The study of microRNA (miRNA) is of particular interest. Indeed, miRNAs are small non-coding RNAs (between 21 and 25 nucleotides) involved in the regulation of gene expression and which are frequently deregulated in cancer. Several studies underline that the variation of free miRNAs in the blood is correlated with the progression of the disease, particularly in colon cancer. However, the stability of free miRNAs is controversial. Therefore, exosomes represent a very advantageous means of transporting miRNAs in the blood, as they are able to protect miRNAs from degradation by RNAase. The hypothesis of the project is that circulating exosomes derived from tumours contain markers including specific miRNAs that could be used as biomarkers of early prognosis (survival and progression), easily measured in blood samples from patients with colon cancer. But other molecules contained in exosomes could also be of interest.

Project description:BackgroundThe immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1+ EV mediate resistance to anti-PD1, instead the role of PD1+ EV is not fully understood.MethodsWe isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1+ EVs and PD1+ EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1+ EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.ResultsThe level of PD-L1+ EVs released from melanoma and CD8+ T cells and that of PD1+ EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1+ EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1+ EVs, from T cells and B cells, and high level of PD-L1+ EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1+ EVs from melanoma and PD1+ EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.ConclusionOur study identified circulating PD1+ EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.

Project description:PurposeSABR has demonstrated clinical benefit in oligometastatic prostate cancer. However, the risk of developing new distant metastatic lesions remains high, and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which patients will benefit from SABR alone versus combination SABR and systemic agents. Herein we provide, to our knowledge, the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a noninvasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR.Methods and materialsWe analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 patients with omCRPC at baseline and days 1, 7, and 14 after SABR using nanoscale flow cytometry and compared with baseline values from cohorts with localized and widely metastatic prostate cancer. The association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models.ResultsLevels of PCEVs were highest in mCRPC followed by omCRPC and were lowest in localized prostate cancer. High PCEV levels at baseline predicted a shorter median time to distant recurrence (3.5 vs 6.6 months; P = .0087). After SABR, PCEV levels peaked on day 7, and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months; P = .003). This suggests that pretreatment PCEV levels reflect tumor burden, whereas early changes in PCEV levels after treatment predict response to SABR. In contrast, radiomic features of 11C-choline positron emission tomography and computed tomography before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+ CD11ahigh) were correlated.ConclusionsThis original study demonstrates that circulating PCEVs can serve as prognostic and predictive markers to SABR to identify patients with "true" omCRPC. In addition, it provides novel insights into the global crosstalk, mediated by PCEVs, between tumors and immune cells that leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies to investigate the underpinnings of metastatic progression and provide new therapeutic targets (eg, PCEVs) to improve SABR efficacy and clinical outcomes in treatment-resistant CRPC.

Dataset Information

Blood Circulating CD133+ Extracellular Vesicles Predict Clinical Outcomes in Patients with Metastatic Colorectal Cancer.

Publications

Blood Circulating CD133+ Extracellular Vesicles Predict Clinical Outcomes in Patients with Metastatic Colorectal Cancer.

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