Research

23 pages, 6030 KiB

Open AccessArticle

Assessment of a Large-Scale Unbiased Malignant Pleural Effusion Proteomics Study of a Real-Life Cohort

by Sara Zahedi, Ana Sofia Carvalho, Mostafa Ejtehadifar, Hans C. Beck, Nádia Rei, Ana Luis, Paula Borralho, António Bugalho and Rune Matthiesen

Cancers 2022, 14(18), 4366; https://doi.org/10.3390/cancers14184366 - 08 Sep 2022

Cited by 2 | Viewed by 2089

Abstract

Background: Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic [...] Read more.

Background: Pleural effusion (PE) is common in advanced-stage lung cancer patients and is related to poor prognosis. Identification of cancer cells is the standard method for the diagnosis of a malignant PE (MPE). However, it only has moderate sensitivity. Thus, more sensitive diagnostic tools are urgently needed. Methods: The present study aimed to discover potential protein targets to distinguish malignant pleural effusion (MPE) from other non-malignant pathologies. We have collected PE from 97 patients to explore PE proteomes by applying state-of-the-art liquid chromatography-mass spectrometry (LC-MS) to identify potential biomarkers that correlate with immunohistochemistry assessment of tumor biopsy or with survival data. Functional analyses were performed to elucidate functional differences in PE proteins in malignant and benign samples. Results were integrated into a clinical risk prediction model to identify likely malignant cases. Sensitivity, specificity, and negative predictive value were calculated. Results: In total, 1689 individual proteins were identified by MS-based proteomics analysis of the 97 PE samples, of which 35 were diagnosed as malignant. A comparison between MPE and benign PE (BPE) identified 58 differential regulated proteins after correction of the p-values for multiple testing. Furthermore, functional analysis revealed an up-regulation of matrix intermediate filaments and cellular movement-related proteins. Additionally, gene ontology analysis identified the involvement of metabolic pathways such as glycolysis/gluconeogenesis, pyruvate metabolism and cysteine and methionine metabolism. Conclusion: This study demonstrated a partial least squares regression model with an area under the curve of 98 and an accuracy of 0.92 when evaluated on the holdout test data set. Furthermore, highly significant survival markers were identified (e.g., PSME1 with a log-rank of 1.68 × 10⁻⁶). Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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23 pages, 6620 KiB

Open AccessArticle

Analysis of Exosomal Cargo Provides Accurate Clinical, Histologic and Mutational Information in Non-Small Cell Lung Cancer

by Elena Duréndez-Sáez, Silvia Calabuig-Fariñas, Susana Torres-Martínez, Andrea Moreno-Manuel, Alejandro Herreros-Pomares, Eva Escorihuela, Marais Mosqueda, Sandra Gallach, Ricardo Guijarro, Eva Serna, Cristian Suárez-Cabrera, Jesús M. Paramio, Ana Blasco, Carlos Camps and Eloisa Jantus-Lewintre

Cancers 2022, 14(13), 3216; https://doi.org/10.3390/cancers14133216 - 30 Jun 2022

Cited by 5 | Viewed by 2849

Abstract

Lung cancer is a malignant disease with high mortality and poor prognosis, frequently diagnosed at advanced stages. Nowadays, immense progress in treatment has been achieved. However, the present scenario continues to be critical, and a full comprehension of tumor progression mechanisms is required, [...] Read more.

Lung cancer is a malignant disease with high mortality and poor prognosis, frequently diagnosed at advanced stages. Nowadays, immense progress in treatment has been achieved. However, the present scenario continues to be critical, and a full comprehension of tumor progression mechanisms is required, with exosomes being potentially relevant players. Exosomes are membranous vesicles that contain biological information, which can be transported cell-to-cell and modulate relevant processes in the hallmarks of cancer. The present research aims to characterize the exosomes’ cargo and study their role in NSCLC to identify biomarkers. We analyzed exosomes secreted by primary cultures and cell lines, grown in monolayer and tumorsphere formations. Exosomal DNA content showed molecular alterations, whereas RNA high-throughput analysis resulted in a pattern of differentially expressed genes depending on histology. The most significant differences were found in XAGE1B, CABYR, NKX2-1, SEPP1, CAPRIN1, and RIOK3 genes when samples from two independent cohorts of resected NSCLC patients were analyzed. We identified and validated biomarkers for adenocarcinoma and squamous cell carcinoma. Our results could represent a relevant contribution concerning exosomes in clinical practice, allowing for the identification of biomarkers that provide information regarding tumor features, prognosis and clinical behavior of the disease. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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17 pages, 2197 KiB

Open AccessArticle

Serum Cartilage Oligomeric Matrix Protein and Golgi Protein-73: New Diagnostic and Predictive Tools for Liver Fibrosis and Hepatocellular Cancer?

by Nikolaos K. Gatselis, Kalliopi Zachou, George Giannoulis, Stella Gabeta, Gary L. Norman and George N. Dalekos

Cancers 2021, 13(14), 3510; https://doi.org/10.3390/cancers13143510 - 13 Jul 2021

Cited by 11 | Viewed by 1930

Abstract

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from [...] Read more.

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(−), 37/288 (12.8%) GP73(−)/COMP(+), and 197 (68.5%) GP73(−)/COMP(−). Positivity for both markers was associated with cirrhosis [23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(−) vs. 25/37 (67.6%) for GP73(−)/COMP(+) vs. 46/197 (23.4%) for GP73(−)/COMP(−); P < 0.001]. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis [AUC (95% CI): 0.916 (0.878–0.946)] or significant liver fibrosis (METAVIR ≥ F2) [AUC (95% CI): 0.832 (0.768–0.883)] than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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16 pages, 2090 KiB

Open AccessArticle

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

by Smadar Kahana-Edwin, Lucy E. Cain, Geoffrey McCowage, Artur Darmanian, Dale Wright, Anna Mullins, Federica Saletta and Jonathan Karpelowsky

Cancers 2021, 13(13), 3365; https://doi.org/10.3390/cancers13133365 - 05 Jul 2021

Cited by 9 | Viewed by 3221

Abstract

Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is [...] Read more.

Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation. Methods: Various pre-analytical conditions tested to optimize circulating-tumor DNA (ctDNA) copy number changes evaluations. Plasma samples from 10 patients diagnosed with neuroblastoma assessed for SCA and MNA using single nucleotide polymorphism (SNP) array approach currently used for neuroblastoma diagnosis, with MNA status assessed independently using digital-droplet PCR (ddPCR). Three patients (one in common with the previous 10) tested for ALK activating mutations p.F1174L and p.F1245I using ddPCR. Results: Copy number detection is highly affected by physical perturbations of the blood sample (mimicking suboptimal sample shipment), which could be overcome using specialized preservative collection tubes. Pre-analytical DNA repair procedures on ctDNA before SNP chromosome microarray processing improved the lower limit of detection for SCA and MNA, defined as 20% and 10%, respectively. We detected SCA in 10/10 (100%) patients using SNP array, 7 of which also presented MNA. Circulating-free DNA (cfDNA) and matched tumor DNA profiles were generally identical. MNA was detected using ddPCR in 7/7 (100%) of MNA and 0/12 (0%) non-MNA cases. MNA and ALK mutation dynamic change was assessed in longitudinal samples from 4 and 3 patients (one patient with both), respectively, accurately reflected response to treatment in 6/6 (100%) and disease recurrence in 5/6 (83%) of cases. Samples taken prior to targeted treatment with the ALK inhibitor Lorlatinib and 6–8 weeks on treatment showed reduction/increase in ALK variants according to response to treatment. Conclusions: These results demonstrate the feasibility of ctDNA profiling for molecular risk-stratification, and treatment monitoring in a clinically relevant time frame and the potential to reduce fresh tissue requirements currently embedded in the management of neuroblastoma. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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16 pages, 2177 KiB

Open AccessArticle

Characterization of Circulating T Cell Receptor Repertoire Provides Information about Clinical Outcome after PD-1 Blockade in Advanced Non-Small Cell Lung Cancer Patients

by Ning Dong, Andrea Moreno-Manuel, Silvia Calabuig-Fariñas, Sandra Gallach, Feiyu Zhang, Ana Blasco, Francisco Aparisi, Marina Meri-Abad, Ricardo Guijarro, Rafael Sirera, Carlos Camps and Eloísa Jantus-Lewintre

Cancers 2021, 13(12), 2950; https://doi.org/10.3390/cancers13122950 - 12 Jun 2021

Cited by 10 | Viewed by 3710

Abstract

Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell [...] Read more.

Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-β chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 between PRE and FR samples showed improved PFS (p = 0.021). Higher TRBV20-1 PRE usage was associated with DCB (p = 0.027). TRBV20-1 levels ≥9.14% in PRE and ≥9.02% in FR significantly increased PFS (p = 0.025 and p = 0.016) and OS (p = 0.035 and p = 0.018). Overall, analysis of circulating TCR-β repertoire may provide information about the immune response in anti-PD-1 treated NSCLC patients; in this scenario, it can also offer important information about the clinical outcome. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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21 pages, 4768 KiB

Open AccessArticle

Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

by Feiyu Zhang, Macarena Ferrero, Ning Dong, Giuseppe D’Auria, Mariana Reyes-Prieto, Alejandro Herreros-Pomares, Silvia Calabuig-Fariñas, Elena Duréndez, Francisco Aparisi, Ana Blasco, Clara García, Carlos Camps, Eloisa Jantus-Lewintre and Rafael Sirera

Cancers 2021, 13(11), 2514; https://doi.org/10.3390/cancers13112514 - 21 May 2021

Cited by 19 | Viewed by 4644

Abstract

Background: The human gut harbors around 10¹³–10¹⁴ microorganisms, collectively referred to as gut microbiota. Recent studies have found that the gut microbiota may have an impact on the interaction between immune regulation and anti-cancer immunotherapies. Methods: In order to characterize [...] Read more.

Background: The human gut harbors around 10¹³–10¹⁴ microorganisms, collectively referred to as gut microbiota. Recent studies have found that the gut microbiota may have an impact on the interaction between immune regulation and anti-cancer immunotherapies. Methods: In order to characterize the diversity and composition of commensal microbiota and its relationship with response to immune checkpoint blockade (ICB), 16S ribosomal DNA (rDNA) sequencing was performed on 69 stool samples from advanced non-small cell lung cancer (NSCLC) patients prior to treatment with ICB. Results: The use of antibiotics and ICB-related skin toxicity were significantly associated with reduced gut microbiota diversity. However, antibiotics (ATB) usage was not related to low ICB efficacy. Phascolarctobacterium was enriched in patients with clinical benefit and correlated with prolonged progression-free survival, whereas Dialister was more represented in patients with progressive disease, and its higher relative abundance was associated with reduced progression-free survival and overall survival, with independent prognostic value in multivariate analysis. Conclusions: Our results corroborate the relation between the baseline gut microbiota composition and ICB clinical outcomes in advanced NSCLC patients, and provide novel potential predictive and prognostic biomarkers for immunotherapy in NSCLC. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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Review

Jump to: Research, Other

24 pages, 2227 KiB

Open AccessReview

Tumor Microenvironment-Derived Metabolites: A Guide to Find New Metabolic Therapeutic Targets and Biomarkers

by Juan C. García-Cañaveras and Agustín Lahoz

Cancers 2021, 13(13), 3230; https://doi.org/10.3390/cancers13133230 - 28 Jun 2021

Cited by 16 | Viewed by 3165

Abstract

Metabolic reprogramming is a hallmark of cancer that enables cancer cells to grow, proliferate and survive. This metabolic rewiring is intrinsically regulated by mutations in oncogenes and tumor suppressors, but also extrinsically by tumor microenvironment factors (nutrient and oxygen availability, cell-to-cell interactions, cytokines, [...] Read more.

Metabolic reprogramming is a hallmark of cancer that enables cancer cells to grow, proliferate and survive. This metabolic rewiring is intrinsically regulated by mutations in oncogenes and tumor suppressors, but also extrinsically by tumor microenvironment factors (nutrient and oxygen availability, cell-to-cell interactions, cytokines, hormones, etc.). Intriguingly, only a few cancers are driven by mutations in metabolic genes, which lead metabolites with oncogenic properties (i.e., oncometabolites) to accumulate. In the last decade, there has been rekindled interest in understanding how dysregulated metabolism and its crosstalk with various cell types in the tumor microenvironment not only sustains biosynthesis and energy production for cancer cells, but also contributes to immune escape. An assessment of dysregulated intratumor metabolism has long since been exploited for cancer diagnosis, monitoring and therapy, as exemplified by 18F-2-deoxyglucose positron emission tomography imaging. However, the efficient delivery of precision medicine demands less invasive, cheaper and faster technologies to precisely predict and monitor therapy response. The metabolomic analysis of tumor and/or microenvironment-derived metabolites in readily accessible biological samples is likely to play an important role in this sense. Here, we review altered cancer metabolism and its crosstalk with the tumor microenvironment to focus on energy and biomass sources, oncometabolites and the production of immunosuppressive metabolites. We provide an overview of current pharmacological approaches targeting such dysregulated metabolic landscapes and noninvasive approaches to characterize cancer metabolism for diagnosis, therapy and efficacy assessment. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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25 pages, 1072 KiB

Open AccessReview

Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

by Maria Alba Sorolla, Anabel Sorolla, Eva Parisi, Antonieta Salud and José M. Porcel

Cancers 2021, 13(11), 2798; https://doi.org/10.3390/cancers13112798 - 04 Jun 2021

Cited by 20 | Viewed by 6169

Abstract

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid [...] Read more.

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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13 pages, 436 KiB

Open AccessReview

Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer

by Ilenia Migliaccio, Angela Leo, Francesca Galardi, Cristina Guarducci, Giulio Maria Fusco, Matteo Benelli, Angelo Di Leo, Laura Biganzoli and Luca Malorni

Cancers 2021, 13(11), 2640; https://doi.org/10.3390/cancers13112640 - 27 May 2021

Cited by 8 | Viewed by 3222

Abstract

CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are the standard treatment for patients with hormone receptor-positive and HER2 negative (HR+/HER2−) metastatic breast cancer. Patients might show intrinsic and acquired resistance, which leads to treatment failure and progression. Circulating biomarkers have the potential advantages of [...] Read more.

CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are the standard treatment for patients with hormone receptor-positive and HER2 negative (HR+/HER2−) metastatic breast cancer. Patients might show intrinsic and acquired resistance, which leads to treatment failure and progression. Circulating biomarkers have the potential advantages of recognizing patients who might not respond to treatment, monitoring treatment effects and identifying markers of acquired resistance during tumor progression with a simple withdrawal of peripheral blood. Genomic alterations on circulating tumor DNA and serum thymidine kinase activity, but also circulating tumor cells, epigenetic or exosome markers are currently being tested as markers of CDK4/6i treatment response, even though none of these have been integrated into clinical practice. In this review, we discuss the recent advancements in the development of circulating biomarkers of CDK4/6i response in patients with HR+/HER2−breast cancer. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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Other

Jump to: Research, Review

15 pages, 5593 KiB

Open AccessSystematic Review

Circulating Cell-Free DNA in Liquid Biopsies as Potential Biomarker for Bladder Cancer: A Systematic Review

by Raquel Herranz, Julia Oto, Emma Plana, Álvaro Fernández-Pardo, Fernando Cana, Manuel Martínez-Sarmiento, César D. Vera-Donoso, Francisco España and Pilar Medina

Cancers 2021, 13(6), 1448; https://doi.org/10.3390/cancers13061448 - 22 Mar 2021

Cited by 9 | Viewed by 5287

Abstract

Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis [...] Read more.

Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis of BC is of paramount importance. To date, several studies have evidenced that cell-free DNA (cfDNA) found in liquid biopsies such as blood and urine may play a role in the particular scenario of urologic tumors, and its analysis may improve BC diagnosis report about cancer progression or even evaluate the effectiveness of a specific treatment or anticipate whether a treatment would be useful for a specific patient depending on the tumor characteristics. In the present review, we have summarized the up-to-date studies evaluating the value of cfDNA as potential diagnostic, prognostic, or monitoring biomarker for BC in several biofluids. Full article

(This article belongs to the Special Issue New Solutions for Old Problems. Can Non-Invasive Biomarkers Be the Clue?)

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