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Liquid Biopsy for Clinical Application
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Liquid Biopsy for Clinical Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2017) | Viewed by 117318

Special Issue Editor

Dr. William Cho

grade E-Mail Website
Guest Editor
Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
Interests: cancer biomarker; evidence-based medicine; extracellular vesicles; genomics; microRNA; molecular diagnostics; non-coding RNAs; nasopharyngeal carcinoma; next-generation sequencing; non-small cell lung cancer; proteomics; drug repurposing and bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

In parallel to conventional biopsy and cytology, studies of liquid biopsy provide a non-invasive means for the diagnosis, prognosis and treatment response prediction of diseases. A variety of body fluids are used in clinical analyses, including plasma, serum, pleural effusion, sputum and urine. For example, we can monitor EGFR T790M with plasma DNA from lung cancer patients; predict the prognosis of breast cancer patients by measuring the number of circulating tumor cells/mL in plasma, as well as analyze tumor DNA in urine for patients with non-muscle invasive bladder cancer. Furthermore, advancements in molecular analysis of circulating tumor cells enable measurement down to the single-cell level and some applications are ready to be used in clinical studies.
With the advance of technologies, sensitive detection and application of liquid biopsy has emerged in every medical field. Thus, I would like to call upon high quality work on this important area to shape our current understanding and management of various diseases.

This Special Issue particularly focuses on how liquid biopsy offers solutions to clinical applications, thereby eventually providing accurate diagnoses and prescribing the right drug and right treatment to the right patient.

Original papers and review articles that focus on the latest advances of liquid biopsy are welcome in the following and associated key areas:

  • Circulating cell-free nucleic acids for cancer diagnosis, prognosis and treatment monitoring
  • Circulating cell-free DNA that reflects epigenetic regulation
  • Circulating tumor cells as surrogate markers for systemic cancer
  • Liquid biopsy for cancer screening, patient stratification and monitoring
  • Liquid biopsy for the detection of actionable oncogenic mutations in human cancers
  • Application of next-generation sequencing in liquid biopsy
  • Development of liquid biopsy platforms for the early detection of cancer
  • Liquid biopsy for protein subtyping
  • Urine for disease and drug screening
  • Applications for therapeutic drug monitoring and toxicology

Dr. William Chi-shing Cho
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (16 papers)

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Research

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672 KiB  
Article
Evaluation of MCT1, MCT4 and CD147 Genes in Peripheral Blood Cells of Breast Cancer Patients and Their Potential Use as Diagnostic and Prognostic Markers
by Maria Cláudia de B. Luz, Matheus M. Perez, Ligia A. Azzalis, Luiz Vinícius de A. Sousa, Fernando Adami, Fernando L. A. Fonseca and Beatriz Da C. A. Alves
Int. J. Mol. Sci. 2017, 18(4), 170; https://doi.org/10.3390/ijms18040170 - 23 Mar 2017
Cited by 14 | Viewed by 4283
Abstract
Background: Patients with breast cancer—the deadliest cancer among women—are at constant risk of developing metastasis. Oxidative stress and hypoxia are common feature of tumor cells that can proliferate even in a resultant metabolic acidosis. Despite the low extracellular pH, intracellular pH of tumor [...] Read more.
Background: Patients with breast cancer—the deadliest cancer among women—are at constant risk of developing metastasis. Oxidative stress and hypoxia are common feature of tumor cells that can proliferate even in a resultant metabolic acidosis. Despite the low extracellular pH, intracellular pH of tumor cells remains relatively normal, or even more alkaline due to the action of a membrane protein family known as monocarboxylate transporters (MCTs). The objective of this study was to verify the diagnostic and prognostic value of MCT1, MCT4 and CD147 in tumor and peripheral blood samples of patients with breast cancer undergoing chemotherapic treatment. Methods: Differential expression of MCT1, MCT4 and CD147 obtained by qPCR was determined by 2−ΔΔCq method between biological samples (tumor and serial samples of peripheral) of patients (n = 125) and healthy women (n = 25). Results: tumor samples with higher histological grades have shown higher expression of these markers; this higher expression was also observed in blood samples obtained at diagnosis of patients when compared to healthy women and in patients with positive progression of the disease (metastasis development). Conclusion: markers studied here could be a promising strategy in routine laboratory evaluations as breast cancer diagnosis and prognosis. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1966 KiB  
Article
Perindopril Induces TSP-1 Expression in Hypertensive Patients with Endothelial Dysfunction in Chronic Treatment
by Valentina Buda, Minodora Andor, Lucian Petrescu, Carmen Cristescu, Dana Emilia Baibata, Mirela Voicu, Melania Munteanu, Ioana Citu, Calin Muntean, Octavian Cretu and Mirela Cleopatra Tomescu
Int. J. Mol. Sci. 2017, 18(2), 348; https://doi.org/10.3390/ijms18020348 - 07 Feb 2017
Cited by 14 | Viewed by 5108
Abstract
Thrombospondin-1 (TSP-1) is a potent endogenous inhibitor of both physiological and pathological angiogenesis, widely studied as a target in drug development for treating cancer. Several studies performed in the cardiovascular field on TSP-1 are contradictory, the role of TSP-1 in the physiopathology of [...] Read more.
Thrombospondin-1 (TSP-1) is a potent endogenous inhibitor of both physiological and pathological angiogenesis, widely studied as a target in drug development for treating cancer. Several studies performed in the cardiovascular field on TSP-1 are contradictory, the role of TSP-1 in the physiopathology of cardiovascular disorders (CVDs) being, for the moment, incompletely understood and may be due to the presence of several domains in its structure which can stimulate many cellular receptors. It has been reported to inhibit NO-mediated signaling and to act on the angiogenesis, tissue perfusion, endothelial cell proliferation, and homeostasis, so we aimed to quantify the effect Perindopril has on TSP-1 plasma levels in hypertensive patients with endothelial dysfunction in comparison with other antihypertensive drugs, such as beta blockers, calcium channel blockers, and diuretics, in a chronic treatment. As a conclusion, patients under treatment with Perindopril had increased plasma levels of TSP-1 compared with other hypertensive patients and with the control group. The results of this study confirms the pleiotropic properties of Perindopril: anti-proliferative, anti-inflammatory, with effects showed by quantifying a single biomarker: TSP-1. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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2115 KiB  
Article
Cell-Free RNA Content in Peripheral Blood as Potential Biomarkers for Detecting Circulating Tumor Cells in Non-Small Cell Lung Carcinoma
by Xin-Min Yu, Yi-Chen Wu, Xiang Liu, Xian-Cong Huang, Xiu-Xiu Hou, Jiu-Li Wang, Xiang-Liu Cheng, Wei-Min Mao and Zhi-Qiang Ling
Int. J. Mol. Sci. 2016, 17(11), 1845; https://doi.org/10.3390/ijms17111845 - 05 Nov 2016
Cited by 14 | Viewed by 5095
Abstract
Circulating tumor cells (CTCs) have been implicated in tumor progression and prognosis. Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma (NSCLC) may help to identify individuals likely to benefit from early systemic treatment. However, the detection of [...] Read more.
Circulating tumor cells (CTCs) have been implicated in tumor progression and prognosis. Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma (NSCLC) may help to identify individuals likely to benefit from early systemic treatment. However, the detection of CTCs with a single marker is challenging, owing to low specificity and sensitivity and due to the heterogeneity and rareness of CTCs. Herein, the probability of cell-free RNA content in the peripheral blood as a potential biomarker for detecting CTCs in cancer patients was investigated. An immunomagnetic enrichment of real-time reverse-transcription PCR (RT-PCR) technology for analysis of CTCs in NSCLC patients was also developed. The mRNA levels of four candidate genes, cytokeratin 7 (CK7), E74-like factor 3 (ELF3), epidermal growth factor receptor (EGFR), and erythropoietin-producing hepatocellular carcinoma receptor B4 (EphB4) that were significantly elevated in tumor tissues and peripheral blood mononuclear cells (PBMCs) were determined. The expression of CK7 and ELF3 in tumor tissues and EGFR in PBMCs was associated with lymph node metastasis (all p < 0.05). The expression of CK7 in PBMCs was correlated with age and EphB4 in PBMCs correlated with histopathological type, respectively (all p < 0.05). The expression of all four genes in tumor tissues and PBMCs was significantly correlated with the clinical stage (all p < 0.01). Survival analysis showed that the patients with enhanced expression of CK7, ELF3, EGFR, and EphB4 mRNA in PBMCs had poorer disease-free survival (DFS) and overall survival (OS) than those without (all p < 0.0001). The present study showed that this alteration of cell-free RNA content in peripheral blood might have clinical ramifications in the diagnosis and treatment of NSCLC patients. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1783 KiB  
Article
Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy
by Mónica Alejandra Anaya-Segura, Héctor Rangel-Villalobos, Gabriela Martínez-Cortés, Benjamín Gómez-Díaz, Ramón Mauricio Coral-Vázquez, Edgar Oswaldo Zamora-González, Silvia García and Luz Berenice López-Hernández
Int. J. Mol. Sci. 2016, 17(8), 1334; https://doi.org/10.3390/ijms17081334 - 13 Aug 2016
Cited by 12 | Viewed by 5729
Abstract
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence [...] Read more.
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a “liquid biopsy” for carrier detection and genetic counseling in DMD. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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640 KiB  
Article
Serum Concentrations of Endothelin-1 and Matrix Metalloproteinases-2, -9 in Pre-Hypertensive and Hypertensive Patients with Type 2 Diabetes
by Krasimir Kostov, Alexander Blazhev, Milena Atanasova and Anelia Dimitrova
Int. J. Mol. Sci. 2016, 17(8), 1182; https://doi.org/10.3390/ijms17081182 - 01 Aug 2016
Cited by 26 | Viewed by 6427
Abstract
Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known to date. While its plasma or serum concentrations are elevated in some forms of experimental and human hypertension, this is not a consistent finding in all forms of hypertension. Matrix metalloproteinases -2 and [...] Read more.
Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known to date. While its plasma or serum concentrations are elevated in some forms of experimental and human hypertension, this is not a consistent finding in all forms of hypertension. Matrix metalloproteinases -2 and -9 (MMP-2 and MMP-9), which degrade collagen type IV of the vascular basement membrane, are responsible for vascular remodeling, inflammation, and atherosclerotic complications, including in type 2 diabetes (T2D). In our study, we compared concentrations of ET-1, MMP-2, and MMP-9 in pre-hypertensive (PHTN) and hypertensive (HTN) T2D patients with those of healthy normotensive controls (N). ET-1, MMP-2, and MMP-9 were measured by ELISA. Concentrations of ET-1 in PHTN and N were very similar, while those in HTN were significantly higher. Concentrations of MMP-2 and MMP-9 in PHTN and HTN were also significantly higher compared to N. An interesting result in our study is that concentrations of MMP-2 and MMP-9 in HTN were lower compared to PHTN. In conclusion, we showed that increased production of ET-1 in patients with T2D can lead to long-lasting increases in blood pressure (BP) and clinical manifestation of hypertension. We also demonstrated that increased levels of MMP-2 and MMP-9 in pre-hypertensive and hypertensive patients with T2D mainly reflect the early vascular changes in extracellular matrix (ECM) turnover. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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226 KiB  
Article
Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma
by Lian-Hua Cui, Zhen-Yu Quan, Jin-Mei Piao, Ting-Ting Zhang, Meng-Hui Jiang, Min-Ho Shin and Jin-Su Choi
Int. J. Mol. Sci. 2016, 17(7), 1032; https://doi.org/10.3390/ijms17071032 - 30 Jun 2016
Cited by 23 | Viewed by 4909
Abstract
Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 [...] Read more.
Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60), 0.33 (0.17–0.65), and 0.19 (0.09–0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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Article
Elevated Preoperative Serum Alanine Aminotransferase/Aspartate Aminotransferase (ALT/AST) Ratio Is Associated with Better Prognosis in Patients Undergoing Curative Treatment for Gastric Adenocarcinoma
by Shu-Lin Chen, Jian-Pei Li, Lin-Fang Li, Tao Zeng and Xia He
Int. J. Mol. Sci. 2016, 17(6), 911; https://doi.org/10.3390/ijms17060911 - 09 Jun 2016
Cited by 39 | Viewed by 6225
Abstract
The level of anine aminotransferase/aspartate aminotransferase (ALT/AST) ratio in the serum was often used to assess liver injury. Whether the ALT/AST ratio (LSR) was associated with prognosis for gastric adenocarcinoma (GA) has not been reported in the literature. Our aim was to investigate [...] Read more.
The level of anine aminotransferase/aspartate aminotransferase (ALT/AST) ratio in the serum was often used to assess liver injury. Whether the ALT/AST ratio (LSR) was associated with prognosis for gastric adenocarcinoma (GA) has not been reported in the literature. Our aim was to investigate the prognostic value of the preoperative LSR in patients with GA. A retrospective study was performed in 231 patients with GA undergoing curative resection. The medical records collected include clinical information and laboratory results. We investigated the correlations between the preoperative LSR and overall survival (OS). Survival analysis was conducted with the Kaplan–Meier method, and Cox regression analysis was used to determine significant independent prognostic factors for predicting survival. A p value of <0.05 was considered to be statistically significant. A total of 231 patients were finally enrolled. The median overall survival was 47 months. Multivariate analysis indicated that preoperative LSR was an independent prognostic factor in GA. Patients with LSR ≤ 0.80 had a greater risk of death than those with LSR > 0.80. The LSR was independently associated with OS in patients with GA (hazard ratio: 0.610; 95% confidence interval: 0.388–0.958; p = 0.032), along with tumor stages (hazard ratio: 3.118; 95% confidence interval: 2.044–4.756; p < 0.001) and distant metastases (hazard ratio: 1.957; 95% confidence interval: 1.119–3.422; p = 0.019). Our study first established a connection between the preoperative LSR and patients undergoing curative resection for GA, suggesting that LSR was a simple, inexpensive, and easily measurable marker as a prognostic factor, and may help to identify high-risk patients for treatment decisions. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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2158 KiB  
Article
Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients
by Ying-Hsien Huang, Ho-Chang Kuo, Fu-Chen Huang, Hong-Ren Yu, Kai-Sheng Hsieh, Ya-Ling Yang, Jiunn-Ming Sheen, Sung-Chou Li and Hsing-Chun Kuo
Int. J. Mol. Sci. 2016, 17(5), 715; https://doi.org/10.3390/ijms17050715 - 12 May 2016
Cited by 28 | Viewed by 7336
Abstract
Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found [...] Read more.
Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD’s acute inflammatory phase. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1486 KiB  
Article
Characterization of Micro-RNA Changes during the Progression of Type 2 Diabetes in Zucker Diabetic Fatty Rats
by Denis Delic, Claudia Eisele, Ramona Schmid, Gerd Luippold, Eric Mayoux and Rolf Grempler
Int. J. Mol. Sci. 2016, 17(5), 665; https://doi.org/10.3390/ijms17050665 - 03 May 2016
Cited by 49 | Viewed by 6452
Abstract
The aim of the present pilot study was the identification of micro-RNA changes over time during the development and progression of type 2 diabetes (T2D) in Zucker diabetic fatty rats (ZDF rats). T2D is a complex metabolic disorder that is characterized, inter alia [...] Read more.
The aim of the present pilot study was the identification of micro-RNA changes over time during the development and progression of type 2 diabetes (T2D) in Zucker diabetic fatty rats (ZDF rats). T2D is a complex metabolic disorder that is characterized, inter alia, by progressive failure of pancreatic β cells to produce insulin, but also by functional or morphological modifications of others organ, such as liver, adipose tissue and the cardiovascular system. Micro-RNAs are a novel class of biomarkers that have the potential to represent biomarkers of disease progression. In this study, the onset and progression of diabetes was followed in ZDF rats from six weeks until 17 weeks of age. After an initial phase of hyperinsulinemia, the animals developed T2D and lost the capacity to produce sufficient insulin. Circulating miRNAs were measured from plasma samples at four time points: pre-diabetes (six weeks of age), hyperinsulinemia (eight weeks), β cell failure (11 weeks) and late-stage diabetes (17 weeks) using TaqMan miRNA arrays. Bioinformatic analysis revealed distinct changes of circulating miRNAs over time. Several miRNAs were found to be increased over the course of the disease progression, such as miR-122, miR-133, miR-210 and miR-375. The most significantly decreased miRNAs were miR-140, miR-151-3p, miR-185, miR-203, miR-434-3p and miR-450a. Some of the miRNAs have also been identified in type 2 diabetic patients recently and, therefore, may have the potential to be useful biomarkers for the disease progression of T2D and/or the treatment response for anti-diabetic medications. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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Review

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1386 KiB  
Review
EDIM-TKTL1/Apo10 Blood Test: An Innate Immune System Based Liquid Biopsy for the Early Detection, Characterization and Targeted Treatment of Cancer
by Johannes F. Coy
Int. J. Mol. Sci. 2017, 18(4), 878; https://doi.org/10.3390/ijms18040878 - 20 Apr 2017
Cited by 15 | Viewed by 8469
Abstract
Epitope detection in monocytes (EDIM) represents a liquid biopsy exploiting the innate immune system. Activated monocytes (macrophages) phagocytose unwanted cells/cell fragments from the whole body including solid tissues. As they return to the blood, macrophages can be used for a non-invasive detection of [...] Read more.
Epitope detection in monocytes (EDIM) represents a liquid biopsy exploiting the innate immune system. Activated monocytes (macrophages) phagocytose unwanted cells/cell fragments from the whole body including solid tissues. As they return to the blood, macrophages can be used for a non-invasive detection of biomarkers, thereby providing high sensitivity and specificity, because the intracellular presence of biomarkers is due to an innate immune response. Flow cytometry analysis of blood enables the detection of macrophages and phagocytosed intracellular biomarkers. In order to establish a pan-cancer test, biomarkers for two fundamental biophysical mechanisms have been exploited. The DNaseX/Apo10 protein epitope is a characteristic of tumor cells with abnormal apoptosis and proliferation. Transketolase-like 1 (TKTL1) is a marker for an anaerobic glucose metabolism (Warburg effect), which is concomitant with invasive growth/metastasis and resistant to radical and apoptosis inducing therapies. The detection of Apo10 and TKTL1 in blood macrophages allowed a sensitive (95.8%) and specific (97.3%) detection of prostate, breast and oral squamous cell carcinomas. Since TKTL1 represents a drugable target, the EDIM based detection of TKTL1 enables a targeted cancer therapy using the vitamin derivatives oxythiamine or benfo-oxythiamine. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1357 KiB  
Review
Analysis of DNA Methylation Status in Bodily Fluids for Early Detection of Cancer
by Keigo Yokoi, Keishi Yamashita and Masahiko Watanabe
Int. J. Mol. Sci. 2017, 18(4), 735; https://doi.org/10.3390/ijms18040735 - 30 Mar 2017
Cited by 26 | Viewed by 6695
Abstract
Epigenetic alterations by promoter DNA hypermethylation and gene silencing in cancer have been reported over the past few decades. DNA hypermethylation has great potential to serve as a screening marker, a prognostic marker, and a therapeutic surveillance marker in cancer clinics. Some bodily [...] Read more.
Epigenetic alterations by promoter DNA hypermethylation and gene silencing in cancer have been reported over the past few decades. DNA hypermethylation has great potential to serve as a screening marker, a prognostic marker, and a therapeutic surveillance marker in cancer clinics. Some bodily fluids, such as stool or urine, were obtainable without any invasion to the body. Thus, such bodily fluids were suitable samples for high throughput cancer surveillance. Analyzing the methylation status of bodily fluids around the cancer tissue may, additionally, lead to the early detection of cancer, because several genes in cancer tissues are reported to be cancer-specifically hypermethylated. Recently, several studies that analyzed the methylation status of DNA in bodily fluids were conducted, and some of the results have potential for future development and further clinical use. In fact, a stool DNA test was approved by the U.S. Food and Drug Administration (FDA) for the screening of colorectal cancer. Another promising methylation marker has been identified in various bodily fluids for several cancers. We reviewed studies that analyzed DNA methylation in bodily fluids as a less-invasive cancer screening. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1722 KiB  
Review
Circulating Cell Free Tumor DNA Detection as a Routine Tool forLung Cancer Patient Management
by Julie A. Vendrell, Frédéric Tran Mau-Them, Benoît Béganton, Sylvain Godreuil, Peter Coopman and Jérôme Solassol
Int. J. Mol. Sci. 2017, 18(2), 264; https://doi.org/10.3390/ijms18020264 - 29 Jan 2017
Cited by 75 | Viewed by 9387
Abstract
Circulating tumoral DNA (ctDNA), commonly named “liquid biopsy”, has emerged as a new promising noninvasive tool to detect biomarker in several cancers including lung cancer. Applications involving molecular analysis of ctDNA in lung cancer have increased and encompass diagnosis, response to treatment, acquired [...] Read more.
Circulating tumoral DNA (ctDNA), commonly named “liquid biopsy”, has emerged as a new promising noninvasive tool to detect biomarker in several cancers including lung cancer. Applications involving molecular analysis of ctDNA in lung cancer have increased and encompass diagnosis, response to treatment, acquired resistance and prognosis prediction, while bypassing the problem of tumor heterogeneity. ctDNA may then help perform dynamic genetic surveillance in the era of precision medicine through indirect tumoral genomic information determination. The aims of this review were to examine the recent technical developments that allowed the detection of genetic alterations of ctDNA in lung cancer. Furthermore, we explored clinical applications in patients with lung cancer including treatment efficiency monitoring, acquired therapy resistance mechanisms and prognosis value. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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1072 KiB  
Review
Cancer Salivary Biomarkers for Tumours Distant to the Oral Cavity
by Óscar Rapado-González, Blanca Majem, Laura Muinelo-Romay, Rafa López-López and María Mercedes Suarez-Cunqueiro
Int. J. Mol. Sci. 2016, 17(9), 1531; https://doi.org/10.3390/ijms17091531 - 12 Sep 2016
Cited by 26 | Viewed by 8861
Abstract
The analysis of saliva as a diagnostic approach for systemic diseases was proposed just two decades ago, but recently great interest in the field has emerged because of its revolutionary potential as a liquid biopsy and its usefulness as a non-invasive sampling method. [...] Read more.
The analysis of saliva as a diagnostic approach for systemic diseases was proposed just two decades ago, but recently great interest in the field has emerged because of its revolutionary potential as a liquid biopsy and its usefulness as a non-invasive sampling method. Multiple molecules isolated in saliva have been proposed as cancer biomarkers for diagnosis, prognosis, drug monitoring and pharmacogenetic studies. In this review, we focus on the current status of the salivary diagnostic biomarkers for different cancers distant to the oral cavity, noting their potential use in the clinic and their applicability in personalising cancer therapies. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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221 KiB  
Review
Circulating MicroRNAs: A Next-Generation Clinical Biomarker for Digestive System Cancers
by Tsutomu Kawaguchi, Shuhei Komatsu, Daisuke Ichikawa, Masahiro Tsujiura, Hiroki Takeshita, Shoji Hirajima, Mahito Miyamae, Wataru Okajima, Takuma Ohashi, Taisuke Imamura, Jun Kiuchi, Hirotaka Konishi, Atsushi Shiozaki, Kazuma Okamoto and Eigo Otsuji
Int. J. Mol. Sci. 2016, 17(9), 1459; https://doi.org/10.3390/ijms17091459 - 01 Sep 2016
Cited by 70 | Viewed by 6990
Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that post-transcriptionally regulate gene expression and play important roles in various physiological and developmental processes such as oncogenic or tumor suppressive regulators. Specific miRNA expression signatures have been identified in a number of human cancers. Cell-free miRNAs [...] Read more.
MicroRNAs (miRNAs) are short noncoding RNAs that post-transcriptionally regulate gene expression and play important roles in various physiological and developmental processes such as oncogenic or tumor suppressive regulators. Specific miRNA expression signatures have been identified in a number of human cancers. Cell-free miRNAs have recently been stably detected in plasma and serum (circulating miRNAs), and their presence in blood has attracted the attention of researchers due to their potential as non-invasive biomarkers. Circulating miRNAs have emerged as tumor-associated biomarkers that reflect not only the existence of early-stage tumors, but also the dynamics and status of advanced stage tumors, tumor recurrence, and drug sensitivities. This methodology for liquid biopsy may provide non-invasive and reproductive biomarkers and individualized therapeutic strategies for cancer patients. We herein review the current phase of biological and clinical research on the circulating miRNAs of solid cancers, particularly digestive tract cancers, and discuss future perspectives. The present review may be beneficial for future research on miRNAs used to detect various cancers. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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Review
Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand?
by Paola Ulivi
Int. J. Mol. Sci. 2016, 17(7), 1186; https://doi.org/10.3390/ijms17071186 - 22 Jul 2016
Cited by 20 | Viewed by 6149
Abstract
The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific [...] Read more.
The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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Review
New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies
by Erika Larrea, Carla Sole, Lorea Manterola, Ibai Goicoechea, María Armesto, María Arestin, María M. Caffarel, Angela M. Araujo, María Araiz, Marta Fernandez-Mercado and Charles H. Lawrie
Int. J. Mol. Sci. 2016, 17(5), 627; https://doi.org/10.3390/ijms17050627 - 27 Apr 2016
Cited by 198 | Viewed by 17732
Abstract
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer [...] Read more.
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these “liquid biopsies” ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice. Full article
(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)
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