Special Issue "Novel Biomarkers of Gastrointestinal Cancer"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 14358

Special Issue Editor

Dr. Takaya Shimura
E-Mail Website
Guest Editor
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan
Interests: urinary biomarkers for gastrointestinal cancer; serum biomarkers for gastrointestinal cancer; liquid biopsy for gastrointestinal cancer; protein biomarkers; miRNA biomarkers; exosomal biomarkers; genetic biomarkers; tumor microenvironment; angiogenesis

Special Issue Information

Dear Colleagues, 

Gastrointestinal (GI) cancer is a major cause of morbidity and mortality in the world. Since early diagnosis and optimal treatment selection are crucial to improve the prognosis of these diseases, the discovery of useful biomarkers has the potential to greatly reduce their burden. Recent technical and mechanical developments have enabled detecting tiny differences in various factors that are modified in physical condition, which might contribute to novel biomarker discovery for some diseases.  

In this Special Issue, we focus on novel biomarkers for GI cancers, including esophageal cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, biliary cancer, and small intestinal cancer. In addition, any samples (tissue, blood, urine, feces, saliva, gastric juice, bile, pancreatic juice, and so on) are welcome as biomarker sources, although body-fluid-based biomarkers are promising as diagnostic biomarkers due to their noninvasiveness. This Special Issue aims to collect novel insights to clarify the current situation and future perspective in this field.

Dr. Takaya Shimura
Guest Editor

Manuscript Submission Information

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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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). 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.

Keywords

  • diagnostic biomarkers for gastrointestinal cancer
  • prognostic biomarkers for gastrointestinal cancer
  • biomarkers to help decision making for gastrointestinal cancer
  • predictive biomarkers for therapeutic outcomes including efficacy and adverse events

Published Papers (14 papers)

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Editorial

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Editorial
Novel Biomarkers of Gastrointestinal Cancer
Cancers 2021, 13(7), 1501; https://doi.org/10.3390/cancers13071501 - 25 Mar 2021
Cited by 1 | Viewed by 721
Abstract
Gastrointestinal (GI) cancer is a major cause of morbidity and mortality worldwide [...] Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)

Research

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Article
A Novel Urinary miRNA Biomarker for Early Detection of Colorectal Cancer
Cancers 2022, 14(2), 461; https://doi.org/10.3390/cancers14020461 - 17 Jan 2022
Cited by 1 | Viewed by 882
Abstract
Since noninvasive biomarkers as an alternative to invasive colonoscopy to detect colorectal cancer (CRC) are desired, we conducted this study to determine the urinary biomarker consisting of microRNAs (miRNAs). In total, 415 age- and sex-matched participants, including 206 patients with CRC and 209 [...] Read more.
Since noninvasive biomarkers as an alternative to invasive colonoscopy to detect colorectal cancer (CRC) are desired, we conducted this study to determine the urinary biomarker consisting of microRNAs (miRNAs). In total, 415 age- and sex-matched participants, including 206 patients with CRC and 209 healthy controls (HCs), were randomly divided into three groups: (1) the discovery cohort (CRC, n = 3; HC, n = 6); (2) the training cohort (140 pairs); and (3) the validation cohort (63 pairs). Among 11 urinary miRNAs with aberrant expressions between the two groups, miR-129-1-3p and miR-566 were significantly independent biomarkers that detect CRC. The panel consisting of two miRNAs could distinguish patients with CRC from HC participants with an area under the curve (AUC) = 0.811 in the training cohort. This panel showed good efficacy with an AUC = 0.868 in the validation cohort. This urinary biomarker combining miR-129-1-3p and miR-566 could detect even stage 0/I CRC effectively with an AUC = 0.845. Moreover, the expression levels of both miR-129-1-3p and miR-566 were significantly higher in primary tumor tissues than in adjacent normal tissue. Our established novel biomarker consisting of urinary miR-129-1-3p and miR-566 enables noninvasive and early detection of CRC. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Predict Early Recurrence of Resectable Hepatocellular Carcinoma Using Multi-Dimensional Artificial Intelligence Analysis of Liver Fibrosis
Cancers 2021, 13(21), 5323; https://doi.org/10.3390/cancers13215323 - 23 Oct 2021
Viewed by 749
Abstract
Background: Liver fibrosis is thought to be associated with early recurrence of hepatocellular carcinoma (HCC) after resection. To recognize HCC patients with higher risk of early recurrence, we used a second harmonic generation and two-photon excitation fluorescence (SHG/TPEF) microscopy to create a fully [...] Read more.
Background: Liver fibrosis is thought to be associated with early recurrence of hepatocellular carcinoma (HCC) after resection. To recognize HCC patients with higher risk of early recurrence, we used a second harmonic generation and two-photon excitation fluorescence (SHG/TPEF) microscopy to create a fully quantitative fibrosis score which is able to predict early recurrence. Methods: The study included 81 HCC patients receiving curative intent hepatectomy. Detailed fibrotic features of resected hepatic tissues were obtained by SHG/TPEF microscopy, and we used multi-dimensional artificial intelligence analysis to create a recurrence prediction model “combined index” according to the morphological collagen features of each patient’s non-tumor hepatic tissues. Results: Our results showed that the “combined index” can better predict early recurrence (area under the curve = 0.917, sensitivity = 81.8%, specificity = 90.5%), compared to alpha fetoprotein level (area under the curve = 0.595, sensitivity = 68.2%, specificity = 47.6%). Using a Cox proportional hazards analysis, a higher “combined index” is also a poor prognostic factor of disease-free survival and overall survival. Conclusions: By integrating multi-dimensional artificial intelligence and SHG/TPEF microscopy, we may locate patients with a higher risk of recurrence, follow these patients more carefully, and conduct further management if needed. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Bacteria-Derived Extracellular Vesicles in Urine as a Novel Biomarker for Gastric Cancer: Integration of Liquid Biopsy and Metagenome Analysis
Cancers 2021, 13(18), 4687; https://doi.org/10.3390/cancers13184687 - 18 Sep 2021
Cited by 1 | Viewed by 914
Abstract
Early detection is crucial for improving the prognosis of gastric cancer, but there are no non-invasive markers for the early diagnosis of gastric cancer in real clinical settings. Recently, bacteria-derived extracellular vesicles (EVs) emerged as new biomarker resources. We aimed to evaluate the [...] Read more.
Early detection is crucial for improving the prognosis of gastric cancer, but there are no non-invasive markers for the early diagnosis of gastric cancer in real clinical settings. Recently, bacteria-derived extracellular vesicles (EVs) emerged as new biomarker resources. We aimed to evaluate the microbial composition in gastric cancer using bacteria-derived EVs and to build a diagnostic prediction model for gastric cancer with the metagenome data. Stool, urine, and serum samples were prospectively collected from 453 subjects (gastric cancer, 181; control, 272). EV portions were extracted from the samples for metagenome analysis. Differences in microbial diversity and composition were analyzed with 16S rRNA gene profiling, using the next-generation sequencing method. Biomarkers were selected using logistic regression models based on relative abundances at the genus level. The microbial composition of healthy groups and gastric cancer patient groups was significantly different in all sample types. The compositional differences of various bacteria, based on relative abundances, were identified at the genus level. Among the diagnostic prediction models for gastric cancer, the urine-based model showed the highest performance when compared to that of stool or serum. We suggest that bacteria-derived EVs in urine can be used as novel metagenomic markers for the non-invasive diagnosis of gastric cancer by integrating the liquid biopsy method and metagenome analysis. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Mutations in Epigenetic Regulation Genes in Gastric Cancer
Cancers 2021, 13(18), 4586; https://doi.org/10.3390/cancers13184586 - 13 Sep 2021
Viewed by 830
Abstract
We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, [...] Read more.
We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, while the majority (n = 41), in histone modifier genes, among which mutations were most commonly found in KMT2D and KMT2C. Somatic mutations in KMT2D, KMT2C, ARID1A and CHD7 were mutually exclusive (p = 0.038). Mutations in ARID1A were associated with distant metastases (p = 0.03). The overall survival of patients in the group with metastases and in the group with tumors with signet ring cells was significantly reduced in the presence of mutations in epigenetic regulation genes (p = 0.036 and p = 0.041, respectively). Separately, somatic mutations in chromatin remodeling genes correlate with low survival rate of patients without distant metastasis (p = 0.045) and in the presence of signet ring cells (p = 0.0014). Our results suggest that mutations in epigenetic regulation genes may be valuable clinical markers and deserve further exploration in independent cohorts. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma
Cancers 2021, 13(17), 4443; https://doi.org/10.3390/cancers13174443 - 03 Sep 2021
Cited by 3 | Viewed by 770
Abstract
Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer [...] Read more.
Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer
Cancers 2021, 13(14), 3642; https://doi.org/10.3390/cancers13143642 - 20 Jul 2021
Cited by 2 | Viewed by 1002
Abstract
The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response [...] Read more.
The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Prognostic Significance of CXCR4 in Colorectal Cancer: An Updated Meta-Analysis and Critical Appraisal
Cancers 2021, 13(13), 3284; https://doi.org/10.3390/cancers13133284 - 30 Jun 2021
Cited by 1 | Viewed by 782
Abstract
Background: This study was conducted to provide an updated estimate of the prognostic power of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC), and analyze modalities of evaluating and reporting its expression. Methods: A systematic review with meta-analysis was performed and [...] Read more.
Background: This study was conducted to provide an updated estimate of the prognostic power of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC), and analyze modalities of evaluating and reporting its expression. Methods: A systematic review with meta-analysis was performed and described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies were identified through PubMed and Google Scholar. The pooled hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS) with 95% confidence interval (CI) were estimated with the random-effect model. Results: Sixteen studies were selected covering a period from 2005 to 2020. An immunohistochemical evaluation of CXCR4 was performed in all studies. Only in three studies assessment of mRNA through RT–PCR was correlated with prognosis; in the remaining studies, the authors identified prognostic categories based on immunohistochemical expression. In pooled analyses, significant associations were found between positive or high or strong expression of CXCR4 and T stage ≥3 (P = 0.0001), and positive or high or strong expression of CXCR4 and left side primary tumor localization (P = 0.0186). The pooled HR for OS was 2.09 (95% CI: 1.30–2.88) in favor of high CXCR4 expression; for PFS, it was 1.42 (95% CI: 1.13–1.71) in favor of high CXCR4 expression. Conclusion: High CXCR4 expression is clearly associated with increased risk of death and progression in CRC. However, strong methodologic heterogeneity in CXCR4 assessment hinders direct translation into clinical practice; thus, a consensus to streamline detection and scoring of CXCR4 expression in CRC is indicated. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Detection of Hepatocellular Carcinoma in a High-Risk Population by a Mass Spectrometry-Based Test
Cancers 2021, 13(13), 3109; https://doi.org/10.3390/cancers13133109 - 22 Jun 2021
Cited by 2 | Viewed by 911
Abstract
Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer-related death. Guidelines recommend obtaining a screening ultrasound with or without alpha-fetoprotein (AFP) every 6 months in at-risk adults. AFP as a screening biomarker is plagued by low sensitivity/specificity, prompting interest in [...] Read more.
Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer-related death. Guidelines recommend obtaining a screening ultrasound with or without alpha-fetoprotein (AFP) every 6 months in at-risk adults. AFP as a screening biomarker is plagued by low sensitivity/specificity, prompting interest in discovering alternatives. Mass spectrometry-based techniques are promising in their ability to identify potential biomarkers. This study aimed to use machine learning utilizing spectral data and AFP to create a model for early detection. Serum samples were collected from three separate cohorts, and data were compiled to make Development, Internal Validation, and Independent Validation sets. AFP levels were measured, and Deep MALDI® analysis was used to generate mass spectra. Spectral data were input into the VeriStrat® classification algorithm. Machine learning techniques then classified each sample as “Cancer” or “No Cancer”. Sensitivity and specificity of the test were >80% to detect HCC. High specificity of the test was independent of cause and severity of underlying disease. When compared to AFP, there was improved cancer detection for all tumor sizes, especially small lesions. Overall, a machine learning algorithm incorporating mass spectral data and AFP values from serum samples offers a novel approach to diagnose HCC. Given the small sample size of the Independent Validation set, a further independent, prospective study is warranted. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Article
Multitarget Stool mRNA Test for Detecting Colorectal Cancer Lesions Including Advanced Adenomas
Cancers 2021, 13(6), 1228; https://doi.org/10.3390/cancers13061228 - 11 Mar 2021
Cited by 2 | Viewed by 1008
Abstract
Current approved non-invasive screening methods for colorectal cancer (CRC) include FIT and DNA-FIT testing, but their efficacy for detecting precancerous lesions that are susceptible to progressing to CRC such as advanced adenomas (AA) remains limited, thus requiring further options to improve the detection [...] Read more.
Current approved non-invasive screening methods for colorectal cancer (CRC) include FIT and DNA-FIT testing, but their efficacy for detecting precancerous lesions that are susceptible to progressing to CRC such as advanced adenomas (AA) remains limited, thus requiring further options to improve the detection of CRC lesions at earlier stages. One of these is host mRNA stool testing. The aims of the present study were to identify specific stool mRNA targets that can predict AA and to investigate their stability under a clinical-like setting. A panel of mRNA targets was tested on stool samples obtained from 102 patients including 78 CRC stage I-III and 24 AA as well as 32 healthy controls. Area under the receiver operating characteristic (ROC) curves were calculated to establish sensitivities and specificities for individual and combined targets. Stability experiments were performed on freshly obtained specimens. Six of the tested targets were found to be specifically increased in the stools of patients with CRC and three in the stools of both AA and CRC patients. After optimization for the choice of the 5 best markers for AA and CRC, ROC curve analysis revealed overall sensitivities of 75% and 89% for AA and CRC, respectively, for a ≥95% specificity, and up to 75% and 95% for AA and CRC, respectively, when combined with the FIT score. Targets were found to be stable in the stools up to 3 days at room temperature. In conclusion, these studies show that the detection of host mRNA in the stools is a valid approach for the screening of colorectal cancerous lesions at all stages and is applicable to a clinical-like setup. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Review

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Review
Novel Biomarkers of Gastric Adenocarcinoma: Current Research and Future Perspectives
Cancers 2021, 13(22), 5660; https://doi.org/10.3390/cancers13225660 - 12 Nov 2021
Cited by 4 | Viewed by 1083
Abstract
Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first [...] Read more.
Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first molecular targeted agent approved for gastric cancer treatment. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are VEGF and Claudin 18.2. Expression of MET has been shown to be a negative prognostic factor in gastric cancer. Targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors has proven efficacy in advanced gastric cancer. Recent technology advances allow the detection of circulating tumor cells that may be used as diagnostic and prognostic indicators and for therapy monitoring in gastric cancer patients. Prognostic molecular subtypes of gastric cancer have been identified using genomic data. In addition, transcriptome profiling has allowed a comprehensive characterization of the immune and stromal microenvironment in gastric cancer and development of novel risk scores. These prognostic and predictive markers highlight the rapidly evolving field of research in gastric cancer, promising improved treatment stratification and identification of molecular targets for individualized treatment in gastric cancer. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
Review
Challenges for Better Diagnosis and Management of Pancreatic and Biliary Tract Cancers Focusing on Blood Biomarkers: A Systematic Review
Cancers 2021, 13(16), 4220; https://doi.org/10.3390/cancers13164220 - 23 Aug 2021
Cited by 1 | Viewed by 981
Abstract
Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for [...] Read more.
Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Review
Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma
Cancers 2021, 13(16), 4097; https://doi.org/10.3390/cancers13164097 - 14 Aug 2021
Cited by 2 | Viewed by 1104
Abstract
Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction [...] Read more.
Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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Other

Systematic Review
Risk-Predictive and Diagnostic Biomarkers for Colorectal Cancer; a Systematic Review of Studies Using Pre-Diagnostic Blood Samples Collected in Prospective Cohorts and Screening Settings
Cancers 2021, 13(17), 4406; https://doi.org/10.3390/cancers13174406 - 31 Aug 2021
Cited by 4 | Viewed by 1159
Abstract
This systematic review summarizes the evidence for blood-based colorectal cancer biomarkers from studies conducted in pre-diagnostic, asymptomatic settings. Of 1372 studies initially identified, the final selection included 30 studies from prospective cohorts and 23 studies from general screening settings. Overall, the investigations had [...] Read more.
This systematic review summarizes the evidence for blood-based colorectal cancer biomarkers from studies conducted in pre-diagnostic, asymptomatic settings. Of 1372 studies initially identified, the final selection included 30 studies from prospective cohorts and 23 studies from general screening settings. Overall, the investigations had high quality but considerable variability in data analysis and presentation of results, and few biomarkers demonstrated a clinically relevant discriminatory ability. One of the most promising biomarkers was the anti-p53 antibody, with consistent findings in one screening cohort and in the 3–4 years prior to diagnosis in two prospective cohort studies. Proteins were the most common type of biomarker assessed, particularly carcinoembryonic antigen (CEA) and C-reactive protein (CRP), with modest results. Other potentially promising biomarkers included proteins, such as AREG, MIC-1/GDF15, LRG1 and FGF-21, metabolites and/or metabolite profiles, non-coding RNAs and DNA methylation, as well as re-purposed routine lab tests, such as ferritin and the triglyceride–glucose index. Biomarker panels generally achieved higher discriminatory performance than single markers. In conclusion, this systematic review highlighted anti-p53 antibodies as a promising blood-based biomarker for use in colorectal cancer screening panels, together with other specific proteins. It also underscores the need for validation of promising biomarkers in independent pre-diagnostic settings. Full article
(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)
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