International Journal of Molecular Sciences

Editorial

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3 pages, 160 KiB

Open AccessEditorial

Special Issue on Basic and Translational Research in Colorectal Cancer

by Paola Ulivi, Emanuela Scarpi and Alessandro Passardi

Int. J. Mol. Sci. 2019, 20(12), 3095; https://doi.org/10.3390/ijms20123095 - 25 Jun 2019

Cited by 1 | Viewed by 3635

Abstract

The present editorial aims to summarize the 17 scientific papers that have contributed to this Special Issue focusing on different aspects of basic and translational research in colorectal cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

Research

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16 pages, 946 KiB

Open AccessArticle

Clinical and Molecular Comparative Study of Colorectal Cancer Based on Age-of-Onset and Tumor Location: Two Main Criteria for Subclassifying Colorectal Cancer

by Edurne Álvaro, Juana M. Cano, Juan L. García, Lorena Brandáriz, Susana Olmedillas-López, María Arriba, Daniel Rueda, Yolanda Rodríguez, Ángel Cañete, Julia Arribas, Lucía Inglada-Pérez, Jessica Pérez, Carlos Gómez, Mariano García-Arranz, Damián García-Olmo, Ajay Goel, Miguel Urioste, Rogelio González-Sarmiento and José Perea

Int. J. Mol. Sci. 2019, 20(4), 968; https://doi.org/10.3390/ijms20040968 - 22 Feb 2019

Cited by 26 | Viewed by 4959

Abstract

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared [...] Read more.

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared each tumor location between both ages-of-onset. In right-sided colon tumors, early-onset cases showed extensive Lynch syndrome (LS) features, with a relatively low frequency of chromosomal instability (CIN), but a high CpG island methylation phenotype. Nevertheless, late-onset cases showed predominantly sporadic features and microsatellite instability cases due to BRAF mutations. In left colon cancers, the most reliable clinical features were the tendency to develop polyps as well as multiple primary CRC associated with the late-onset subset. Apart from the higher degree of CIN in left-sided early-onset cancers, differential copy number alterations were also observed. Differences among rectal cancers showed that early-onset rectal cancers were diagnosed at later stages, had less association with polyps, and more than half of them were associated with a familial LS component. Stratifying CRC according to both location and age-of-onset criteria is meaningful, not only because it correlates the resulting categories with certain molecular bases, but with the confirmation across larger studies, new therapeutical algorithms could be defined according to this subclassification. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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15 pages, 4960 KiB

Open AccessArticle

High-Throughput Omics and Statistical Learning Integration for the Discovery and Validation of Novel Diagnostic Signatures in Colorectal Cancer

by Nguyen Phuoc Long, Seongoh Park, Nguyen Hoang Anh, Tran Diem Nghi, Sang Jun Yoon, Jeong Hill Park, Johan Lim and Sung Won Kwon

Int. J. Mol. Sci. 2019, 20(2), 296; https://doi.org/10.3390/ijms20020296 - 12 Jan 2019

Cited by 33 | Viewed by 6115

Abstract

The advancement of bioinformatics and machine learning has facilitated the discovery and validation of omics-based biomarkers. This study employed a novel approach combining multi-platform transcriptomics and cutting-edge algorithms to introduce novel signatures for accurate diagnosis of colorectal cancer (CRC). Different random forests (RF)-based [...] Read more.

The advancement of bioinformatics and machine learning has facilitated the discovery and validation of omics-based biomarkers. This study employed a novel approach combining multi-platform transcriptomics and cutting-edge algorithms to introduce novel signatures for accurate diagnosis of colorectal cancer (CRC). Different random forests (RF)-based feature selection methods including the area under the curve (AUC)-RF, Boruta, and Vita were used and the diagnostic performance of the proposed biosignatures was benchmarked using RF, logistic regression, naïve Bayes, and k-nearest neighbors models. All models showed satisfactory performance in which RF appeared to be the best. For instance, regarding the RF model, the following were observed: mean accuracy 0.998 (standard deviation (SD) < 0.003), mean specificity 0.999 (SD < 0.003), and mean sensitivity 0.998 (SD < 0.004). Moreover, proposed biomarker signatures were highly associated with multifaceted hallmarks in cancer. Some biomarkers were found to be enriched in epithelial cell signaling in Helicobacter pylori infection and inflammatory processes. The overexpression of TGFBI and S100A2 was associated with poor disease-free survival while the down-regulation of NR5A2, SLC4A4, and CD177 was linked to worse overall survival of the patients. In conclusion, novel transcriptome signatures to improve the diagnostic accuracy in CRC are introduced for further validations in various clinical settings. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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22 pages, 2983 KiB

Open AccessArticle

Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome

by Katerina Jiraskova, David J. Hughes, Stefanie Brezina, Tanja Gumpenberger, Veronika Veskrnova, Tomas Buchler, Michaela Schneiderova, Miroslav Levy, Vaclav Liska, Sona Vodenkova, Cornelia Di Gaetano, Alessio Naccarati, Barbara Pardini, Veronika Vymetalkova, Andrea Gsur and Pavel Vodicka

Int. J. Mol. Sci. 2019, 20(1), 97; https://doi.org/10.3390/ijms20010097 - 27 Dec 2018

Cited by 20 | Viewed by 5991

Abstract

DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility [...] Read more.

DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (REV3L, POLQ, and NEIL3) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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13 pages, 3241 KiB

Open AccessArticle

The Prognostic Value of the Combination of Low VEGFR-1 and High VEGFR-2 Expression in Endothelial Cells of Colorectal Cancer

by Nicky D’Haene, Caroline Koopmansch, Yves-Rémi Van Eycke, Françoise Hulet, Justine Allard, Sarah Bouri, Sandrine Rorive, Myriam Remmelink, Christine Decaestecker, Calliope Maris and Isabelle Salmon

Int. J. Mol. Sci. 2018, 19(11), 3536; https://doi.org/10.3390/ijms19113536 - 9 Nov 2018

Cited by 12 | Viewed by 3505

Abstract

Research on tumor angiogenesis has mainly focused on the vascular endothelial growth factor (VEGF) family and on methods to block its actions. However, reports on VEGF receptor (VEGFR) expression in tumor-associated endothelial cells (ECs) are limited. Thus, we evaluated VEGF, VEGFR-1 and VEGFR-2 [...] Read more.

Research on tumor angiogenesis has mainly focused on the vascular endothelial growth factor (VEGF) family and on methods to block its actions. However, reports on VEGF receptor (VEGFR) expression in tumor-associated endothelial cells (ECs) are limited. Thus, we evaluated VEGF, VEGFR-1 and VEGFR-2 expression in ECs of colorectal cancer (CRC) using immunohistochemistry. VEGF, VEGFR-1 and -2 expression in ECs was quantitatively evaluated by digital image analysis in a retrospective series of 204 tumor tissue samples and related to clinical variables. The data show that the VEGF, VEGFR-1 and VEGFR-2 expression in ECs is heterogeneous. Multivariate analysis including a set of clinicopathological variables reveals that high EC VEGFR-1 expression is an independent prognostic factor for overall survival (OS). The combination of low VEGFR-1 and high VEGFR-2 expression in ECs outperforms models integrating VEGFR-1 and VEGFR-2 as separate markers. Indeed, this VEGFR-1_VEGFR-2 combination is an independent negative prognostic factor for OS (p = 0.012) and metastasis-free survival (p = 0.007). In conclusion, this work illustrates the importance of studying the distribution of VEGF members in ECs of CRC. Interestingly, our preliminary data suggest that high VEGFR-1 and low VEGFR-2 expression in ECs appear to be involved in the progression of CRC, suggesting that targeting EC VEGFR-1 could offer novel opportunities for CRC treatment. However, a prospective validation study is needed. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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16 pages, 4283 KiB

Open AccessArticle

lncRNAs in Non-Malignant Tissue Have Prognostic Value in Colorectal Cancer

by Jana-Aletta Thiele, Petr Hosek, Eva Kralovcova, Pavel Ostasov, Vaclav Liska, Jan Bruha, Ondrej Vycital, Jachym Rosendorf, Alena Opattova, Josef Horak, Milena Kralickova, Pavel Vodicka and Pavel Pitule

Int. J. Mol. Sci. 2018, 19(9), 2672; https://doi.org/10.3390/ijms19092672 - 8 Sep 2018

Cited by 27 | Viewed by 3802

Abstract

Although colorectal cancer (CRC) is the third most frequent cause of cancer related death in Europe, clinically relevant biomarkers for therapy guidance and prognosis are insufficiently reliable. Long non-coding RNAs (lncRNAs) are RNAs over 200 nucleotides long that are not translated into proteins [...] Read more.

Although colorectal cancer (CRC) is the third most frequent cause of cancer related death in Europe, clinically relevant biomarkers for therapy guidance and prognosis are insufficiently reliable. Long non-coding RNAs (lncRNAs) are RNAs over 200 nucleotides long that are not translated into proteins but can influence biological processes. There is emerging evidence for their involvement in solid cancer as oncogenes, tumour suppressors or regulators of cell proliferation and metastasis development. The goal of this study was to evaluate the prognostic effect of selected lncRNAs in a retrospective study on CRC patients from the Czech Republic. We used a quantitative PCR approach to measure the expression in paired non-malignant and tumour tissue samples of CRC patients of nine lncRNAs previously shown to be involved in cancer progression—ANRIL, CCAT1, GAS5, linc-ROR, MALAT1, MIR155HG, PCAT1, SPRY4-IT1 and TUG1. Associations between expression and expression ratios and clinical characteristics and survival were assessed by using univariable Cox proportional hazards models, Kaplan-Meier estimations with the Gehan-Wilcoxon test, the Mann-Whitney U test, the Kruskal-Wallis test and Spearman’s correlations. A comparison of expression in tumour tissue (TT) and non-malignant mucosa tissue (MT) showed significant upregulation of CCAT1 and linc-ROR in TT (p < 0.001 and p = 0.001, respectively) and downregulation of ANRIL, MIR155HG and MALAT1 (p = 0.001, p = 0.010, p = 0.001, respectively). Linc-ROR was significantly associated with the presence of synchronous metastases (p = 0.033). For individual tissue types, lower MIR155HG expression in TT was correlated with both shorter overall survival (p = 0.008) and shorter disease-free survival (p = 0.040). In MT, expression ratios of CCAT1/ANRIL and CCAT1/MIR155HG were associated with overall survival (p = 0.005 and p = 0.006, respectively). Our results revealed that changes in expression of lncRNAs between MT and TT hold potential to be used as prognostic biomarkers in CRC patients. Moreover, the ratios of CCAT1 to ANRIL and MIR155HG in MT also exhibit potential for prognosis assessment without tumour sampling. Our results also indicate that cancer progression is associated with detrimental system-wide changes in patient tissue, which might govern patient survival even after successful elimination of tumour or cancerous cells. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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8 pages, 989 KiB

Open AccessArticle

Differential Tissue Fatty Acids Profiling between Colorectal Cancer Patients with and without Synchronous Metastasis

by Maria Notarnicola, Dionigi Lorusso, Valeria Tutino, Valentina De Nunzio, Giampiero De Leonardis, Gisella Marangelli, Vito Guerra, Nicola Veronese, Maria Gabriella Caruso and Gianluigi Giannelli

Int. J. Mol. Sci. 2018, 19(4), 962; https://doi.org/10.3390/ijms19040962 - 23 Mar 2018

Cited by 28 | Viewed by 4387

Abstract

The early detection of colorectal cancer and determination of its metastatic potential are important factors to set up more efficacious therapeutic strategies. In the present study, we hypothesize that fatty acids analysis in colorectal cancer patients can discriminate between metastatic and non-metastatic patients. [...] Read more.

The early detection of colorectal cancer and determination of its metastatic potential are important factors to set up more efficacious therapeutic strategies. In the present study, we hypothesize that fatty acids analysis in colorectal cancer patients can discriminate between metastatic and non-metastatic patients. Fifty-one consecutive patients with histologically proven colorectal cancer were enrolled in the study and the presence of synchronous metastasis was detected in 25 of these 51 patients. Fatty acid profile analysis in red blood cell membranes was not able to discriminate the metastatic colorectal cancer patients from those without metastasis. However, significant differences in the tumor tissue fatty acid profile were found in metastatic cancer patients when compared to patients without metastasis. Metastatic patients showed significantly lower percentages of Eicosapentaenoic acid (EPA) and higher levels of γ-linolenic acid (GLA), a n-3- and n-6-Polyunsaturated fatty acid (PUFA), respectively. Our findings, suggesting that membrane lipid rearrangement could influence the cellular function and make the cell more prone to metastasis, offer the opportunity to develop nutritional strategies that may be helpful in the prevention and treatment of colorectal cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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Review

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11 pages, 974 KiB

Open AccessReview

MRN (MRE11-RAD50-NBS1) Complex in Human Cancer and Prognostic Implications in Colorectal Cancer

by Yiling Situ, Liping Chung, Cheok Soon Lee and Vincent Ho

Int. J. Mol. Sci. 2019, 20(4), 816; https://doi.org/10.3390/ijms20040816 - 14 Feb 2019

Cited by 43 | Viewed by 9576

Abstract

The MRE11-RAD50-NBS1 (MRN) complex has been studied in multiple cancers. The identification of MRN complex mutations in mismatch repair (MMR)-defective cancers has sparked interest in its role in colorectal cancer (CRC). To date, there is evidence indicating a relationship of MRN expression with [...] Read more.

The MRE11-RAD50-NBS1 (MRN) complex has been studied in multiple cancers. The identification of MRN complex mutations in mismatch repair (MMR)-defective cancers has sparked interest in its role in colorectal cancer (CRC). To date, there is evidence indicating a relationship of MRN expression with reduced progression-free survival, although the significance of the MRN complex in the clinical setting remains controversial. In this review, we present an overview of the function of the MRN complex, its role in cancer progression, and current evidence in colorectal cancer. The evidence indicates that the MRN complex has potential utilisation as a biomarker and as a putative treatment target to improve outcomes of colorectal cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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14 pages, 733 KiB

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The Role of Tumor-Associated Neutrophils in Colorectal Cancer

by Rei Mizuno, Kenji Kawada, Yoshiro Itatani, Ryotaro Ogawa, Yoshiyuki Kiyasu and Yoshiharu Sakai

Int. J. Mol. Sci. 2019, 20(3), 529; https://doi.org/10.3390/ijms20030529 - 27 Jan 2019

Cited by 203 | Viewed by 12210

Abstract

Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide and the number of CRC patients is increasing progressively. Despite the improvement of the surgical techniques and chemotherapy, we have not completely overcome this disease yet due to the [...] Read more.

Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide and the number of CRC patients is increasing progressively. Despite the improvement of the surgical techniques and chemotherapy, we have not completely overcome this disease yet due to the metastases. Therefore, understanding the mechanisms through which metastasis occurs is important for overcoming CRC. Normal host cells in the tumor microenvironment, such as macrophages and fibroblasts, have been reported to promote the growth of CRCs. Although neutrophils were originally considered to have defensive functions against tumor cells, it has been revealed that some populations of neutrophils, called as tumor-associated neutrophils (TANs), have tumor-supportive functions. The plasticity between tumor-suppressive and -supportive neutrophils are regulated by transforming growth factor (TGF)-β and Interferon-β signaling. Some studies have demonstrated that TANs promote the spread of cancer cells to distant organs. TANs contribute to the tumor invasion and angiogenesis through the production of matrix metalloproteinase-9 (MMP9), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) in the primary and metastatic sites. Neutrophils also promotes tumor cell dissemination by capturing circulating tumor cells using neutrophil extracellular traps and promote their migration to distant sites. The neutrophil-to-lymphocyte ratio is a well-defined predictive marker for CRC patients. In this review, we highlight the molecular signaling between TANs and CRC cells and the possibility of TANs as a potential target for cancer therapy. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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9 pages, 856 KiB

Open AccessReview

Polycystins in Colorectal Cancer

by Antonios N. Gargalionis, Efthimia K. Basdra and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2019, 20(1), 104; https://doi.org/10.3390/ijms20010104 - 28 Dec 2018

Cited by 10 | Viewed by 4205

Abstract

Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in [...] Read more.

Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in signal transduction mechanisms and during alterations in calcium influx, which regulate cellular functions such as proliferation, differentiation, orientation, and migration in cancer cells. Recent findings implicate polycystins in the deregulation of such functions and the formation of CRC invasive phenotypes. Polycystins participate in all aspects of the cell’s biomechanical network, from the perception of extracellular mechanical cues to focal adhesion protein and nuclear transcriptional complexes. Therefore, polycystins could be employed as novel biomarkers and putative targets of selective treatment in CRC. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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18 pages, 675 KiB

Open AccessReview

Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine?

by Chiara Molinari, Giorgia Marisi, Alessandro Passardi, Laura Matteucci, Giulia De Maio and Paola Ulivi

Int. J. Mol. Sci. 2018, 19(12), 3733; https://doi.org/10.3390/ijms19123733 - 23 Nov 2018

Cited by 154 | Viewed by 8998

Abstract

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, [...] Read more.

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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22 pages, 1230 KiB

Open AccessReview

The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

by Ovidiu Balacescu, Daniel Sur, Calin Cainap, Simona Visan, Daniel Cruceriu, Roberta Manzat-Saplacan, Mihai-Stefan Muresan, Loredana Balacescu, Cosmin Lisencu and Alexandru Irimie

Int. J. Mol. Sci. 2018, 19(12), 3711; https://doi.org/10.3390/ijms19123711 - 22 Nov 2018

Cited by 119 | Viewed by 11056

Abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. [...] Read more.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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29 pages, 4109 KiB

Open AccessReview

Circulating Cell-Free DNA and Colorectal Cancer: A Systematic Review

by Veronika Vymetalkova, Klara Cervena, Linda Bartu and Pavel Vodicka

Int. J. Mol. Sci. 2018, 19(11), 3356; https://doi.org/10.3390/ijms19113356 - 26 Oct 2018

Cited by 78 | Viewed by 9363

Abstract

There is a strong demand for the identification of new biomarkers in colorectal cancer (CRC) diagnosis. Among all liquid biopsy analysts, cell-free circulating DNA (cfDNA) is probably the most promising tool with respect to the identification of minimal residual diseases, assessment of treatment [...] Read more.

There is a strong demand for the identification of new biomarkers in colorectal cancer (CRC) diagnosis. Among all liquid biopsy analysts, cell-free circulating DNA (cfDNA) is probably the most promising tool with respect to the identification of minimal residual diseases, assessment of treatment response and prognosis, and identification of resistance mechanisms. Circulating cell-free tumor DNA (ctDNA) maintains the same genomic signatures that are present in the matching tumor tissue allowing for the quantitative and qualitative evaluation of mutation burdens in body fluids. Thus, ctDNA-based research represents a non-invasive method for cancer detection. Among the numerous possible applications, the diagnostic, predictive, and/or prognostic utility of ctDNA in CRC has attracted intense research during the last few years. In the present review, we will describe the different aspects related to cfDNA research and evidence from studies supporting its potential use in CRC diagnoses and the improvement of therapy efficacy. We believe that ctDNA-based research should be considered as key towards the introduction of personalized medicine and patient benefits. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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18 pages, 2144 KiB

Open AccessReview

Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

by Gianluca Lopez, Francesca Boggio, Stefano Ferrero, Nicola Fusco and Alessandro Del Gobbo

Int. J. Mol. Sci. 2018, 19(10), 3014; https://doi.org/10.3390/ijms19103014 - 3 Oct 2018

Cited by 10 | Viewed by 4327

Abstract

Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and [...] Read more.

Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state of knowledge of CRCLM biomarkers and to outline impending clinical perspectives, in particular focusing on the cutting-edge tools available for their characterization. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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13 pages, 487 KiB

Open AccessReview

Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications

by Ibrahim El Halabi, Rachelle Bejjany, Rihab Nasr, Deborah Mukherji, Sally Temraz, Farah J. Nassar, Haidar El Darsa and Ali Shamseddine

Int. J. Mol. Sci. 2018, 19(9), 2752; https://doi.org/10.3390/ijms19092752 - 13 Sep 2018

Cited by 33 | Viewed by 7467

Abstract

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus [...] Read more.

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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24 pages, 477 KiB

Open AccessReview

Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer

by Stephan Paschke, Sakhavat Jafarov, Ludger Staib, Ernst-Dietrich Kreuser, Catharina Maulbecker-Armstrong, Marc Roitman, Torbjörn Holm, Curtis C. Harris, Karl-Heinrich Link and Marko Kornmann

Int. J. Mol. Sci. 2018, 19(9), 2577; https://doi.org/10.3390/ijms19092577 - 30 Aug 2018

Cited by 154 | Viewed by 10922

Abstract

Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the [...] Read more.

Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term “CRC” should no longer be used as a single entity in basic and clinical research as well as other areas of classification. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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16 pages, 600 KiB

Open AccessReview

The Winding Roadmap of Biomarkers Toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer

by Carlotta Antoniotti, Elena Ongaro, Alfredo Falcone and Chiara Cremolini

Int. J. Mol. Sci. 2018, 19(8), 2298; https://doi.org/10.3390/ijms19082298 - 5 Aug 2018

Cited by 4 | Viewed by 3843

Abstract

In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors [...] Read more.

In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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14 pages, 730 KiB

Open AccessReview

Inflammatory Markers and MicroRNAs: The Backstage Actors Influencing Prognosis in Colorectal Cancer Patients

by Rihab Nasr, Miza Salim Hammoud, Farah Nassar, Deborah Mukherji, Ali Shamseddine and Sally Temraz

Int. J. Mol. Sci. 2018, 19(7), 1867; https://doi.org/10.3390/ijms19071867 - 26 Jun 2018

Cited by 21 | Viewed by 5911

Abstract

Background: Colorectal cancer (CRC) remains a deadly disease, afflicting the lives of millions worldwide. The prognosis of CRC patients is best predicted by surgical resection and pathological analysis of specimens. Emerging evidence has attributed a significant role to inflammatory markers and microRNAs (miRNAs) [...] Read more.

Background: Colorectal cancer (CRC) remains a deadly disease, afflicting the lives of millions worldwide. The prognosis of CRC patients is best predicted by surgical resection and pathological analysis of specimens. Emerging evidence has attributed a significant role to inflammatory markers and microRNAs (miRNAs) in the prognosis and survival of CRC patients. Aim: Here, we review the literature on inflammatory markers and miRNAs with an established role on survival rates, response to systemic chemotherapy, and other clinic-pathological parameters in CRC patients. Results: Our literature review revealed a critical role of inflammatory markers—specifically, the acute-phase proteins, inflammatory cytokines, and blood cell ratios—on prognostic outcomes in CRC patients. MiRNAs, on the other hand, were useful in predicting prognosis and clinical response and accordingly stratifying CRC patients for optimal drug selection. Conclusion: These biomarkers are easily measured in routine blood exams and can be used in adjunct to the tumor-node-metastasis (TNM) staging system to identify high-risk patients and those who are more likely to benefit from chemotherapy and other targeted therapies. However, more prospective studies are needed for the validation of these discussed prognostic and predictive biomarkers. Full article

(This article belongs to the Special Issue Basic and Translational Research in Colorectal Cancer)

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