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Special Issue "Molecular and Translational Research on Colorectal Cancer"

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: 31 March 2020.

Special Issue Editors

Prof. Dr. Emanuela Scarpi
E-Mail Website
Guest Editor
Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy
Interests: biostatistics; clinical Trials; observational study; tumor epidemiology; oncology; palliative care; biomarkers
Special Issues and Collections in MDPI journals
Dr. Paola Ulivi
E-Mail Website
Guest Editor
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; targeted therapy; biomarkers; liquid biopsy; colorectal cancer
Special Issues and Collections in MDPI journals
Dr. Alessandro Passardi
E-Mail Website
Guest Editor
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy
Interests: translational research; angiogenesis; colorectal cancer; pancreatic cancer
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females. The genome of colon cancer cells is altered at several sites as a result of point mutations or changes in chromosome integrity. The mutation-associated changes affect oncogenes, tumor suppressor genes, and several metastasis-related genes. Other factors including epigenetic alterations as well as the deregulation of miRNA-mediated control of mRNA functions, contribute to the incidence of cancer and metastasis. 

Translational research has led to significant benefits in CRC screening and patient management, and precision medicine is fast becoming the aim of scientific research. Individualized treatment for CRC in both adjuvant and metastatic settings is increasingly emphasized. The introduction of molecular-targeted agents with anti-epidermal growth factor receptor (EGFR) or anti-angiogenic mechanisms of action has significantly improved patient outcome, but predictive markers of efficacy, especially for angiogenesis inhibition, are still lacking. Furthermore immunotherapy has recently been implemented into clinical practice. 

A new approach to biomarker detection is the use of liquid biopsy. Free circulating tumor DNA (fctDNA) can be monitored quantitatively and qualitatively for diagnostic, prognostic, or predictive purposes. Liquid biopsy has the potential to replace tumor tissue analysis in clinical practice and could be used to monitor the extent of tumor burden and to detect tumor heterogeneity and molecular resistance to therapy.

Prof. Dr. Emanuela Scarpi
Dr. Paola Ulivi
Dr. Alessandro Passardi
Guest Editors

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 papers will be 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.

Keywords

  • Adenoma-carcinoma sequence
  • Predictive biomarkers of response and toxicity in the adjuvant and metastatic settings
  • Genetic and epigenetic marker
  • Immunotherapy
  • Prognostic biomarkers
  • Angiogenesis
  • EGFR pathways
  • Tumor biopsies
  • Circulating tumor cells
  • Tumor heterogeneity
  • Early diagnosis
  • Screening
  • Liquid biopsy
  • Molecular pathology
  • Tumor biology

Published Papers (10 papers)

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Research

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Open AccessArticle
VEGFR-1 Regulates EGF-R to Promote Proliferation in Colon Cancer Cells
Int. J. Mol. Sci. 2019, 20(22), 5608; https://doi.org/10.3390/ijms20225608 - 09 Nov 2019
Abstract
The relationship between epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways in tumor growth is well established. EGF induces VEGF production in cancer cells, and the paracrine VEGF activates vascular endothelial cells to promote tumor angiogenesis and thus supports tumor [...] Read more.
The relationship between epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways in tumor growth is well established. EGF induces VEGF production in cancer cells, and the paracrine VEGF activates vascular endothelial cells to promote tumor angiogenesis and thus supports tumor cell growth in an angiogenesis-dependent manner. In this study, we found angiogenesis-independent novel crosstalk between the VEGF and the EGF pathways in the regulation of colon cancer cell proliferation. Stimulation of colon cancer cells with VEGF-A and placental growth factor (PlGF) activated VEGF receptor-1 (VEGFR-1) and increased proliferation activity in an autocrine EGF/EGF receptor (EGF-R)-dependent manner. Mechanistically, VEGFR-1 interacted with and stabilized EGF-R, leading to increased EGF-R protein levels and prolonged its expression on cell surface plasma membrane. In contrast, VEGFR-1 blockade by a neutralizing antibody and an antagonistic peptide of VEGFR-1 suppressed the complex formation of VEGFR-1 and EGF-R and decreased EGF-R expression via a lysosome-dependent pathway, resulting in the suppression of proliferation activity. Our results indicated that VEGFR-1 regulated EGF-R expression to promote proliferation activity in a cell-autonomous-dependent manner. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessArticle
The Histochemical Alterations of Mucin in Colorectal Carcinoma Quantified by Two Efficient Algorithms of Digital Image Analysis
Int. J. Mol. Sci. 2019, 20(18), 4580; https://doi.org/10.3390/ijms20184580 - 16 Sep 2019
Abstract
The practical use of knowledge on the diagnostic-prognostic role of polysaccharide components of mucins in colorectal cancer (CRC) has been difficult, due to the number of histochemical (HC) reaction types, as well as lack of standard methods of computer-assisted analysis of tissue expression [...] Read more.
The practical use of knowledge on the diagnostic-prognostic role of polysaccharide components of mucins in colorectal cancer (CRC) has been difficult, due to the number of histochemical (HC) reaction types, as well as lack of standard methods of computer-assisted analysis of tissue expression of these molecules. Using two algorithms of digital image analysis (by application of Image-Pro Premier and our originally designed program Filter HSV), we evaluated the expression of polysaccharides in tissue samples of CRC patients (n = 33), and fragments of normal colorectal tissue from the same patients (control) using periodic acid Schiff reaction (PAS) (neutral mucins) and alcian blue staining (AB) (acidic mucins). Our results indicate lower expression of the PAS+ and AB+ mucins in CRC, as compared to the control samples. The higher expression of PAS+ polysaccharides was detected in flat tumors than in protruded CRC, while higher AB+ mucins expression was a feature of mucinous CRC subtypes. Positive correlation between mutual PAS+ and AB+ expression, as well as correlations with glucose concentration (PAS+ mucins), and hemoglobin level (AB+ mucins) were observed exclusively in unchanged colorectal samples (control). Both algorithms of digital image analysis (smart segmentation and Filter HSV) work properly and can be used interchangeably in daily practice of pathologists, as useful tools of quantitative evaluation of HC reaction in both normal and cancerous tissues. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessArticle
SILAC-Based Quantification of TGFBR2-Regulated Protein Expression in Extracellular Vesicles of Microsatellite Unstable Colorectal Cancers
Int. J. Mol. Sci. 2019, 20(17), 4162; https://doi.org/10.3390/ijms20174162 - 26 Aug 2019
Abstract
Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs [...] Read more.
Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency causes overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to determine TGFBR2-dependent EV protein signatures in a quantitative manner. Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs. Overall, TGFBR2 deficiency caused upregulation of several EV proteins related to the extracellular matrix and nucleosome as well as downregulation of proteasome-associated proteins. The present study emphasizes the general overlap of proteins between EVs and their parental CRC cells but also highlights the impact of TGFBR2 deficiency on EV protein composition. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessArticle
The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(16), 3849; https://doi.org/10.3390/ijms20163849 - 07 Aug 2019
Abstract
Colorectal cancer (CRC) is a heterogeneous disease resulting from the combined influence of many genetic factors. This complexity has caused the molecular characterization of CRC to remain uncharacterized, with a lack of clear gene markers associated with CRC and the prognosis of this [...] Read more.
Colorectal cancer (CRC) is a heterogeneous disease resulting from the combined influence of many genetic factors. This complexity has caused the molecular characterization of CRC to remain uncharacterized, with a lack of clear gene markers associated with CRC and the prognosis of this disease. Thus, highly sensitive tumor markers for the detection of CRC are the most essential determinants of survival. In this study, we examined the simultaneous downregulation of the mRNA levels of six metallothionein (MT) genes in CRC cell lines and public CRC datasets for the first time. In addition, we detected downregulation of these six MT mRNAs’ levels in 30 pairs of tumor (T) and adjacent non-tumor (N) CRC specimens. In order to understand the potential prognostic relevance of these six MT genes and CRC, we presented a four-gene signature to evaluate the prognosis of CRC patients. Further discovery suggested that the four-gene signature (MT1F, MT1G, MT1L, and MT1X) predicted survival better than any combination of two-, three-, four-, five-, or six-gene models. In conclusion, this study is the first to report that simultaneous downregulation of six MT mRNAs’ levels in CRC patients, and their aberrant expression together, accurately predicted CRC patients’ outcomes. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Review

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Open AccessReview
Long Noncoding RNA (lncRNA)-Mediated Competing Endogenous RNA Networks Provide Novel Potential Biomarkers and Therapeutic Targets for Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(22), 5758; https://doi.org/10.3390/ijms20225758 - 16 Nov 2019
Abstract
Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs [...] Read more.
Colorectal cancer (CRC) is the third most common cancer and has a high metastasis and reoccurrence rate. Long noncoding RNAs (lncRNAs) play an important role in CRC growth and metastasis. Recent studies revealed that lncRNAs participate in CRC progression by coordinating with microRNAs (miRNAs) and protein-coding mRNAs. LncRNAs function as competitive endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thus sequestering the miRNAs and changing the expression of their downstream target genes. Such ceRNA networks formed by lncRNA/miRNA/mRNA interactions have been found in a broad spectrum of biological processes in CRC, including liver metastasis, epithelial to mesenchymal transition (EMT), inflammation formation, and chemo-/radioresistance. In this review, we summarize typical paradigms of lncRNA-associated ceRNA networks, which are involved in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the competitive crosstalk among RNA transcripts and the novel targets for CRC prognosis and therapy. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessReview
BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights
Int. J. Mol. Sci. 2019, 20(21), 5369; https://doi.org/10.3390/ijms20215369 - 28 Oct 2019
Abstract
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessReview
The Landscape of Actionable Gene Fusions in Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(21), 5319; https://doi.org/10.3390/ijms20215319 - 25 Oct 2019
Abstract
The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in [...] Read more.
The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessReview
Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer—From Basic Research to Potential Clinical Applications
Int. J. Mol. Sci. 2019, 20(19), 4915; https://doi.org/10.3390/ijms20194915 - 03 Oct 2019
Abstract
Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as [...] Read more.
Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessReview
Epigenetic Biomarkers in Colorectal Cancer Patients Receiving Adjuvant or Neoadjuvant Therapy: A Systematic Review of Epidemiological Studies
Int. J. Mol. Sci. 2019, 20(15), 3842; https://doi.org/10.3390/ijms20153842 - 06 Aug 2019
Abstract
Colorectal cancer (CRC) represents the third-most common cancer worldwide and one of the main challenges for public health. Despite great strides in the application of neoadjuvant and adjuvant therapies for rectal and colon cancer patients, each of these treatments is still associated with [...] Read more.
Colorectal cancer (CRC) represents the third-most common cancer worldwide and one of the main challenges for public health. Despite great strides in the application of neoadjuvant and adjuvant therapies for rectal and colon cancer patients, each of these treatments is still associated with certain adverse effects and different response rates. Thus, there is an urgent need for identifying novel potential biomarkers that might guide personalized treatments for specific subgroups of patients. However, until now, there are no biomarkers to predict the manifestation of adverse effects and the response to treatment in CRC patients. Herein, we provide a systematic review of epidemiological studies investigating epigenetic biomarkers in CRC patients receiving neoadjuvant or adjuvant therapy, and their potential role for the prediction of outcomes and response to treatment. With this aim in mind, we identified several epigenetic markers in CRC patients who received surgery with adjuvant or neoadjuvant therapy. However, none of them currently has the robustness to be translated into the clinical setting. Thus, more efforts and further large-size prospective studies and/or trials should be encouraged to develop epigenetic biomarker panels for personalized prevention and medicine in CRC cancer. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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Open AccessReview
Vaccinations for Colorectal Cancer: Progress, Strategies, and Novel Adjuvants
Int. J. Mol. Sci. 2019, 20(14), 3403; https://doi.org/10.3390/ijms20143403 - 11 Jul 2019
Abstract
Although cancer is a leading cause of death, significant breakthroughs have been made in its treatment in recent years. In particular, increasingly effective cancer vaccines are being developed, including some for colorectal cancer. There are also currently a variety of compounds that can [...] Read more.
Although cancer is a leading cause of death, significant breakthroughs have been made in its treatment in recent years. In particular, increasingly effective cancer vaccines are being developed, including some for colorectal cancer. There are also currently a variety of compounds that can act as adjuvants, such as signalling molecules called cytokines. Other adjuvants target and inhibit the specific mechanisms by which cancers evade the immune system. One of them is a galectin inhibitor, which targets galectins—proteins produced by cancer cells that can cause the death of immune cells. Likewise, immune checkpoint inhibitors affect immune checkpoints—natural host proteins that usually control inflammation but can be exploited by cancers to weaken the body’s defences. Equally, regulatory T cells may contribute to the progression of cancer by inhibiting the functions of other T cells. The main advantages of cancer vaccines include their low toxicity and their ability to strengthen the immune system. Nevertheless, significant limitations include their slow effects and their inability to treat cancer at times due to immunosuppression. Ultimately, ongoing trials provide hope for the development of more effective methods of immunotherapeutic inoculation that can target a greater variety of cancers. Full article
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
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