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Special Issue "Latest Advances in Colorectal Cancer Research: Molecular Mechanisms and Therapies"

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

Deadline for manuscript submissions: closed (28 February 2017)

Special Issue Editor

Guest Editor
Prof. Peter J.K. Kuppen

Department of Surgical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
Website | E-Mail
Interests: colorectal cancer; tumor-immmune interactions; cancer genetics and epigenetics; immunotherapy; biomarkers

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most frequent cancer type, with approximately one million new cases per year world-wide, and more than half a million deaths annually. In the past few decades, important advances have been made in screening, staging, treatment, and molecular characterization of CRC. For non-metastasized CRC, surgery is the cornerstone for curative treatment. However, up to 50% of CRC patients show distant metastases, either at the time of diagnosis or during clinical follow-up. A major challenge in CRC is the development of curative treatment options for these patients. Recent advancements in molecular biological techniques and analyses have led to a much better understanding of the biology of CRC. Both genetic and epigenetic aberrations appear to be common in CRC. In addition, different subtypes of CRC have been defined, based on specific DNA mutations and on molecular pathways involved. Furthermore, accumulating evidence proved that the tumor microenvironment, including the immune system, plays an important role in CRC development. Traditionally, the treatment of choice for CRC is dependent on the tumor location (rectum vs. colon) and TNM classification. New treatment modalities become available that interfere in specific molecular pathways. Therefore, future treatment will be based on the underlying biology in specific cases of CRC. It has also become clear that therapeutic interventions can result in selective outgrowth of resistant subtypes. This is the result of tumor heterogeneity, with genetic and epigenetic instability as a driving force. Therefore, treatment outcome is the result of a competition between treatment efficacy and outgrowth of escape variants.

In this Special Issue of IJMS, the focus will be on this competition by considering the biology of CRC in relation with new treatment options.

Dr. Peter J.K. Kuppen
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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

  • colorectal cancer
  • genetics
  • epigenetics
  • molecular pathway
  • tumor microenvironment
  • biological
  • immunotherapy

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessArticle Molecular and Clinicopathological Differences by Age at the Diagnosis of Colorectal Cancer
Int. J. Mol. Sci. 2017, 18(7), 1441; https://doi.org/10.3390/ijms18071441
Received: 10 June 2017 / Revised: 27 June 2017 / Accepted: 28 June 2017 / Published: 5 July 2017
Cited by 4 | PDF Full-text (1691 KB) | HTML Full-text | XML Full-text
Abstract
We compared the clinicopathological and molecular profiles between different age groups of sporadic colorectal cancer (CRC) patients (age <50, 56–60, 60–70, 70–80, and >80); 1475 CRC patients were enrolled after excluding 30 individuals with Lynch syndrome. The mutation spectra for APC, TP53
[...] Read more.
We compared the clinicopathological and molecular profiles between different age groups of sporadic colorectal cancer (CRC) patients (age <50, 56–60, 60–70, 70–80, and >80); 1475 CRC patients were enrolled after excluding 30 individuals with Lynch syndrome. The mutation spectra for APC, TP53, KRAS, PIK3CA, FBXW7, BRAF, NRAS, HRAS, TGFbR, Akt1, and PTEN were analyzed using polymerase chain reaction (PCR), followed by MassArray and microsatellite (MSI-high) analysis by performing genotyping. Male patients (74.1%) were significantly predominant to females (25.9%) in the older age group (70–80, >80). There was an insignificantly linear trend between TNM staging and age-onset of CRC diagnosis. Patients aged < 50 had 58.7% diseases in the advanced stages (Stage III: 36.5% and IV: 22.2% respectively), while this decreased to 40.2% (Stage III: 26.2% and IV; 14.0% respectively) in patients >80. The distributions of mutation frequency were similar in majority of the genes studied among different age groups. Additionally, patients aged <50 had significantly higher frequency of MSI-high, PTEN, and HRAS mutations than those of other groups. Age-onset at diagnosis significantly affected overall survival (HR = 1.46; 95% CI: 1.35–1.58), but not cancer-specific survival (HR = 1.08; 95% CI: 0.99–1.18) in multivariate analysis. In conclusion, molecular and clinicopathological differences were not as significant among different age groups of CRC patients as previously suspected. Full article
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Open AccessArticle Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study
Int. J. Mol. Sci. 2017, 18(6), 1265; https://doi.org/10.3390/ijms18061265
Received: 10 March 2017 / Revised: 6 June 2017 / Accepted: 7 June 2017 / Published: 13 June 2017
Cited by 2 | PDF Full-text (1469 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize,
[...] Read more.
Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ≤ 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ≤ 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan. Full article
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Open AccessArticle Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy
Int. J. Mol. Sci. 2017, 18(6), 1240; https://doi.org/10.3390/ijms18061240
Received: 28 April 2017 / Revised: 26 May 2017 / Accepted: 29 May 2017 / Published: 9 June 2017
Cited by 6 | PDF Full-text (356 KB) | HTML Full-text | XML Full-text
Abstract
There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the
[...] Read more.
There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter “Italian Trial in Advanced Colorectal Cancer (ITACa)”, randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1α), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors. Full article
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Open AccessArticle Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome
Int. J. Mol. Sci. 2017, 18(5), 999; https://doi.org/10.3390/ijms18050999
Received: 3 March 2017 / Revised: 21 April 2017 / Accepted: 2 May 2017 / Published: 6 May 2017
Cited by 5 | PDF Full-text (1133 KB) | HTML Full-text | XML Full-text
Abstract
Abstract: Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct
[...] Read more.
Abstract: Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members. Full article
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Open AccessArticle AF1q Mediates Tumor Progression in Colorectal Cancer by Regulating AKT Signaling
Int. J. Mol. Sci. 2017, 18(5), 987; https://doi.org/10.3390/ijms18050987
Received: 26 February 2017 / Revised: 13 April 2017 / Accepted: 2 May 2017 / Published: 5 May 2017
Cited by 1 | PDF Full-text (6414 KB) | HTML Full-text | XML Full-text
Abstract
The up-regulation of ALL1-fused gene from chromosome 1q (AF1q) is commonly seen in aggressive hematologic malignancies as well as in several solid tumor tissues. However, its expression and intrinsic function in human colorectal cancer (CRC) remains largely undefined. To explore the role
[...] Read more.
The up-regulation of ALL1-fused gene from chromosome 1q (AF1q) is commonly seen in aggressive hematologic malignancies as well as in several solid tumor tissues. However, its expression and intrinsic function in human colorectal cancer (CRC) remains largely undefined. To explore the role of AF1q in human CRC progression, AF1q expression was analyzed in human CRC tissue samples and CRC cell lines. Clinical specimens revealed that AF1q was up-regulated in human CRC tissues, and that this up-regulation was associated with tumor metastasis and late tumor, lymph node, metastasis (TNM) stage. AF1q knockdown by shRNA inhibited tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro, as well as tumorigenesis and liver metastasis in vivo, whereas these effects were reversed following AF1q overexpression. These AF1q-mediated effects were modulated by the protein kinase B (AKT) signaling pathway, and inhibition of AKT signaling attenuated AF1q-induced tumor promotion. Thus, AF1q contributes to CRC tumorigenesis and progression through the activation of the AKT signaling pathway. AF1q might therefore serve as a promising new target in the treatment of CRC. Full article
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Open AccessArticle Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer
Int. J. Mol. Sci. 2017, 18(5), 922; https://doi.org/10.3390/ijms18050922
Received: 8 March 2017 / Revised: 6 April 2017 / Accepted: 13 April 2017 / Published: 27 April 2017
Cited by 2 | PDF Full-text (4229 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Colorectal cancer (CRC) cells undergo the remodeling of intracellular Ca2+ homeostasis, which contributes to cancer hallmarks such as enhanced proliferation, invasion and survival. Ca2+ remodeling includes critical changes in store-operated Ca2+ entry (SOCE) and Ca2+ store content. Some changes
[...] Read more.
Colorectal cancer (CRC) cells undergo the remodeling of intracellular Ca2+ homeostasis, which contributes to cancer hallmarks such as enhanced proliferation, invasion and survival. Ca2+ remodeling includes critical changes in store-operated Ca2+ entry (SOCE) and Ca2+ store content. Some changes have been investigated at the molecular level. However, since nearly 100 genes are involved in intracellular Ca2+ transport, a comprehensive view of Ca2+ remodeling in CRC is lacking. We have used Next Generation Sequencing (NGS) to investigate differences in expression of 77 selected gene transcripts involved in intracellular Ca2+ transport in CRC. To this end, mRNA from normal human colonic NCM460 cells and human colon cancer HT29 cells was isolated and used as a template for transcriptomic sequencing and expression analysis using Ion Torrent technology. After data transformation and filtering, exploratory analysis revealed that both cell types were well segregated. In addition, differential gene expression using R and bioconductor packages show significant differences in expression of selected voltage-operated Ca2+ channels and store-operated Ca2+ entry players, transient receptor potential (TRP) channels, Ca2+ release channels, Ca2+ pumps, Na+/Ca2+ exchanger isoforms and genes involved in mitochondrial Ca2+ transport. These data provide the first comprehensive transcriptomic analysis of Ca2+ remodeling in CRC. Full article
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Open AccessArticle Commitment of Scaffold Proteins in the Onco-Biology of Human Colorectal Cancer and Liver Metastases after Oxaliplatin-Based Chemotherapy
Int. J. Mol. Sci. 2017, 18(4), 891; https://doi.org/10.3390/ijms18040891
Received: 22 February 2017 / Revised: 15 April 2017 / Accepted: 19 April 2017 / Published: 22 April 2017
Cited by 2 | PDF Full-text (2467 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing
[...] Read more.
Scaffold proteins play pivotal roles in the regulation of signaling pathways, integrating external and internal stimuli to various cellular outputs. We report the pattern of cellular and subcellular expression of scaffoldins angiomotin-like 2 (AmotL2), FK506 binding protein 5 (FKBP51) and IQ motif containing GTPase-activating protein 1 (IQGAP1) in colorectal cancer (CRC) and metastases in liver resected after oxaliplatin-based chemotherapy (CT). Positive immunostaining for the three scaffoldins was found in most cells in healthy colon, tumor, healthy liver and metastasized liver. The patterns of expression of AmotL2, FKBP51 and IQGAP1 show the greatest variability in immune system cells and neurons and glia cells and the least in blood vessel cells. The simultaneous subcellular localization in tumor cells and other cell types within the tumor suggest an involvement of these three scaffoldins in cancer biology, including a role in Epithelial Mesenchymal Transition. The display in differential localization and quantitative expression of AmotL2, FKBP51, and IQGAP1 could be used as biomarkers for more accurate tumor staging and as potential targets for anti-cancer therapeutics by blocking or slowing down their interconnecting functions. Tough further research needs to be done in order to improve these assessments. Full article
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Open AccessArticle Evaluation of EphA2 and EphB4 as Targets for Image-Guided Colorectal Cancer Surgery
Int. J. Mol. Sci. 2017, 18(2), 307; https://doi.org/10.3390/ijms18020307
Received: 23 November 2016 / Revised: 30 December 2016 / Accepted: 21 January 2017 / Published: 3 February 2017
Cited by 3 | PDF Full-text (2210 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Targeted image-guided oncologic surgery (IGOS) relies on the recognition of cell surface-associated proteins, which should be abundantly present on tumor cells but preferably absent on cells in surrounding healthy tissue. The transmembrane receptor tyrosine kinase EphA2, a member of the A class of
[...] Read more.
Targeted image-guided oncologic surgery (IGOS) relies on the recognition of cell surface-associated proteins, which should be abundantly present on tumor cells but preferably absent on cells in surrounding healthy tissue. The transmembrane receptor tyrosine kinase EphA2, a member of the A class of the Eph receptor family, has been reported to be highly overexpressed in several tumor types including breast, lung, brain, prostate, and colon cancer and is considered amongst the most promising cell membrane-associated tumor antigens by the NIH. Another member of the Eph receptor family belonging to the B class, EphB4, has also been found to be upregulated in multiple cancer types. In this study, EphA2 and EphB4 are evaluated as targets for IGOS of colorectal cancer by immunohistochemistry (IHC) using a tissue microarray (TMA) consisting of 168 pairs of tumor and normal tissue. The IHC sections were scored for staining intensity and percentage of cells stained. The results show a significantly enhanced staining intensity and more widespread distribution in tumor tissue compared with adjacent normal tissue for EphA2 as well as EphB4. Based on its more consistently higher score in colorectal tumor tissue compared to normal tissue, EphB4 appears to be a promising candidate for IGOS of colorectal cancer. In vitro experiments using antibodies on human colon cancer cells confirmed the possibility of EphB4 as target for imaging. Full article
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Open AccessArticle Tumor LINE-1 Methylation Level in Association with Survival of Patients with Stage II Colon Cancer
Int. J. Mol. Sci. 2017, 18(1), 36; https://doi.org/10.3390/ijms18010036
Received: 22 November 2016 / Revised: 17 December 2016 / Accepted: 19 December 2016 / Published: 27 December 2016
Cited by 5 | PDF Full-text (765 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in
[...] Read more.
Genome-wide DNA hypomethylation is associated with a worse prognosis in early-stage colorectal cancer. To measure genome-wide DNA methylation levels, long interspersed nucleotide element (LINE-1) repeats are used as a surrogate marker. Cohort studies on the clinical impact of genome-wide DNA methylation level in patients with only early-stage colon cancer, are currently lacking. This study aimed to investigate the prognostic value of LINE-1 methylation in a stage II colon cancer cohort (n = 164). Manual needle microdissection of tumor areas was performed on formalin-fixed paraffin-embedded tumor tissue sections followed by DNA extraction. Bisulfite converted DNA was used to assess tumor LINE-1 methylation level by qPCR. Patients with LINE-1 hypomethylated tumors had a significantly worse overall survival compared to patients with a higher level of LINE-1 tumor DNA methylation (HR 1.68, 95% CI 1.03–2.75; p = 0.04). This effect was more prominent in patients aged over 65 years (HR 2.00, 95% CI 1.13–3.52; p = 0.02), although the test for age interaction was not significant. No significant effect on recurrence-free survival was observed. Based on these results, tumor LINE-1 hypomethylation is associated with a worse overall survival in stage II colon cancer. Whether the origin of this causation is cancer-specific or age-related can be debated. Full article
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Open AccessArticle Knockdown of ELMO3 Suppresses Growth, Invasion and Metastasis of Colorectal Cancer
Int. J. Mol. Sci. 2016, 17(12), 2119; https://doi.org/10.3390/ijms17122119
Received: 4 October 2016 / Revised: 5 December 2016 / Accepted: 12 December 2016 / Published: 16 December 2016
Cited by 3 | PDF Full-text (5533 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The engulfment and cell motility (ELMOs) family of proteins plays a crucial role in tumor cell migration and invasion. However, the function of ELMO3 is poorly defined. To elucidate its role in the development and progression of colorectal cancer (CRC), we examined the
[...] Read more.
The engulfment and cell motility (ELMOs) family of proteins plays a crucial role in tumor cell migration and invasion. However, the function of ELMO3 is poorly defined. To elucidate its role in the development and progression of colorectal cancer (CRC), we examined the expression of ELMO3 in 45 cases of paired CRC tumor tissues and adjacent normal tissues. Furthermore, we assessed the effect of the knockdown of ELMO3 on cell proliferation, cell cycle, migration, invasion and F-actin polymerization in HCT116 cells. The result shows that the expression of ELMO3 in CRC tissues was significantly increased in comparison to the adjacent normal colorectal tissues. Moreover, this overexpression was associated with tumor size (p = 0.007), tumor differentiation (p = 0.001), depth of invasion (p = 0.009), lymph node metastasis (p = 0.003), distant metastasis (p = 0.013) and tumor, node, metastasis (TNM)-based classification (p = 0.000). In in vitro experiments, the silencing of ELMO3 inhibited cell proliferation, invasion, metastasis, and F-actin polymerization, and induced Gap 1 (G1) phase cell cycle arrest. Our study demonstrates that ELMO3 is involved in the processes of growth, invasion and metastasis of CRC, and could be used a potential molecular diagnostic tool or therapy target of CRC. Full article
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Review

Jump to: Research

Open AccessReview Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications
Int. J. Mol. Sci. 2017, 18(10), 2229; https://doi.org/10.3390/ijms18102229
Received: 11 September 2017 / Revised: 6 October 2017 / Accepted: 20 October 2017 / Published: 24 October 2017
Cited by 4 | PDF Full-text (2440 KB) | HTML Full-text | XML Full-text
Abstract
The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of colorectal cancer (CRC) has led to
[...] Read more.
The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of colorectal cancer (CRC) has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs) based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS. Full article
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Open AccessReview Non-Coding RNAs as Predictive Biomarkers to Current Treatment in Metastatic Colorectal Cancer
Int. J. Mol. Sci. 2017, 18(7), 1547; https://doi.org/10.3390/ijms18071547
Received: 30 April 2017 / Revised: 13 July 2017 / Accepted: 14 July 2017 / Published: 17 July 2017
Cited by 4 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
The onset and selection of resistant clones during cancer treatment with chemotherapy or targeted therapy is a major issue in the clinical management of metastatic colorectal cancer patients. It is possible that a more personalized treatment selection, using reliable response-to-therapy predictive biomarkers, could
[...] Read more.
The onset and selection of resistant clones during cancer treatment with chemotherapy or targeted therapy is a major issue in the clinical management of metastatic colorectal cancer patients. It is possible that a more personalized treatment selection, using reliable response-to-therapy predictive biomarkers, could lead to an improvement in the success rate of the proposed therapies. Although the process of biomarker selection and validation could be a long one, requiring solid statistics, large cohorts and multicentric validations, non-coding RNAs (ncRNAs) and in particular microRNAs, proved to be extremely promising in this field. Here we summarize some of the main studies correlating specific ncRNAs with sensitivity/resistance to chemotherapy, anti-VEGF therapy, anti-EGFR therapy and immunotherapy in colorectal cancer (CRC). Full article
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Open AccessReview Immune Checkpoints as a Target for Colorectal Cancer Treatment
Int. J. Mol. Sci. 2017, 18(6), 1324; https://doi.org/10.3390/ijms18061324
Received: 10 May 2017 / Revised: 14 June 2017 / Accepted: 16 June 2017 / Published: 21 June 2017
Cited by 13 | PDF Full-text (875 KB) | HTML Full-text | XML Full-text
Abstract
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents,
[...] Read more.
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition. Full article
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Open AccessReview Adiponectin and Intelectin-1: Important Adipokine Players in Obesity-Related Colorectal Carcinogenesis
Int. J. Mol. Sci. 2017, 18(4), 866; https://doi.org/10.3390/ijms18040866
Received: 13 March 2017 / Revised: 12 April 2017 / Accepted: 17 April 2017 / Published: 19 April 2017
Cited by 10 | PDF Full-text (913 KB) | HTML Full-text | XML Full-text
Abstract
Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their
[...] Read more.
Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer. Full article
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Open AccessReview Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer
Int. J. Mol. Sci. 2017, 18(4), 752; https://doi.org/10.3390/ijms18040752
Received: 7 March 2017 / Revised: 25 March 2017 / Accepted: 28 March 2017 / Published: 2 April 2017
Cited by 16 | PDF Full-text (438 KB) | HTML Full-text | XML Full-text
Abstract
Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that
[...] Read more.
Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy. In the current review, we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC. Full article
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Open AccessReview Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients
Int. J. Mol. Sci. 2017, 18(1), 107; https://doi.org/10.3390/ijms18010107
Received: 20 September 2016 / Revised: 26 December 2016 / Accepted: 30 December 2016 / Published: 6 January 2017
Cited by 13 | PDF Full-text (221 KB) | HTML Full-text | XML Full-text
Abstract
Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%–20%
[...] Read more.
Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%–20% of colorectal cancer (CRC) cases. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed. The association between the MSI status and the efficacy of the therapy based on anti-programmed death-1 receptor inhibitors requires further studies. Full article
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