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Cancers
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Colorectal Cancer Metastasis
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Colorectal Cancer Metastasis

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

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 29324

Special Issue Editors

Prof. Dr. Alessandro Ottaiano

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Guest Editor
SSD-Innovative Therapies for Abdominal Metastases, Department of Abdominal Oncology, Istituto Nazionale Tumori di Napoli IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy
Interests: cancer genetics; gastro-intestinal oncology; oligo-metastatic disease; molecular oncology; precision oncology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Michele Caraglia

E-Mail Website
Guest Editor
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
Interests: noncoding RNAs; micro-RNAs; prostate cancer; nanotechnological delivery of anticancer drugs and nucleic acids; diagnostic markers in cancer; urotensin II receptor; next-generation sequencing; predictive markers of response; circulating tumor cells
Special Issues, Collections and Topics in MDPI journals
Dr. Luisa Circelli

E-Mail Website
Guest Editor
AMES-Centro Polidiagnostico Strumentale srl, via Padre Carmine Fico, 24, Casalnuovo di Napoli, Naples, Italy
Interests: colorectal cancer; biomark; immune

Special Issue Information

Dear Colleagues,

Excluding some very rare inherited forms, colorectal cancer (CRC) is a multigenic disease. The study on correlations between genotype and phenotype in metastatic CRC (mCRC) requires a considerable multidisciplinary effort (oncologist, molecular biologist, biostatistician, geneticist, bioinformatician, etc.), and it is extremely challenging because of the great genetic heterogeneity of tumor progeny in space and time. The identification of driver mutations that significantly influence the biological behavior of cancer cells represents a further difficulty. However, information from such genotype/phenotype correlations may be crucial for identifying new key driver genes and for improving the knowledge of gene function itself. The increasing availability of targeted and whole exome DNA sequencing techniques has allowed researchers to start the exploration of (epi)genotype/phenotype correlations in CRC. These molecular changes involve nucleic acids, both intratumoral and circulating, and include not only gene mutations but also epigenetic modifications such as noncoding RNAs and DNA methylation patterns. Furthermore, the continuous refinement of methods to take and assess tumor nucleic acids (both DNA and RNA), including so-called “liquid biopsy”, makes it possible to follow the genetic changes of tumor cells during the evolution of cancer and after the different treatments administered in the different lines of therapy. In this way, tumor plasticity can be studied and defined in each single patient, correlating it with the clinical outcome and allowing to achieve the final aim of precision medicine, detecting prognostic markers and molecular targets for the design of the most adequate treatment.

The present research topic in mCRC has been established to prompt researchers to provide insights into:

  • Prognostic and predictive correlations of specific cancer genetics;
  • Emerging methods to make correlations between (epi)genotype (including gene expression and mutation, noncoding RNAs and DNA methylation status) and phenotype (metastatic behavior);
  • Novel techniques and novel models to interpret genetic CRC behavior;
  • Novel biomarkers and biologic surrogates to study cancer plasticity from primary to metastatic lesions.

Articles consisting exclusively of bioinformatics or computational analyses of public databases will not be accepted. Analyses and studies coming from real practice and independent clinical cohorts of patients are the preferred target of this research topic. Reviews are also appreciated.

Prof. Dr. Alessandro Ottaiano
Prof. Dr. Michele Caraglia
Dr. Luisa Circelli
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 submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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
  • metastases
  • prognosis
  • cancer evolution
  • precision medicine

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 196 KiB  
Editorial
Multifaceted Insights into Innovative Approaches to Treating Colorectal Cancer Metastasis: From Emerging Biological Factors to Radiomics
by Alessandro Ottaiano, Luisa Circelli, Mariachiara Santorsola and Michele Caraglia
Cancers 2023, 15(18), 4644; https://doi.org/10.3390/cancers15184644 - 20 Sep 2023
Cited by 1 | Viewed by 917
Abstract
We extend our appreciation to the authors who have made substantial contributions to the Special Issue focusing on “Colorectal Cancer Metastasis” [...] Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
3 pages, 613 KiB  
Editorial
The Tumor Dynamism Is the Dark Matter of the NGS Galaxy: How to Understand It?
by Alessandro Ottaiano, Luisa Circelli and Michele Caraglia
Cancers 2021, 13(21), 5476; https://doi.org/10.3390/cancers13215476 - 30 Oct 2021
Viewed by 1477
Abstract
Since its discovery, there has been a great enthusiasm around NGS (next generation sequencing) technology due to extensive (from restricted gene panels to entire genomes) and rapid (few hours) DNA sequencing [...] Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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Research

Jump to: Editorial, Review

18 pages, 3560 KiB  
Article
Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease
by Antonio Di Grazia, Davide Di Fusco, Eleonora Franzè, Marco Colella, Georgios Strimpakos, Silvia Salvatori, Vincenzo Formica, Federica Laudisi, Claudia Maresca, Alfredo Colantoni, Angela Ortenzi, Carmine Stolfi, Ivan Monteleone and Giovanni Monteleone
Cancers 2022, 14(21), 5294; https://doi.org/10.3390/cancers14215294 - 27 Oct 2022
Cited by 10 | Viewed by 3177
Abstract
Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We [...] Read more.
Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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10 pages, 3348 KiB  
Article
Identification of Biomarkers Associated with Liver Metastasis Progression from Colorectal Cancer Using Exosomal RNA Profiling
by Soohyeon Lee, Young Soo Park, Jwa Hoon Kim, Ah Reum Lim, Myung Han Hyun, Boyeon Kim, Jong Won Lee, Saet Byeol Lee and Yeul Hong Kim
Cancers 2022, 14(19), 4723; https://doi.org/10.3390/cancers14194723 - 28 Sep 2022
Cited by 6 | Viewed by 2111
Abstract
This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and [...] Read more.
This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and cancer recurrence or progression after metastasectomy. The up- and down-regulated RNA expression profiles were screened and analyzed using H-cluster, principle component analysis and gene ontology. The tissue expression profile of the liver metastases was compared with the GSE 41258 set using GSEA tools. We identified two distinctive biological process gene sets (IFNA and PCDB families) related to metastatic progression. The interferon-α response gene set was enriched, especially when the tumor volume was ≥1 cm3. CXCL10, CXCL11 and SAMD 9 mRNA were highly expressed in the plasma exosome samples of patients with mCRC to the liver. Furthermore, high expression of CXCL10 but not CXCL11 or SAMD9 was associated with a poor prognosis and shorter progression-free survival. Conclusions: Cancer-derived exosomal CXCL10 may be a novel biomarker for liver metastasis of mCRC and a potential target for the prevention and treatment of mCRC with liver metastasis. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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13 pages, 2369 KiB  
Article
Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens
by Jun Li, Pascal Steffen, Benita C. Y. Tse, Mahsa S. Ahadi, Anthony J. Gill, Alexander F. Engel and Mark P. Molloy
Cancers 2022, 14(12), 2933; https://doi.org/10.3390/cancers14122933 - 14 Jun 2022
Cited by 6 | Viewed by 2318
Abstract
Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are rare and greatly under-represented in large-scale genomic mapping projects. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) [...] Read more.
Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are rare and greatly under-represented in large-scale genomic mapping projects. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4 to 77.2/Mb sequenced. No stage-related mutational differences were observed, consistent with reanalysis of The Cancer Genome Atlas (TCGA) Stage I and IIIA datasets. We next examined mutational burdens and observed that the top five cancers were microsatellite stable (MSS) genotypes (mean TMB 49.3/Mb), while the other 16 MSS cancers had a mean TMB of 5.9/Mb. To facilitate comparison with TCGA hypermutator CRC, we included four microsatellite instability-high (MSI-H) samples with the high mutation burden MSS cases to form a TMB-High group. Comparison of TMB-High with TMB-Low groups revealed differences in mutational frequency of ATM, ALK, NSD1, UBR5, BCL9, CARD11, KDM5C, MN1, PTPRT and PIK3CA, with ATM and UBR5 validated in reanalysis of TCGA hypermutator Stages I and IIIA samples. Variants in ATM were restricted to the TMB-High group, and in four of five MSS specimens, we observed the co-occurrence of mutations in homologous recombination repair (HRR) genes in either two of ATM, CDK12, PTEN or ATR, with at least one of these being a likely pathogenic truncating mutation. No MSI-H specimens carried nonsense mutations in HRR genes. These findings add to our knowledge of early T stage CRC and highlight a potential therapeutic vulnerability in the HRR pathway of TMB-H MSS CRC. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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21 pages, 3007 KiB  
Article
EOB-MR Based Radiomics Analysis to Assess Clinical Outcomes following Liver Resection in Colorectal Liver Metastases
by Vincenza Granata, Roberta Fusco, Federica De Muzio, Carmen Cutolo, Sergio Venanzio Setola, Federica Dell’Aversana, Alessandro Ottaiano, Guglielmo Nasti, Roberta Grassi, Vincenzo Pilone, Vittorio Miele, Maria Chiara Brunese, Fabiana Tatangelo, Francesco Izzo and Antonella Petrillo
Cancers 2022, 14(5), 1239; https://doi.org/10.3390/cancers14051239 - 27 Feb 2022
Cited by 32 | Viewed by 3628
Abstract
The aim of this study was to assess the efficacy of radiomics features obtained by EOB-MRI phase in order to predict clinical outcomes following liver resection in Colorectal Liver Metastases Patients, and evaluate recurrence, mutational status, pathological characteristic (mucinous) and surgical resection margin. [...] Read more.
The aim of this study was to assess the efficacy of radiomics features obtained by EOB-MRI phase in order to predict clinical outcomes following liver resection in Colorectal Liver Metastases Patients, and evaluate recurrence, mutational status, pathological characteristic (mucinous) and surgical resection margin. This retrospective analysis was approved by the local Ethical Committee board of National Cancer of Naples, IRCCS “Fondazione Pascale”. Radiological databases were interrogated from January 2018 to May 2021 in order to select patients with liver metastases with pathological proof and EOB-MRI study in pre-surgical setting. The cohort of patients included a training set (51 patients with 61 years of median age and 121 liver metastases) and an external validation set (30 patients with single lesion with 60 years of median age). For each segmented volume of interest by 2 expert radiologists, 851 radiomics features were extracted as median values using PyRadiomics. non-parametric test, intraclass correlation, receiver operating characteristic (ROC) analysis, linear regression modelling and pattern recognition methods (support vector machine (SVM), k-nearest neighbors (KNN), artificial neural network (NNET), and decision tree (DT)) were considered. The best predictor to discriminate expansive versus infiltrative front of tumor growth was HLH_glcm_MaximumProbability extraxted on VIBE_FA30 with an accuracy of 84%, a sensitivity of 83%, and a specificity of 82%. The best predictor to discriminate tumor budding was Inverse Variance obtained by the original GLCM matrix extraxted on VIBE_FA30 with an accuracy of 89%, a sensitivity of 96% and a specificity of 65%. The best predictor to differentiate the mucinous type of tumor was the HHL_glszm_ZoneVariance extraxted on VIBE_FA30 with an accuracy of 85%, a sensitivity of 46% and a specificity of 95%. The best predictor to identify tumor recurrence was the LHL_glcm_Correlation extraxted on VIBE_FA30 with an accuracy of 86%, a sensitivity of 52% and a specificity of 97%. The best linear regression model was obtained in the identification of the tumor growth front considering the height textural significant metrics by VIBE_FA10 (an accuracy of 89%; sensitivity of 93% and a specificity of 82%). Considering significant texture metrics tested with pattern recognition approaches, the best performance for each outcome was reached by a KNN in the identification of recurrence with the 3 textural significant features extracted by VIBE_FA10 (AUC of 91%, an accuracy of 93%; sensitivity of 99% and a specificity of 77%). Ours results confirmed the capacity of radiomics to identify as biomarkers, several prognostic features that could affect the treatment choice in patients with liver metastases, in order to obtain a more personalized approach. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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17 pages, 3825 KiB  
Article
Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors
by Jean Descarpentrie, Marcos J. Araúzo-Bravo, Zongsheng He, Alexia François, Álvaro González, Patricia Garcia-Gallastegi, Iker Badiola, Serge Evrard, Simon Pernot, John W. M. Creemers and Abdel-Majid Khatib
Cancers 2022, 14(5), 1195; https://doi.org/10.3390/cancers14051195 - 25 Feb 2022
Cited by 10 | Viewed by 2887
Abstract
Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and [...] Read more.
Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca2+-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers’ expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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13 pages, 1803 KiB  
Article
Spatial Immunology in Liver Metastases from Colorectal Carcinoma according to the Histologic Growth Pattern
by Gemma Garcia-Vicién, Artur Mezheyeuski, Patrick Micke, Núria Ruiz, José Carlos Ruffinelli, Kristel Mils, María Bañuls, Natàlia Molina, Ferran Losa, Laura Lladó and David G. Molleví
Cancers 2022, 14(3), 689; https://doi.org/10.3390/cancers14030689 - 29 Jan 2022
Cited by 5 | Viewed by 2483
Abstract
Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not [...] Read more.
Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not find statistically significant differences of immune cell densities in the central regions of desmoplastic (dHGP) and non-desmoplastic (ndHGP) metastases. The spatial evaluation reported that dHGP-metastases displayed higher infiltration by CD8+ and CD20+ cells in peripheral regions as well as CD4+ and CD45RO+ cells in ndHGP-metastases. However, the reactive stroma regions at the invasive margin (IM) of ndHGP-metastases displayed higher density of CD4+, CD20+, and CD45RO+ cells. The antitumor status of the TIL infiltrates measured as CD8/CD4 reported higher values in the IM of encapsulated metastases up to 400 μm towards the tumor center (p < 0.05). Remarkably, the IM of dHGP-metastases was characterized by higher infiltration of CD8+ cells in the epithelial compartment parameter assessed with the ratio CD8epithelial/CD8stromal, suggesting anti-tumoral activity in the encapsulating lesions. Taking together, the amount of CD8+ cells is comparable in the IM of both HGP metastases types. However, in dHGP-metastases some cytotoxic cells reach the tumor nests while remaining retained in the stromal areas in ndHGP-metastases. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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Review

Jump to: Editorial, Research

26 pages, 2050 KiB  
Review
Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia
by Kevin D. Seely, Amanda D. Morgan, Lauren D. Hagenstein, Garrett M. Florey and James M. Small
Cancers 2022, 14(4), 1019; https://doi.org/10.3390/cancers14041019 - 17 Feb 2022
Cited by 23 | Viewed by 8710
Abstract
While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between [...] Read more.
While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial–mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection. Full article
(This article belongs to the Special Issue Colorectal Cancer Metastasis)
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