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Cancers
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Molecular Aspects of Tumor Microenvironment of Colorectal Cancers
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Molecular Aspects of Tumor Microenvironment of Colorectal Cancers

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

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 23824

Special Issue Editor

Prof. Maria Cristina Curia

E-Mail Website
Guest Editor
Department of Medical, Oral and Biotechnological Sciences, University of G. d'Annunzio Chieti and Pescara, Chieti, Italy
Interests: Major research interests include genetic alterations in the predisposition of colorectal cancer; the role of impaired DNA repair in colon polyposis and cancer; methylation in development and progression of pancreatic cancer; oral microbiota in colon cancer and in systemic disease

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most common cancer worldwide, and the risk of developing CRC is influenced by environmental and genetic factors. Molecular aspects of CRC concern the relationships between risk factors, such as oxidative stress and microbiota, and genetic factors.

The tumor microenvironment is composed of different cell types, such as fibroblasts, immune cells, vascular cells and extracellular matrix cells. The normal microenvironment becomes tumoral when cells first become pre-malignant and then are transformed. The transformation is associated with the activation of oncogenic pathways that establish a molecular crosstalk between epithelial cells and the surrounding stroma. This interplay impairs membrane integrity by promoting the formation of the tumor microenvironment. Metalloproteinase expression by the activation of oncogenic pathways promotes carcinoma cell migration and invasion by the degradation of the basement membrane structure.

Inflammation is one of the major causes of tumor formation with the presence of intratumoral inflammatory cells and proinflammatory cytokines. One of the causes of inflammation is bacterial infection. Bacterial infection exerts a pro-tumorigenic effect by promoting the development of a pro-inflammatory tumor environment, by inducing the expression of genes that encode pro-inflammatory cytokines, and by influencing the function of immune cells. The inflammatory microenvironment may determine the production of reactive oxygen species (ROS) in the intracellular environment which can favor oncogenic mutations in DNA. It is well known that reactive oxygen species (ROS) production in the colon epithelium can impair the Wnt/b-Catenin.

In recent decades, significant evidence has emerged implicating microbiota in the etiology of some cancer types, and despite different mechanisms having been proposed, others are still to be clarified. The activation of Wnt/β-catenin and NF-κB oncogenic signalling pathways in epithelial cells represents a well-elucidated mechanism.

Complex interactions among microbiota, inflammation, environmental exposure and host genetics are needed for intestinal carcinogenesis.

This Special Issue will highlight the molecular mechanisms of the cellular environment in colon carcinogenesis by taking into account environmental and genetic factors.

Prof. Maria Cristina Curia
Guest Editor

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 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. 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
  • Tumor microenvironment
  • Wnt signalling
  • Microbiota
  • Inflammation
  • Risk factors

Published Papers (8 papers)

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Research

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14 pages, 16827 KiB  
Article
Phenotypic Characterization of Colorectal Liver Metastases: Capsule versus No Capsule and the Potential Role of Epithelial Mesenchymal Transition
by Claudia Fleig, Katja Evert, Hans J. Schlitt, Stefan Fichtner-Feigl and Stefan M. Brunner
Cancers 2023, 15(4), 1056; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041056 - 07 Feb 2023
Viewed by 1254
Abstract
Background: Colorectal liver metastases (CRLM) can be encased in a fibrous capsule separating cancer from normal liver tissue, which correlates with increased patient survival. This study investigated the cellular and molecular components of capsule formation and the possible role of epithelial mesenchymal transition [...] Read more.
Background: Colorectal liver metastases (CRLM) can be encased in a fibrous capsule separating cancer from normal liver tissue, which correlates with increased patient survival. This study investigated the cellular and molecular components of capsule formation and the possible role of epithelial mesenchymal transition (EMT). Methods: From 222 patients with CRLM, 84 patients (37.8%) were categorized to have CRLM encased with a capsule. A total of 34 CRLM from 34 selected patients was analyzed in detail by EMT pathway-profiling and custom PCR arrays to identify differences in gene expression between CRLM with (n = 20) and without capsule (n = 14). In parallel, those 34 CRLM were used to analyze 16 gene products at the metastasis margin via immunohistochemistry. Results: Encapsulated CRLM showed an elevated expression of signal transduction pathways and effector molecules involved in EMT. E-cadherin and keratin-19 were more prevalent, and transcription as well as translation (immunohistochemistry) of pGSK-3-β, SOX10, tomoregulin-1, and caldesmon were increased. By contrast, the loss of E-cadherin and the prevalence of snail-1 were increased in CRLM without capsule. Collagen I and III and versican were identified as capsule components with extracellular matrix fibers running concentrically around the malignant tissue and parallel to the invasive front. Caldesmon was also demonstrated as a capsule constituent. Conclusions: The fibrous capsule around CRLM can be produced by cells with mesenchymal characteristics. It functions as a protective border by both the features of fiber architecture and the inhibition of invasive growth through EMT recruiting mesenchymal cells such as myofibroblasts by transformation of surrounding epithelial or even carcinoma cells. By contrast, EMT demonstrated in non-encapsulated CRLM may lead to a more mesenchymal, mobile, and tissue-destructive carcinoma cell phenotype and facilitate malignant spread. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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21 pages, 11425 KiB  
Article
Identification of Endoplasmic Reticulum Stress-Related Subtypes, Infiltration Analysis of Tumor Microenvironment, and Construction of a Prognostic Model in Colorectal Cancer
by Baike Liu, Xiaonan Yin, Guangfu Jiang, Yang Li, Zhiyuan Jiang, Liming Qiang, Na Chen, Yating Fan, Chaoyong Shen, Lei Dai, Yuan Yin and Bo Zhang
Cancers 2022, 14(14), 3326; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143326 - 08 Jul 2022
Cited by 3 | Viewed by 2473
Abstract
Recently, endoplasmic reticulum (ER) stress has been shown to influence tumor progression and immune cell function in the tumor microenvironment (TME). However, the underlying role of ER stress-related gene patterns in colorectal cancer (CRC) development remains unclear. We analyzed the ER stress-related gene [...] Read more.
Recently, endoplasmic reticulum (ER) stress has been shown to influence tumor progression and immune cell function in the tumor microenvironment (TME). However, the underlying role of ER stress-related gene patterns in colorectal cancer (CRC) development remains unclear. We analyzed the ER stress-related gene patterns in 884 patients with CRC from the Gene Expression Omnibus database and evaluated the cell-infiltrating patterns in the TME. Two ER stress-related patterns were identified in patients with CRC that had distinct cell-infiltrating patterns in the TME and clinical characteristics. A risk score and nomogram based on 14 screened prognosis-correlated genes was built and validated to predict patient survival. Patients with a higher risk score were shown to have an unfavorable prognosis, and the risk score was associated with cell infiltration and drug sensitivity. Furthermore, spatial transcriptomics data were utilized to explore ER stress-related gene patterns in CRC tissues, and it was shown that ER stress phenotype involves in the formation of the immunosuppressive TME. This study demonstrated that ER stress-related gene patterns play a role in influencing the TME and predicting prognosis. These analyses of ER stress in the TME of CRC might deepen our understanding of CRC progression and immune escape and provide novel insights into therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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18 pages, 4540 KiB  
Article
Ficus dubia Latex Extract Induces Cell Cycle Arrest and Apoptosis by Regulating the NF-κB Pathway in Inflammatory Human Colorectal Cancer Cell Lines
by Rentong Hu, Weerachai Chantana, Pornsiri Pitchakarn, Subhawat Subhawa, Bhanumas Chantarasuwan, Piya Temviriyanukul and Teera Chewonarin
Cancers 2022, 14(11), 2665; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112665 - 27 May 2022
Cited by 6 | Viewed by 1683
Abstract
Colorectal cancer is one of the most diagnosed cancers that is associated with inflammation. Ficus dubia latex is recognized as a remedy with various therapeutic effects in traditional medicine, including anti-inflammatory and antioxidant activity. The present study aims to compare the anti-tumor activity [...] Read more.
Colorectal cancer is one of the most diagnosed cancers that is associated with inflammation. Ficus dubia latex is recognized as a remedy with various therapeutic effects in traditional medicine, including anti-inflammatory and antioxidant activity. The present study aims to compare the anti-tumor activity of Ficus dubia latex extract (FDLE) against HCT-116 and HT-29 human colorectal cancer cell lines in normal and inflammatory condition and explore its mechanism of action. FDLE exhibited remarkable antiproliferative activity against HCT-116 and HT-29 colorectal cancer cell lines in both conditions using MTT and colony formation assays and more effective anti-proliferation was observed in inflammatory condition. Mechanistically, FDLE induced cell cycle arrest at G0/G1 phase by down-regulating NF-κB, cyclin D1, CDK4 and up-regulatingp21 in both cell in normal condition. In inflammatory condition, FDLE not only exhibited stronger induction of cell cycle arrest in both cells by down-regulating NF-κB, cyclin D1, CDK4 and down-regulating p21, but also selectively induced apoptosis in HCT-116 cells by down-regulating NF-κB and Bcl-xl and up-regulating Bid, Bak, cleaved caspase-7 and caspase-3 through stronger ability to regulate these proteins. Our results demonstrated that the phytochemical agent in the latex of Ficus dubia could potential be used for treatment and prevention of human colorectal cancer, especially in inflammation-induced hyperproliferation progression. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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27 pages, 11412 KiB  
Article
Oxidative Distress Induces Wnt/β-Catenin Pathway Modulation in Colorectal Cancer Cells: Perspectives on APC Retained Functions
by Teresa Catalano, Emira D’Amico, Carmelo Moscatello, Maria Carmela Di Marcantonio, Alessio Ferrone, Giuseppina Bologna, Federico Selvaggi, Paola Lanuti, Roberto Cotellese, Maria Cristina Curia, Rossano Lattanzio and Gitana Maria Aceto
Cancers 2021, 13(23), 6045; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236045 - 30 Nov 2021
Cited by 10 | Viewed by 2856
Abstract
Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss [...] Read more.
Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss of proper APC functions. Cancer recurrence/relapse has been attributed to altered ROS levels, produced in a cancerous microenvironment. The effect of oxidative distress on Wnt/β-Catenin signaling in the light of APC functions is unclear. This study evaluated the effect of H2O2-induced short-term oxidative stress in HCT116, SW480 and SW620 cells with different phenotypes of APC and β-Catenin. The modulation and relationship of APC with characteristic molecules of Wnt/β-Catenin were assessed in gene and protein expression. Results indicated that CRC cells, even when deprived of growth factors, under acute oxidative distress conditions by H2O2 promote β-Catenin expression and modulate cytoplasmic APC protein. Furthermore, H2O2 induces differential gene expression depending on the cellular phenotype and leading to favor both Wnt/Catenin-dependent and -independent signaling. The exact mechanism by which oxidative distress can affect Wnt signaling functions will require further investigation to reveal new scenarios for the development of therapeutic approaches for CRC, in the light of the conserved functions of APC. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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18 pages, 1194 KiB  
Article
The Potential of Colonic Tumor Tissue Fusobacterium nucleatum to Predict Staging and Its Interplay with Oral Abundance in Colon Cancer Patients
by Pamela Pignatelli, Lorena Iezzi, Martina Pennese, Paolo Raimondi, Anna Cichella, Danilo Bondi, Rossella Grande, Roberto Cotellese, Nicola Di Bartolomeo, Paolo Innocenti, Adriano Piattelli and Maria Cristina Curia
Cancers 2021, 13(5), 1032; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051032 - 01 Mar 2021
Cited by 23 | Viewed by 2754
Abstract
Background. Intestinal microbiota dysbiosis may enhance the carcinogenicity of colon cancer (CC) by the proliferation and differentiation of epithelial cells. Oral Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) have the ability to invade the gut epithelium, promoting tumor progression. [...] Read more.
Background. Intestinal microbiota dysbiosis may enhance the carcinogenicity of colon cancer (CC) by the proliferation and differentiation of epithelial cells. Oral Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) have the ability to invade the gut epithelium, promoting tumor progression. The aim of the study was to assess whether the abundance of these odontopathogenic bacteria was associated with colon cancer. We also investigated how lifestyle factors could influence the oral Fn and Pg abundance and CC. Methods. Thirty-six CC patients were included in the study to assess the Pg and Fn oral and colon tissue abundance by qPCR. Oral health data, food habits and lifestyles were also recorded. Results. Patients had a greater quantity of Fn in the oral cavity than matched CC and adjacent non-neoplastic mucosa (adj t) tissues (p = 0.004 and p < 0.001). Instead, Pg was not significantly detected in colonic tissues. There was an association between the Fn quantity in the oral and CC tissue and a statistically significant relation between the Fn abundance in adenocarcinoma (ADK) and staging (p = 0.016). The statistical analysis revealed a tendency towards a greater Fn quantity in CC (p = 0.073, η2p = 0.12) for high-meat consumers. Conclusion. In our study, Pg was absent in colon tissues but was correlated with the oral inflammation gingival and plaque indices. For the first time, there was evidence that the Fn oral concentration can influence colon tissue concentrations and predict CC prognosis. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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Review

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30 pages, 1866 KiB  
Review
The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis
by Raghav Chandra, John D. Karalis, Charles Liu, Gilbert Z. Murimwa, Josiah Voth Park, Christopher A. Heid, Scott I. Reznik, Emina Huang, John D. Minna and Rolf A. Brekken
Cancers 2021, 13(24), 6206; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246206 - 09 Dec 2021
Cited by 59 | Viewed by 7855
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well [...] Read more.
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME. Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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Other

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3 pages, 405 KiB  
Comment
Controlled Trial Data Casts Doubt on the Supposed Benefit of Lung Metastasectomy. Comment on Chandra et al. The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers 2021, 13, 6206
by Fergus Macbeth and Tom Treasure
Cancers 2022, 14(17), 4235; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174235 - 31 Aug 2022
Viewed by 953
Abstract
We read with interest the comprehensive review by Chandra et al. [...] Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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19 pages, 1512 KiB  
Systematic Review
The Complex Network between Inflammation and Colorectal Cancer: A Systematic Review of the Literature
by Rossana Percario, Paolo Panaccio, Fabio Francesco di Mola, Tommaso Grottola and Pierluigi Di Sebastiano
Cancers 2021, 13(24), 6237; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246237 - 12 Dec 2021
Cited by 14 | Viewed by 2739
Abstract
Background: colorectal cancer (CRC) has a multifactorial etiology which comprises microbiota, genetic predisposition, diet, environmental factors, and last but not least, a substantial contribution by inflammation. The aim of this study is to conduct a systematic review of the literature regarding the strong [...] Read more.
Background: colorectal cancer (CRC) has a multifactorial etiology which comprises microbiota, genetic predisposition, diet, environmental factors, and last but not least, a substantial contribution by inflammation. The aim of this study is to conduct a systematic review of the literature regarding the strong link between inflammation and colorectal cancer. Methods: A systematic review of the literature on PubMed (Medline), Scopus, Cochrane and EMBase databases was performed, following the PRISMA 2020 guidelines. Each paper was reviewed by two groups of researchers in a single-blind format by using a pre-planned Microsoft© Excel® grid. Results: Using automated research filters, 14,566 studies were included, but 1% was found significant by the reviewers. Seventy pathways of inflammation were described in the sequence of inflammation-carcinogenesis, and anti-tumorigenic molecules were also found. Conclusion: several studies suggest a strong role of inflammation in the tumorigenesis of colorectal cancer through different pathways: this may have a diagnostic and clinical role and also therapeutic purpose in preventing carcinogenesis by treating inflammation. In vitro tests support this theory, even if many other clinical trials are necessary. The present paper was registered in the OpenScience Framework registry (Identifier: DOI 10.17605/OSF.IO/2KG7T). Full article
(This article belongs to the Special Issue Molecular Aspects of Tumor Microenvironment of Colorectal Cancers)
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