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Special Issue "Tumor Microenvironment in Colorectal Cancer"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editor

Dr. Cristina Peña
E-Mail Website
Guest Editor
1. Medical Oncology Department, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá University, 28034 Madrid, Spain
2. Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain
Interests: tumor microenvironment; colorectal cancer; cancer-associated fibroblasts; exosomes; migration and invasion; tumor biomarkers

Special Issue Information

Experimental studies and analyses of clinical material have convincingly demonstrated that colorectal cancer initiation, growth, and progression do not depend exclusively on cell-autonomous properties of cancer cells themselves but are also deeply influenced by the local microenvironment. The stromal elements of tumors consist of a variety of non-epithelial cell types and their interactions which involve reciprocal paracrine signaling, including growth factors, exosomes, and extracellular matrix components.

Extracellular matrix, blood vessels, immune cells, and fibroblasts are the main components of what is known as the tumor microenvironment. Fibroblasts are one of the most abundant and active cell types of the tumor microenvironment. Fibroblast-like cells, usually named as cancer-associated fibroblasts (CAFs), seem to regulate many aspects of tumorigenesis and can exert tumor-suppressing and -promoting effects, involving interactions between the malignant cells and other cells of the tumor microenvironment. Moreover, CAFs actively participate in extracellular matrix deposition and remodeling, which are also related to disease progression.

In addition, endothelial cells play the role of communicating tumor cells with surrounding areas by generating new vascular networks or modifying pre-existing vessels, thus conditioning tumor oxygen and nutrient supply. Since endothelial cells, as well as CAFs and tumor cells, affect immune cell recruitment within the tumor, it can be assumed that the tumor microenvironment will condition immune response. T-cell activation can end up either stimulating or inhibiting the immune system, depending on many factors, such as tumor antigen production, regulation of inhibitory ligands, angiogenesis, CAFs’ chemokine secretion, etc.

This Special Issue will include papers investigating the different mechanisms related with tumor microenvironment involved in CRC initiation, growth, and progression. Furthermore, experimental clinical and preclinical studies including bimolecular experiments to examine potential new approaches for CRC patients’ survival increase and improvement are welcome.

This Special Issue welcomes original research and review papers. Potential topics include but are not limited to the following:

  1. Molecular mechanisms of tumor microenvironment cross-talk in CRC;
  2. Epigenetic regulation of tumor microenvironment in CRC;
  3. Molecular imaging approaches to study tumor microenvironment in CRC;
  4. Tumor biomarkers related with tumor microenvironment in CRC patients;
  5. “Omics” studies of tumor microenvironment components in CRC;
  6. Therapeutic approaches of CRC patients based in the tumor microenvironment target.

Dr. Cristina Peña
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 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

  • Colorectal cancer
  • Tumor microenvironment
  • Cancer-associated fibroblasts
  • Endothelial cells
  • Immune cells
  • Extracellular matrix
  • Tumor microenvironment biomarkers
  • Tumor microenvironment-based clinical approaches

Published Papers (7 papers)

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Research

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Article
Development of a Multiplex Immunohistochemistry Workflow to Investigate the Immune Microenvironment in Mouse Models of Inflammatory Bowel Disease and Colon Cancer
Int. J. Mol. Sci. 2021, 22(20), 11001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011001 - 12 Oct 2021
Viewed by 200
Abstract
Multiplex immunohistochemistry (mIHC) enables simultaneous staining of multiple immune markers on a single tissue section. Mounting studies have demonstrated the versatility of mIHC in evaluating immune infiltrates in different diseases and the tumour microenvironment (TME). However, the majority of published studies are limited [...] Read more.
Multiplex immunohistochemistry (mIHC) enables simultaneous staining of multiple immune markers on a single tissue section. Mounting studies have demonstrated the versatility of mIHC in evaluating immune infiltrates in different diseases and the tumour microenvironment (TME). However, the majority of published studies are limited to the analysis of human patient samples. Performing mIHC on formalin-fixed paraffin-embedded (FFPE) mouse tissues, particularly with sensitive antigens, remain challenging. The aim of our study was to develop a robust and reproducible protocol to uncover the immune landscape in mouse FFPE tissues. Effective antibody stripping while maintaining sensitivity to antigens and tissue adhesion to the glass slide is critical in developing an mIHC panel to allow successive rounds of staining. Thus, we identified a highly efficient stripping method that preserves signal intensity and antigenicity to allow multiple rounds of staining. We subsequently optimised an mIHC workflow with antibodies specific against CD4, CD8α, FOXP3 and B220 to identify distinct T and B cell populations on mouse FFPE tissues. Lastly, the application of this mIHC panel was validated in a mouse model of inflammatory bowel cancer, two allograft mouse models of spontaneous colon adenocarcinoma and a sporadic mouse model of colon cancer. Together, these demonstrate the utility of the aforementioned protocol in establishing the quantity and spatial localisation of immune cells in different pathological tissues. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Article
The Preventive Effect of the Phenotype of Tumour-Associated Macrophages, Regulated by CD39, on Colon Cancer in Mice
Int. J. Mol. Sci. 2021, 22(14), 7478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147478 - 13 Jul 2021
Viewed by 676
Abstract
Background: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. Methods: An in vivo study of co-culture with colon cancer cells [...] Read more.
Background: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. Methods: An in vivo study of co-culture with colon cancer cells and immune cells from the bone marrow (BM) of mice was performed. After the confirmation of the effect of polyoxotungstate (POM-1) as an inhibitor of CD39 on TAMs, the mice were randomly divided into a control group without POM-1 and a study group with POM-1, respectively, after subcutaneous injection of CT26 cells. On day 14 after the injection, the mice were sacrificed, and TAMs were evaluated using fluorescence-activated cell sorting. Results: In the in vivo study, the co-culture with POM-1 significantly increased the apoptosis of CT26 cells. The cell population from the co-culture with POM-1 showed significant increases in the expression of CD11b+ for myeloid cells, lymphocyte antigen 6 complex, locus C (Ly6C+) for monocytes, M1-tumour phenotypes from TAMs, and F4/80+ for macrophages. In the in vivo study, tumour growth in the study group with POM-1 was significantly limited, compared with the control group without POM-1. The expressions of Ly6C+ and major histocompatibility complex class II+ for M1-tumour phenotypes from TAMs on F4/80+ from the tumour tissue in the study group had significantly higher values compared with the control group. Conclusion: The inhibition of CD39 with POM-1 prevented the growth of colon cancer in mice, and it was associated with the increased expression of M1-tumour phenotypes from TAMs in the cancer tissue. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Article
Effect of Proton Pump Inhibitors on Colorectal Cancer
Int. J. Mol. Sci. 2020, 21(11), 3877; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113877 - 29 May 2020
Cited by 4 | Viewed by 1063
Abstract
Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and [...] Read more.
Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with Clostridium perfringens enterotoxin (CPE) in CRC lesions. CPE treatment activated yes-associated protein (YAP) signals to enhance proliferation and stemness. The orthotopic colon cancer model of CMT93 cells with long-term PPI administration showed enhanced tumor growth and liver metastasis due to gastrin and YAP activation, as indicated by gastrin receptor knockdown and treatment with a YAP inhibitor. These findings suggest that PPI promotes CRC growth and metastasis by increasing gastrin concentration and YAP activation, resulting in gut flora alteration and fecal alkalization. These findings suggest that PPI use in colorectal cancer patients might create a risk of cancer promotion. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Review

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Review
Organ Specificity and Heterogeneity of Cancer-Associated Fibroblasts in Colorectal Cancer
Int. J. Mol. Sci. 2021, 22(20), 10973; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010973 - 11 Oct 2021
Viewed by 256
Abstract
Fibroblasts constitute a ubiquitous mesenchymal cell type and produce the extracellular matrix (ECM) of connective tissue, thereby providing the structural basis of various organs. Fibroblasts display differential transcriptional patterns unique to the organ of their origin and they can be activated by common [...] Read more.
Fibroblasts constitute a ubiquitous mesenchymal cell type and produce the extracellular matrix (ECM) of connective tissue, thereby providing the structural basis of various organs. Fibroblasts display differential transcriptional patterns unique to the organ of their origin and they can be activated by common stimuli such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) signaling. Cancer-associated fibroblasts (CAFs) reside in the cancer tissue and contribute to cancer progression by influencing cancer cell growth, invasion, angiogenesis and tumor immunity. CAFs impact on the tumor microenvironment by remodeling the ECM and secreting soluble factors such as chemokines and growth factors. Differential expression patterns of molecular markers suggest heterogeneous features of CAFs in terms of their function, pathogenic role and cellular origin. Recent studies elucidated the bimodal action of CAFs on cancer progression and suggest a subgroup of CAFs with tumor-suppressive effects. This review attempts to describe cellular features of colorectal CAFs with an emphasis on their heterogeneity and functional diversity. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Review
The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia
Int. J. Mol. Sci. 2021, 22(4), 1565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041565 - 04 Feb 2021
Cited by 4 | Viewed by 1309
Abstract
Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause [...] Read more.
Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Review
The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns
Int. J. Mol. Sci. 2021, 22(4), 1544; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041544 - 03 Feb 2021
Cited by 1 | Viewed by 951
Abstract
Colorectal carcinoma (CRC) is the third most common cancer. Likewise, it is a disease that has a long survival if it is prematurely detected. However, more than 50% of patients will develop metastases, mainly in the liver (LM-CRC), throughout the evolution of their [...] Read more.
Colorectal carcinoma (CRC) is the third most common cancer. Likewise, it is a disease that has a long survival if it is prematurely detected. However, more than 50% of patients will develop metastases, mainly in the liver (LM-CRC), throughout the evolution of their disease, which accounts for most CRC-related deaths. Treatment it is certainly a controversial issue, since it has not been shown to increase overall survival in the adjuvant setting, although it does improve disease free survival (DFS). Moreover, current chemotherapy combinations are administered based on data extrapolated from primary tumors (PT), not considering that LM-CRC present a very particular tumor microenvironment that can radically condition the effectiveness of treatments designed for a PT. The liver has a particular histology and microenvironment that can determine tumor growth and response to treatments: double blood supply, vascularization through fenestrated sinusoids and the presence of different mesenchymal cell types, among other particularities. Likewise, the liver presents a peculiar immune response against tumor cells, a fact that correlates with the poor response to immunotherapy. All these aspects will be addressed in this review, putting them in the context of the histological growth patterns of LM-CRC, a particular pathologic feature with both prognostic and predictive repercussions. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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Review
Hedgehog Signaling in Colorectal Cancer: All in the Stroma?
Int. J. Mol. Sci. 2021, 22(3), 1025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031025 - 20 Jan 2021
Cited by 1 | Viewed by 798
Abstract
Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand [...] Read more.
Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Colorectal Cancer)
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