scholarly journals Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Michelle Hanus ◽  
Daniela Parada-Venegas ◽  
Glauben Landskron ◽  
Ana Maria Wielandt ◽  
Claudia Hurtado ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Gut Microbiota ◽  
Tumor Progression ◽  
Intestinal Mucosa ◽  
Immune Cells ◽  
Close Contact ◽  
Colorectal Carcinogenesis ◽  
Microbial Metabolites ◽  
Ample Evidence

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet‐derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

scholarly journals Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 159
Author(s):  
Yao Peng ◽  
Yuqiang Nie ◽  
Jun Yu ◽  
Chi Chun Wong
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Cancer Diagnosis ◽  
Intestinal Tract ◽  
Clinical Applications ◽  
Diagnosis And Treatment ◽  
Clinical Implications ◽  
Microbial Metabolites ◽  
Colorectal Tumorigenesis ◽  
Technology Studies

Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment.

scholarly journals Tumor-Associated Neutrophils and Macrophages—Heterogenous but Not Chaotic

2020 ◽  
Vol 11 ◽  
Author(s):  
Ling Wu ◽  
Xiang H.-F. Zhang
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Immune Cells ◽  
Mutual Influence ◽  
Therapeutic Resistance ◽  
Tumor Associated Macrophages ◽  
Tumor Associated Neutrophils ◽  
Shed Light ◽  
Lines Of Evidence

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this review, we collectively discussed many lines of evidence supporting the mutual influence between cancer cells and TAMs/TANs. We focused on how direct interactions among these cells dictate co-evolution involving not only clonal competition of cancer cells, but also landscape shift of the entire tumor microenvironment (TME). This co-evolution may take distinct paths and contribute to the heterogeneity of cancer cells and immune cells across different tumors. A more in-depth understanding of the cancer-TAM/TAN co-evolution will shed light on the development of TME that mediates metastasis and therapeutic resistance.

scholarly journals The Immune Endocannabinoid System of the Tumor Microenvironment

2020 ◽  
Vol 21 (23) ◽  
pp. 8929
Author(s):  
Melanie Kienzl ◽  
Julia Kargl ◽  
Rudolf Schicho
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Cannabinoid Receptors ◽  
Immune Cell ◽  
Tumor Development ◽  
Endocannabinoid System ◽  
Cell Functions ◽  
In Vitro Effects

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.

Association of TGF-β expression with intratumoral infiltration of cytotoxic T lymphocytes in patients with microsatellite-stable colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3577-3577
Author(s):  
Amir Mehrvarz Sarshekeh ◽  
Riham Katkhuda ◽  
Anuj Verma ◽  
Shailesh M Advani ◽  
Michael J. Overman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Rna Expression ◽  
Continuous Variables ◽  
Expression Levels

3577 Background: Transforming growth factor- β pathway (TGF-β) has an established role in promoting growth, invasion, metastasis as well as epithelial to mesenchymal (EMT) transition. Among 4 different described molecular subtypes of colorectal cancer (CRC), consensus molecular subtype 4 (CMS4) comprises up to 25% of CRC pts, distinguished by activation of this pathway, and is associated with higher relapse rate and poor prognosis. Recently, it has also been proposed that TGF-β activation drives immune evasion in murine models, but these findings have not been clinically validated. Methods: Using multi-gene RNA expression profiling, fresh-frozen paraffin-embedded samples of 35 patients with CRC were analyzed to determine TGF-β and EMT expression levels. Multiplexed IHC staining was performed on FFPE tumor blocks by using the Opal 7-Color fIHC Kit and the stained slides were scanned by a Vectra multispectral microscope (PerkinElmer) to measure infiltration of immune cells (i.e., T lymphocytes, cytotoxic T lymphocytes (CTL), T cell antigen-experienced, macrophages, etc.) in the tumor, stroma, and both components. TGF-β and EMT expression levels – as continuous variables - were compared with the infiltration of various immune cells using Spearman’s rank correlation analysis. Results: Among 35 pts, 28 pts had non-CMS1/MSS CRC. TGF-β RNA expression in the tumor microenvironment of these samples was inversely associated with the infiltration of CTL into the tumor (r=-0.43, p= 0.022). In contrast, there was no association of TGF-β with non-cytotoxic T-cells or macrophage infiltration. The tumor and stromal CTL infiltration differed substantially by CMS ( p=0.04, p=0.02, respectively) with tumor infiltration lowest in CMS4 (n=7). Consistent with this, EMT gene signature, which includes TGF-β expression, showed a similar inverse correlation with CTL infiltration (r=-0.48, p=0.009). Conclusions: TGF-β and EMT gene signatures have important roles in the exclusion of CTL in the tumor microenvironment of CRC pts. Inhibiting TGF-β pathway can potentially increase the intratumoral infiltration of CTL, which is a necessary (but not sufficient) step for immunotherapy response in MSS CRC. Clinical trials evaluating this hypothesis are currently ongoing (NCT03436563).

scholarly journals Comprehensive analysis of tumor microenvironment landscape and potential therapeutic agents based on tumor-infiltrating immune cells in colorectal cancer

2021 ◽  
Author(s):  
Wenhui Zhong ◽  
Feng Zhang ◽  
Xin Lu ◽  
Kaijun Huang ◽  
Junming Bi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Cancer Therapeutics ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Chemotherapy Drugs ◽  
Drug Compounds

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results：In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.

scholarly journals A comprehensive analysis of the microbiota composition and gene expression in colorectal cancer

2019 ◽  
Author(s):  
Qian Zhang ◽  
Huan Zhao ◽  
Dedong Wu ◽  
Dayong Cao ◽  
Wang Ma
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Bile Secretion ◽  
Colorectal Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Rrna Gene ◽  
Microbiota Composition ◽  
Sequencing Data ◽  
Keywords Colorectal Cancer

Abstract Subject: The dysbiosis of gut microbiota is pivotal in colorectal carcinogenesis. However, the synergy between an altered gut microbiota composition and differential gene expression of specific genes in colorectal cancer (CRC) remains elusive. Method: The gut microbiota dataset with number SRP158779, which contained 19 CRC samples and 19 normal samples, was downloaded from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database. The 16S rRNA gene sequences from this dataset were clustered into operational taxonomic units (OTUs); thereafter, the OTUs that were differentially enriched in CRC were identified and classified, followed by prediction of their functions. Additionally, RNA sequencing data from CRC samples was obtained from The Cancer Genome Atlas project (TCGA), and the differentially expressed genes (DEGs) and enriched pathways were identified. Finally, similar pathways that were significantly enriched in both differential OTUs and DEGs were screened. Key genes related to these pathways were executed the prognosis analysis. Results: The presence of Proteobacteria and Fusobacteria increased considerably in CRC samples; conversely, the abundance of Firmicute and Spirochaetes decreased markedly. In particular, the genera Fusobacterium , Catenibacterium , and Shewanella were detectable in tumor samples. Moreover, 246 DEGs were identified between tumor and normal tissues. Both DEGs and microbiota were involved in bile secretion and steroid hormone biosynthesis pathways. Finally, CYP3A4 and ABCG2 expression in CRC was related to the prognostic outcomes of CRC patients. Conclusion: Identifying the complicated interplay between gut microbiota and the DEGs could help in further understanding the pathogenesis of CRC, and these findings would enable better diagnosis and treatment of CRC patients. Keywords: colorectal cancer, gut microflora, gene expression, pathways enrichment, survival analysis

scholarly journals Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 137
Author(s):  
Zhi-Jian Han ◽  
Yang-Bing Li ◽  
Lu-Xi Yang ◽  
Hui-Juan Cheng ◽  
Xin Liu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Development Of Resistance ◽  
Immunosuppressive Cells

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

scholarly journals Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 124
Author(s):  
Paulina Czajka-Francuz ◽  
Sylwia Cisoń-Jurek ◽  
Aleksander Czajka ◽  
Maciej Kozaczka ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Advanced Colorectal Cancer ◽  
Experimental Studies ◽  
The Body ◽  
Lymphoid Cells ◽  
T Helper

Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients’ prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.

scholarly journals Prognostic Value and Immune Infiltration of Novel Biomarkers in Glioma: Evidence From a Comprehensive Analysis of Tumor Microenvironment

2020 ◽  
Author(s):  
Bolun Zhang ◽  
Feng Guan ◽  
Bin Dai ◽  
Guangtong Zhu ◽  
Beibei Mao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Stromal Cells ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
Ppi Network ◽  
Cox Regression Analysis ◽  
Intersection Analysis ◽  
Genome Atlas

Abstract BackgroundIn the glioma microenvironment, infiltrating immune cells has been shown to possess beneficial effects for tumor progression. Immune cells and stromal cells dominate the tumor microenvironment in glioma. The complex interplay between the tumor progression with immune cells or stromal cells was still unknown. MethodsIn this study, we used Estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) calculations to calculate the proportion of tumour-infiltrating immune cells (TIC) and the number of immune and stromal components in glioma cases from the cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEG) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, JAK3, IL2RB and CD3E were identified as predictors by the intersection analysis of univariate COX and PPI, and further analysis showed that the expression of them were positively correlated with survival and clinicopathological characteristics of glioma patients. Finally, the Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) deconvolution algorithm was applied to quantify the fraction and infiltration of 22 types of immune cells in glioma. ResultsOur results showed that ESTIMATEScores Were Correlated with the Survival of glioma Patients, DEGs Shared by ImmuneScore and StromalScore were predominantly presented as the enrichment of immune-related genes gene set enrichment analysis (GSEA). The intersection analysis of PPI network and univariate COX regression enabled us to identify three genes (JAK3, IL2RB and CD3E) that had never been reported before, whose expression was correlated with clinical characteristics such as survival and WHO grading of these patients. CITICSORT analysis of TIC ratio showed that B cell memory and CD8 + T cells were positively correlated with JAK3, IL2RB and CD3E expression, suggesting that these genes may be responsible for maintaining the immunodominant state of TME. CIBERSORT analysis for the proportion of TICs revealed that the levels of JAK3, IL2RB and CD3E affected the immune activity of TME.ConclusionOur results confirmed that the JAK3, IL2RB and CD3E can be used as diagnostic and prognostic biomarkers for glioma and may be used as therapeutic targets in the future.

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