scholarly journals Prognostic and Predictive Value of BGN in Colon Cancer Outcomes and Response to Immunotherapy

2022 ◽  
Vol 11 ◽  
Author(s):  
Zi-Xuan He ◽  
Sheng-Bing Zhao ◽  
Xue Fang ◽  
Ji-Fu E ◽  
Hong-Yu Fu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Response ◽  
Cancer Patients ◽  
Immune Cells ◽  
Matrix Protein ◽  
Cox Regression ◽  
Extracellular Matrix Protein ◽  
Great Promise ◽  
Clinical Prognosis ◽  
Expression Levels

BackgroundColon cancer is one of the most frequent malignancies and causes high mortality worldwide. Exploring the tumor-immune interactions in the tumor microenvironment and identifying new prognostic and therapeutic biomarkers will assist in decoding the novel mechanism of tumor immunotherapy. BGN is a typical extracellular matrix protein that was previously validated as a signaling molecule regulating multiple processes of tumorigenesis. However, its role in tumor immunity requires further investigation.MethodsThe differentially expressed genes in three GEO datasets were analyzed, and BGN was identified as the target gene by intersection analysis of PPIs. The relevance between clinical outcomes and BGN expression levels was evaluated using data from the GEO database, TCGA and tissue microarray of colon cancer samples. Univariable and multivariable Cox regression models were conducted for identifying the risk factors correlated with clinical prognosis of colon cancer patients. Next, the association between BGN expression levels and the infiltration of immune cells as well as the process of the immune response was analyzed. Finally, we predicted the immunotherapeutic response rates in the subgroups of low and high BGN expression by TIS score, ImmuCellAI and TIDE algorithms.ResultsBGN expression demonstrated a statistically significant upregulation in colon cancer tissues than in normal tissues. Elevated BGN was associated with shorter overall survival as well as unfavorable clinicopathological features, including tumor size, serosa invasion and length of hospitalization. Mechanistically, pathway enrichment and functional analysis demonstrated that BGN was positively correlated with immune and stromal scores in the TME and primarily involved in the regulation of immune response. Further investigation revealed that BGN was strongly expressed in the immunosuppressive phenotype and tightly associated with the infiltration of multiple immune cells in colon cancer, especially M2 macrophages and induced Tregs. Finally, we demonstrated that high BGN expression presented a better immunotherapeutic response in colon cancer patients.ConclusionBGN is an encouraging predictor of diagnosis, prognosis and immunotherapeutic response in patients with colon cancer. Assessment of BGN expression represents a novel approach with great promise for identifying patients who may potentially benefit from immunotherapy.

scholarly journals Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling

2021 ◽  
Vol 22 (16) ◽  
pp. 8485
Author(s):  
Iranzu Gómez de Segura ◽  
Patricia Ahechu ◽  
Javier Gómez-Ambrosi ◽  
Amaia Rodríguez ◽  
Beatriz Ramírez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Extracellular Matrix ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Mrna Levels ◽  
Expression Levels ◽  
The Impact ◽  
Ht 29 ◽  
Gene Expression Levels

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.

scholarly journals Development of prognosis model for colon cancer based on autophagy-related genes

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xu Wang ◽  
Yuanmin Xu ◽  
Ting Li ◽  
Bo Chen ◽  
Wenqi Yang
Keyword(s):  
Colon Cancer ◽  
Regression Analysis ◽  
High Risk ◽  
Cancer Patients ◽  
Risk Score ◽  
Cox Regression ◽  
Patient Survival ◽  
Expression Profiles ◽  
Cox Regression Analysis ◽  
Risk Patients

Abstract Background Autophagy is an orderly catabolic process for degrading and removing unnecessary or dysfunctional cellular components such as proteins and organelles. Although autophagy is known to play an important role in various types of cancer, the effects of autophagy-related genes (ARGs) on colon cancer have not been well studied. Methods Expression profiles from ARGs in 457 colon cancer patients were retrieved from the TCGA database (https://portal.gdc.cancer.gov). Differentially expressed ARGs and ARGs related to overall patient survival were identified. Cox proportional-hazard models were used to investigate the association between ARG expression profiles and patient prognosis. Results Twenty ARGs were significantly associated with the overall survival of colon cancer patients. Five of these ARGs had a mutation rate ≥ 3%. Patients were divided into high-risk and low-risk groups based on Cox regression analysis of 8 ARGs. Low-risk patients had a significantly longer survival time than high-risk patients (p < 0.001). Univariate and multivariate Cox regression analysis showed that the resulting risk score, which was associated with infiltration depth and metastasis, could be an independent predictor of patient survival. A nomogram was established to predict 1-, 3-, and 5-year survival of colon cancer patients based on 5 independent prognosis factors, including the risk score. The prognostic nomogram with online webserver was more effective and convenient to provide information for researchers and clinicians. Conclusion The 8 ARGs can be used to predict the prognosis of patients and provide information for their individualized treatment.

Humoral immune response to thymidylate synthase in colon cancer patients after 5-FU chemotherapy

2005 ◽  
Vol 100 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Yuriy V. Shebzukhov ◽  
Ekaterina P. Koroleva ◽  
Svetlana V. Khlgatian ◽  
Maria A. Lagarkova ◽  
Andrey A. Meshcheryakov ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Response ◽  
Cancer Patients ◽  
Thymidylate Synthase ◽  
Humoral Immune Response ◽  
Humoral Immune

Abstract 15539: Single-cell Analysis of Aortic Tissues From Patients With Marfan Syndrome Reveals Changes in Smooth Muscle Cell Differentiation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ashley Dawson ◽  
Yanming Li ◽  
Pingping Ren ◽  
Hernan Vasquez ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Single Cell ◽  
Marfan Syndrome ◽  
Immune Cells ◽  
Matrix Protein ◽  
Immune Cell ◽  
Aortic Aneurysms ◽  
Extracellular Matrix Protein ◽  
Cardiac Transplant ◽  
Control Tissue

Background: Thoracic aortic aneurysms associated with Marfan syndrome (MFS) carry a high risk of mortality; however, the molecular and cellular processes leading to aortopathy in this population remain poorly understood. We aimed to use single-cell RNA (scRNA) sequencing to define the non-immune cell populations present within the aortic wall in MFS, hypothesizing that these would differ from those of non-aneurysmal control tissue. Methods: We performed scRNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and of age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). The Seurat package in R was used for analysis. Differentially expressed genes were identified using edgeR. Results: Eighteen non-immune cell clusters were identified, with conserved gene expression of the largest of the clusters consistent with smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (n=3). The SMCs and fibroblasts exhibited graded changes in their expression of contractile and extracellular matrix protein genes, supportive of a phenotypic continuum. Additionally, we identified differences in the proportions of non-immune cells in MFS tissues compared to controls. In control tissues, the most common non-immune cells expressed markers of contractile SMC maturity including CNN1 , MYH11 , and SMTN . In contrast, the largest clusters in MFS tissue were most closely related to SMCs on correlation analysis, but displayed increased expression of cyclin genes as well as immune, endothelial, and fibroblast genes indicative of de-differentiated, proliferative SMCs. Additionally, expression of genes associated with SMC phenotypic maturity, including MYH11 and MYOCD , were significantly downregulated in several of the MFS SMC clusters. Conclusion: Our data demonstrate a phenotypic continuum between fibroblasts and SMCs, with aortas from patients with MFS exhibiting an increased proportion of de-differentiated, proliferative SMCs compared to controls. Additionally, markers of SMC maturity were downregulated in SMCs in MFS compared to controls. This may be due to disruption of signaling pathways that promote differentiation.

scholarly journals Evaluating macrophage migration inhibitory factor 1 expression as a prognostic biomarker in colon cancer

Tumor Biology ◽  
2020 ◽  
Vol 42 (6) ◽  
pp. 101042832092452
Author(s):  
Lina Olsson ◽  
Gudrun Lindmark ◽  
Marie-Louise Hammarström ◽  
Sten Hammarström ◽  
Basel Sitohy
Keyword(s):  
Colon Cancer ◽  
Lymph Nodes ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Expression Levels ◽  
Significant Difference ◽  
Mrna Expression Levels ◽  
Inhibitory Factor 1

Objective: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker. Methods: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I–IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase–polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry. Results: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan–Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up. Conclusion: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.

Association of immune-regulatory (FoxP3+)-T-cell tumor infiltration status with benefit from chemoimmunotherapy with gemcitabine, oxaliplatin, 5-FU/FA plus GM-CSF and aldesleukine (GOLFIG) in metastatic colon cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3045-3045
Author(s):  
P. Correale ◽  
P. Tagliaferri ◽  
M. T. Del Vecchio ◽  
C. Remondo ◽  
C. Migali ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Cox Regression ◽  
Treg Cells ◽  
Phase Iii ◽  
Metastatic Colon Cancer ◽  
Tumor Infiltration ◽  
Gm Csf ◽  
Independent Variable

3045 Background: GOLFIG is a novel chemoimmunotherapy regimen, combining gemcitabine, oxaliplatin, 5-FU/FA with immunoadjuvant GM-CSF and aldesleukine, which resulted safe and very active in colon cancer patients. Antitumor activity and immunity feedback to the treatment resulted strictly correlated. The best outcome was observed in patients showing autoimmunity signs, rise in central-memory-T cells, and decline in peripheral and tumor infiltrating immuno-regulatory T (Treg) cells. On these bases, we investigated a possible correlation between Treg tumor infiltration at diagnosis and clinical outcome of these patients. Methods: An immunohistochemistry study was carried out to quantify the infiltration of Treg (FoxP3+) lymphocytes in tumor samples of 41 colon cancer patients who received FOLFOX-4 chemotherapy or GOLFIG chemo-immunotherapy as enrolled in the ongoing phase III GOLFIG-2 trial. Treg tumor infiltration score (range 0 to 5) was then correlated with survival (OS) and time to progression (TTP). Results: A higher Treg tumor infiltration score (score 3–5) was associated to a longer OS and TTP in the whole patient population (high vs low score; TTP=18 vs 9.4 months; p=0.002; OS=55.7 vs 28.9 months; p=0.001); however, those patients with high tumor infiltration of FoxP3+-T cells who received GOLFIG regimen showed the most favorable outcome (high vs low score; TTP=20.8 vs 11.6 months; p=0.04; OS=68.1 vs 41 months; p=0.04). A Cox regression model demonstrated in these patients that a high Treg tumor infiltration score is an independent variable of long survival and prolonged TTP. Conclusions: Our results suggest that GOLFIG chemoimmunotherapy is highly effective in colon carcinoma patients with high FoxP3+ infiltration score and that Treg-tumor infiltration score may be a favorable prognostic marker in colon cancer patients. No significant financial relationships to disclose.

scholarly journals DOCK2 is a Biomarker for Predicting the Prognosis of Lung Adenocarcinoma and Associated with Immune Infiltration

2021 ◽  
Author(s):  
Jie He ◽  
Tongtong Zhang ◽  
Jian Sun ◽  
Guangnan Liu
Keyword(s):  
Immune Response ◽  
Lung Adenocarcinoma ◽  
Immune Cells ◽  
Bioinformatics Analysis ◽  
Cox Regression ◽  
Clinical Sample ◽  
Clinical Samples ◽  
Data Set ◽  
Immune Infiltration ◽  
Low Expression

Abstract Background: dedicator of cytokinesis 2 is an atypical guanine exchange factor, which is particularly expressed in hematopoietic cells and modulates the activation along with the migration of immune cells by activating Ras--related C3 botulinum toxin substrate (Rac). Nevertheless, the role of DOCK2 in lung adenocarcinoma (LUAD) remains unclear.Methods: Herein, we performed bioinformatics analysis of lung adenocarcinoma data abstracted from TCGA (The Cancer Genome Altas) and GEO (Gene Expression Omnibus) data resources, and combined with web tools consisting of LinkedOmics, TIMER, and TISIDB. Finally, combined with clinical lung adenocarcinoma samples, we verified the expression of DOCK2 in tissue and its effect on the prognosis of lung adenocarcinoma.Results: In the TCGA lung adenocarcinoma data set, the expression of DOCK2 was down-regulated in tumor tissues and verified in multiple independent cohorts. In addition, the low expression of DOCK2 indicates a poor overall survival(OS) in both TCGA and other GEO data sets and in our clinical samples. COX regression data illustrated that the low expression of DOCK2 was an independent predictor for OS. Functional network analysis shows that DOCK2 participates in immune response through interleukin production, neuroinflammatory response, acquired immune response, leukocyte migration and activation of lymph node cells, and is related to multiple immune-related pathways. Besides, the expression of DOCK2 was remarkably related with many kinds of tumor infiltrating immune cells.Conclusion: combined with bioinformatics analysis and clinical sample verification, our study shows that DOCK2 can independently estimate the prognosis of lung adenocarcinoma and is related to immune infiltration. As a promising prognostic indicator and potential target of immunotherapy, the potential effect of DOCK2 on lung adenocarcinoma and its molecular mechanism are worthy of further discussion.

scholarly journals SERPINE1 associated with remodeling of the tumor microenvironment in colon cancer progression: a novel therapeutic target

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shaokun Wang ◽  
Li Pang ◽  
Zuolong Liu ◽  
Xiangwei Meng
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
The Relationship

Abstract Background The change of immune cell infiltration essentially influences the process of colorectal cancer development. The infiltration of immune cells can be regulated by a variety of genes. Thus, modeling the immune microenvironment of colorectal cancer by analyzing the genes involved can be more conducive to the in-depth understanding of carcinogenesis and the progression thereof. Methods In this study, the number of stromal and immune cells in malignant tumor tissues were first estimated by using expression data (ESTIMATE) and cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) to calculate the proportion of infiltrating immune cell and stromal components of colon cancer samples from the Cancer Genome Atlas database. Then the relationship between the TMN Classification and prognosis of malignant tumors was evaluated. Results By investigating differentially expressed genes using COX regression and protein-protein interaction network (PPI), the candidate hub gene serine protease inhibitor family E member 1 (SERPINE1) was found to be associated with immune cell infiltration. Gene Set Enrichment Analysis (GSEA) further projected the potential pathways with elevated SERPINE1 expression to carcinogenesis and immunity. CIBERSORT was subsequently utilized to investigate the relationship between the expression differences of SERPINE1 and immune cell infiltration and to identify eight immune cells associated with SERPINE1 expression. Conclusion We found that SERPINE1 plays a role in the remodeling of the colon cancer microenvironment and the infiltration of immune cells.

scholarly journals Effect of Aging-Related Genes on the Prognosis of Colon Cancer

2021 ◽  
Author(s):  
Yushu Liu ◽  
Jiantao Gong ◽  
Yanyi Huang ◽  
Qunguang Jiang
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Clinical Characteristics ◽  
Cox Regression ◽  
Validation Cohort ◽  
External Validation ◽  
Predictive Ability ◽  
Lasso Regression ◽  
Internal Validation ◽  
Cox Regression Analysis

Abstract Background:Colon cancer is a common malignant cancer with high incidence and poor prognosis. Cell senescence and apoptosis are important mechanisms of tumor occurrence and development, in which aging-related genes(ARGs) play an important role. This study aimed to establish a prognostic risk model based on ARGs for diagnosis and prognosis prediction of colon cancer .Methods: We downloaded transcriptome data and clinical information of colon cancer patients from the Cancer Genome Atlas(TCGA) database and the microarray dataset(GSE39582) from the Gene Expression Omnibus(GEO) database. Univariate COX, least absolute shrinkage and selection operator(LASSO) regression algorithm and multivariate COX regression analysis were used to construct a 6-ARG prognosis model and calculated the riskScore. The prognostic signatures is validated by internal validation cohort and external validation cohort(GSE39582).In addition, functional enrichment pathways and immune microenvironment of aging-related genes(ARGs) were also analyzed. We also analyzed the correlation between rsikScore and clinical features and constructed a nomogram based on riskScore. We are the first to construct prognostic nomogram based on ARGs.Results: Through univariate COX,LASSO regression algorithm and multivariate COX regression analysis,6 prognostic ARGs (PDPK1,RAD52,GSR,IL7,BDNF and SERPINE1) were screened out and riskScore was constructed. We have verified that riskScore has good prognostic value in both internal validation cohort and external validation cohort. Pathway enrichment and immunoanalysis of ARGs provide a direction for the treatment of colon cancer patients. We also found that riskScore was closely related to the clinical characteristics of patients. Based on riskScore and related clinical features, we constructed a nomogram, which has good predictive performance.Conclusion: The 6-ARG prognostic signature we constructed has a certain clinical predictive ability. Its riskScore is also closely related to clinical characteristics, and nomogram based on this has stronger predictive ability than a single indicator. ARGs and the nomogram we constructed may provide a promising treatment for colon cancer patients.

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