Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients.
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ABSTRACT:
SUBMITTER: Fouad MA
PROVIDER: S-EPMC8040557 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite great progress has been made in treatment strategies, colorectal cancer (CRC) remains the predominant life-threatening malignancy with the feature of high morbidity and mortality. It has been widely acknowledged that the dysfunction of immune system, including aberrantly expressed cytokines, is strongly correlated with the pathogenesis and progression of colorectal cancer. As one of the most well-known cytokines that were discovered centuries ago, interleukins are now uncovering new insights into colorectal cancer therapy. Herein, we divide currently known interleukins into 6 families, including IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family and IL-17 family. In addition, we comprehensively reviewed the oncogenic or antitumour function of each interleukin involved in CRC pathogenesis and progression by elucidating the underlying mechanisms. Furthermore, by providing interleukins-associated clinical trials, we have further driven the profound prospect of interleukins in the treatment of colorectal cancer.
| S-EPMC7378639 | biostudies-literature
Project description:Interleukins and associated cytokines serve as the means of communication for innate and adaptive immune cells as well as non-immune cells and tissues. Thus, interleukins have a critical role in cancer development, progression and control. Interleukins can nurture an environment enabling and favouring cancer growth while simultaneously being essential for a productive tumour-directed immune response. These properties of interleukins can be exploited to improve immunotherapies to promote effectiveness as well as to limit side effects. This Review aims to unravel some of these complex interactions.
| S-EPMC8173513 | biostudies-literature
Project description:The use of combined antiretroviral therapy (cART) inhibits the replication of the Human Immunodeficiency Virus (HIV) and thus may affect the functioning of the immune system, e.g., induce changes in the expression of certain cytokines. The aim was to examine the effect of cART on the expression of selected cytokines: interleukin -4, -7 and -15 in HIV-infected subjects. The test material was the plasma of HIV-infected men and healthy men (C, control group). The levels of interleukin were measured by immunoenzymatic method before cART and one year after treatment in relation to the C group. HIV-infected men were analyzed in subgroups depending on the HIV-RNA viral load, CD4+ and CD8+T-cell counts, and the type of therapeutic regimen. A significantly higher level of IL-4 was demonstrated in HIV-infected men before cART compared to those after treatment and in the control group. The use of cART resulted in a significant decrease in the level of IL-7 in HIV-infected men; however, high levels of IL-7 were associated with a low number of CD4+ T cells and CD8+ T cells. An increase in the level of IL-15 in HIV-infected men was noted after the use of cART. There was no difference in the expression of interleukins depending on the treatment regimen used. The study showed the effect of cART on the expression of interleukins, especially IL-4 and IL-7. Further research in this direction seems promising, confirming the role of these interleukins in the course of the disease.
| S-EPMC9144358 | biostudies-literature
Project description:Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, underscoring a need for better understanding of the disease and development of novel diagnostic biomarkers and therapeutic interventions. Herein, we performed transcriptome analyses on peripheral blood mononuclear cells (PBMCs), CRC tumor tissue and adjacent normal tissue from 10 CRC patients and PBMCs from 15 healthy controls. Up regulated transcripts from CRC PBMCs were associated with functions related to immune cell trafficking and cellular movement, while downregulated transcripts were enriched in cellular processes related to cell death. Most affected signaling networks were those involved in tumor necrosis factor (TNF) and interleukin signaling. The expression of selected immune-related genes from the RNA-Seq data were further validated using qRT-PCR. Transcriptome analysis of CRC tumors and ingenuity pathway analysis revealed enrichment in several functional categories related to cellular movement, cell growth and proliferation, DNA replication, recombination and repair, while functional categories related to cell death were suppressed. Upstream regulator analysis revealed activation of ERBB2 and FOXM1 networks. Interestingly, there were 18 common upregulated and 36 common downregulated genes when comparing PBMCs and tumor tissue, suggesting transcriptomic changes in the tumor microenvironment could be reflected, in part, in the periphery with potential utilization as disease biomarkers.
| S-EPMC6966620 | biostudies-literature
Project description:Background: Although increasing evidences showed a correlation between cholecystectomy and the prevalence rate of colorectal cancer (CRC), and shed light on gut microbiota in colorectal pathogenesis, only a few studies focused on microbial alterations after cholecystectomy, and its sequent role in carcinogenesis and progression of CRC has not been reported. Thus, we aimed to investigate the bacterial alterations and tried to clarify their clinical significance. Methods: 104 subjects were enrolled and divided into post-cholecystectomy patients (PC, n = 52) and healthy controls (HC, n = 52). To investigate the bacterial role in carcinogenesis, PC patients were further separated into preCA_CRC (patients with precancerous lesions and/or CRC, n = 9) and non-CA (patients without precancerous lesions and CRC, n = 43) based on the histopathology. Qualified stool samples were collected for 16S rRNA gene sequencing to analyze the bacterial profile. Results: Our data showed noteworthy compositional and abundant alterations of bacterial microbiota in PC patients, characterized as Bacteroides ovatus, Prevotella copri, and Fusobacterium varium remarkably increased; Faecalibacterium prausnitzii, Roseburia faecis, and Bifidobacterium adolescentis significantly decreased. Additionally, the duration after cholecystectomy was the critical factor that affected bacterial composition. Machine learning-based analysis showed a pivotal role of Megamonas funiformis in discriminating PC from HC subjects and involving in the progression of CRC. Conclusions: The bacterial dysbiosis may associate with CRC in PC patients, and the duration after cholecystectomy was highlighted as an important factor. Altered bacterial microbiota was likely to play a pivotal role in related-disease in the long-term follow-up of PC patients.
| S-EPMC7434860 | biostudies-literature
Project description:Competent human DNA mismatch repair (MMR) corrects DNA polymerase mistakes made during cell replication to maintain complete DNA fidelity in daughter cells; faulty DNA MMR occurs in the setting of inflammation and neoplasia, creating base substitutions (e.g. point mutations) and frameshift mutations at DNA microsatellite sequences in progeny cells. Frameshift mutations at DNA microsatellite sequences are a detected biomarker termed microsatellite instability (MSI) for human disease, as this marker can prognosticate and determine therapeutic approaches for patients with cancer. There are two types of MSI: MSI-High (MSI-H), defined by frameshifts at mono- and di-nucleotide microsatellite sequences, and elevated microsatellite alterations at selected tetranucleotide repeats or EMAST, defined by frameshifts in di- and tetranucleotide microsatellite sequences but not mononucleotide sequences. Patients with colorectal cancers (CRCs) manifesting MSI-H demonstrate improved survival over patients without an MSI-H tumor, driven by the generation of immunogenic neoantigens caused by novel truncated proteins from genes whose sequences contain coding microsatellites; these patients' tumors contain hundreds of somatic mutations, and show responsiveness to treatment with immune checkpoint inhibitors. Patients with CRCs manifesting EMAST demonstrate poor survival over patients without an EMAST tumor, and may be driven by a more dominant defect in double strand break repair attributed to the MMR protein MSH3 over its frameshift correcting function; these patients' tumors often have a component of inflammation (and are also termed inflammation-associated microsatellite alterations) and show less somatic mutations and lack coding mononucleotide frameshift mutations that seem to generate the neoantigens seen in the majority of MSI-H tumors. Overall, both types of MSI are biomarkers that can prognosticate patients with CRC, can be tested for simultaneously in marker panels, and informs the approach to specific therapy including immunotherapy for their cancers.
| S-EPMC7523708 | biostudies-literature
Project description:Fluoropyrimidine-induced cardiotoxicity in colorectal cancer patients
| PRJNA900295 | ENA
Project description:A tumor consists of a group of cells with abnormal growth, capable of acquiring unique characteristics that provide them with the ability to display mercurial migration patterns, adapting to microenvironments and their chemical and physical factors. Interleukins are small proteins secreted mainly by CD3+ and CD4+ T lymphocytes that mediate the "essential for cancer progression" interactions between cells. Interleukins are implicated in both the development and differentiation of different cells (NK, B, and T leukocytes) and, in general, play a major role in many diseases, including breast cancer, due to their unique participation in systemic inflammation and immune system modulation. During the past decade, interleukins proved to be decisive for future immunotherapy, predisposing a more reliable treatment with fewer side effects on normal proliferating cells. The aim of this review is to provide an overview of the role of interleukins implicated in breast cancer progression.
| S-EPMC6324869 | biostudies-other
Project description:BackgroundMetabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense search for mechanisms that modulate cell metabolism during anti-tumor therapy. We set out to define how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efficiently.MethodsWe incubated p53-positive and p53-negative permanent CRC cells and short-term cultured primary CRC cells with the topoisomerase-1 inhibitor irinotecan and other drugs that cause DNA replication stress and consequently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with flow cytometry. We evaluated cellular metabolism with immunoblotting of electron transport chain (ETC) complex subunits, analysis of mitochondrial mRNA expression by qPCR, MTT assay, measurements of oxygen consumption and reactive oxygen species (ROS), and metabolic flux analysis with the Seahorse platform. Global metabolic alterations were assessed using targeted mass spectrometric analysis of extra- and intracellular metabolites.ResultsChemotherapeutics that cause DNA replication stress induce metabolic changes in p53-positive and p53-negative CRC cells. Irinotecan enhances glycolysis, oxygen consumption, mitochondrial ETC activation, and ROS production in CRC cells. This is connected to increased levels of electron transport chain complexes involving mitochondrial translation. Mass spectrometric analysis reveals global metabolic adaptations of CRC cells to irinotecan, including the glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways. P53-proficient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-deficient counterparts. This metabolic switch is a vulnerability of p53-positive cells to irinotecan-induced apoptosis under glucose-restricted conditions.ConclusionDrugs that cause DNA replication stress increase the metabolism of CRC cells. Glucose restriction might improve the effectiveness of classical chemotherapy against p53-positive CRC cells. The topoisomerase-1 inhibitor irinotecan and other chemotherapeutics that cause DNA damage induce metabolic adaptations in colorectal cancer (CRC) cells irrespective of their p53 status. Irinotecan enhances the glycolysis and oxygen consumption in CRC cells to deliver energy and biomolecules necessary for DNA repair and their survival. Compared to p53-deficient cells, p53-proficient CRC cells have a more active metabolism and use their intracellular metabolites more extensively. This metabolic switch creates a vulnerability to chemotherapy under glucose-restricted conditions for p53-positive cells.
| S-EPMC9251592 | biostudies-literature
Project description:Fluoropyrimidines (FP) are the backbone chemotherapy in colorectal cancer (CRC) treatment; however, their use is associated with cardiotoxicity, which is underreported. In the present study, we aimed to prospectively determining the incidence rates and related risk factors of FP-induced cardiotoxicity (FIC) in CRC patients and at identifying predictive biomarkers. One hundred and twenty-nine consecutive previously untreated CRC patients underwent active cardiological monitoring, including 5-items simplified questionnaire on symptoms, electrocardiogram (ECG) and plasma sample collection during FP chemotherapy. FIC was defined as the presence of ECG alterations and/or the arising of at least one symptom of chest pain, dyspnoea, palpitations or syncope. The primary objective was the evaluation of FIC incidence. Secondary objectives were the correlation of FIC with well-known cardiological risk factors and the identification of circulating biomarkers (serum levels of TnI, proBNP; miRNA analysis) as predictors of FIC. Twenty out of 129 (15.5%) patients experienced FIC. The most common symptoms were dyspnoea (60%) and chest pain (40%), while only 15% of patients presented ECG alterations, including one acute myocardial infarction. Retreatment with FP was attempted in 90% of patients with a favourable outcome. Despite 48% of patients having cardiological comorbidities, we did not observe an increased FIC in this subgroup. Only the subgroup of females with the habit of alcohol consumption showed an increased risk of FIC. None of the circulating biomarkers evaluated demonstrated a clinical utility as FIC predictors. FIC can be an unexpected, life-threatening adverse event that can limit the subsequent treatment choices in CRC patients. In this prospective study, well-known cardiological comorbidities were not related to higher FIC risk and circulating biomarkers predictive of toxicity could not be found. With careful monitoring, mainly based on symptoms, almost all patients completed the FP treatment.
2023-01-18 | GSE217768 | GEO