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Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients.

ABSTRACT: This study monitored the changes in the expression of inflammatory IL-6 and IL-1β during the treatment period of Fluoropyrimidine (FP) based therapy. RNA was extracted from the peripheral blood of 102 CRC patients before treatment with FP therapy, and from 48 and 32 patients after 3 and 6 months of treatment, respectively. The genetic transcription of IL-6 and IL-1β was determined by real time PCR. Patients were stratified according to their levels of IL-6 and IL-1β genes expression for subgroup and survival analyses. Baseline CRC patients showed overexpression of IL-6 and IL-1β compared to healthy control. FP therapy significantly induced IL-6 and IL-1β expression. Subgroup analysis showed that patients with right colon tumors had significant elevation in both IL-6 and IL-1β with FP therapy. FP therapy significantly induced IL-1β expression in patients ⩽45 years, smokers, with high baseline level of CA19.9, right colon tumors, low grade pathology, T3 tumors and positive lymph nodes. Survival analysis showed that baseline levels of interleukins expression had insignificant effect on overall survival and event free survival. FP therapy has an impact on the level of interleukins expression declared in certain clinicopathological subgroups of CRC patients, but without a prognostic significance on patients' survival.

SUBMITTER: Fouad MA

PROVIDER: S-EPMC8040557 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients.

Fouad Mariam A MA Salem Salem E SE Osman Afaf S AS Badr Doaa M DM Hussein Marwa M MM Zekri Abdelrahman N AN Hafez Hafez F HF Kamel Mahmoud M MM Kamel Mahmoud M MM Shouman Samia A SA

International journal of immunopathology and pharmacology 20210101

This study monitored the changes in the expression of inflammatory IL-6 and IL-1β during the treatment period of Fluoropyrimidine (FP) based therapy. RNA was extracted from the peripheral blood of 102 CRC patients before treatment with FP therapy, and from 48 and 32 patients after 3 and 6 months of treatment, respectively. The genetic transcription of IL-6 and IL-1β was determined by real time PCR. Patients were stratified according to their levels of IL-6 and IL-1β genes expression for subgroup ...[more]

PMID: 33832346

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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.

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.

Dataset Information

Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients.

Publications

Fluoropyrimdine therapy induced alterations in interleukins expression in colorectal cancer patients.

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