wzb117 and Adenocarcinoma

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Cell Proliferation; Cytoprotection; Drug Resistance, Neoplasm; Glucose Transporter Type 1; Glycolysis; Humans; Hydroxybenzoates; Inflammation; Interleukin-1beta; Killer Cells, Natural; Macrophages; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatic Neoplasms; Survival Analysis; T-Lymphocytes, Cytotoxic; Tumor Burden

Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Line, Tumor; Cohort Studies; Deoxyglucose; Female; Fluorodeoxyglucose F18; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glucose; Glucose Transporter Type 1; Glycolysis; Humans; Hydroxybenzoates; Lung; Lung Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Phenotype; Positron-Emission Tomography; Prognosis; Survival Analysis; Up-Regulation; Xenograft Model Antitumor Assays

5-Fluorouracil (5-FU) is the most commonly used drug in colon cancer therapy. However, despite impressive clinical responses initially, development of drug resistance to 5-Fu in human tumor cells is the primary cause of failure of chemotherapy. In this study, we established a 5-Fu-resistant human colon cancer cell line for comparative chemosensitivity studies.. Real time PCR and Western blotting were used to determine gene expression levels. Cell viability was measured by MTT assay. Glucose uptake was assess using an Amplex Red Glucose/Glucose Oxidase assay kit.. We found that 5-Fu resistance was associated with the overexpression of Glut1 in colon cancer cells. 5-Fu treatment at low toxic concentration induced Glut1 expression. At the same time, upregulation of Glut1 was detected in 5-Fu resistant cells when compared with their parental cells. Importantly, inhibition of Glut1 by a specific inhibitor, WZB117, significantly increased the sensitivity of 5-Fu resistant cells to the drug.. This study provides novel information for the future development of targeted therapies for the treatment of chemo-resistant colon cancer patients. In particular it demonstrated that Glut1 inhibitors such as WZB117 may be considered an additional treatment options for patients with 5-Fu resistant colon cancers.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Glucose Transporter Type 1; HT29 Cells; Humans; Hydroxybenzoates; Real-Time Polymerase Chain Reaction