ABSTRACT
BACKGROUND: We aimed to study the effect of socioeconomic differences and molecular characteristics on survival in patients with young-onset pancreatic neuroendocrine tumors (YOPNET) and typical-onset PNET (TOPNET). METHODS: We identified the patients with YOPNET (<50 years) and TOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2016 using the National Cancer Database. We evaluated overall survival (OS) using the Kaplan-Meier and Cox regression methods before and after propensity score matching. A publicly available genomic dataset was used to compare mutation frequencies among the two groups. RESULTS: A total of 6259 patients with PNET were included, of which 27% were YOPNET. Patients with YOPNET were more likely to be Black, Hispanic, female, and have private insurance versus patients with TOPNET (all p < 0.001). Patients with YOPNET had a lower comorbidity score, but higher stage and tumor size (all p < 0.001). YOPNET was associated with a greater improved OS than TOPNET before and after propensity score matching (p < 0.001). On multivariable analysis, this survival difference persisted for YOPNET as an independent prognostic factor (unmatched p = 0.008; matched p = 0.01). For genomic analysis, patients with YOPNET had a lower rate of multiple endocrine neoplasia type-1 (MEN-1) mutation than patients with TOPNET (26% vs. 56%, p < 0.001). CONCLUSIONS: YOPNET represents a disease with distinct clinical features. Patients with YOPNET who underwent definitive surgery had better OS than patients with TOPNET despite having higher stage and tumor size. YOPNET also had lower rate of MEN-1 mutation.
ABSTRACT
Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer.
Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Colonic Neoplasms/drug therapy , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Neoplastic Stem Cells/drug effects , Oxidative Phosphorylation , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antioxidants/metabolism , Biomarkers, Tumor/metabolism , Carrier Proteins/metabolism , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Enzyme Inhibitors/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Female , HT29 Cells , Humans , Membrane Proteins/metabolism , Mice, Nude , Mitochondria/drug effects , Mitochondria/metabolism , NADP/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Oxidation-Reduction , Oxidative Phosphorylation/drug effects , Phenotype , Pyruvate Kinase/metabolism , Thyroid Hormones/metabolism , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , Thyroid Hormone-Binding ProteinsABSTRACT
The oncogenic Epstein-Barr virus (EBV) expresses 44 mature microRNAs and two non-coding EBER RNAs of 167 (EBER1) and 172 (EBER2) nt length. MiRNA profiling of NK/T cell lines and primary cells and Northern blotting of EBV-infected cell lines and primary tumors revealed processing of EBER1 to short 5'-derived RNAs of approximately 23, 52 and 70 nt (EBER123, EBER152, and EBER170) and of EBER2 to 3' fragments. The biogenesis of these species is independent of Dicer, and EBER123 does not act like a miRNA OPEN ACCESS Non-Coding RNA 2015, 1 171 to target its complementary sequence. EBER1, EBER2 and EBER123 were bound by the lupus antigen (La), a nuclear and cytoplasmic protein that facilitates RNAi. Consistent with this, the EBERs affect regulation of interleukin 1alpha (IL1α) and RAC1 reporters harboring miR target sequences, targets of miR-142-3p. However, the EBERs have no effect upon another target of miR-142-3p, ADCY9, nor on TOMM22, a target of ebv-miR-BART16, indicative of selective modulation of gene expression by the EBERs.
