ABSTRACT
OBJECTIVE: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. METHODS: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non-small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. RESULTS: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. CONCLUSIONS: We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Lewis Lung/enzymology , Carcinoma, Non-Small-Cell Lung/enzymology , Cell Movement , Lung Neoplasms/enzymology , Matrix Metalloproteinase 12/metabolism , Animals , Biomarkers, Tumor/genetics , Carcinoma, Lewis Lung/genetics , Carcinoma, Lewis Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Matrix Metalloproteinase 12/genetics , Mice, Inbred C57BL , Mice, Knockout , Neoplasm Invasiveness , Signal TransductionABSTRACT
CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.
Subject(s)
Brain Neoplasms/pathology , MicroRNAs/metabolism , Neuroblastoma/pathology , Receptors, CXCR4/metabolism , Animals , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Cell Line, Tumor , Cyclin D1/genetics , Cyclin D1/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , MicroRNAs/genetics , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Peptides/pharmacology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Following gastric bypass surgery (GBP), there is a post-prandial rise of incretin and satiety gut peptides. The mechanisms of enhanced incretin release in response to nutrients after GBP is not elucidated and may be in relation to altered nutrient transit time and/or malabsorption. METHODS: Seven morbidly obese subjects (BMI = 44.5 ± 2.8 kg/m(2)) were studied before and 1 year after GBP with a D: -xylose test. After ingestion of 25 g of D: -xylose in 200 mL of non-carbonated water, blood samples were collected at frequent time intervals to determine gastric emptying (time to appearance of D: -xylose) and carbohydrate absorption using standard criteria. RESULTS: One year after GBP, subjects lost 45.0 ± 9.7 kg and had a BMI of 27.1 ± 4.7 kg/m(2). Gastric emptying was more rapid after GBP. The mean time to appearance of D: -xylose in serum decreased from 18.6 ± 6.9 min prior to GBP to 7.9 ± 2.7 min after GBP (p = 0.006). There was no significant difference in absorption before (serum D: -xylose concentrations = 35.6 ± 12.6 mg/dL at 60 min and 33.9 ± 9.1 mg/dL at 180 min) or 1 year after GBP (serum D: -xylose = 31.5 ± 18.1 mg/dL at 60 min and 27.2 ± 11.9 mg/dL at 180 min). CONCLUSIONS: These data confirm the acceleration of gastric emptying for liquid and the absence of carbohydrate malabsorption 1 year after GBP. Rapid gastric emptying may play a role in incretin response after GBP and the resulting improved glucose homeostasis.