ABSTRACT
Cancer tissues exhibit an acidic microenvironment owing to the accumulation of protons and lactic acid produced by cancer and inflammatory cells. To examine the role of an acidic microenvironment in lymphatic cancer metastasis, gene expression profiling was conducted using human dermal lymphatic endothelial cells (HDLECs) treated with a low pH medium. Microarray and gene set enrichment analysis revealed that acid treatment induced the expression of inflammation-related genes in HDLECs, including genes encoding chemokines and adhesion molecules. Acid treatment-induced chemokines C-X3-C motif chemokine ligand 1 (CX3CL1) and C-X-C motif chemokine ligand 6 (CXCL6) autocrinally promoted the growth and tube formation of HDLECs. The expression of vascular cell adhesion molecule 1 (VCAM-1) increased in HDLECs after acid treatment in a time-dependent manner, which, in turn, enhanced their adhesion to melanoma cells. Among various acid-sensing receptors, HDLECs basally expressed G protein-coupled receptor 4 (GPR4), which was augmented under the acidic microenvironment. The induction of chemokines or VCAM-1 under acidic conditions was attenuated by GPR4 knockdown in HDLECs. In addition, lymph node metastases in a mouse melanoma model were suppressed by administering an anti-VCAM-1 antibody or a GPR4 antagonist. These results suggest that an acidic microenvironment modifies the function of lymphatic endothelial cells via GPR4, thereby promoting lymphatic cancer metastasis. Acid-sensing receptors and their downstream molecules might serve as preventive or therapeutic targets in cancer.
Subject(s)
Endothelial Cells , Lymphatic Metastasis , Receptors, G-Protein-Coupled , Animals , Humans , Mice , Cell Adhesion , Cell Line, Tumor , Chemokines/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Hydrogen-Ion Concentration , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Tumor Microenvironment , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
PURPOSE: To evaluate the effect of high-frequency jet ventilation (HFJV) and continuous positive airway pressure (CPAP) on oxygenation and the shunt fraction (Qs/Qt) during one-lung ventilation (OLV). METHODS: Twenty-five patients who were undergoing resection of a descending aortic aneurysm were studied. Arterial oxygenation, Qs/Qt, and hemodynamics were evaluated just before the initiation of OLV (T1), 15 min after OLV (T2), and 15 min (T3) and 30 min (T4) after the application of HFJV or CPAP to the nondependent lung. RESULTS: There were no significant changes in the mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP), or mixed venous partial pressure of oxygen throughout this study. The arterial partial pressure of oxygen (Pa(O2)) values after the application of HFJV or CPAP increased significantly, from 173.8 +/- 39.6 mmHg (T2) to 344.1 +/- 87.9 mmHg (T3) and 359.9 +/- 82.4 mmHg (T4) in the HFJV group (P < 0.05), and from 153 +/- 38.5 mmHg (T2) to 243 +/- 48.5 mmHg (T3) and 249.7 +/- 55.0 mmHg (T4) in the CPAP group (P < 0.05). The shunt fraction decreased significantly after the initiation of HFJV or CPAP, from 38.7% +/- 8.9% (T2) to 27.0% +/- 8.0% (T3) and 25.9% +/- 8.7% (T4) in the HFJV group (P < 0.05), and from 44.6% +/- 8.6% (T2) to 34.3% +/- 10.2% (T3) and 32.6% +/- 8.5% (T4) in the CPAP group (P < 0.05). The arterial saturation of oxygen (Sa(O) (2)) increased significantly after the application of either HFJV or CPAP (P < 0.05). CONCLUSIONS: Both HFJV and CPAP can improve oxygenation during OLV.
