Dopamine in Angiogenesis, Immunity and Lung Tumor Progression
The Tumor Angiogenesis and Vascular Biology Laboratory investigates how the neurotransmitter dopamine affects the ability of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to act in lung tumors.
Dr. Mukhopadhyay's research team found that at nontoxic levels, dopamine strongly and selectively inhibits the vascular permeabilizing and angiogenic activities of VPF/VEGF.
Dopamine acts through D2 dopamine receptors (D2R) to induce the endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. Dopamine action was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration.
In a follow-up study, Dr. Mukhopadhyay's lab demonstrated that D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models by inhibiting tumor angiogenesis and reducing tumor-infiltrating myeloid-derived suppressor cells.
Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Patients who had lung cancer and a history of smoking exhibited greater levels of D2R in lung endothelium.
The lab's results suggest that D2R agonists may represent a promising individualized therapy for patients who have lung cancer with high levels of endothelial D2R expression and a smoking history.
The Tumor Angiogenesis and Vascular Biology Lab's ongoing studies continue to identify potential therapeutic strategies to target D2R signaling in lung cancer.