Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter.
The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper-dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper-dopaminergic transmission in the nerve terminals of dopaminergic neurons. Here, we hypothesized that tumor growth was reduced in a mouse model of schizophrenia, lacking the dopamine transporter (DAT), and investigated tumor growth and angiogenesis in DAT knockout mice. The subcutaneous tumor in mice inoculated with cancer cells was smaller in DAT-/- mice than in the wild type (p < 0.05); however, the level of plasma dopamine in DAT-/- mice was lower than that of control littermates. Using human umbilical vascular endothelial cells (HUVEC), we examined dopamine signaling through dopamine D(1) receptor (D(1)R) and D(2)R. Dopamine stimulation slightly decreased the surface expression of vascular endothelial growth factor receptor-2 (VEGF-R2) but induced the phosphorylation of VEGF-R2 through Src in HUVEC. In addition, DAT-/- mice had less D(1)R. Both pharmacological and genetic interruption of D(1)R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy.
Asada
Masanori
M
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan. masanori.asada@gmail.com
Ebihara
Satoru
S
Numachi
Yohtaro
Y
Okazaki
Tatsuma
T
Yamanda
Shinsuke
S
Ikeda
Kazutaka
K
Yasuda
Hiroyasu
H
Sora
Ichiro
I
Arai
Hiroyuki
H
D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000097:blood / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine