Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter
Corresponding Author
Masanori Asada
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Fax: +81-22-717-7186
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, JapanSearch for more papers by this authorSatoru Ebihara
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorYohtaro Numachi
Department of Psychobiology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
Search for more papers by this authorTatsuma Okazaki
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorShinsuke Yamanda
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorKazutaka Ikeda
Department of Molecular Psychiatry, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo, Japan
Search for more papers by this authorHiroyasu Yasuda
Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorIchiro Sora
Department of Psychobiology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
Search for more papers by this authorHiroyuki Arai
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorCorresponding Author
Masanori Asada
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Fax: +81-22-717-7186
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, JapanSearch for more papers by this authorSatoru Ebihara
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorYohtaro Numachi
Department of Psychobiology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
Search for more papers by this authorTatsuma Okazaki
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorShinsuke Yamanda
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorKazutaka Ikeda
Department of Molecular Psychiatry, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo, Japan
Search for more papers by this authorHiroyasu Yasuda
Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorIchiro Sora
Department of Psychobiology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
Search for more papers by this authorHiroyuki Arai
Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan
Search for more papers by this authorAbstract
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 D1 receptor (D1R) and D2R. 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 D1R. Both pharmacological and genetic interruption of D1R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy. © 2008 Wiley-Liss, Inc.
References
- 1 Lichtermann D,Ekelund J,Pukkala E,Tanskanen A,Lonnqvist J. Incidence of cancer among persons with schizophrenia and their relatives. Arch Gen Psychiatry 2001; 58: 573–8.
- 2 Barak Y,Achiron A,Mandel M,Mirecki I,Aizenberg D. Reduced cancer incidence among patients with schizophrenia. Cancer 2005; 104: 2817–21.
- 3 de Leon J,Dadvand M,Canuso C,White AO,Stanilla JK,Simpson GM. Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry 1995; 152: 453–5.
- 4 Zammit S,Allebeck P,Dalman C,Lundberg I,Hemmingsson T,Lewis G. Investigating the association between cigarette smoking and schizophrenia in a cohort study. Am J Psychiatry 2003; 160: 2216–21.
- 5 Fowler IL,Carr VJ,Carter NT,Lewin TJ. Patterns of current and lifetime substance use in schizophrenia. Schizophr Bull 1998; 24: 443–55.
- 6 Sora I,Wichems C,Takahashi N,Li XF,Zeng Z,Revay R,Lesch KP,Murphy DL,Uhl GR. Cocaine reward models: conditioned place preference can be established in dopamine-and in serotonin-transporter knockout mice. Proc Natl Acad Sci USA 1998; 95: 7699–704.
- 7 Bosse R,Fumagalli F,Jaber M,Giros B,Gainetdinov RR,Wetsel WC,Missale C,Caron MG. Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron 1997; 19: 127–38.
- 8 Giros B,Jaber M,Jones SR,Wightman RM,Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–12.
- 9 Gainetdinov RR,Wetsel WC,Jones SR,Levin ED,Jaber M,Caron MG. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 1999; 283: 397–401.
- 10 Bergers G,Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401–10.
- 11 Basu S,Nagy JA,Pal S,Vasile E,Eckelhoefer IA,Bliss VS,Manseau EJ,Dasgupta PS,Dvorak HF,Mukhopadhyay D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001; 7: 569–74.
- 12 Dasgupta P,Rastogi S,Pillai S,Ordonez-Ercan D,Morris M,Haura E,Chellappan S. Nicotine induces cell proliferation by β-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest 2006; 116: 2208–17.
- 13 Heeschen C,Jang JJ,Weis M,Pathak A,Kaji S,Hu RS,Tsao PS,Johnson FL,Cooke JP. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 2001; 7: 833–9.
- 14 Thaker PH,Han LY,Kamat AA,Arevalo JM,Takahashi R,Lu C,Jennings NB,Armaiz-Pena G,Bankson JA,Ravoori M,Merritt WM,Lin YG, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 2006; 12: 939–44.
- 15 Missale C,Nash SR,Robinson SW,Jaber M,Caron MG. Dopamine receptors: from structure to function. Physiol Rev 1998; 78: 189–225.
- 16 Chakroborty D,Sarkar C,Mitra RB,Banerjee S,Dasgupta PS,Basu S. Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin Cancer Res 2004; 10: 4349–56.
- 17 Basu S,Sarkar C,Chakroborty D,Nagy J,Mitra RB,Dasgupta PS,Mukhopadhyay D. Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis. Cancer Res 2004; 64: 5551–5.
- 18 Alonso G,Koegl M,Mazurenko N,Courtneidge SA. Sequence requirements for binding of Src family tyrosine kinases to activated growth factor receptors. J Biol Chem 1995; 270: 9840–8.
- 19 Andreev J,Galisteo ML,Kranenburg O,Logan SK,Chiu ES,Okigaki M,Cary LA,Moolenaar WH,Schlessinger J. Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J Biol Chem 2001; 276: 20130–5.
- 20 Lemmer K,Ahnert-Hilger G,Hopfner M,Hoegerle S,Faiss S,Grabowski P,Jockers-Scherubl M,Riecken EO,Zeitz M,Scherubl H. Expression of dopamine receptors and transporter in neuroendocrine gastrointestinal tumor cells. Life Sci 2002; 71: 667–78.
- 21 Okazaki T,Ebihara S,Takahashi H,Asada M,Kanda A,Sasaki H. Macrophage colony-stimulating factor induces vascular endothelial growth factor production in skeletal muscle and promotes tumor angiogenesis. J Immunol 2005; 174: 7531–8.
- 22 Seno H,Oshima M,Ishikawa TO,Oshima H,Takaku K,Chiba T,Narumiya S,Taketo MM. Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res 2002; 62: 506–11.
- 23 Eliceiri BP,Paul R,Schwartzberg PL,Hood JD,Leng J,Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 1999; 4: 915–24.
- 24 Fauchey V,Jaber M,Caron MG,Bloch B,Le Moine C. Differential regulation of the dopamine D1. D2 and. D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter. Eur J Neurosci 2000; 12: 19–26.
- 25 Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988; 1: 179–86.
- 26 Zhuang X,Oosting RS,Jones SR,Gainetdinov RR,Miller GW,Caron MG,Hen R. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci USA 2001; 98: 1982–7.
- 27 Sedvall G,Pauli S,Karlsson P,Farde L,Nordstrom AL,Nyberg S,Halldin C. PET imaging of neuroreceptors in schizophrenia. Eur. Neuropsychopharmacol 1995; 5 ( Suppl): 25–30.
- 28 Drago J,Gerfen CR,Lachowicz JE,Steiner H,Hollon TR,Love PE,Ooi GT,Grinberg A,Lee EJ,Huang SP,Barttlett PF,Jose PA. Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci USA 1994; 91: 12564–8.
- 29 Amenta F Light microscope autoradiography of peripheral dopamine receptor subtypes. Clin Exp Hypertens 1997; 19: 27–41.
- 30 Balmforth AJ,Ball SG,Freshney RI,Graham DI,McNamee HB,Vaughan PF. D-1 dopaminergic and beta-adrenergic stimulation of adenylate cyclase in a clone derived from the human astrocytoma cell line G-CCM. J Neurochem 1986; 47: 715–19.
- 31 Zhen X,Uryu K,Wang HY,Friedman E. D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. Mol Pharmacol 1998; 54: 453–8.
- 32 Chan AS,Wong YH. Gq-mediated activation of c-Jun N-terminal kinase by the gastrin-releasing peptide-preferring bombesin receptor is inhibited upon costimulation of the Gs-coupled dopamine D1 receptor in COS-7 cells. Mol Pharmacol 2005; 68: 1354–64.
- 33 Clague MJ,Urbe S. The interface of receptor trafficking and signalling. J Cell Sci 2001; 114: 3075–81 (Review).
- 34 Summy JM,Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 2003; 22: 337–58.
- 35 Helms MN,Chen XJ,Ramosevac S,Eaton DC,Jain L. Dopamine regulation of amiloride-sensitive sodium channels in lung cells. Am J Physiol Lung Cell Mol Physiol 2006; 290: 710–22.
- 36 Summy JM,Trevino JG,Lesslie DP,Baker CH,Shakespeare WC,Wang Y,Sundaramoorthi R,Metcalf CA3rd,Keats JA,Sawyer TK,Gallick GE. AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes. Mol Cancer Ther 2005; 4: 1900–11.
- 37 Singh AJ,Meyer RD,Band H,Rahimi N. The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation. Mol Biol Cell 2005; 16: 2106–18.
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