Complementary actions of dopamine D2 receptor agonist and anti-vegf therapy on tumoral vessel normalization in a transgenic mouse model.
Angiogenesis contributes in multiple ways to disease progression in tumors and reduces treatment efficiency. Molecular therapies targeting Vegf signaling combined with chemotherapy or other drugs exhibit promising results to improve efficacy of treatment. Dopamine has been recently proposed to be a novel safe anti-angiogenic drug that stabilizes abnormal blood vessels and increases therapeutic efficacy. Here, we aimed to identify a treatment to normalize tumoral vessels and restore normal blood perfusion in tumor tissue with a Vegf receptor inhibitor and/or a ligand of dopamine G protein-coupled receptor D2 (D2R). Dopamine, via its action on D2R, is an endogenous effector of the pituitary gland, and we took advantage of this system to address this question. We have used a previously described Hmga2/T mouse model developing haemorrhagic prolactin-secreting adenomas. In mutant mice, blood vessels are profoundly altered in tumors, and an aberrant arterial vascularization develops leading to the loss of dopamine supply. D2R agonist treatment blocks tumor growth, induces regression of the aberrant blood supply and normalizes blood vessels. A chronic treatment is able to restore the altered balance between pro- and anti-angiogenic factors. Remarkably, an acute treatment induces an upregulation of the stabilizing factor Angiopoietin 1. An anti-Vegf therapy is also effective to restrain tumor growth and improves vascular remodeling. Importantly, only the combination treatment suppresses intratumoral hemorrhage and restores blood vessel perfusion, suggesting that it might represent an attractive therapy targeting tumor vasculature. Similar strategies targeting other ligands of GPCRs involved in angiogenesis may identify novel therapeutic opportunities for cancer.
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Norbert
N
Chauvet
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Nicola
N
Romanò
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Chrystel
C
Lafont
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Anne
A
Guillou
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Evelyne
E
Galibert
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Xavier
X
Bonnefont
Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, United Kingdom.
Paul
P
Le Tissier
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR e/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, 80131, Italy.
Monica
M
Fedele
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR e/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, 80131, Italy.
Alfredo
A
Fusco
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Patrice
P
Mollard
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Nathalie
0000-0001-5830-4013
N
Coutry
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D017448:Receptors, Dopamine D2; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor
GPCR ligand; angiogenesis; combination therapy; mouse model; pituitary adenomas