Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts.
Serotonin, a neurotransmitter with numerous functions in the central nervous system (CNS), is emerging as an important signaling molecule in biological processes outside of the CNS. Recent advances have implicated serotonin as a regulator of inflammation, proliferation, regeneration, and repair. The role of serotonin in tumor biology in vivo has not been elucidated. Using a genetic model of serotonin deficiency (Tph1(-/-)) in mice, we show serotonin to be crucial for the growth of s.c. colon cancer allografts in vivo. Serotonin does not enhance tumor cell proliferation but acts as a regulator of angiogenesis by reducing the expression of matrix metalloproteinase 12 (MMP-12) in tumor-infiltrating macrophages, entailing lower levels of angiostatin-an endogenous inhibitor of angiogenesis. Accordingly, serotonin deficiency causes slower growth of s.c. tumors by reducing vascularity, thus increasing hypoxia and spontaneous necrosis. The biological relevance of these effects is underscored by the reconstitution of serotonin synthesis in Tph1(-/-) mice, which restores allograft phenotype in all aspects. In conclusion, we show how serotonin regulates angiogenesis in s.c. colon cancer allografts by influencing MMP-12 expression in tumor-infiltrating macrophages, thereby affecting the production of circulating angiostatin.
Nocito
Antonio
A
Department of Surgery, Swiss Hepato-Pancreato-Biliary Centre, University Hospital Zurich, Zurich, Switzerland.
Dahm
Felix
F
Jochum
Wolfram
W
Jang
Jae Hwi
JH
Georgiev
Panco
P
Bader
Michael
M
Graf
Rolf
R
Clavien
Pierre-Alain
PA
D043168:Angiostatins / Q000378:metabolism; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000473:pathology; D004195:Disease Models, Animal; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000209:etiology*; D012701:Serotonin / Q000172:deficiency / Q000502:physiology*; D040521:Subcutaneous Tissue / Q000473:pathology; D014184:Transplantation, Homologous; D014365:Tryptophan Hydroxylase / Q000235:genetics; D047368:Tumor Burden
D012701:Serotonin; D043168:Angiostatins; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D053508:Matrix Metalloproteinase 12