An in vivo role for Trypanosoma cruzi calreticulin in antiangiogenesis.
Angiogenesis leads to neovascularization from existing blood vessels. It is associated with tumor growth and metastasis and is regulated by pro- and antiangiogenic molecules, some of them currently under clinical trials for cancer treatment. During the last few years we have cloned, sequenced and expressed a Trypanosoma cruzi calreticulin gene (TcCRT). Its product, TcCRT, a 45 kDa protein, is more than 50% identical to human CRT (HuCRT). TcCRT, present on the surface of trypomastigotes, binds both C1q and mannan binding lectin and inhibits the classical activation pathway of human complement. Since TcCRT is highly homologous to a functional antiangiogenic fragment from HuCRT (aa 120-180), recombinant (r) and native (n) TcCRT were tested in their antiangiogenic effects, in the chick embryonic chorioallantoid membrane (CAM) assay. Both proteins mediated highly significant antiangiogenic effects in the in vivo CAM assay. This effect was further substantiated in experiments showing that the plasmid construct pSecTag/TcCRT also displayed significant antiangiogenic properties, as compared to the empty vector. Most likely, the fact that antiangiogenic substances act preferentially on growing neoplasic tissues, but not on already established tumors, is due to their effects on emerging blood vessels. The results shown here indicate that TcCRT, like its human counterpart, has antiangiogenic properties. These properties may explain, at least partly, the reported antineoplasic effect of experimental T. cruzi infection.
Molina
María C
MC
Programa Disciplinario de Inmunología, ICBM, Facultad de Medicina, Universidad de Chile, Independencia, 1027 Santiago, Chile.
Ferreira
Viviana
V
Valck
Carolina
C
Aguilar
Lorena
L
Orellana
Juana
J
Rojas
Alvaro
A
Ramirez
Galia
G
Billetta
Rosario
R
Schwaeble
Wilhelm
W
Lemus
David
D
Ferreira
Arturo
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D037282:Calreticulin / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010957:Plasmids; D011994:Recombinant Proteins / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D037282:Calreticulin; D011994:Recombinant Proteins