Angiogenic and antiangiogenic balance regulates concomitant antitumoral resistance.
Concomitant antitumoral resistance (CAR), the phenomenon by which the growth of distant secondary tumor implants or metastases in some tumor-bearing hosts is inhibited by the presence of a primary tumor, has been previously ascribed to an antiangiogenic process. Here, we investigated vascular endothelial growth factor (VEGF) and endostatin serum levels in nude or BALB/c mice bearing human lung tumors (Calu-6 and H460) or murine mammary tumors (M3MC, M-234p and M-234m), respectively. In these experimental models we previously found an association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin. Serum endostatin level in CAR+ Calu-6-bearing mice was significantly higher than in CAR- H460 counterpart. Sera from mammary tumor-bearing mice showed similar levels of endostatin, regardless of their ability to induce CAR. Conversely, serum VEGF levels in mice bearing CAR+ tumors were lower than those found in CAR- tumor-bearing hosts. Immunostaining with an anti-CD31 antibody revealed that secondary tumors subjected to CAR were significantly less vascularized than primary tumors, while this difference was not observed in CAR- tumors. In vitro studies showed an inhibitory effect of sera from CAR-inducing tumors on endothelial cell proliferation as compared to normal sera, whereas sera from non-CAR-inducing tumors did not alter endothelial proliferation and, in some instances, even caused stimulation of endothelial proliferation. These data suggest that the antiangiogenic mechanism operating in concomitant antitumoral resistance is the result of an increase in the ratio of antiangiogenic/proangiogenic regulators. The levels of the factors involved in this phenomenon can vary in the different tumor models, but the trend favoring the inhibition of angiogenesis is always conserved.
Scharovsky
O Graciela
OG
Instituto de Genética Experimental, School of Medical Sciences, University of Rosario, Rosario, Argentina.
Binda
M Mercedes
MM
Rozados
Viviana R
VR
Bhagat
Sunita
S
Cher
Michael L
ML
Bonfil
R Daniel
RD
D000230:Adenocarcinoma / Q000097:blood / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000502:physiology*; D042501:Angiogenic Proteins / Q000502:physiology*; D043168:Angiostatins / Q000097:blood / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured / Q000187:drug effects; D043169:Endostatins / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000097:blood / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010958:Plasminogen / Q000378:metabolism; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000502:physiology
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D043169:Endostatins; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D010958:Plasminogen