Molecular fingerprinting and autocrine growth regulation of endothelial cells in a murine model of hepatocellular carcinoma.
In a mouse model of hepatocellular carcinogenesis, highly vascularized tumors develop through two distinct morphologic phases of neovascularization. We show that increased vascular caliber occurs first, followed by extensive vessel sprouting in late-stage carcinomas. To define molecular pathways in tumor neovascularization, endothelial cells were directly purified from normal liver and advanced tumors. Gene expression profiling experiments were then designed to identify genes enriched in the vascular compartment. We report that Cathepsin S is the major protease specifically overexpressed during vessel sprouting. We also show that the CC chemokines CCL2 and CCL3 are secreted by neovessels and stimulate proliferation through their cognate receptors in an autocrine fashion. This suggests that chemokine signaling represents the most prominent signaling pathway in tumor-associated endothelial cells and directly regulates vessel remodeling. Furthermore, high angiogenic activity is associated with attenuated lymphocyte extravasation and correlates with expression of the immunomodulatory cytokine interleukin 10. This is the first comprehensive study addressing liver-specific vascular changes in a murine autochthonous tumor model. These novel insights into liver angiogenesis infer an environmental control of neovascularization and have important implications for the design of antiangiogenic therapies.
Ryschich
Eduard
E
Department of Surgery, University of Heidelberg, Germany.
Lizdenis
Paulius
P
Ittrich
Carina
C
Benner
Axel
A
Stahl
Simone
S
Hamann
Alf
A
Schmidt
Jan
J
Knolle
Percy
P
Arnold
Bernd
B
Hämmerling
Günter J
GJ
Ganss
Ruth
R
D000818:Animals; D002450:Cell Communication / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
D018925:Chemokines; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2