Altered angiogenesis and survival in human tumor-derived endothelial cells.
Knowledge on the functional properties of tumor-derived endothelial cells (TEC) can be relevant for the development of antiangiogenic therapeutic strategies. In the present study, we obtained and characterized endothelial cell lines from human renal carcinomas. TEC did not undergo senescence and showed constant expression of markers of endothelial activation and angiogenesis. In vitro, TEC, in contrast to normal endothelial cells, were resistant to apoptosis, proadhesive for renal carcinoma cells, and able to grow and organize in the absence of serum in persistent capillary-like structures. In vivo, TEC were able to grow in immunodeficient mice and to form vascular structures connected with the circulation. At a molecular level, gene array analysis showed an increased expression of genes involved in survival and cell adhesion compared with expression in normal microvascular endothelial cells. Moreover, expression of angiopoietin-1 and vascular endothelial growth factor (VEGF)-D and the Akt survival pathway were up-regulated. Inhibition of interaction of VEGFR-2 or VEGFR-3 with VEGF-D but not of Tie-2-angiopoietin-1 interaction with soluble receptors abrogated Akt activation and survival of TEC. These results indicate that at least some of the TEC within a tumor display abnormal characteristics in terms of survival and angiogenic properties and also indicate the presence of a functional autocrine pathway related to VEGF-D.
Bussolati
Benedetta
B
Dipartimento di Medicina Interna, Ospedale S. Giovanni Battista, Corso Dogliotti 14, 10126, Torino, Italy. giovanni.camussi@unito.it
Deambrosis
Ilaria
I
Russo
Simona
S
Deregibus
Maria Chiara
MC
Camussi
Giovanni
G
D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis; D042683:Angiopoietin-1; D000818:Animals; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002470:Cell Survival; D016922:Cellular Senescence; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D042643:Vascular Endothelial Growth Factor D; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human