title: Vascular endothelial growth factor expression, angiogenesis, and necrosis in renal cell carcinomas.
abstract: Rapidly growing tumors often develop necrosis. In the present study the expression of vascular endothelial growth factor (VEGF) was investigated and compared to microvessel density and necrosis of renal cell carcinomas. In the tumor-host interface the microvessel density was significantly increased compared to central tumor areas. Tumor necrosis was associated with a decrease of microvessel density and an increase of the VEGF protein expression within the perinecrotic rim. VEGF protein was focally upregulated in vital tumor tissue. An increase of the apoptotic rate of endothelia and vital tumor tissue in tumors with necrosis could not be detected. VEGF(121,165) mRNA was decreased in proliferatively active carcinomas compared to less proliferative tumors. Multicellular renal cell cancer spheroids as a model of chronic hypoxia developed central apoptosis but no necrosis. VEGF was upregulated in the spheroid. Tumor microvessels expressed matrix metalloproteinase -2 and -9 and an incomplete pericyte covering in comparison to tumor-free tissue indicating immature active angiogenesis. We conclude that highly proliferative renal cell carcinomas outgrow their vascular supply and develop chronic hypoxia inducing a decrease of proliferation and an increase of VEGF expression. However, chronic hypoxia does not cause significant necrosis or apoptosis. Tumor necrosis is more likely induced by acute hypoxia due to immature microvessels. Furthermore, VEGF expression associated with concomitant tumor necrosis may help identify renal cell carcinomas susceptible to antiangiogenic therapy.
authors.affiliation: Department of Pathology, Georg-August University, Medizinische Fakultät, Göttingen, Germany. hemmer@med.uni-goettingen.de
authors.forename: B
authors.initials: B
authors.lastname: Hemmerlein
authors.forename: A
authors.initials: A
authors.lastname: Kugler
authors.forename: R
authors.initials: R
authors.lastname: Ozisik
authors.forename: R H
authors.initials: RH
authors.lastname: Ringert
authors.forename: H J
authors.initials: HJ
authors.lastname: Radzun
authors.forename: P
authors.initials: P
authors.lastname: Thelen
mesh_terms: D034961:Antigens, Nuclear; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007680:Kidney Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008833:Microcirculation; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D034961:Antigens, Nuclear; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9