title: Osteosarcoma cells induce endothelial cell proliferation during neo-angiogenesis.
abstract: Understanding the mechanisms inducing endothelial cell (EC) proliferation following tumor microenvironment stimuli may be important for the development of antiangiogenic therapies. Here, we show that cyclin-dependent kinase 2 and 5 (Cdk2, Cdk5) are important mediators of neoangiogenesis in in vitro and in vivo systems. Furthermore, we demonstrate that a specific Yin Yang 1 (YY1) protein-dependent signal from osteosarcoma (SaOS) cells determines proliferation of human aortic endothelial cells (HAECs). Following tumor cell stimuli, HAECs overexpress Cdk2 and Cdk5, display increased Cdk2 activity, undergo enhanced proliferation, and form capillary-like structures. Moreover, Roscovitine, an inhibitor of Cdks, blunted overexpression of Cdk2 and Cdk5 and Cdk2 activity induced by the YY1-dependent signal secreted by SaOS cells. Furthermore, Roscovitine decreased HAEC proliferation and angiogenesis (the latter by 70% in in vitro and 50% in in vivo systems; P < 0.01 vs. control). Finally, the finding that Roscovitine triggers apoptosis in SaOS cells as well as in HAECs by activating caspase-3/7 indicates multiple mechanisms for the potential antitumoral effect of Roscovitine. Present work suggests that Cdk2 and Cdk5 might be pharmacologically accessible targets for both antiangiogenic and antitumor therapy.
authors.affiliation: Department of General Pathology, UOC Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy. filomena.denigris@unina2.it
authors.forename: Filomena
authors.initials: F
authors.lastname: de Nigris
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Mancini
authors.forename: Concetta
authors.initials: C
authors.lastname: Schiano
authors.forename: Teresa
authors.initials: T
authors.lastname: Infante
authors.forename: Alberto
authors.initials: A
authors.lastname: Zullo
authors.forename: Pellegrino Biagio
authors.initials: PB
authors.lastname: Minucci
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003470:Culture Media; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D015854:Up-Regulation; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003470:Culture Media; D011687:Purines; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; C495894:CDK2 protein, human; C495905:CDK5 protein, human; D051357:Cyclin-Dependent Kinase 2; D053148:Caspase 3; D053179:Caspase 7