title: CEACAM1/VEGF cross-talk during neuroblastic tumour differentiation.
abstract: The role of angiogenesis in tumour progression is a major subject in modern oncology and a correlation between angiogenesis and poor outcome has been demonstrated for human neuroblastomas. However, the role of angiogenesis in the maturation phase of neuroblastic tumours has never been considered. Human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a potent pro-angiogenic factor and mediator of vascular endothelial growth factor (VEGF)-induced angiogenesis, plays a crucial role during the activation phase of angiogenesis and it has been shown to be expressed in the microvessels of the developing central nervous system as well as in newly formed immature blood vessels in many different tumours and under physiological conditions. The present study has investigated the role of CEACAM1/VEGF-mediated angiogenesis across the whole spectrum of neuroblastic tumours, from undifferentiated to fully differentiated mature ganglioneuromas. CEACAM1 is peculiarly expressed in the microvessels of areas of active tumour maturation among differentiating neuroblastic/ganglion cells, whereas it is completely absent in the vessels of poorly differentiated/undifferentiated as well as in entirely mature Schwannian-rich areas. Interestingly, VEGF expression has been found in differentiating neuroblastic/ganglion cells adjacent to CEACAM1-positive microvessels. In keeping with these observations, VEGF expression was found in human neuroblastoma SH-SY5Y cells during differentiation after retinoic acid treatment. Moreover, conditioned medium from SH-SY5Y cells collected at different stages of differentiation induced progressive in vitro up-regulation of CEACAM1 expression in human umbilical vein endothelial cells (HUVECs) that was abrogated by the specific VEGF receptor-2/KDR inhibitor SU5416. Taken together, these data point to a role for CEACAM1/VEGF cross-talk during the maturation phase of neuroblastic tumours. This may mimic physiological events leading to maturation of the vasculature in the developing normal central nervous system. On the other hand, in poorly differentiated/undifferentiated lesions, VEGF-sustained angiogenesis does not reproduce physiological steps, but rather is associated with tumour aggressiveness and may involve other molecular pathways.
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: P L
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Mitola
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ravanini
authors.affiliation: Unit of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ferrari-Toninelli
authors.affiliation: Department of Paediatrics, University of Brescia, Brescia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: D'Ippolito
authors.affiliation: Department of Paediatrics, University of Brescia, Brescia, Italy.
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bercich
authors.affiliation: Department of Clinical Chemistry, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wagener
authors.affiliation: Unit of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Memo
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Presta
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Facchetti
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000098:blood supply / Q000503:physiopathology*; D000311:Adrenal Glands / Q000098:blood supply; D015703:Antigens, CD / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D005724:Ganglia / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007223:Infant; D008297:Male; D008479:Mediastinal Neoplasms / Q000098:blood supply / Q000503:physiopathology*; D008482:Mediastinum / Q000098:blood supply; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009447:Neuroblastoma / Q000098:blood supply / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A