ABSTRACT
Tumour-induced hem- and lymph-angiogenesis are frequently associated with tumour progression. Vascular endothelial growth factor-C (VEGF-C) is a potent inducer of lymphangiogenesis, while the endogenous soluble splice-variant of VEGF receptor-2, esVEGFR-2, acts as a natural inhibitor. Previously we have shown down-regulation of esVEGFR-2 mRNA in progressed stages of neuro-blastoma (NB), a tumour derived from sympatho-adrenal precursor cells. Here we studied the immunolocalization of esVEGFR-2 in human embryos, infantile adrenal gland and primary NB. We also quantified esVEGFR-2 mRNA in NB cell lines after differentiation-induction by all-trans retinoic acid (ATRA). By immunoperoxidase staining we observed expression of esVEGFR-2 in both the sympathetic trunk and the adrenal medulla. Additionally, esVEGFR-2 was found in spinal ganglia, floor plate of the neural tube, choroid plexus, notochord, arterial endothelium, skeletal muscle, epidermis and gut epithelium. Developing and circulating leukocytes showed the strongest signal. In NB, esVEGFR-2 was considerably stronger in differentiating low grade tumours with neuronal phenotype than in undifferentiated lesions. Differentiation-induction of the NB cell line SMS-Kan with 5-10 µM ATRA resulted in a significant increase of esVEGFR-2 mRNA after 6, 9 and 12 days. We show that esVEGFR-2 is widely expressed in embryonic tissues. Especially, the adrenal medulla and circulating leukocytes seem to be potent inhibitors of lymphangiogenesis. We provide additional evidence for a role of esVEGFR-2 in NB. Thereby, high levels of esVEGFR-2 correlate with a more differentiated phenotype, and may inhibit tumour progression by inhibition of lymphangiogenesis.
Subject(s)
Adrenal Glands/metabolism , Cell Differentiation/drug effects , Lymphangiogenesis , Neuroblastoma/metabolism , Sympathetic Nervous System/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Adrenal Glands/embryology , Cell Line, Tumor , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Gestational Age , Humans , Immunohistochemistry , Neuroblastoma/genetics , Neuroblastoma/pathology , Neuroblastoma/physiopathology , Protein Isoforms , RNA, Messenger/metabolism , Sympathetic Nervous System/embryology , Time Factors , Tissue Array Analysis , Tretinoin/pharmacology , Vascular Endothelial Growth Factor Receptor-2/geneticsABSTRACT
The recently identified nidogen-2 is a matrix protein showing homology to the well-known basement membrane molecule nidogen-1. Nidogen-1 might well serve as a link between laminin-1 and collagen type IV and thus stabilise certain basement membranes in vivo and play a major role in embryogenesis. However, the exact tissue distribution of nidogen-1 and nidogen-2 during human embryogenesis is still unclear. As a first step towards the elucidation of their possible cell biological functions during human development, we compared the distribution of both nidogens during human organogenesis at the light microscope level. Nidogen-2 and nidogen-1 were found to be ubiquitous components of basement membrane zones underneath developing epithelia of most of the major organ systems. However, in the developing intestine and the pancreas anlage, only nidogen-1 was present in the epithelial basement membrane zones of all developmental stages investigated. Our data suggest that nidogen-2 and nidogen-1, as is known for mouse development, could well participate in cell biological functions during human development. These two proteins might well be able to fulfil identical functions during human organogenesis.
