Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms
Φόρτωση...
Ημερομηνία
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Cancer Res
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
The tumor suppressor function of activin A, together with our findings that activin A is an inhibitor of angiogenesis, which is down-regulated by the N-MYC oncogene, prompted us to investigate in more detail its role in the malignant transformation process of neuroblastomas. Indeed, neuroblastoma cells with restored activin A expression exhibited a diminished proliferation rate and formed smaller xenograft tumors with reduced vascularity, whereas lung metastasis rate remained unchanged. In agreement with the decreased vascularity of the xenograft tumors, activin A inhibited several crucial angiogenic responses of cultured endothelial cells, such as proteolytic activity, migration, and proliferation. Endothelial cell proliferation, activin A, or its constitutively active activin receptor-like kinase 4 receptor (ALK4T206D), increased the expression of CDKN1A (p21), CDKN2B (p15), and CDKN1B (p27) CDK inhibitors and down-regulated the expression of vascular endothelial growth factor receptor-2, the receptor of a key angiogenic factor in cancer. The constitutively active forms of SMAD2 and SMAD3 were both capable of inhibiting endothelial cell proliferation, whereas the dominant-negative forms of SMAD3 and SMAD4 released the inhibitory effect of activin A on endothelial cell proliferation by only 20%. Thus, the effects of activin A on endothelial cell proliferation seem to be conveyed via the ALK4/SMAD2-SMAD3 pathways, however, non-SMAD cascades may also contribute. These results provide novel information regarding the role of activin A in the malignant transformation process of neuroblastomas and the molecular mechanisms involved in regulating angiogenesis thereof.
Περιγραφή
Λέξεις-κλειδιά
Activin Receptors/metabolism, Activins/*therapeutic use, Angiogenesis Inhibitors/*therapeutic use, Animals, Antineoplastic Agents/*therapeutic use, Cell Cycle Proteins/metabolism, Cell Movement/drug effects, Cell Proliferation/drug effects, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA-Binding Proteins/metabolism, Endothelial Cells/*drug effects/metabolism, Female, *Gene Expression Regulation, Neoplastic, Humans, Inhibin-beta Subunits/*therapeutic use, Mice, Mice, Inbred BALB C, Mice, Nude, Neovascularization, Pathologic, Neuroblastoma/metabolism/pathology/*prevention & control, *Signal Transduction, Smad2 Protein, Smad3 Protein, Trans-Activators/metabolism, Tumor Cells, Cultured, Tumor Suppressor Proteins/metabolism, Vascular Endothelial Growth Factor Receptor-2/metabolism, Xenograft Model Antitumor Assays
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/15753386
http://cancerres.aacrjournals.org/content/65/5/1877.full.pdf
http://cancerres.aacrjournals.org/content/65/5/1877.full.pdf
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής