Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms
Φόρτωση...
Ημερομηνία
Συγγραφείς
Panopoulou, E.
Murphy, C.
Rasmussen, H.
Bagli, E.
Rofstad, E. K.
Fotsis, T.
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