Activin A Suppresses Neuroblastoma Xenograft Tumor Growth via Antimitotic and Antiangiogenic Mechanisms
Open Access
- 1 March 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (5), 1877-1886
- https://doi.org/10.1158/0008-5472.can-04-2828
Abstract
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.This publication has 59 references indexed in Scilit:
- Mechanisms of TGF-β Signaling from Cell Membrane to the NucleusCell, 2003
- Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial CellsCirculation, 2002
- TGF-β signaling: positive and negative effects on tumorigenesisCurrent Opinion in Genetics & Development, 2002
- The Hallmarks of CancerCell, 2000
- Targeted Disruption in Murine Cells Reveals Variable Requirement for Smad4 in Transforming Growth Factor β-related SignalingOnline Journal of Public Health Informatics, 2000
- Transforming growth factor β-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cellsProceedings of the National Academy of Sciences of the United States of America, 1997
- Regulation of Growth and Prostatic Marker Expression by Activin A in an Androgen-Sensitive Prostate Cancer Cell Line LNCAPBiochemical and Biophysical Research Communications, 1997
- Functional analysis of activins during mammalian developmentNature, 1995
- The role of growth factors in embryonic induction in Xenopus laevisMolecular Reproduction and Development, 1992
- Urokinase-type plasminogen activator is induced in migrating capillary endothelial cells.The Journal of cell biology, 1987