CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Muscarinic signalling promotes tumour angiogenesis: Role of Muscarinic receptor in breast cancer.
Autor/es:
GIAMBALVO GÓMEZ, DILEYVIC; SALES, MARIA ELENA; OROÑO, MANUEL; MARTINEZ PULIDO, PAOLA; LOMBARDI, GABRIELA
Lugar:
Mar del Plata
Reunión:
Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica-LXIV Reunión Anual de la Sociedad Argentina de Inmunología-XLVIII Reunión Anual de la Sociedad Argentina de Farmacología Experimental 2016; 2016
Institución organizadora:
SAIC-SAI-SAFE
Resumen:
Angiogenesis is one of the most important steps in tumor progression. The development of new capillaries involves the participation of pro-angiogenic factors like vascular endothelial growth factor-A (VEGF-A) and extracellular matrix remodelation by metalloproteinases (MMP). Our previous works demonstrated that muscarinic acetylcholine receptors (mAChR) are over-expressed in human breast cancer tumors in comparison to normal breast tissue. We reported that non-tumorigenic human breast cells, MCF-10A neither show immunolabelling for mAChR, VEGF-A and MMP-9 nor stimulate angiogenic response in NUDE mice. Here, we developed stable MCF-10A cell lines that express different mAChR subtypes (mAChR-lines) and we investigated the effect of mAChR activation on VEGF-A levels, MMP-9 activity and tumor neovascular response induced in vivo. We demonstrated by Western blot that the transfection of mAChR induced de novo VEGF-A and MMP9 synthesis in comparison to non-transfected MCF-10A cells. Both effects were potentiated by the addition of the cholinergic agonist carbachol (CARB) and reverted by the preincubation with muscarinic antagonists or by silencing mAChRs with specific interference RNA (iRNA). CARB also increased MMP-9 activity in the supernatants of mAChR-lines. We also observed that mAChR-lines inoculated in the skin of NUDE mice induced a strong neovascular response (vessel mean density±SD) (mAChR3:5.0±1.1; mAChR4:6.4±0.7; mAChR3R4:4.8±0.5) and CARB significantly enhanced angiogenic response (mAChR3:6.7±0.8; mAChR4: 6.4±0.6; mAChR3R4: 8.6±0.9) (p0.05; N=6). The effects on MMP-9 activity and neovascular response were reverted by muscarinic antagonists and iRNA treatment. In conclusion, our results indicate that mAChRs over- expression on non-tumorigenic breast cells induced an angiogenic response mediated by VEGF-A and MMP-9 that may promote tumor progression.