Producción CyT
Congreso
Autoría
Fernández María Celia
;
MARTIN, AYELEN
;
Mathó Cecilia
;
Venara Marcela
;
Pennisi Patricia A
Fecha
2013
Editorial y Lugar de Edición
The Endocrine Society
ISSN
1945-7189
Resumen
Información suministrada por el agente en
SIGEVA
We have previously shown that circulating IGF-I has a critical role in maintaining tumor phenotype and survival of already transformed pheochromocytoma cells (MPC4/30), and is required for the initial establishment of these tumors. However, the role of the local IGF-I/IGF-IR system that is present in the tumor microenvironment -which includes endothelial cells, fibroblasts and extracellular matrix- has not been fully understood. Herein, we used a murine model of pheochromocytoma by subcutaneous...
We have previously shown that circulating IGF-I has a critical role in maintaining tumor phenotype and survival of already transformed pheochromocytoma cells (MPC4/30), and is required for the initial establishment of these tumors. However, the role of the local IGF-I/IGF-IR system that is present in the tumor microenvironment -which includes endothelial cells, fibroblasts and extracellular matrix- has not been fully understood. Herein, we used a murine model of pheochromocytoma by subcutaneous injection of 1x106 MPC4/30 cells in heterozygous IGF-IR knockout mice (IGF-IR+/n) and we found that the time of noticeable tumor appearance was delayed in IGF-IR+/n group (n=53) compared to control IGF-IR+/+ mice (C, n=79) [6 vs 5 weeks, Hazard Ratio: 0.27; 95% CI: 0.16- 0.46]. Additionally, 9.43% of IGF-IR+/n mice did not develop tumor (p<0.0001, Logrank Test, IGF-IR+/n vs. C) while proliferation assessed by BrdU incorporation, vascularization measured as the number of positive endothelial cells for Von Willebrand factor and tumor volume did not differ between groups. To evaluate the impact of IGF-IR deficiency in the initial steps of pheo development, primary fibroblast cultures from IGF-IR+/n and C mice were used to generate conditioned media (CM) and differential matrix on which MPC4/30 were seeded. In vitro MPC4/30 cell proliferation was higher when cultured with CM from C murine fibroblasts (20±1 vs. 13±2 x104 cells C vs. IGF-IR+/n, day 7, p= 0.025). Moreover, similar results were obtained when MPC4/30 cell were cultured in differential matrix generated by C murine fibroblasts (23±2 vs. 17±1 x104 cells, C vs. IGF-IR+/n, day 5, p<0.05) with a significantly increased of BrdU uptake on day 5 (38±2% vs. 28±2% positive nuclei, C vs. IGF-IR+/n, p <0.005). Our data suggest that IGF-I through its type 1 IGF-IR may be involved in early stages of tumor establishment, contributing to tumor cells anchorage by interaction with both matrix and soluble factors produced by tumor microenvironment fibroblasts.
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Palabras Clave
PHEOCHOMOCYTOMAIGF-1RIGF-1