Fibroblast deficiency of insulin-like growth factor 1 receptor type 1 (IGF1R) impairs initial steps of murine pheochromocytoma development

Abstract

Insulin-like growth factor 1 (IGF1) has a critical role in maintaining tumor phenotype and survival of already transformed murine pheochromocytoma (pheo) cells (MPC4/30) and it is required for the initial establishment of these tumors. However, the role of local IGF1/IGF1R system in tumor microenvironment has not been fully understood. In vivo, by subcutaneous injection of pheo cells in heterozygous IGF1R knockout mice (L/n), we found that the time of noticeable tumor appearance was delayed, and incidence was decreased in L/n group compared to control (L/L) mice. Once established, tumor proliferation, vascularization or growth rate did not differ between groups. In vitro, fibroblast from L/n and L/L mice were cultured to generate conditioned media (CM) and differential matrixes on which pheo cells were seeded. Proliferation rate was higher when pheo cells were cultured with CM, or in differential matrix generated by L/L murine fibroblasts. A diminished fibronectin (FN) expression and secretion from L/n fibroblast was associated with decreased expression of integrin subunits in tumor cells. Also, soluble factors as IGF1 and insulin-like growth factor binding protein 2 (IGFBP2) were reduced. Our data suggest that IGF1 signaling through IGF1R may contribute to tumor cells anchorage and survival by interaction with both matrix and soluble factors produced by tumor microenvironment fibroblasts.

Keywords: Fibronectin; IGF1; IGF1R haploinsufficiency; IGFBP2; Pheochromocytoma.