anti-egfr antibody efficiently and specifically inhibits human tsc2？？ smooth muscle cell proliferation. possible treatment options for tsc and lamanti-egfr抗体有效,特别是抑制人类tsc2 平滑肌细胞增殖。.pdfVIP

Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC22 2 / Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM 1 1 1 1 1 1,2 Elena Lesma *, Vera Grande , Silvia Ancona , Stephana Carelli , Anna Maria Di Giulio , Alfredo Gorio 1 Laboratory of Pharmacology , Department of Medicine, Surgery and Dentistry- Polo H. San Paolo, Faculty of Medicine, University of Milan, Milan, Italy, 2 Clinical Pharmacology, IRCCS Humanitas, Milan, Italy Abstract Background: Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC22/ 2 ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2 2/ 2 ASM cell proliferation is EGF-dependent. Methods and Findings: Effects of EGF on proliferation of TSC22/ 2 ASM cells and TSC22/ 2 ASM cells transfected with TSC2 gene were determined. In contrast to TSC22/ 2 ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC22/ 2 ASM cells. Exposure of TSC22/ 2 ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC22/ 2 cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2 2/ 2 ASM cells to rapamycin reduced the p