TSC2 epigenetic defect in primary LAM cells. Evidence of an anchorage‐independent survival

Journal of Cellular and Molecular Medicine

Elena Lesma²  Silvia Ancona²  Silvia M. Sirchia¹  Emanuela Orpianesi²  Vera Grande²  Patrizia Colapietro¹  Eloisa Chiaramonte²  Anna Maria Di Giulio² 

[1] Laboratory of Medical Genetics, Dept. of Health Sciences, Università degli Studi di Milano, Milano, Italy;Laboratory of Pharmacology, Dept. of Health Sciences, Università degli Studi di Milano, Milano, Italy

关键词: tuberous sclerosis complex;    lymphangioleiomyomatosis;    epigenetic modification;    mesenchymal transition;   

DOI  :  10.1111/jcmm.12237

来源: Wiley

【 摘 要 】

Abstract

Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes. Lymphangioleiomyomatosis (LAM) can be sporadic or associated with TSC and is characterized by widespread pulmonary proliferation of abnormal α-smooth muscle (ASM)-like cells. We investigated the features of ASM cells isolated from chylous thorax of a patient affected by LAM associated with TSC, named LAM/TSC cells, bearing a germline TSC2 mutation and an epigenetic defect causing the absence of tuberin. Proliferation of LAM/TSC cells is epidermal growth factor (EGF)-dependent and blockade of EGF receptor causes cell death as we previously showed in cells lacking tuberin. LAM/TSC cells spontaneously detach probably for the inactivation of the focal adhesion kinase (FAK)/Akt/mTOR pathway and display the ability to survive independently from adhesion. Non-adherent LAM/TSC cells show an extremely low proliferation rate consistent with tumour stem-cell characteristics. Moreover, LAM/TSC cells bear characteristics of stemness and secrete high amount of interleukin (IL)-6 and IL-8. Anti-EGF receptor antibodies and rapamycin affect proliferation and viability of non-adherent cells. In conclusion, the understanding of LAM/TSC cell features is important in the assessment of cell invasiveness in LAM and TSC and should provide a useful model to test therapeutic approaches aimed at controlling their migratory ability.

【 授权许可】

CC BY   
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.