title: TSC2 epigenetic defect in primary LAM cells. Evidence of an anchorage-independent survival.
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.
authors.affiliation: Laboratory of Pharmacology, Dept. of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lesma
authors.forename: Silvia
authors.initials: S
authors.lastname: Ancona
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Sirchia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Orpianesi
authors.forename: Vera
authors.initials: V
authors.lastname: Grande
authors.forename: Patrizia
authors.initials: P
authors.lastname: Colapietro
authors.forename: Eloisa
authors.initials: E
authors.lastname: Chiaramonte
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giulio
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gorio
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D020123:Sirolimus / Q000494:pharmacology; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D016209:Interleukin-8; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020123:Sirolimus
keywords: epigenetic modification; lymphangioleiomyomatosis; mesenchymal transition; tuberous sclerosis complex