title: Development of a lymphangioleiomyomatosis model by endonasal administration of human TSC2-/- smooth muscle cells in mice.
abstract: Lymphangioleiomyomatosis (LAM) is an interstitial lung disease characterized by invasion and proliferation of abnormal smooth muscle (ASM) cells in lung parenchyma and axial lymphatics. LAM cells bear mutations in tuberous sclerosis (TSC) genes. TSC2(-/-) ASM cells, derived from a human renal angiomyolipoma, require epidermal growth factor (EGF) for proliferation. Blockade of EGF receptors (EGFR) causes cell death. TSC2(-/-) ASM cells, previously labeled with PKH26-GL dye, were endonasally administered to 5-week-old immunodeficient female nude mice, and 4 or 26 weeks later anti-EGFR antibody or rapamycin was administered twice a week for 4 consecutive weeks. TSC2(-/-) ASM cells infiltrated lymph nodes and alveolar lung walls, causing progressive destruction of parenchyma. Parenchymal destruction was efficiently reversed by anti-EGFR treatment and partially by rapamycin treatment. Following TSC2(-/-) ASM cell administration, lymphangiogenesis increased in lungs as indicated by more diffuse LYVE1 expression and high murine VEGF levels. Anti-EGFR antibody and rapamycin blocked the increase in lymphatic vessels. This study shows that TSC2(-/-) ASM cells can migrate and invade lungs and lymph nodes, and anti-EGFR antibody is more effective than rapamycin in promoting lung repair and reducing lymphangiogenesis. The development of a model to study metastasis by TSC cells will also help to explain how they invade different tissues and metastasize to the lung.
authors: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Italy. elena.lesma@unimi.it
authors: Elena
authors: E
authors: Lesma
authors: Chiaramonte
authors: C
authors: Eloisa
authors: Eleonora
authors: E
authors: Isaia
authors: Vera
authors: V
authors: Grande
authors: Silvia
authors: S
authors: Ancona
authors: Emanuela
authors: E
authors: Orpianesi
authors: Anna Maria
authors: AM
authors: Di Giulio
authors: Alfredo
authors: A
authors: Gorio
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation*; D010766:Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000906:Antibodies; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus