title: Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis.
abstract: EGFR belongs to the HER/ErbB family of tyrosine kinase receptors and its activation in cancer cells has been linked with increased proliferation, angiogenesis, and metastasis. Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that occurs sporadically or in association with tuberous sclerosis complex (TSC), a genetic, multisystem disorder characterized by hamartomas in several organs. From chylous of a LAM/TSC patient, we previously isolated smooth muscle-like LAM/TSC cells whose proliferation depends on EGF and monoclonal anti-EGFR antibodies reduced proliferation and caused cell death. We demonstrated that the dependency from EGF was caused by the absence of tuberin. To study the role of EGFR pathway in vivo, we developed a mouse model by administration of LAM/TSC cells to female nude mice. LAM/TSC cells caused pulmonary airspace enlargement and, after 30 weeks, nodule formation which express EGFR. Anti-EGFR antibody decreased the number and dimension of lung nodules likely for the inhibition of Erk and S6 signaling, reversed the pulmonary alterations, and reduced lymphatic and blood vessels. Moreover, in pulmonary nodules anti-EGFR antibody reduced the positivity to estrogen and progesterone receptors which enhance survival of LAM cells and Snail expression. These results suggest that the inhibition of EGFR signalling has a potential in treatment of LAM/TSC lung alterations.
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Elena
authors.identifier: 0000-0002-9096-713X
authors.initials: E
authors.lastname: Lesma
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Eloisa
authors.identifier: 0000-0001-5122-1522
authors.initials: E
authors.lastname: Chiaramonte
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ancona
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Orpianesi
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giulio
authors.affiliation: Laboratories of Pharmacology, Department of Health Sciences, University of Milano, Via di Rudini' 8, 20142 Milano, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gorio
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors