Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis

Biomed Res Int. 2015:2015:315240. doi: 10.1155/2015/315240. Epub 2015 Jan 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / administration & dosage*
  • Antibodies, Anti-Idiotypic / immunology
  • Cell Proliferation / drug effects
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Lymphangioleiomyomatosis / genetics
  • Lymphangioleiomyomatosis / immunology*
  • Lymphangioleiomyomatosis / pathology
  • Mice
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Signal Transduction / drug effects
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antibodies, Anti-Idiotypic
  • Receptors, Estrogen
  • Receptors, Progesterone
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors