title: EGF potentiation of VEGF production is cell density dependent in H292 EGFR wild type NSCLC cell line.
abstract: Non-small cell lung cancer (NSCLC) affects millions of patients each year worldwide. Existing therapies include epidermal growth factor receptor (EGFR) inhibition using small molecules or antibodies with good efficacy. Unfortunately, intrinsic and acquired resistance to EGFR therapy remains a persistent complication for disease treatment. A greater understanding of the role of EGFR in NSCLC etiology is crucial to improving patient outcomes. In this study, the role of EGFR in tumor angiogenesis was examined in H292 NSCLC cells under the pretense that confluent cells would exhibit a more angiogenic and growth-centered phenotype. Indeed, confluent H292 cells potentiated endothelial cell angiogenesis in co-culture models in an EGFR-dependent manner. While confluent H292 cells did not exhibit any change in EGFR protein expression, EGFR localization to the extracellular membrane was increased. EGFR membrane localization coincided with a comparable potentiation of maximal EGFR phosphorylation and was followed by a 3-fold increase in vascular endothelial growth factor A (VEGF-A) production as compared to subconfluent cells. EGFR-mediated VEGF-A production was determined to be dependent on signal transducer and activator of transcription 3 (STAT3) activation and not phosphoinositide 3-kinase (PI3K) signaling. These results identify unique cell density dependent phenotypes within a monoclonal NSCLC cell line and provide a potential mechanism of resistance to anti-EGFR therapy in metastatic NSCLC.
authors.affiliation: Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. djr61@pitt.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ranayhossaini
authors.affiliation: Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. jlu9@its.jnj.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Cardiovascular & Metabolic Disease, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. jmabus@its.jnj.com.
authors.forename: John
authors.initials: J
authors.lastname: Mabus
authors.affiliation: Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. agervais@its.jnj.com.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gervais
authors.affiliation: Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. rlingham@its.jnj.com.
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.affiliation: Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. nfursov@its.jnj.com.
authors.forename: Natalie
authors.initials: N
authors.lastname: Fursov
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D018920:Coculture Techniques; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab