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Int. J. Mol. Sci. 2014, 15(10), 17686-17704; doi:10.3390/ijms151017686

EGF Potentiation of VEGF Production Is Cell Density Dependent in H292 EGFR Wild Type NSCLC Cell Line

1
Biologics Research, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA
2
Department of Pharmacology & Chemical Biology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
3
Cardiovascular & Metabolic Disease, Janssen Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA
*
Author to whom correspondence should be addressed.
Received: 26 June 2014 / Revised: 29 August 2014 / Accepted: 15 September 2014 / Published: 30 September 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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. View Full-Text
Keywords: non-small cell lung cancer; vascular endothelial growth factor; epidermal growth factor receptor; cell density non-small cell lung cancer; vascular endothelial growth factor; epidermal growth factor receptor; cell density
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ranayhossaini, D.J.; Lu, J.; Mabus, J.; Gervais, A.; Lingham, R.B.; Fursov, N. EGF Potentiation of VEGF Production Is Cell Density Dependent in H292 EGFR Wild Type NSCLC Cell Line. Int. J. Mol. Sci. 2014, 15, 17686-17704.

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