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.
Highlights
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has an unacceptably poor prognosis and represents 18% of all cancer deaths [1]
Our data indicate that within a monoclonal NSCLC cell line (H292), two distinctly different cell phenotypes can develop as a result of cell density
We attribute this paracrine effect to differential responses to epidermal growth factor (EGF) ligand treatment and subsequent vascular endothelial growth factor A (VEGF-A) production
Summary
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has an unacceptably poor prognosis and represents 18% of all cancer deaths [1]. As tumors exceed the nutritional capabilities of interstitial fluid, the tumor begins two processes necessary for its continued growth survival: Invasion into its surroundings and angiogenesis We hypothesized that these distinctly different process mandate that phenotypically identical, monoclonal NSCLC cells (cell line H292) adapt to their different functions and phenotypically separate. As both EGFR and cMet are major oncogenic proteins in NSCLC with major contributions to tumor angiogenesis and contact-inhibition, we focused our efforts on determining whether EGFR and/or cMet mechanistically support phenotypic distinctions in monoclonal tumor cells. This process is not a result of increased EGFR expression, but rather an optimization of EGFR organization at the plasma membrane, enhancing EGFR phosphorylation and subsequent STAT3 signal transduction and VEGF-A secretion
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