Abstract
Factors associated with tumor sensitivity to epidermal growth factor receptor (EGFR) inhibitors in the context of wild-type EGFR remain elusive. This study investigates the mechanistic basis of responsiveness to EGFR inhibitors in the RIP1-Tag2 (RT2) mouse model of pancreatic neuroendocrine tumorigenesis (PNET). Upon treatment of RT2 mice with EGFR inhibitors, PNET tumors harboring wild-type, nonamplified alleles of Egfr grow at a markedly reduced rate and display a significant increase in tumor cell apoptosis, as well as reduced neovascularization. The authors identify Tgf-α and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-α mutant tumors present with an elevated apoptotic index, whereas Hb-egf mutant lesions exhibit decreased angiogenic switching and neovascularization. This study not only associates Tgf-α and Hb-egf expression with wild-type Egfr oncogenicity but also ascribes the proangiogenic activity of Egfr in this tumor model to a novel mesenchymal Hb-egf/Egfr signaling axis, whereby endothelial and pericyte-derived Hb-egf activates Egfr specifically in tumor-associated perivascular cells, leading to increased pericyte coverage of the tumor endothelium and enhanced angiogenesis.
Highlights
Members of the ErbB family of receptor tyrosine kinases, comprising ErbB1, ErbB2 (Her2/Neu), ErbB3, and ErbB4, have pathological functions in a wide range of tumors, as they activate a variety of signaling pathways inside tumor and stromal cells to sustain proliferation, survival, angiogenesis, invasion, and metastasis.[1,2,3] Signaling cascades that lie downstream of ErbB activation include the mitogenactivated protein (MAP) kinase and PI3K/Akt pathways.[4]
We surveyed the activation of Egfr and the concurrent activation of two signaling circuits that lie downstream of epidermal growth factor receptor (EGFR) activation: mitogen-activated protein kinase (MAPK) and PI3K/Akt
Mutations in the EGFR kinase domain[12] and chromosomal amplification of the EGFR receptor[17] are the only clinically validated genetic factors with positive predictive value of EGFR inhibitor sensitivity, whereas the presence of a Kras mutation is a genetic factor with negative predictive value.[41]
Summary
Members of the ErbB family of receptor tyrosine kinases, comprising ErbB1 (epidermal growth factor receptor [EGFR]), ErbB2 (Her2/Neu), ErbB3, and ErbB4, have pathological functions in a wide range of tumors, as they activate a variety of signaling pathways inside tumor and stromal cells to sustain proliferation, survival, angiogenesis, invasion, and metastasis.[1,2,3] Signaling cascades that lie downstream of ErbB activation include the mitogenactivated protein (MAP) kinase and PI3K/Akt pathways.[4] During normal development, ErbB signaling results from the binding of individual ErbB receptors with cognate ligands of the EGF family, which comprises epidermal growth factor (EGF), transforming growth factor–α (TGFα), amphiregulin (AREG), epigen (EPGN), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EPR), and neuregulin 1 to 4 (NRG1-4). In non–small cell lung cancer (NSCLC), the presence of mutations in the EGFR kinase domain is a Supplementary material for this article is available on the Genes & Cancer Web site at http://ganc.sagepub.com/supplemental
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