Differential contribution to neuroendocrine tumorigenesis of parallel egfr signaling in cancer cells and pericytes

O Nolan-Stevaux, MC Truitt, JC Pahler… - Genes & …, 2010 - journals.sagepub.com
O Nolan-Stevaux, MC Truitt, JC Pahler, P Olson, C Guinto, DC Lee, D Hanahan
Genes & cancer, 2010journals.sagepub.com
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 …
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.
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