1. Differential Contribution to Neuroendocrine Tumorigenesis of Parallel Egfr Signaling in Cancer Cells and Pericytes
- Author
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David C. Lee, Olivier Nolan-Stevaux, Peter Olson, Morgan L. Truitt, Jessica C. Pahler, Cristina Guinto, and Douglas Hanahan
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,TGF-α ,Angiogenesis ,EGFR ,medicine.disease_cause ,Neovascularization ,03 medical and health sciences ,0302 clinical medicine ,pericyte ,Genetics ,medicine ,cancer ,Epidermal growth factor receptor ,030304 developmental biology ,EGFR inhibitors ,0303 health sciences ,biology ,business.industry ,Original Articles ,Tumor progression ,030220 oncology & carcinogenesis ,Hb-egf ,Cancer cell ,Cancer research ,biology.protein ,Cyclin-dependent kinase 8 ,medicine.symptom ,Carcinogenesis ,business - 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.
- Published
- 2010