Differential Contribution To Neuroendocrine Tumorigenesis Of Parallel Egfr Signaling In Cancer Cells And Pericytes  

Oleh:

Nolan-Stevaux, Olivier ; Truitt, Morgan C. ; Pahler, Jessica C. ; Olson, Peter ; Guinto, Cristina ; Lee, David C. ; Hanahan, Douglas

Jenis: Article from Article
Dalam koleksi: Genes and Cancer vol. 1 no. 2 (May 2010), page 125-141.
Topik: EGFR; Hb-egf; TGF-a; Pericyte; Cancer
Fulltext: 125.full.pdf (1.32MB)

Isi artikel

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-a and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-aa 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-aa 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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