Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSLSignaling (Cell, 2012, 149, P 1207–1220)

報告日期: 2014/04/18
報告時間: 3:10/4:00
報告學生: 吳菁山(以英文報告)
講評老師: 王育民
附件下載: 下載[1396-1396958565-1.pdf] 

Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling

 

Bing Hu, Einar Castillo, Louise Harewood, Paola Ostano, Alexandre Reymond, Reinhard Dummer, Wassim Raffoul, Wolfram Hoetzenecker, Gu¨ nther F.L. Hofbauer, and G. Paolo Dotto

Cell 149, 1207–1220, June 8, 2012

 

Speaker: Jing-Shan Wu (吳菁山)                 Time: 15:10-16:00 2014/4/18

Commentator: : Ju-Ming Wang (王育民) Ph.D.           Place: Room 602

 

Abstract

Squamous cell carcinomas (SCCs) are very common malignant tumors in humans. However, the mechanism of SCCs associated changes of both epithelial and mesenchymal tissues beyond the neoplastic area is still unclear. In addition, genetic and epigenetic changes of the epithelium have been implicated as likely primary determinants of the field cancerization process, whereas alterations of the underlying mesenchyme have received relatively little attention. The reasons for stromal alterations, including widespread atrophic changes, are also not understood. The mammalian Notch gene family codes for four closely related transmembrane receptors, whose activation depends on similar mechanisms of ligand binding, proteolytic cleavage and nuclear translocation. The activated Notch intracellular domain associates with the DNA binding protein CSL (CBF-1 in human and RBP-Jk in mouse) converting it from a repressor into an activator of transcription. In the skin, Notch pathway plays a well-established function in keratinocyte differentiation and tumor suppression through both intracellular and paracrine growth control mechanisms. The authors show that mesenchymal loss of the CSL/RBP-Jk gene is sufficient to induce in the skin several features associated with field cancerization, which are also relative to increase AP1 levels and activity. Through human samples studies, these findings seem that clinical significance, as suppression of Notch/CSL signaling and associated gene expression events occur in stromal fields adjacent to cutaneous premalignant actinic keratosis lesions, which can be induced by UVA exposure, a major cause of skin chronic and cancer-predisposing alterations. From these data, authors demonstrate that loss of mesenchymal Notch/CSL signaling may involve in multifocal epithelial tumors and field cancerization.

 

Reference

Demehri, S., Turkoz, A., and Kopan, R. (2009). Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16, 55–66.