Signaling pathways regulating the expression of proteases during tumor progression.

Citation
Ebd. Joffe et al., Signaling pathways regulating the expression of proteases during tumor progression., MEDICINA, 60, 2000, pp. 34-40
Citations number
37
Language
SPAGNOLO
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
MEDICINA-BUENOS AIRES
ISSN journal
0025-7680 → ACNP
Volume
60
Year of publication
2000
Supplement
2
Pages
34 - 40
Database
ISI
SICI code
0025-7680(2000)60:<34:SPRTEO>2.0.ZU;2-T
Abstract
Deregulation of several signaling pathways have been found to be critical f or the development of different types of tumors, both in transgenic and spo ntaneous models. The role of proteases and adhesion molecules during the ea rly stages of tumor progression induced by oncogenes in epithelial and mese nchymal tumors has remained relatively unexplored. This review summarizes r ecent work showing that different but overlapping signaling effector module s (PKC, v-Ras-RalA-PLD1 or v-Src-RalA-PLD1) induce changes in the productio n of proteases (uPA and MMPs) and adhesion molecules (fibronectin, CD44, be ta1-integrin) in normal epithelial or mesenchymal cell lines, associated wi th tumor development in vivo. Overexpression of PKC gamma in normal mammary epithelial cells or of v-Src and v-Ras in NIH3T3 fibroblasts induced in al l cases overproduction of uPA and MMPs and a tumorigenic phenotype. Proteas es production and tumorigenicity in transformed NIH3T3 cells were dependent on the GTPase RalA. In contrast to the common outcome in protease producti on by the different tumor promoting stimuli, fibronectin production was hig h in PKC-overexpressing mammary epithelial cells and it was organized into a rich fibrillar matrix, while oncogene transformed fibroblasts displayed r educed fibronectin production and a total loss of FN fibrillogenesis, an ef fect also dependent on RalA. These results show that protease overexpressio n is a common denominator in the acquisition of a malignant phenotype both in mesenchymal and epithelial cells. In contrast there is a dramatic differ ence in the expression and function of adhesion molecules like fibronectin between these two cell types, suggesting different regulatory roles for thi s glycoprotein during tumor progression, in cells of different tissular ori gin.