A. Menke et al., Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines, CANCER RES, 61(8), 2001, pp. 3508-3517
E-cadherin-mediated cell-cell adhesion is reduced in epithelial tumors, whi
ch is thought to be a prerequisite to acquire invasive properties. We obser
ved that several pancreatic carcinoma cell lines with high metastatic poten
tial expressed normal levels of E-cadherin and possessed functional E-cadhe
rin/catenin adhesion complexes. When the cell: lines PANG-I, BxPC-3, and Pa
Tu8988s were cultured either on type I or type III collagen, E-cadherin gen
e expression was repressed, and E-cadherin and catenin protein concentratio
ns mere reduced In contrast, growth on fibronectin and collagen type IV had
no influence, Collagen type I- or type III-dependent reduction of E-cadher
in expression led to decreased cell-cell adhesion, increased proliferation,
and migratory activity as cell as morphological transformation. Overexpres
sion of activated c-Src in PANG-I cells mimicked collagen-induced E-cadheri
n down-regulation and changed the elevated cell proliferation and migration
. Conversely, treatment of cells with the Src-inhibitors PP1 or herbimycin
A resulted in complete suppression of collagen type I-induced E-cadherin de
crease. Our data demonstrate that specific collagens are able to promote me
tastatic behavior by down-regulation of E-cadherin gene expression in a Src
-kinase-dependent manner. This points toward a novel mechanism for substrat
e-dependent signaling and underlines the significance of extracellular matr
ix environment for tumor growth and invasiveness.