INTRODUCTION

The extracellular matrix (ECM) plays a salient role for proliferation and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression and the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas.

AIMS

To examine the role of integrins and related signaling events for differentiation.

METHODOLOGY AND RESULTS

We established an in vitro model for ECM-induced differentiation of poorly differentiated pancreatic carcinoma cells and found that a specific pattern of ECM proteins resembling basal laminas (matrigel) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta1- and beta4-integrins are required for cellular differentiation. Integrin-associated signaling events include activation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs). However, beta1- and beta4-integrin-mediated differentiation of PaTu-II cells was independent from FAK, ERK, and JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a reduction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel.

CONCLUSION

The integrin-mediated differentiation of PaTu-II cells is regulated and maintained through FAK- and MAPK-independent signal transduction pathways.