Modified: Thursday, Apr 10, 2024

Significance of the tissue microenvironment and pericellular proteolysis in epithelial integrity and tumor progression.

In higher organisms, numerous cells serve as constituents of the different tissues. To operate successfully within the context of the organisms, all cells must be integrated into an architectural and signaling framework in each tissue and must respond to commands at any given time to maintain homeostasis. In this process, cell-stroma and cell-cell interactions are critical, and failure results in a spectrum of dysfunctions, including tumor. Ample evidence indicates that normal microenvironment suppresses tumorigenesis even in the presence of strong oncogene expression. On the other hand, in established tumor tissue, interaction between tumor cells and tumor stroma in microenvironment is important determinant of malignant phenotypes such as sustained angiogenesis, escape from apoptosis and invasion/metastasis. Therefore, pericellular microenvironment can function both as a suppressor of tumorigenesis and as a promoter of tumor progression.
Proteolysis is an important post-translational system to regulate the fate of all the proteins. Pericellular proteolysis is required in turnover and remodeling of extracellular matrix as well as activation or processing of growth factors and other bioactive molecules, and thereby has significant influences on the quality of microenvironment. Most of the enzymes involved in these processes belong to serine proteases or metalloproteases. Our research group has been studying the roles of pericellular microenvironment on the integrity of normal epithelial tissue and progression of tumors, particularly focusing on the regulation of membrane-anchored serine proteases by a membrane-anchored Kunitz-type inhibitor, HAI-1 (hepatocyte growth factor activator inhibitor-1). By using genetically engineered mouse models, cultured cells and surgically resected tissue specimens, we have revealed critical roles of HAI-1 in the integrity of normal epithelial tissues and invasive growth of carcinoma cells, through specific interaction with its cognate cell surface protease expressed in each epithelial tissue and tumor cell. A better understanding of the physiological roles of this interaction will be an important goal for developing innovative therapies targeting the disorders of epithelial tissue and tumor invasion.

Hiroaki Kataoka, MD, PhD,
Section of Oncopathology and Regenerative Biology
Department of Pathology,
Faculty of Medicine, University of Miyazaki