Proteinases and their receptors in liver tumor invasion

The spread of cancer cells from a primary tumour to more distant sites in the body represents a major problem in current cancer therapies. ln the liver, the cancerous foci are often surrounded by extracellular matrix that separates the tumours from the normal tissue. However, aggressive cancer cells have the ability to break through this barrier, invade into the adjacent hepatic parenchyma and ultimately enter the circulation. This project aims to explore the molecular mechanisms that permit liver tumour cells to spread in this organ and to other parts of the body. Two traits are frequently associated with invasive cancer cells: the potential to degrade extracellular matrix components, and the capacity to elicit a migratory response. Recent research has established that various proteolytic enzymes and their cellular receptors play key roles in invasive processes. However, normal quiescent liver cells produce not all proteinases required for the breakdown of extracellular matrix. Furthermore, normal hepatocytes lack the intrinsic propensity to migrate. We have found that cultured liver tumour cells can migrate through extracellular matrix barriers. This phenotype is accompanied by the enhanced production of matrix- degrading proteinases and the acquisition of cellular motility. Hence, these cells are well suited to study the network of matrix-degrading proteinases and their receptors involved in liver tumour invasion. The objectives of this project are to characterise the matrix-degrading potential of invasive liver tumour cells, to identify the proteinases involved in the invasion process, and to assess the impact of a major proteinase receptor, the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) an the invasive capacity of these cells. The results of ihese studies shall pave the path towards novel therapeutic strategies to treat invasive liver cancer.