Proteases and cancer invasion: from belief to certainty

A large number of scholars in the field of proteases and cancer arrived in the small town of Nyborg on the island of Fynen (Denmark) on 14 June, the very day in which the beautiful and impressive bridge that connects Sealand to Fynen was officially opened to traffic. The reason for the gathering was obviously not simply to watch the bridge, nor the Royals arriving for the official ceremony, nor the beautiful collection of old cars that took the opportunity to cross the bridge on the first day, nor to assist at the last trips of the ferries. It was in fact to discuss the role of proteases in cancer, and to consider possibilities to attack cancer by blocking them. That the phenotypes of multiple human cancers very much depend on the presence of proteases was first suggested over 50 years ago [1]. In recent years, however, the elucidation of the great complexity of this system has resulted in a rigorous demonstration of this assertion. The opening of the Fynen bridge, indeed, signaled the moment of general agreement that proteases represent a truly valid target in future cancer therapy. The meeting covered most of the known proteases, but the main focus was on metalloproteases, plasminogen activators and cathepsins [2], [3]. That proteases have functions other than cleaving/clearing unwanted proteins is a fact. The large amount of biochemical evidence can now be coupled with in vivo tests of the effects of their absence or overexpression in various physiological and pathological processes, including cancer. In particular, extracellular proteases modulate cellular behavior by altering cell surface-extracellular matrix interactions and regulating the processing of growth factors. In addition, it is increasingly clear that these enzymes can play non-proteolytic roles through the interaction of non-catalytic domains (EGF-like, disintegrin, hemopexin etc.) with other proteins, thereby regulating cell migration and adhesion, egg-sperm interactions, angiogenesis, and the cell cycle. A large body of evidence supports a role for proteases in proliferation, migration, invasion and apoptosis, likely through complex mechanisms which are still under investigation. A major outcome of this meeting was the realization that proteases are relevant in cancer development and progression, as well as in stroma-tumor cell interactions.