Book of abstract 2008

Proteases in cancer: progression or protection?
Angela Moncada Pazos, Ana Gutiérrez Fernández, Guillermo Mariño, Cristina G. Viloria,
Santiago Cal, Carlos López Otín
Dept. of Biochemistry and Molecular Biology, Medical Faculty, University Institute of Oncology,
University of Oviedo, Spain
Proteolytic enzymes have long been associated with cancer progression because of their
ability to degrade extracellular matrix components, which facilitates tumour invasion and
metastasis. These facts provided the rationale for clinical trials with protease inhibitors,
which, unfortunately, have not been positive in most cases. Recent studies have revealed
how proteases contribute with both pro-tumour and anti-tumour activities in all tumourprogression
stages, what has forced a re-evaluation of the prevailing concepts in this field.
To date, more than 30 proteolytic enzymes belong to the growing group of anti-tumour
proteases which mainly includes different caspases, deubiquitylases, kallikreins, and
members of the MMP and ADAMTS families.
We have recently described several intracellular and extracellular proteases with antitumour
properties. Thus, autophagin 3 (Atg4c) is an intracellular cysteine protease
involved in processing events associated with autophagy. Mice lacking autophagin-3 show
a high incidence of carcinogen-induced fibrosarcomas, which has been correlated with
the decrease in autophagy found in Atg4c -/- fibroblasts. Among extracelullar proteases, we
have previously described that MMP-8 reduces skin tumour susceptibility by modulating
inflammatory response to chemical carcinogens. We have recently extended these results
with the finding that MMP-8 expression in mice also prevents metastasis by reducing
invasion capability and altering cellular adhesion. Moreover, MMP-8 levels in human
breast cancer are associated with good clinical prognosis, reinforcing the idea of the
protective role of this enzyme. Parallel studies on different members of the ADAMTS
family have allowed us to propose novel tumour-defying functions for ADAMTS-12
and ADAMTS-15. Thus, ADAMTS-12 controls tumour progression by modulation of
the Ras-dependent ERK signalling pathway. Further work has revealed that this gene is
l23
epigenetically silenced in colon carcinomas, suggesting that this mechanism may operate
in vivo to inactivate the tumour-suppressor actions of this metalloproteinase. Finally,
mutational analysis of different proteases presumably associated with cancer has shown
that ADAMTS-15 is inactivated by mutation but not by epigenetic silencing, in several
carcinomas. On the basis of these results, we can conclude that tumour protective roles
of proteases are much more relevant than originally anticipated, thereby contributing to
expand the functional complexity of the cancer degradome, which is the complete set of
proteases produced by a malignant tumour.
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