Cancer Research - Europa

Keywords | Metalloproteinase | protease | metastasis | diagnostics | tumour imaging |
CANCERDEGRADOME
Extracellular proteases and
the cancer degradome:
innovative diagnostic markers,
therapeutic targets and tumour
imaging agents
Summary
Extracellular proteases have complex roles with distinct
functions at diff erent stages of tumour development and
progression, and may have confl icting eff ects on malignancy.
The complete repertoire of extracellular proteases
through which cells regulate their local environment is
termed the Degradome. Extracellular proteases remain an
attractive target for intervention against cancer and we
propose to transfer recent insights into their function to
pre-clinical and clinical settings.
Problem
The critical defi ning feature of a malignant tumour is the
presence of cells that have broken through tissue boundaries
and penetrated into surrounding normal tissues. It has
long been recognised that cellular invasion of basement
membranes and connective tissue stroma involves the
actions of diverse extracellular proteases from multiple
enzymatic classes, including the metalloproteinases (MPs)
and the serine, threonine, thiol and aspartic proteases, which
can be produced either by cancer cells themselves or by
neighbouring host cells. These cellular proteases participate
also in the formation of new blood vessels that support the
burgeoning energy demands of a rapidly growing tumour,
and in the ability of cancer cells to metastasize to distant
organs. They constitute the Degradome – the complete repertoire
of proteases that cells and tissues coordinatively
regulate in order to modulate their local environment.
We now understand that pericellular proteolysis is important
in the regulation of:
• growth factor activation, bioavailability and receptor
signalling;
• cell adhesion and motility;
• apoptosis and survival mechanisms;
• angiogenesis;
• specifi cation of cellular identity;
• infl ammatory responses and immune surveillance.
EARLY DETECTION, DIAGNOSIS AND PROGNOSIS
In the battle against cancer, the Degradome is important in
three principal areas.
• Cellular proteases and their inhibitors are components of
the molecular machinery of malignancy, and thus are
attractive as therapeutic targets.
• Degradome genes are valuable as prognostic and diagnostic
markers of disease that can improve the accuracy
of conventional clinical and histopathological assessment.
• Cellular proteases are target molecules for improving
tumour detection and imaging.
The goals in molecular diagnostics are to develop molecular
profi ling technologies and markers of disease status that are
broadly applicable to the selection of patients for therapy,
or to screening of disease-free individuals who may benefi t
from prophylactic interventions.
Aim
The aim of this project is to defi ne new molecular targets for
drug design and to develop novel specifi c interventions that
are based on thorough knowledge of the pathophysiological
roles of target proteases and related molecules, and to
understand how and when to use them. The identifi cation of
new molecular diagnostic and prognostic indicators of
patient risk, together with new ways to enhance visualisation
of tumours in the clinic, will improve health care delivery
based on an individualised, patient-oriented approach to
cancer therapy.
Overview of human, chimpanzee, rat and mouse degradomes
The fi gure represents the complete set of protease and protease homologue genes from the
indicated species. Catalytic classes are indicated at the bottom.
X.S. Puente, L.M. Sánchez, A. Gutiérrez-Fernández, G. Velasco and C. López-Otín, A genomic view of
the complexity of mammalian proteolytic system. Biochem. Soc. Trans. (2005) 33, (331–334).
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