Book of abstract 2008

Cysteine cathepsins in tumors and their microenvironment
Bonnie F. Sloane, Dora Cavallo Medved, Christopher Jedeszko, Kamiar Moin, Izabela
Podgorski, Mansoureh Sameni, Bernadette C. Victor
Dept. of Pharmacology and Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI
48201 USA
Cysteine cathepsins, which are endopeptidases belonging to the papain family (C1) of
the CA clan of cysteine proteases, are highly upregulated in a wide variety of cancers by
mechanisms ranging from gene amplification to post-transcriptional modification. There
are eleven human cysteine cathepsins that function in normal tissues primarily within
intracellular lysosomes. There are, however, intracellular non-lysosomal functions and
extracellular functions for some cysteine cathepsins. An example of the former is the
participation of cysteine cathepsins in apoptosis and of the latter is cathepsin K, which
participates in bone degradation in the resorptive pits formed between osteoclasts and
the underlying bone. Extracellular roles for cysteine cathepsins also occur in tumors due
to the secretion of both inactive and active forms of these proteases. Secreted cysteine
cathepsins associate with binding partners in membrane microdomains on the tumor cell
surface where proteases of other classes are also found. For example, cathepsin B binds
to S100A10, a subunit of the annexin II heterotetramer (AIIt); plasmin(ogen) and tissue
plasminogen activator (tPA) bind to AIIt; urokinase plasminogen activator (uPA) binds to
its receptor uPAR in association with beta1 integrin; matrix metalloproteinase (MMP)-2
binds to alphaVbeta3 integrin; and MMP-14 or membrane type 1-MMP is a transmembrane
protein. Similar localizations of these proteases have been observed on endothelial cells,
consistent with cell-surface proteolysis facilitating the angiogenesis required for growth
of tumors. The juxtaposition on the cell surface of a cysteine cathepsin, serine proteases
of the plasminogen cascade and MMPs has been shown to produce a proteolytic cascade,
resulting in activation of growth factors and focal proteolysis of basement membrane.
Direct proof that cysteine cathepsins play causal roles in tumor growth, migration, invasion,
angiogenesis and metastasis has been shown by downregulating or ablating the expression
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of individual cysteine cathepsins in tumor cells and in transgenic mouse models of human
cancer. The latter studies have identified roles for cysteine cathepsins in tumor-associated
cells that enhance malignant progression including endothelial cells and also fibroblasts
and inflammatory cells (macrophages). On the other hand, studies in transgenic mice have
also identified protective roles for cysteine cathepsins in tumor-associated cells such as mast
cells. The specific cysteine cathepsins that enhance or reduce malignant progression differ
with tumor type. Clinically, the levels, activities and localization of cysteine cathepsins
and their endogenous inhibitors have been shown to be of diagnostic and prognostic value.
Given that it is active cysteine cathepsins that play causal roles in malignant progression,
it is intriguing that one of the endogenous cysteine cathepsin inhibitors, i.e., cystatin
M, seems to be a tumor suppressor in breast cancer and is epigenetically silenced by
methylation of its promoter. To effectively target these enzymes for anti-cancer therapies,
we need a more complete understanding of how cysteine cathepsins function in neoplastic
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