Biology Reference
In-Depth Information
was found to be an important factor in invasion (Bervar et al.
2003
; Premzl et al.
2003
; Sameni et al.
2003
; Szpaderska and Frankfater
2001
). In many cancers the
ratio of cathepsin to endogenous inhibitor is used as a prognostic indicator of the
tumor invasive and metastatic potential.
Cathepsin B has also been shown to degrade the ECM protein tenascin C, thereby
promoting angiogenesis in gliomas (Mai et al.
2002
; Mai et al.
2000
). Cathepsin S has
been suggested to promote angiogenesis and tumor progression through the degrada-
tion of collagen type IV-derived fragments canstatin and arresten (Wang et al.
2006
).
These antiangiogenic peptides are released through the degradation of type IV
collagen in the basement membrane (Colorado et al.
2000
;Kamphausetal.
2000
).
The degradation of these antiangiogenic peptides by cathepsin S could promote
tumor growth, as the presence of canstatin and arresten have been shown to function
as tumor growth inhibitors (Colorado et al.
2000
;Heetal.
2003
).
Cathepsin S can also release cryptic bioactive peptides from the lamin-5 com-
plex, another component of the basement matrix. It was shown to produce proan-
giogenic fragments:
2
0
and
. These fragments have been shown to promote
cancer cell migration and invasion (Seftor et al.
2001
).
A recent study has shown that the degradation and processing of bone matrix
protein SPARC (secreted protein acidic and rich in cysteine) and osteonectin by
cathepsin K promotes tumor progression in the bone (Podgorski et al.
2009
).
SPARC is a matrix protein, which undergoes proteolytic processing resulting in a
variety of physiological and pathological functions (Lane and Sage
1994
; Tai and
Tang
2008
). Biological processing unveils numerous cryptic functions distinct
from those of the native protein. Cathepsin K has been previously shown to cleave
this protein; however, new studies have suggested that this cleavage may propa-
gate bone tumor progression, a frequent site of pancreatic tumor metastasis.
Although the mechanism is unclear, it is thought that cathepsin K is involved in
the colonization and growth of tumors in the skeleton through its cleavage of
SPARC which results in the release of proinflammatory factors into the tumor
microenvironment (Podgorski et al.
2009
). The role of cathepsins in cancer has
been recently extensively reviewed (Gocheva and Joyce
2007
; Gocheva et al.
2006
; Palermo and Joyce
2008
).
g
g
2
w
2.6 Cathepsins as Drug Targets to Control ECM Degradation
The first potent cathepsin inhibitors were isolated from various microbial strains
about 40 years ago (Aoyagi et al.
1969
;Hanadaetal.
1978
;Umezawa
1982
).
Classical examples are peptide aldehydes such as leupeptin and peptidyl epoxides
such as E-64. E64, a pan-cysteine cathepsin inhibitor, showed some efficacy to slow
down muscle wasting in muscular dystrophy in animal models but failed in human
trials (Satoyoshi
1992
). Preclinical trials using cathepsin inhibitors were also
expanded into the cancer and arthritis fields. The main problem of the earlier trials
was the lack of specificity of the inhibitors used as well as a limited understanding of
