Biology Reference
In-Depth Information
bacterial cell walls. Cleavage of OmpA in
E. coli
, for example, causes bacterial cell
lysis (Belaaouaj et al.
2000
). The antimicrobial properties of NE have been
extended to include the enteritides and other organisms (Weinrauch et al.
2002
).
Similar to MMP12, it does not appear that NE requires its catalytic domain to kill
bacteria. Additionally, NE preferentially kills bacteria within the neutrophil,
although it remains microbicidal after secretion into the extracellular space.
9.6.2 Functions of Elastases Within the Tumor
Microenvironment
The functions of proteinases within the tumor microenvironment have traditionally
been limited proteolysis of ECM structures to allow for expansion and invasion of
the tumor. Some elastases perform critical functions both for and against the host
with respect to tumorigenesis. These functions do not involve the degradation of
elastin, and may or may not involve substrates encountered within the ECM.
Vascular endothelial growth factor (VEGF), commonly found sequestered with
the ECM, is an essential mediator of tumor-associated angiogenesis. Although
several proteinases are capable of releasing bioactive VEGF (Lee et al.
2005
),
animal studies suggest that MMP9 is required to perform this function in vivo.
Using bone marrow transfer studies, several independent studies have demonstrated
that bone marrow derived MMP9 (either from mast cells, macrophages, or neutro-
phils) is an essential event for tumor-associated blood vessel formation (Bergers
et al.
2000
; Coussens et al.
2000
; Nozawa et al.
2006
). In these studies, the
inhibition of either MMP9 or VEGF eliminated tumor growth and angiogenesis.
Although MMP2 is also capable of releasing VEGF from matrix, this does not
appear to be the predominant function of MMP2 in vivo. MMP2 directly ligates and
activates the
3 integrin located on endothelial cells and promotes angiogenesis
via matrix-independent means (Brooks et al.
1996
). Whether or not MMP9 and/or
MMP2 mediates degradation of basement membrane structures allowing for tumor
invasion and subsequent metastasis remains a topic of debate (Hotary et al.
2006
).
In contrast to the tumor-promoting functions of the gelatinases, MMP12 actually
functions for the host within the tumor microenvironment. Macrophage-derived
MMP12 generates angiostatic factors from tumor-associated matrix. The generation
of angiostatin from plasminogen and of endostatin from collagen type XVIII can be
performed by MMPs other than MMP12 (Cornelius et al.
1998
). However, their
generation is dependent upon MMP12 in vivo, as MMP12 null mice display increased
tumor growth and vessel density in tumor xenograft models (Houghton et al.
2006a
,
b
).
Neutrophils have been identified at sites of tumorigenesis but their function is
poorly understood. Neutrophils are actually recruited to sites of tumorigenesis by
tumor cells themselves (Sparmann and Bar-Sagi
2004
; Ji et al.
2006
). NE has
recently been shown to promote tumor growth via a matrix-independent mechanism
(Houghton et al.
2010
). Tumor-associated PMN release NE near the tumor cell
surface in modest concentrations. NE then enters tumor endosomes and can be
a
v
b
