Biology Reference
In-Depth Information
including overexpressed
MMP3
and
MMP12
, were identified in the earliest
incipient neoplasias and persisted during neoplastic progression to invasive can-
cer (Erez et al.
2010
).
7.7.2 Contributions of Inflammatory Cell MMPs
to Tumor Invasion and Angiogenesis
Inflammatory cells infiltrating primary tumors, i.e., tumor-associated monocytes/
macrophages (TAMs), tumor-associated neutrophils (TANs), mast cells, and lym-
phocytes, represent other important types of cells which produce or deliver MMPs
into the tumor microenvironment (Coussens and Werb
2002
; Balkwill et al.
2005
;
van Kempen et al.
2006
; De Nardo et al.
2008
; Hojilla et al.
2008
; Murdoch et al.
2008
; Aggarwal and Gehlot
2009
).
Histologically, TAMs are the most frequently observed inflammatory cells as
they almost invariably are found at the periphery of solid tumors. In addition to
potent proangiogenic cytokines and growth factors, such as VEGF, TNF
, IL-8, and
FGF-2, TAMs release a number of MMPs, including MMP-2, MMP-7, MMP-9, and
MMP-12 (macrophage metalloelastase), all of which might assist in tumor invasion
(Pollard
2004
; Lewis and Pollard
2006
; Solinas et al.
2009
). It appears that among
all MMPs produced by TAMs, MMP-9 has become obligatory in many processes
involved in tumor progression, especially in tumor angiogenesis. Thus, MMP-9
produced by monocytes/macrophages releases and makes bioavailable VEGF
sequestered in the ECM, thereby triggering the onset of angiogenesis in primary
tumors developing
de novo
in genetically engineered mice (Bergers et al.
2000
).
This angiogenic switch, which is regarded as a critical event in turning benign
adenoma into malignant adenocarcinoma, has been initially attributed to MMP-9
delivered exclusively by tumor-infiltrating monocytes/macrophages (Bergers and
Benjamin
2003
; Giraudo et al.
2004
).
Recently, MMP-9 derived from another inflammatory cell type, i.e., TANs,
earned its spotlight in cancer progression (Murdoch et al.
2008
; Mantovani
2009
).
In several cancer models, neutrophil infiltration of developing primary tumors was
linked to their accelerated growth, angiogenesis, and metastasis (Fridlender et al.
2009
; Tazzyman et al.
2009
). Importantly, MMP-9-delivering TANs become not
just an alternative, but a major inflammatory cell type that supports tumor angio-
genesis and progression when tumor-promoting macrophages are suppressed, e.g.,
in CCR2 null mice (Pahler et al.
2008
). In addition, MMP-9-delivering neutrophils
have been the largest contributor facilitating the development of lung metastases in
the transgenic mammary gland model (Martin et al.
2008
).
At first glance it should not matter whether secreted MMP-9 is produced by
monocytes/macrophages or any other cell type, including tumor cells. However,
a distinct neutrophil origin of MMP-9 has proved to confer this MMP with unique
qualities. It has been demonstrated that MMP-9 released by neutrophils is an
a
