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depletion of tumor cell-derived CCL2 blocks the recruitment of mono-
cytes, inhibits tumor metastasis and prolongs the survival of tumor-bearing
mice (
Qian et al., 2011
). Other chemokines, such as CCL3 (macrophage
inflammatory protein-1α, MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES),
CCL7 (MCP-3), CXCL8 (IL-8), and CXCL12 (stromal cell-derived factor
1, SDF-1) (
Murdoch et al., 2004
,
2008
;
Scotton et al., 2001
), S100A8 and
S100A9 (
Hiratsuka et al., 2006
,
2008
), are also involved in monocytes recruit-
ment into tumors or/and premetastastic sites. Furthermore, these chemokines
directly stimulate monocytes to express some related molecules/chemoat-
tractants that contribute to not only monocyte recruitment but also tumor
progression. For example, CCL5 promotes the expression of CCL2, CCL3,
CCL4, CXCL8 and CCR1 in human monocytes, thus induces a positive
amplification loop for chemokines production in tumors that accelerate
monotytes recruitment (
Locati et al., 2002
;
Murdoch et al., 2004
).
In addition to chemokines, cytokines are also implicated in the recruit-
ment of monocytes into tumors.VEGF and macrophage colony stimulating
factor (M-CSF) are two prominent cytokines that are commonly produced
by tumors. They promote monocytes recruitment by acting tyrosine kinase
receptors (
Mantovani et al., 2004
). It was shown that CSF-1 and its recep-
tor, CSF-1R, are overexpressed in a wide variety of human tumors, and
they are positively correlated with macrophage infiltration in tumors (
Mur-
doch et al., 2004
). Studies in mouse models suggested that overexpression
of CSF-1 in tumors promotes TAM infiltration (
Dorsch et al., 1993
), while
CSF-1 knockout decreases this infiltration (
Lin et al., 2001
). In addition to
its proangiogenic effect, VEGF also functions as a chemotactic factor that is
responsible for monocytes recruitment. It was shown that VEGF promotes
monocytes migration through its receptors, VEGF-R1 (
Barleon et al.,
1996
;
Sawano et al., 2001
) and VEGF-R2 (
Dineen et al., 2008
). VEGF-R1
depletion in macrophages induces the decrease of macrophage migration
in response to VEGF stimulation (
Hiratsuka et al., 1998
). In vivo studies
demonstrated that the elevated VEGF expression is positively correlated by
the number of macrophage infiltration in breast cancer (
Leek et al., 2000
).
Furthermore, recent studies suggested thatVEGF expression in skin cancers
is also correlated with macrophage infiltration (
Linde et al., 2012
). These
findings highlight the important role of M-CSF and VEGF in monocytes
recruitment into tumors.
More recent studies demonstrated that some other factors, such as tissue
factor (TF), transcription factor and chitinase, are also involved in monocytes
recruitment. TF expression in tumor is usually correlated with metastasis in
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