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experimental settings and poor prognosis in human tumors (
Gil-Bernabe
et al., 2012
;
Laubli and Borsig, 2010
;
Palumbo and Degen, 2007
).TF-induced
clot formation indirectly enhances tumor cell survival and metastasis by
recruiting macrophages. Genetic or pharmacologic inhibition of coagula-
tion, by induction of TF pathway inhibitor expression, abrogates macro-
phage recruitment and tumor cell survival (
Gil-Bernabe et al., 2012
). These
data suggested that TF is a significant player in macrophage recruitment into
tumors. The expression of forkhead Box m1 (Foxm1) transcription factor
is increased in many human tumors (
Kalin et al., 2011
;
Myatt and Lam,
2007
), and its expression is associated with poor prognosis in cancer patients
(
Xia et al., 2012a
,
2012b
).
Balli et al. (2011)
generated a mouse model with
macrophage-specific Foxm1 deletion, and found that this deletion decreases
macrophage recruitment into tumors by downregulating some chemokines,
such as IL-6, CCL3 and MIP-2, and chemokine receptors CXCR1 and
CXCR4, suggesting Foxm1 transcription factor is required for macrophage
migration. Chitinase 3-like 1 (CHI3L1) is a member of chitinase family,
which is expressed in several types of human cancers (
Eurich et al., 2009
;
Johansen et al., 2006
). CHI3L1 expression in tumors is positively associ-
ated with macrophage infiltration and poor prognosis. Overexpression of
CHI3L1 in macrophages enhances their abilities of migration in vitro, while
CHI3L1 antibody has the opposite effect. Mechanistic studies demonstrated
that CHI3L1-induced macrophage recruitment is mediated by the upregu-
lation of IL-8 and CCL2, and activation of mitogen-activated protein kinase
(MAPK) signaling pathway (
Kawada et al., 2011
). These studies provide fur-
ther insights into the mechanisms of in monocytes recruitment into tumors.
4. MACROPHAGES AND MACROPHAGE
POLARIZATION IN THE TUMORIGENESIS
4.1. Macrophages and Cancer
Studies from patient biopsies strongly suggest that macrophages contribute
to tumorigenesis.
Table 1.2
lists the current knowledge on the correlation
between TAM levels and patient survival in a wide range of human tumors.
The clinical data suggest that TAM density is correlated with poor progno-
sis in most tumors. These clinical observations are well supported by experi-
mental studies using macrophages depletion or overexpression approaches.
For example, genetic ablation of the M-CSF in different murine tumor
models, such as the polyoma middle T (PyMT) oncoprotein breast can-
cer model, the colon cancer spontaneous model (
Oguma et al., 2008
)
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