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(CSF-1) induces the enhancement of macrophage recruitment, causing an
increase of tumor angiogenesis ( Lewis and Pollard, 2006 ; Lin et al., 2001 ).
Angiogenesis is well known to promote tumor growth and metasta-
sis. However, unlike the healthy vasculature, tumor vessels are highly cha-
otic, poorly organized and dysfunctional (vessel abnormalization), due to
the excessive production of proangiogenic factors ( De et al., 2011 ; Jain,
2005 ). These abnormalities of tumor vessels result in a hypoxic tumor
microenvironment and represent physiological barriers for the delivery of
cancer therapeutic agents ( Fokas et al., 2012 ). The restoration of the balance
between pro- and antiangiogenic factors production in tumor microenvi-
ronment may play a pivotal role in modulating the normalization of the
structure of tumor blood vessels ( Jain, 2005 ). Some important molecules,
such as vascular endothelial growth factor (VEGF) ( Jain, 2005 ), placental
growth factor (PlGF) ( Fischer et al., 2007 ; Fokas et al., 2012 ; Hedlund et al.,
2009 ; Van et al., 2010 ), platelet-derived growth factors (PDGFs), angiopoi-
etins, HIF-prolyl hydroxylases (PHD) ( De et al., 2011 ), Rgs5 ( Hamzah et al.,
2008 ), CD160 receptor ( Chabot et al., 2011 ), nitric oxide (NO) and EGF recep-
tor ( Kashiwagi et al., 2008 ), derived from either tumor cells or stromal cells,
were reported to participate in regulating vessel normalization. In addi-
tion, intracellular signaling pathways, such as PI3K/mTOR pathway ( Fokas
et al., 2012 ; Qayum et al., 2012 ), are also involved in regulating vessel nor-
malization. Understanding molecular mechanisms of vessel normalization
may ultimately lead to more effective therapeutic strategies against cancer.
Interestingly, VEGF ablation in inflammatory cells promotes vessel nor-
malization and vessel maturation ( Stockmann et al., 2008 ), suggesting that
inflammatory cells, such as macrophages, play a significant role in these
processes. Depending on the activation states induced by the microenvi-
ronment, macrophages can be designated as either classically activated (M1
phenotype) or alternatively activated (M2 phenotype) ( Sica et al., 2008 ).The
different phenotypes of macrophages may exhibit opposing effects in blood
vessels modeling and tumor progression. M2, rather than M1, macrophages
were defined as the proangiogenic phenotype due to their ability to secrete
factors that promote angiogenesis ( Lamagna et al., 2006 ). Moreover, M2
macrophages induce vessel abnormalization, while M1 macrophages lead
to vessel normalization ( Rolny et al., 2011 ). These evidences suggest the
significant role of TAM polarization from the M2 phenotype to the M1
phenotype in the regulation of tumor angiogenesis and vessel normaliza-
tion. Thus, tumor vascular network, including angiogenesis and vessel nor-
malization, is affected by the dynamic changes in macrophages phenotypes.
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