Role of Macrophage Polarization in Tumor Angiogenesis and Vessel Normalization: Implications for New Anticancer Therapies - International Review of Cell and Molecular Biology - page 19

early stage of tumors as well as in regressing and nonprogressing tumors,
TAMs mainly resemble the M1 (antiangiogenic) phenotype, which causes
angiogenesis inhibition and antitumor immune response, due to secretion
of IFN-γ, IL-12 ( Lamagna et al., 2006 ; Tsung et al., 2002 ) and/or TNF-α
( Blankenstein et al., 1991 ; Lamagna et al., 2006 ). In vitro studies showed
that the conditioned medium from resting macrophages inhibits endothelial
cells proliferation, while the conditioned medium from activated macro-
phages displays the opposite effect ( Pakala et al., 2002 ). Resting macro-
phages inhibit the proliferation of endothelial cells by releasing a variety of
endothelial cell growth inhibitors, such as oncostatin M (OSM) and leuke-
mia inhibitory factor (LIF) ( Takashima and Klagsbrun, 1996 ). Furthermore,
recent findings showed that TAM polarization from the M2 to the M1 phe-
notype by HRG or AMA inhibits tumor angiogenesis in vivo ( Chen et al.,
2011 ; Rolny et al., 2011 ). These evidences support the concept that the
different macrophage activation states contribute to their opposite effects
in regulating tumor angiogenesis. It is conceivable to target TAMs in order
to limit tumor angiogenesis by modifying their activation status toward
the antiangiogenic phenotype. Thus, the combination of the inhibition of
TAM recruitment and their polarization from the M2 to the M1 pheno-
type should be considered as a new potential strategy in antiangiogenic
studies and therapies.
6. ROLE OF TAM s AND THEIR POLARIZATION IN
VESSEL NORMALIZATION
In the hypoxic microenvironment, TAMs produce an excess of angio-
genic molecules, which not only promote tumor angiogenesis but also induce
tumor vessel abnormalization. By impairing oxygen delivery, abnormal ves-
sels trigger a vicious cycle of nonproductive angiogenesis, which creates a
hostile microenvironment from where cancer cells escape through leaky
vessels, thus rendering tumors less responsive to chemoradiation ( De et al.,
2011 ; Jain, 2005 ). Indeed, antiangiogenic vessel normalization strategies not
only improve the chemotherapy drug delivery but also convert the malignant
invasive and metastatic tumors into more benign and less aggressive cancers
( De et al., 2011 ; Rolny et al., 2011 ). Thus, these strategies are gaining more
attention, and are emerging as a new concept in cancer therapies ( Jain, 2001 ).
Past work on treatment strategies aimed at vessel normalization mostly
focused on the abnormalities of vascular endothelial cells and pericytes.
However, the other components in the tumor microenvironment, such as