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2016 ; 7
(41
): 66835-66850
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Tumor suppressor ARF regulates tissue microenvironment and tumor growth through
modulation of macrophage polarization
#MMPMID27572316
Jiménez-García L
; Herranz S
; Higueras MA
; Luque A
; Hortelano S
Oncotarget
2016[Oct]; 7
(41
): 66835-66850
PMID27572316
show ga
Tumor microenvironment has been described to play a key role in tumor growth,
progression, and metastasis. Macrophages are a major cellular constituent of the
tumor stroma, and particularly tumor associated macrophages (TAMs or M2-like
macrophages) exert important immunosuppressive activity and a pro-tumoral role
within the tumor microenvironment. Alternative-reading frame (ARF) gene is widely
inactivated in human cancer. We have previously demonstrated that ARF deficiency
severely impairs inflammatory response establishing a new role for ARF in the
regulation of innate immunity. On the basis of these observations, we
hypothesized that ARF may also regulates tumor growth through recruitment and
modulation of the macrophage phenotype in the tumor microenvironment. Xenograft
assays of B16F10 melanoma cells into ARF-deficient mice resulted in increased
tumor growth compared to those implanted in WT control mice. Tumors from
ARF-deficient mice exhibited significantly increased number of TAMs as well as
microvascular density. Transwell assays showed crosstalk between tumor cells and
macrophages. On the one hand, ARF-deficient macrophages modulate migratory
ability of the tumor cells. And on the other, tumor cells promote the skewing of
ARF-/- macrophages toward a M2-type polarization. In conclusion, these results
demonstrate that ARF deficiency facilitates the infiltration of macrophages into
the tumor mass and favors their polarization towards a M2 phenotype, thus
promoting tumor angiogenesis and tumor growth. This work provides novel
information about the critical role of ARF in the modulation of tumor
microenvironment.