Research Papers:

Tumor suppressor ARF regulates tissue microenvironment and tumor growth through modulation of macrophage polarization

Lidia Jiménez-García, Sandra Herranz, María Angeles Higueras, Alfonso Luque and Sonsoles Hortelano _

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Oncotarget. 2016; 7:66835-66850. https://doi.org/10.18632/oncotarget.11652

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Lidia Jiménez-García1, Sandra Herranz1, María Angeles Higueras1, Alfonso Luque1,*, Sonsoles Hortelano1,*

1Unidad de Terapias Farmacológicas. Instituto de Investigaciones de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid, Spain

*These authors contributed equally to this work

Correspondence to:

Sonsoles Hortelano, email: [email protected]

Keywords: ARF, M2-polarization, tumor-microenvironment, angiogenesis, macrophage

Received: March 15, 2016     Accepted: August 24, 2016     Published: August 27, 2016


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.

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