Immune-Mediated and Hypoxia-Regulated Programs: Accomplices in Resistance to Anti-angiogenic Therapies

  • Diego O. CrociEmail author
  • Santiago P. Mendez-Huergo
  • Juan P. Cerliani
  • Gabriel A. RabinovichEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


In contrast to mechanisms taking place during resistance to chemotherapies or other targeted therapies, compensatory adaptation to angiogenesis blockade does not imply a mutational alteration of genes encoding drug targets or multidrug resistance mechanisms but instead involves intrinsic or acquired activation of compensatory angiogenic pathways. In this article we highlight hypoxia-regulated and immune-mediated mechanisms that converge in endothelial cell programs and preserve angiogenesis in settings of vascular endothelial growth factor (VEGF) blockade. These mechanisms involve mobilization of myeloid cell populations and activation of cytokine- and chemokine-driven circuits operating during intrinsic and acquired resistance to anti-angiogenic therapies. Particularly, we focus on findings underscoring a role for galectins and glycosylated ligands in promoting resistance to anti-VEGF therapies and discuss possible strategies to overcome or attenuate this compensatory pathway. Finally, we highlight emerging evidence demonstrating the interplay between immunosuppressive and pro-angiogenic programs in the tumor microenvironment (TME) and discuss emerging combinatorial anticancer strategies aimed at simultaneously potentiating antitumor immune responses and counteracting aberrant angiogenesis.


Angiogenesis Anti-angiogenic therapy Galectins Hypoxia Immunotherapy Resistance 



Work in G.A.R’s lab is supported by grants from the Argentinean Agency for Promotion of Science and Technology (PICT V 2014-367; PICT 2012-2440), CONICET, University of Buenos Aires, Bunge & Born Foundation and Sales Foundation.


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Buenos AiresArgentina
  2. 2.Departamento de Química Biológica, Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresBuenos AiresArgentina

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