One of the main consequences of vessel pruning and inhibition of neovessel growth produced by angiogenesis inhibitors is increased intra-tumor hypoxia. Nevertheless, growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. Indeed, we and others have described a pro-invasive and pro-metastatic adaptation to VEGFR-targeted antiangiogenic therapy that implicates hypoxia as a triggering event.
Using the spontaneous mouse model of pancreatic neuroendocrine cancer (RIP1-Tag2) we describe here the vascular targeting and antitumor effects of Sema4D pro-angiogenic molecule blockade that consequently impairs tumor growth and prolongs survival. Mechanistically, vessel structure is altered at the pericyte coverage level, while vessel density is maintained. Consistently, there is no vascular trimming or induction of intra-tumor hypoxia by anti-Sema4D therapy, but surprisingly there is a significant increase in local invasion and distant metastases, comparable with VEGFR inhibition. When dissecting the mechanisms of these hypoxia-independent pro-invasive and pro-metastatic effects, we discovered a novel Sema4D-positive population of macrophages that are actively recruited by Sema4D blockade to the tumor parenchyma and tumor invasive fronts. Furthermore, in vitro studies demonstrate that Sema4D blockade in macrophages alters their secretome to promote tumor cell invasion and dissemination.
Overall, this study demonstrates beneficial anti-tumor and pro-survival effects of Sema4D blocking antibody but also unravels a novel mechanism of tumor aggressivity that implicates Sema4D+ macrophages that mediate local tumor cell invasion and distant metastasis.
Publication List (related to the topic of the talk): Moserle, Jiménez-Valerio & Casanovas Cancer Discovery 2014
Moserle & Casanovas J. Internal Medicine 2013
Casanovas O. Nature 2012
Moserle & Casanovas EMBO-MM 2012
Casanovas O. J. Clin. Invest. 2011
Pàez-Ribes et al. Cancer Cell 2009
Casanovas et al. Cancer Cell 2005
Casanovas et al. Oncogene 2005
17 - 19 Feb 2016
European Society of Endocrinology