A vaccine targeting angiomotin induces an antibody response which alters tumor vessel permeability and hampers the growth of established tumors

Abstract

Angiomotin (Amot) is one of several identified angiostatin receptors expressed by the endothelia of angiogenic tissues. We have shown that a DNA vaccine targeting Amot overcome immune tolerance and induce an antibody response that hampers the progression of incipient tumors. Following our observation of increased Amot expression on tumor endothelia concomitant with the progression from pre-neoplastic lesions to full-fledged carcinoma, we evaluated the effect of anti-Amot vaccination on clinically evident tumors. Electroporation of plasmid coding for the human Amot (pAmot) significantly delayed the progression both of autochthonous tumors in cancer prone BALB-neuT and PyMT genetically engineered mice and transplantable TUBO tumor in wild-type BALB/c mice. The intensity of the inhibition directly correlated with the titer of anti-Amot antibodies induced by the vaccine. Tumor inhibition was associated with an increase of vessels diameter with the formation of lacunar spaces, increase in vessel permeability, massive tumor perivascular necrosis and an effective epitope spreading that induces an immune response against other tumor associated antigens. Greater tumor vessel permeability also markedly enhances the antitumor effect of doxorubicin. These data provide a rationale for the development of novel anticancer treatments based on anti-Amot vaccination in conjunction with chemotherapy regimens.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-012-9263-3) contains supplementary material, which is available to authorized users.

Cluster analysis of quantitative parametric maps from DCE-MRI: application in evaluating heterogeneity of tumor response to antiangiogenic treatment

“…Conversely, we observed for treated mice an increase of voxels showing medium K trans and v p values in the central region of tumor (set #2 for a three-group subdivision, Figure 3). The increased values of tumor K trans and v p in specific tumor sub-regions correctly reflected previous findings of histological and immunofluorescence analysis, where vascular morphology and vessel permeability were shown to be markedly changed in pAmot-treated tumors [45]. The effect of an enhanced microvasculature permeability following the antiangiogenic treatment has already been reported in several cases, a process known as vasculature normalization [49].…”

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

“…Vaccinated females were then mated with a BALBneuT male and neu C offspring was evaluated for mammary tumor development. We have previously shown that vaccinationinduced anti-Amot antibodies impair tumor vascularization 26 and significantly delay autochthonous tumor progression 27 in female BALB-neuT mice. Post-vaccination anti-Amot antibody induction was confirmed in pAmot-vaccinated mother sera and milk as well as in the sera of their offspring (pAmot offspring) ( Fig.…”

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

“…24) BALB/c mice were maintained at the Molecular Biotechnology Center, University of Torin, and treated in accordance with the University Ethical Committee and European guidelines under Directive 2010/63. Vaccination, performed either before or after tumor challenge, consisted of two intramuscular electroporations at 2 weeks interval, of pVAX1 or pVAX1-xCT plasmids as previously described (25).…”