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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.
Highlights
Oncoantigens are self-molecules expressed at the tumor site that play a significant role in promoting tumor growth and can be the targets of anti-tumor vaccines [1]
Amot expression evaluated by Western blot from protein extracts of mammary glands of BALB-neuT transgenic mice bearing foci of hyperplasia, in situ carcinomas, or microscopic invasive cancer, and from autochthonous carcinomas of progressive size (Fig. 1a), showed that the level of Amot protein increases from pre-neoplastic lesions to full-fledged lobular carcinoma (Fig. 1a). quantitative real time PCR (qPCR) analysis on total RNA harvested from the same samples showed that Amot transcript level increases until the 22nd week (Fig. S1a), while no differences of Amot expression were found between tumors of different size (Fig. S1a)
These results show that Amot transcription and expression coincides with the angiogenic switch characterized by burgeoning capillary sprouts that accompanies the progression of preneoplastic lesions towards invasive cancer [15, 21]
Summary
Oncoantigens are self-molecules expressed at the tumor site that play a significant role in promoting tumor growth and can be the targets of anti-tumor vaccines [1]. Cellular [2] and DNA [3] vaccines may overcome immune tolerance and trigger a protective immune response against oncoantigens overexpressed by tumor cells [4, 5] or in tumor microenvironment [1]. While oncoantigen vaccines effectively and persistently hamper the expansion of incipient tumors, their efficacy fades away when they are administered to mice bearing advanced tumors. Their protective potential is restricted to tumor prevention [5, 7]
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