Tumor-associated neovascularization: Innate immunity and therapeutic intervention

Tumor growth and metastasis are dependent on the development of a tumor-associated blood supply. Abrogation of this vascular network would result in tumor stasis. This process is dependent on the intricate balance between pro- and anti-angiogenic factors in the tumor microenvironment and a significant number of these factors have been identified. The mechanisms which ultimately control or shift the balance of these factors, recognized as the angiogenic switch, have been extensively studied yet remain to be clearly elucidated. Further understanding of these mechanisms is critical to the future development of diagnostic assays for early detection of cancer as well as for preventative and therapeutic intervention strategies.;Studies presented here sought to further understand the potential anti-angiogenic role of endogenous type I and II interferons in the physiological tumor-bearing state. Intradermal tumors were induced in type I and II interferon receptor knock out (IFN-R -/-) mice with transplanted syngeneic methylcholanthrene-induced sarcoma cells. Tumor growth rates and microvessel density (MVD) in both type I and II IFN-R-/- mice exceeded those of wild type (wt) mice, thus supporting a role of endogenous type I and II interferons in anti-angiogenesis and tumor surveillance. Characterization of tumor infiltrating leukocytes revealed increased numbers of dendritic cells (DCs) in tumors from IFN-R-/- mice while initial experiments evaluating circulating endothelial progenitor cells (CEPs) demonstrated a decrease in CEPs in IFNR-/- mice over the course of tumor development. These results suggest interferons may elicit their anti-vascular effects, at least in part, by regulating DCs and CEPs respectively.;Additional studies consisted of clinical trials in canines with spontaneously occurring soft tissue sarcoma. These studies explored strategies of therapeutic intervention seeking to inhibit or retard tumor-associated vascular production by altering the balance or effects of angiogenic regulatory factors. The first of the two studies sought to examine the effects of intravenous gene therapy utilizing plasmid DNA encoding the anti-angiogenic, collagen-derived protein, endostatin complexed with cationic liposomes while the second study explored the effects of intradermal xenovaccination with recombinant human vascular endothelial growth factor (rhVEGF). Anti-angiogenic and anti-tumor effects were observed in both studies via mechanisms which are described within.