Mechanistic Studies On the Role of Polyamines and Microvesicles in Tumor Growth and Hypoxia-mediated Angiogenesis

Solid tumors are composed of cancer cells, as well as resident or infiltrating non-malignant cells that contribute to the malignant state in an ecosystem generally accepted as the tumor microenvironment. Microenvironmental tumor hypoxia is the foremost leading cause of angiogenesis, i.e. the formation of new blood vessels from pre-existing vasculature, and its correlation to tumor growth and aggressiveness has included hypoxia-induced angiogenesis into the hallmarks of cancer. Accordingly, anti-angiogenic therapy was developed for the treatment of cancer patients; however, clinical studies have shown benefit only for a small group of patients, thus challenging the preceding expectations on anti-angiogenic targeting of tumors and underscoring the complex biology of human cancer disease.
This thesis aims at investigating mechanistic roles of polyamines and microvesicles in tumor biology and hypoxia-mediated angiogenesis. We considered the option of inhibiting cancer cell proliferation by the combination of polyamine synthesis inhibition with phage display-derived antibodies targeting the polyamine uptake system. Further, we found a novel role of polyamines in the hypoxic stress response of cancer cells. The findings resulted in a strategy for enhancing the sensitivity of polyamine biosynthesis inhibition in experimental glioblastoma, i.e. highly aggressive brain tumors, through simultaneous anti-angiogenic induction of tumor hypoxia. We have elucidated the role of protease-activated receptors in the hypoxic responses of endothelial cells, and found a specific role of protease activated receptor-2. We show that hypoxic coagulation system activation in glioblastoma cell derived microvesicles elicits pro-angiogenic signaling in hypoxic endothelial cells through protease activated receptor-2. Further studies investigated the uptake mechanism of glioblastoma cell-derived microvesicles, and present the still hypothetical possibility of multicellular transfer of complex, molecular information through microvesicles.
In conclusion, further studies aim at understanding the limitations of current anti-angiogenic treatments as well as identifying new targets or combinations of therapies. Data presented in this thesis identify new pathways of hypoxia-mediated tumor development with possible implications for therapeutic intervention.