The tumor vasculature : functional reactivity and therapeutic implications

(en) In the past decades, tumors have progressively been perceived as highly integrated systems in which the genetically unstable tumor cells and the genetically stable host cells cooperate to promote tumor growth. This view suggests that, beside tumor cells (that are targeted by conventional anticancer treatments such as radio- and chemotherapy), host cells within the tumor microenvironment can be targeted by antitumor therapy. Such alternative strategies are strongly supported by the need to overcome several limitations of the conventional therapies targeting tumor cells, such as collateral toxicity due to lack of tumor selectivity, limited tumor accessibility, and the selection of treatment-resistant variants. By contrast to tumor cells, the genetically stable host cells should not develop resistance to treatments. In this context, the observation that tumor growth is fundamentally dependent on the onset of a private tumor neovasculature (tumor angiogenesis) has revolutionized the field of cancer research. Several treatments have been developed aimed to prevent tumor angiogenesis (anti-angiogenic strategies) or to erase the existent tumor vasculature (anti-vascular approaches) supporting the survival and growth of thousands of tumor cells. However, although such therapies achieved cancer cure in animal models, they turned out to be rather inefficient when tested in patients. This can be attributed to differences in the angiogenic status between fast-growing animal tumors and slow-growing human tumors at the time of clinical detection. Another reading of the above-mentioned observations is that anticancer treatments could benefit from interventions aimed at increasing their efficiency. For instance, radiotherapy could benefit from tumor reoxygenation while a decrease in tumor interstitial pressure could facilitate tumor accessibility to circulating agents. In this context, the mature vasculature is an attractive target since it controls tumor blood supply and is highly accessible for therapy. Therefore, strategies aimed at exploiting its functional reactivity by inducing vasorelaxation have the potential to improve tumor perfusion/drug delivery and oxygenation/radiosensitivity. To be exploited in the clinics, such pro-vascular approaches have to fulfill essential requirements. First, they need to achieve high selectivity for tumor vessels. It should prevent systemic toxicity as well as the stealing of the blood flow towards the peripheral vasculature. Second, vasodilation has to be transient, so that the tumor should not take advantage of an increased energetic supply to grow faster. Third, the therapeutic effects have to be achieved in several tumor types and in different host strains to gain a wide therapeutic range of applicability. Finally, vasomodulation has to be achieved with interventions relevant to the clinical situation, ensuring direct therapeutic significance. However, the therapeutic exploitation of agents modulating tumor perfusion was generally hampered by confounding effects on the systemic blood pressure.

Affiliations

UCLouvainMD/MINT - Département de médecine interne

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Sonveaux, P. (2004). The tumor vasculature : functional reactivity and therapeutic implications. https://hdl.handle.net/2078.5/93143