Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters intoin therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years more focus has been put into the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetical pre-requisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extra cellular signalling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may be taken advantage of for new tumor labelling/imaging and treatment strategies. One of the Achilles’ heels of hypoxia research has always been exact measurements of tissue oxygenation as well as control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed Euroxy, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross talk with responses to pH and redox changes. The carbon anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has lead to marketable culture flaks with sensors and incubation equipment and the synthesis of new drug candidates against new molecular targets. New labelling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue now are being tested in xeno-graft models and also are in early clinical testing while new potential anticancer drugs are undergoing tests using xenografted tumor cancers. The present paper describes the above results in individual consortium partner presentations