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Hypoxia, HIF-1 Regulation and Cancer Therapy

By A.J. Groot

Abstract

Oxygen insufficiency (hypoxia) is a common feature of human cancer and associated with tumor aggressiveness and poor clinical outcome. Furthermore, hypoxic tumors are more resistant to ionizing radiation and chemotherapy contributing to their unfavorable prognosis. The oxygen sensing pathway is controlled by the transcription factor: hypoxia inducible factor or HIF. HIFs control the expression of genetic cascades involved in the adaptation to the hypoxic microenvironment resulting in increased glucose transport and metabolism, and induced vascularization and motility to secure tumor cell survival under low oxygen. Resolving the molecular networks engaged by HIF proteins could offer new opportunities for targeted treatment of hypoxic tumors. One of these, COMMD1 was identified by us as a HIF interacting protein whose loss of function in mice is critical for the normal HIF responses. In vitro studies demonstrated that reduced COMMD1 expression caused increased HIF-1alpha protein stability and HIF-1 activity. COMMD1 interacts directly with HIF-1alpha and promotes ubiquitin-independent degradation by competition with the chaperone HSP90. Since silencing of COMMD1 dramatically increases HIF-1 activity together even under normal oxygen tension makes COMMD1 a candidate tumor suppressor that when mutated could lead to uncontrolled HIF activity. This hypothesis is currently being investigated. The use of engineered therapeutic antibodies as drugs is currently increasing. Especially single-domain antibodies are promising. The family of Camelidae encode, in addition to their normal IgG repertoire, single domains variable heavy chain antibodies (VHH). Due to their molecular nature these antibodies can be cloned and used for phage display. We selected and engineered two anti-HIF-1 VHH into hetero-bivalent antibodies that could be used in a number of immunological applications. Furthermore, when conditional expression of these VHH in mammalian cells we could inhibit HIF-1 activity. In addition, employing selections of VHH on whole hypoxic cells we identified alpha3beta1 (VLA-3) integrin by use of reverse proteomics as upregulated under hypoxia. It would be worthwhile to explore if this VHH may be employed for imaging selectively hypoxic tumors. Clostridium is an obligate anaerobe bacterium that colonizes and propagates in hypoxic regions of solid cancers and causes partial destruction of the cancer by bacteriolysis. We proposed the use of Clostridium strains as a vehicle for targeted antibody therapy specific for hypoxic tumors. For the first time we demonstrate that VHH encoding plasmids can be transduced and expressed in these Clostridium. This is the first step towards Clostridium directed antibody therapy or CDAT that hold promise as a carrier of anti-cancer therapeutics targeting the most resistant regions in human solid cancer

Publisher: Utrecht University
Year: 2008
OAI identifier: oai:dspace.library.uu.nl:1874/27681
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