In order for tumors to grow above a few millimetres in size they must establish a (neo-) vasculature. One of the major stimuli for the development of new blood vessels is tissue hypoxia. The aim of this research line is to study the functional genomics of hypoxia in order to optimise radiotherapy and chemotherapy, to look for new targets in angiogenic blood vessels by using genetic profiling of tumour endothelium and to develop novel therapeutics for the treatment of patients based upon laboratory models of angiogenesis.
Angiogenesis
The mission of the Angiogenesis Laboratory is two-fold. Firstly, it is aimed to unravel fundamental processes and mechanisms of angiogenesis. Secondly, it is aimed to apply research and new technology for development of novel (cancer) treatment modalities in the clinic. The mission is elaborated in several interconnective and collaborative research projects i.e.:
Genetic profiling of tumor endothelium. This research project focuses on the identification of specific targets on tumor endothelium. Several molecular biological techniques have been applied to identify a series of 17 genes that are specifically overexpressed on tumor endothelium.
Identification and development of new angiostatic agents. The angiostatic designer peptide anginex and its mimetic KM0118 have been developed in our laboratory. The current research focuses on the identification of the cellular receptors for these molecules. These compounds are planned for clinical testing in the near future.
Study of the cross-talk between the vasculature and the immune system. The major achievement of this research is the recognition that anti-angiogenesis can improve anti-tumor immunity, which implies that it can improve immunotherapy as well.
Vasculogenic mimicry. Plasticity of tumor cells can de-dedifferentiate them into endothelial-like structures. We have demonstrated that this process is highly associated to aggressiveness in Ewing's sarcoma. In addition, we propose an important role of hypoxia in this process.
Tumor Hypoxia
Poor oxygenation (hypoxia) is a common feature of solid human tumors and is associated with increased malignancy, resistance to therapy and poor prognosis. Tumor cells actively sense and respond to hypoxia by initiating changes in gene expression that affect their phenotype. In order to understand the various biological responses to hypoxia it is necessary to both understand how hypoxia effects gene expression and to identify which genes are differentially expressed. Furthermore, tumor hypoxia can be exploited with bacteria based therapy and for tumor imaging purposes. We are focusing on:
The regulation of mRNA translation during hypoxia, and have shown that overall translation is rapidly and severely inhibited during hypoxic conditions. In addition to the effects that hypoxia exhibit upon overall mRNA translation, we are particularly interested in the consequences of regulating translation for differential gene expression, since different mRNA species are affected to a different extent. We are identifying mRNAs that remain efficiently translated during hypoxia, in spite of the overall repression of translation, and study the molecular mechanisms responsible for ensuring the efficient translation of these mRNA species during hypoxia. Finally, we are identifying novel hypoxia-induced proteins through a proteomic approach. In particular we are attempting to define molecular determinants of hypoxia tolerance and tumor growth to pursue novel molecular markers and targets for clinical use.
Imaging aspects. The ability for non-invasive imaging of hypoxia or hypoxia associated molecular markers is examined. This will ultimately allow earlier detection and phenotyping of tumors and provide an opportunity to tailor therapies to individual patients. We will focus on two approaches. The first is based upon optical imaging in small animals, taking advantage of genetically modified tumors and bacteria used for gene therapy purposes. In a second approach we will take advantage of the first CPT-PET stimulator of the world available in Maastricht to extend the basic research into more clinically relevant questions concerning quantification of hypoxia treatment.
Bacteria based gene therapy. We are investigating alternative gene delivery systems based on the use of non-pathogenic bacteria. The presence of hypoxic and/or necrotic areas provides a haven for a number of anaerobic bacteria and over the past 60 years, several strains of anaerobic bacteria have been shown to localize within and cause cell lysis of experimental animal tumors. One of the most important strains in that context is Clostridium. Other bacteria have also been implicated in experimental anti-cancer settings. Of these, attenuated Salmonella strains capable of both selective amplification within tumors and expression of effector genes encoding therapeutic proteins are probably the most promising.
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