Recent research in oncology has shed new light on the critical role of microvasculature regulation of  tumor regression. Destruction of endothelial cells forming blood vessels causes development of anaerobic zones and the subsequent death of cells therein. Suppression of tumor blood vessel development by drugs or antibodies that inhibit angiogenic factors induces tumor regression. The aforementioned therapies, however, targeted the angiogenic endothelium and completely disregarded quiescent endothelial cells. In order to enhance therapeutic efficacy, anti-vascular treatments should be directed against all tumor endothelial cells.
  While the ultimate goal of anticancer treatments is reduction and suppression of tumors, the results are often limited by their own toxicity to neighboring normal tissues and by tumor resistance. Our previous studies showed that endothelial cell apoptosis is directly involved in the loss of tissue integrity and regression of tumors after exposure to ionizing radiation, identifying the endothelial compartment located in the tumor microenvironment as a major target of ionizing radiation. Yet these findings go against a strong dogma in radiobiology: clonogens and stem cells are the primary targets of radiation, and tissue sensitivity is based on the most resistant clonogens. In this new project developed at  INSERM Unit UMR892, we propose to study the endothelial compartment, a new cellular target in oncotherapy, and its specific involvement in tissue and tumor radiation response. Our final goal is to better discriminate tumor endothelium response, which leads to tumor regression, and radiotoxicity of normal endothelium, which limits the impact of external and molecular targeted radiotherapies.

  Our team works in four different  subject areas:

1. Understanding of radiation-induced molecular pathways in endothelial cells initiated by the generation of the proapoptotic sphingolipid ceramide and inhibited by sphingosine 1 phosphate. Strong emphasis will be to determine the implication of membrane remodeling in ceramide-enriched domains and the role of the small GTPases Rho, key regulators of the actin cytoskeleton, in the endothelial response to irradiation.
2. Study of the bystander effects induced by irradiated endothelial cells on clonogenic cells from normal tissue and tumor are especially studied. Identification of molecular factors secreted by irradiated endothelial cells which induce death of neighboring tumor cells will help to better define the physiological impact of endothelial cells on normal tissue toxicity and tumor regression.
3. Targeting the tumor endothelium or modulating its radiosensitivity also represents  a major aspect of our project. Because of our expertise on sphingolipids, gangliosides overexpressed more specifically by tumor endothelium will be studied, and  monoclonal antibodies directed against these glycolipids antigens will be generated for the development of monoclonal antibodies-based immunotherapy.
4. Development of new preclinical and clinical approaches to external and molecular targeted radiotherapy in strong partnership with the CLCC-Nantes and the University Hospital (CHU) at Nantes and also with other projects of axes 2 and 3 of the INSERM UMR892 -Oncology Research Center.