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Home > Neurosurgery Research > BTRC > Bergers Laboratory  
Bergers Laboratory
Principal Investigator: Gabriele Bergers PhD
Current Research Projects
Hypoxia/HIF-dependent mechanisms of blood vessel formation in tumors
Principal Investigator: Gabriele Bergers PhD
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor of adults and among the most lethal of all cancers partly due to their fast and diffusive growth pattern. Characterized by hypoxic and necrotic tumor cores, GBMs are also one of the most angiogenic tumors. The hypoxic response is triggered in large part by the hypoxia-inducible factor-1 (HIF-1), a dimeric transcription factor that, among many other targets, induces expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF). Thus, HIF-1 and VEGF are highly expressed in GBMs and their levels correlate with poor prognosis. The Bergers lab has developed various orthotopic models of genetically engineered mouse GBMs closely mimicking the human disease to study brain tumor growth and neovascularization and invasion in vivo. These mouse tumor models allow genetic and pharmacological manipulations to reveal molecules and mechanistic pathways that drive neovascularization of tumor vessels and tumor cell invasion. We found that GBM do not only initiate blood vessel formation by activating preexisting endothelial cells within the tumors but also by recruiting a heterogeneous population of bone marrow-derived cells to support new blood vessel growth. Among these BMD cells are vascular progenitor cells, which include endothelial progenitor cells (EPCs) and pericyte progenitor cells (PPCs). A further group of BMD cells that are not physically part of the vasculature, but rather function to support vessel formation by secreting pro-angiogenic cytokines and proteases, appear to be CD45+ monocytic accessory cells. We found that HIF-and VEGF-deficiency impairs the angiogenic response of GBMs partly by impairing recruitment of BMD cells to the tumor site. These results underscore the functional importance of BMDC in neovascularization of GBMs. Surprisingly, we found that tumors adapt when HIF- or VEGF-signaling is blocked because they induce an invasive evasion pathway in which GBM cells move preferentially along blood vessels deep into the brain parenchyma (perivascular invasion). The Bergers lab is interested in the nature and recruitment mechanisms of BMD cells and their specific roles in tumor blood vessel formation and tumor progression, and intends to reveal the mechanisms of evasive tumor adaption in response to impaired neovascularization.
Vascular progenitor cells in tumor neovascularization
Principal Investigator: Gabriele Bergers PhD
Blood vessels consist of endothelial cells that form the inner lining of the vessel wall and of pericytes that wrap around blood vessels. Having utilized RIP1-Tag2 transgenic mice as a prototypical mouse model of multistage carcinogenesis, wherein targeted expression of a dominant oncogene (the SV40 T-antigens) to endocrine pancreas elicits a synchronous and step-wise progression to invasive carcinomas, we identified vascular progenitor cells that are recruited from the bone marrow and differentiate into pericytes. Pericytes are instrumental in microvascular homeostasis and blood vessel formation. In tumors, although pericytes are less abundant and more loosely attached, we found that depletion of pericyte progenitors results in deficiency of mature pericytes in tumors. The absence of pericytes on blood vessels in turn increases endothelial cell apoptosis and vessel hyperdilation, providing evidence that tumor pericytes are implicated in vessel maintenance and endothelial cell survival. Based on their functional importance, pericytes present a complimentary target to endothelial cells in tumors. Therefore, combinatorial targeting of both cell types might have the potential to more efficiently diminish tumor vessels and halt subsequent tumor growth. In support of this hypothesis, we observed that combinations of receptor tyrosine kinase inhibitors that target endothelial cells and pericytes by blocking VEGF and PDGF signaling, respectively, more efficiently diminished tumor blood vessels and tumors than any of the inhibitors individually. We are currently expanding our studies to glioblastoma by using pharmacological and genetic approaches to interfere with VEGF and PDGF signaling.
Studying the origin and development of tumor stem cells in oligodendrogliomas
Principal Investigator: Gabriele Bergers PhD
Co-Principal Investigator: Claudia Petritsch PhD
Co-Investigator: William A. Weiss MD, PhD
The Tumor Stem Cell (TSC) hypothesis is based on the conceptual idea that normal adult stem cells undergo malignant transformation concomitant with aberrant differentiation and proliferation capacities, and thereby give rise to a heterogeneous tumor population. A key feature of stem cells is their ability to self-renew and to simultaneously generate more specialized cells by asymmetrically distributing specific protein/RNA complexes to the two daughter cells (asymmetric cell division aka ACD). Thereby, one daughter cell remains a stem cell and continues to divide asymmetrically while the other daughter becomes a progenitor or differentiated cell. In the brain, normal neural stem cells (NSC) are able to differentiate into astrocytes, oligodendrocytes and neurons. Tumor stem cells (TSC) in brain tumors have also extensive self-renewal capacities, but in contrast to NSC, form tumors in xenografts and do so much more efficiently than the "differentiated" tumor cell pool. While the existence of TSC has been documented for several tumor types it remains yet to be determined how they are generated and whether indeed TSC are derived from NSC. The Bergers lab intends to elucidate the underlying cell intrinsic and extrinsic mechanisms that turn normal neural stem cells into tumorigenic oligodendroglioma stem cells (TSC). We are investigating whether a defect in asymmetric cell division is the initiating critical step in the transition from NSC to TSC and how extrinsic signals derived from endothelial cells in the perivascular niche regulate tumor stem cells.
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