BBB seminar: Lorenz Poellinger
Regulation of tumor cell differentiation status by hypoxia
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden
As they expand, solid tumors can rapidly outgrow the carrying capacity of the local vasculature. This phenomenon is typically aggravated by the chaotic vascular structures that form during malignant growth. Thus, tumors are often characterized by areas of lowered oxygen content, or hypoxia, carrying a number of therapeutic ramifications. First, hypoxic regions of tumors are much more resistant to radiation, an important problem in radiotherapy. Second, hypoxia induces release of angiogenic factors such as vascular endothelial growth factor (VEGF), and thus contributes to tumor vascularization. Finally, chronic hypoxia within tumors can select for cells resistant to hypoxia-induced apoptosis; these cells often have mutations in the p53 gene. Therefore, hypoxia can indirectly contribute to the process of malignant progression at the genetic level. Many of the response processes to hypoxia are regulated in whole or in part by a heterodimeric transcription factor complex, known as the Hypoxia-inducible Factor-1, or HIF-1. Our laboratory has investigated the mechanism of signal transduction and gene regulation by HIFs. Recently we have investigated in neuroblastoma tumor models the molecular mechanism by which hypoxia and the HIF system, in addition to inducing pro-angiogenic responses, induce de-differentiation of neuroblastoma cells from a highly differentiated phenotype expressing high differentiation markers of the sympathetic nervous system. Oxygen availability is thus an important parameter in regulation of the cell differentiation status. The lecture will address important mechanisms relevant for maintenance of an immature (stem cell-like) cell phenotype via regulatory cooperation between the HIF and Notch transcription factors. In addition, hypoxia is an important inducing stimulus of epithelial-mesenchymal transition, linking hypoxia to tumor metastasis, and the critical role of HIF in this process will be discussed.
Host: Marit Bakke, Department of Biomedicine