Imaging tumor hallmarks: hypoxia signaling and angiogenesis

Research Group: Prof. Dr. Markus Rudin


A key player regulating the cellular response to low tissue oxygen concentration is hypoxia inducible factor (HIF), a heterodimeric transcription factor consisting of a a- and a b-subunit. The a-subunits (HIF1a or HIF2a) are subject to oxygen dependent regulation: under normal oxygen conditions, HIFa is hydroxylated by the enzyme prolyl hydroxylase (PHD), an a-ketoglutarate (aKG) dependent dioxygenase, which uses molecular oxygen as a substrate. Hydroxylated HIFa undergoes proteasomal degradation following ubiquitination by the E3 ubiquitin ligase complex. During hypoxic conditions, PHD activity is decreased and HIFa correspondingly stabilized. HIFa then dimerizes with the b subunit, the HIF complex migrates to the nucleus and initiates transcription of more than a hundred genes upon binding to a hypoxia response element (HRE) consensus sequence on DNA. Prominent genes activated through the HIF pathways are associated with anaerobic glycolysis and angiogenesis, two critical factors promoting tumorigenesis.
Koloncarcinomazellen, Luciferase-Biolumineszenz

In this subproject, we will further develop imaging assays for measuring tissue hypoxia, HIF1a stabilization, HIF activity as well as angiogenesis in established tumor cells; in particular we will focus on orthotopic mammary tumors. This will allow us to assess the influence of the tumor-microenvironment on the vessel formation process. The remodeling of the extracellular matrix (ECM) is a critical determinant in this process. ECM degradation by proteases is essential for vascular growth, infiltration of tumor cells in to the adjacent tissue as well as the infiltration of cells of the immune cells. A second objective is to correlate hypoxia signaling with the non-invasive readouts of protease activity using protease specific fluorescent probes and angiogenesis using MRI readouts. Moreover, we would like to link between tumor hypoxia and the migratory behavior of tumor cells. In the second phase of the subproject, we plan to transfer these tools to head and neck cancer (HNC) cell lines and establish a subcutaneous tumor model in mice.

Significance
These models will be used to assess tumor hypoxia, hypoxia signaling as well as the consequences on angiogenesis, ECM remodeling and cell migration.