Tumor growth and hypoxia: it's all about location, location and location

Abstract

In response to hypoxia during tumor growth, a number of genetic changes are induced that allow the cancer cells to survive. These changes are orchestrated by the Hypoxia Inducible Factors (HIFs), respectively HIF-1alpha, HIF-2alpha and HIF-3alpha. HIF-1alpha is the main regulator of this response and can initiate the switch to glycolysis, angiogenesis and invasion. As a consequence, for most solid tumors including the Glioblastoma Multiforme (GBM), a high expression of HIF-1alpha and its target genes such as vascular endothelial growth factor (VEGF) is correlated with a worse prognosis. In order to establish the role of these factors in the formation of GBM, astrocytes lacking HIF-1alpha or VEGF, were implanted in the flank and brain of immunocompromised mice. When grown in the flank, loss of HIF-1alpha reduced tumor growth. In contrast, tumor formation by these cells was not reduced when grown in the brain. In both locations, loss of HIF-1alpha impaired angiogenesis. This was not a disadventage when grown in the brain; in this highly vascular organ the HIF-1alpha null cells grew around the existing blood vessels and thus survived. This was not possible in the relatively vessel poor area of the flank, resulting therefore in a reduced tumor growth in this location. An increased expression of the HIFs and their target genes is also detected in tumors formed as a result of loss of the negative HIF regulator, the Von Hippel-Lindau (VHL) tumor suppressor gene. In order to determine how these factors contribute to tumor formation mediated by loss of VHL, astrocytes lacking VHL alone, or in combination with either HIF-1alpha or VEGF, were grown in the flank and brain of mice. Tumor growth as a result of loss of VHL was independent of HIF-1alpha. Loss of VEGF impaired VHL mediated tumor growth only in the flank and not in the brain, indicating that VEGF is not an essential growth factor in cancer associated with VHL disease. HIF-1alpha is required for the switch to glycolysis, and cells grown under hypoxia are sensitized to inhibitors of this pathway, such as 2-deoxy-D-glucose (2DG). To test whether cells that show an increased expression of HIF-1alpha are also sensitized to 2DG, VHL null astrocytes were exposed to 2DG both during cell culture and when grown as tumors in mice. In cell culture, astrocytes lacking VHL showed an increased growth inhibition when exposed to 2DG, but this effect was not recapitulated when the same cells were grown in the flank of mice. Targeting the glycolytic or hypoxic pathway seems an attractive method to reduce tumor growth. As described in this thesis however, depending on the organ in which the cells are grown, unexpected mechanisms can be activated which can reduce the potency of such inhibitors.