At the Crossroads of Cancer and Inflammation: Ras Rewires an HIF-driven IL-1 Autocrine Loop

Malignant tumors of the central nervous system are the leading cause of cancer death for people under 35 years of age. Glioblastoma multiforme (GBM), the most malignant brain tumor in adults is characterized histologically by pseudopalisading necrosis and abnormal vascular development (Fig. 1). These tumors show infiltration by inflammatory cells and the occurrence of hypoxia (lower than physiological O2 levels) in the pseudopalisading cells surrounding the micronecrotic areas. Microenvironmental hypoxia is not restricted to regions adjacent to the large central necrotic areas of gliomas; in fact, it is present in close proximity to the leading/actively growing edge of GBM, where the tumor is actively expanding radially [1]. The hypoxic cells are active participants in the tumor biology and are refractive to conventional therapies, contributing thus to poor patient survival. Currently, the life expectancy for GBM patients is 1–2 years, stressing the need to better understand the signaling mechanisms that underlie their aggressive growth so that new therapies can be designed. Adaptive changes by which cells respond to hypoxia are mediated largely by the transcription factor hypoxia-inducible factor 1 (HIF-1), which transactivates genes whose products play a role in all hallmarks of cancer and is a major target for anticancer therapy [2]. This is evidenced in GBM by the strong expression of HIF-1α on pseudopalisading cells, which activates the mRNA expression for vascular endothelial growth factor (VEGF), a major inducer of tumor angiogenesis (Fig. 1). HIF-1 is a heterodimeric transcription factor composed of the constitutively expressed HIF-1β and the O2-regulated HIF-1α subunits. The protein levels and activation of the α subunit are tightly controlled by two independent but co-regulated post-translational mechanisms [2]. A family of prolylhydroxylases (PHDs) hydroxylates HIF-1α in the presence of O2. This modification allows binding of the tumor suppressor Von Hippel–Lindau, the substrate recognition unit of an E3 ubiquitin ligase complex, polyubiquitylation, and degradation in the proteasome [3]. Factor-inhibiting HIF (FIH), an asparagine hydroxylase, controls transcriptional activity of HIF-1α by modifying a critical asparagine in the C-terminal activation domain. This modification is also O2-dependent and prevents interaction with the transcriptional co-activators p300/CBP. In the absence of O2, both PHDs and FIH are inactive; HIF accumulates in transcriptionally active form and transactivates hypoxia-inducible genes via binding to the hypoxiaresponsive elements (HREs) in their regulatory regions (Fig. 2). Although the availability of themolecular O2 is the primary physiological regulator of HIF-1 through PHDs and FIH, there is a number of other stimuli (cellular oncogenes, loss of tumor suppressor phosphatase and tensin homolog (PTEN), growth factors, cytokines, vascular hormones, viral proteins) that can lead to induction and activation of HIF under normoxic conditions [4]. In this case, enhanced translation of HIF-1α, mediated via activation of cellular signaling pathways (Ras and PI3-Kinase) overcomes the limiting hydroxS. Kaluz : E. G. Van Meir (*) Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA e-mail: evanmei@emory.edu