1. ¹Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
2. ²Departments of Surgery (Neurosurgery), Neurology and Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence: Dr L Uhrbom, Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden. E-mail: lene.uhrbom@genpat.uu.se

³Current address: Ludwig Institute for Cancer Research, Karolinska Institutet, Box 240, SE-171 77 Stockholm, Sweden.

Received 29 June 2006; Revised 6 February 2007; Accepted 2 March 2007; Published online 16 April 2007.

Abstract

In a subset of gliomas, the platelet-derived growth factor (PDGF) signaling pathway is perturbed. This is usually an early event occurring in low-grade tumors. In high-grade gliomas, the subsequent loss of the INK4a-ARF locus is one of the most common mutations. Here, we dissected the separate roles of Ink4a and Arf in PDGFB-induced oligodendroglioma development in mice. We found that there were differential functions of the two tumor suppressor genes. In tumors induced from astrocytes, both Ink4a-loss and Arf-loss caused a significantly increased incidence compared to wild-type mice. In tumors induced from glial progenitor cells there was a slight increase in tumor incidence in Ink4a-/- mice and Ink4a-Arf-/- mice compared to wild-type mice. In both progenitor cells and astrocytes, Arf-loss caused a pronounced increase in tumor malignancy compared to Ink4a-loss. Hence, Ink4a-loss contributed to tumor initiation from astrocytes and Arf-loss caused tumor progression from both glial progenitor cells and astrocytes. Results from in vitro studies on primary brain cell cultures suggested that the PDGFB-induced activation of the mitogen-activated protein kinase pathway via extracellular signal-regulated kinase was involved in the initiation of low-grade oligodendrogliomas and that the additional loss of Arf may contribute to tumor progression through increased levels of cyclin D1 and a phosphoinositide 3-kinase-dependent activation of p70 ribosomal S6 kinase causing a strong proliferative response of tumor cells.