Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma.
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.
Tchougounova
E
E
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Kastemar
M
M
Bråsäter
D
D
Holland
E C
EC
Westermark
B
B
Uhrbom
L
L
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D046509:Tissue Culture Techniques
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020574:Proto-Oncogene Proteins c-sis