Upsala Journal of Medical Sciences. 2012; 117: 99–112 REVIEW ARTICLE PDGF and PDGF receptors in glioma INGA NAZARENKO1, SANNA-MARIA HEDE1,3, XIAOBING HE 1 , ANNA HEDRÉN1, JAMES THOMPSON1,2, MIKAEL S. LINDSTRÖM1 & MONICA NISTÉR1,2 1Department of Oncology-Pathology, Karolinska Institutet, CCK R8:04, Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden, 2Karolinska Healthcare Research Biobank (KHRBB), Clinical Pathology/Cytology, Karolinska University Hospital, SE-17176 Stockholm, Sweden, and 3(currently) Uppsala University, Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, SE-751 85 Uppsala, Sweden Abstract The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-a and -b. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-a autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-b. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this ﬁeld. Key words: Animal tumor model, brain tumor, cancer stem cell, glioma, neural stem cell, platelet-derived growth factor (PDGF), PDGF receptor Introduction Gliomas are the most common form of primary malignancies of the central nervous system (CNS) mainly affecting adults. These tumors have a histo- logical resemblance to different types of glial cells and are categorized into astrocytomas, oligodendroglio- mas, oligoastrocytomas, and ependymomas, based on the predominant cell type(s) in the respective tumor (1). Initial discovery and extensive studies of the epi- dermal growth factor (EGF) and transforming growth factor alpha (TGF-a), as well as the platelet- derived growth factor (PDGF) family, revealed their presence in glioblastoma cell cultures and tissues. These growth factors, by signaling via their cell sur- face tyrosine kinase receptors, EGFR and PDGFR-a and -b, were able not only to induce normal mitogenic and migratory responses, but when aberrantly activated they were also able to transform cells. Knowledge gained from in vitro experiments was transferred to in vivo systems, and several mouse models were created showing that gliomas can be induced by forced expression of PDGF-B in the brain. However, treatment with single tyrosine kinase inhibitors (TKIs) given to glioma patients has gener- ally not been successful. Ever since the initial discoveries, investigations on the molecular mechanisms and signaling pathways involved in glioma have provided a more detailed insight into the key events behind brain tumor initi- ation, maintenance, and progression and have resulted in signiﬁcantly improved cancer drug discov- eries. However, the prognosis for patients with aggres- sive brain tumors is still very poor. One intriguing hypothesis is that glioblastoma resistance to therapy and its rapid recurrence is due to the presence of a subpopulation of tumor cells displaying stem cell Correspondence: Monica Nistér MD PhD, Department of Oncology-Pathology, Karolinska Institutet, CCK R8:04, Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden. E-mail: Monica.Nister@ki.se (Received 24 January 2012; accepted 6 February 2012) ISSN 0300-9734 print/ISSN 2000-1967 online 2012 Informa Healthcare DOI: 10.3109/03009734.2012.665097