Mini reviewPlatelet-derived growth factor (PDGF) and glial tumorigenesis
Introduction
Platelet-derived growth factor (PDGF) was first identified as the serum component responsible for the proliferation of arterial smooth muscle cells [1]. It has now been shown to be expressed in a wide range of tissues and be involved in a variety of functions [2]. The link between PDGF and tumor formation was demonstrated early on when the transforming gene in the Simian Sarcoma Virus, sis, was found to encode PDGFB [3]. Expression of PDGF and its receptor was subsequently found in multiple tumor types including central nervous system (CNS) tumors, sarcomas, germ cell tumors, and gastrointestinal system carcinomas. In particular, the PDGF pathway is well established to be involved in gliomas, tumors of the glial support cells (astrocytes and oligodendrocytes) in the CNS. The role that PDGF plays in glial tumorigenesis can be understood from its signal transduction functions, regulation of normal development, expression in tumors, and effects in mouse modeling.
Section snippets
PDGF ligands and receptors
The PDGF family consists of four ligands, PDGFA-D and two receptors, PDGFRα and PDGFRβ. PDGFs are disulfide-linked covalent dimers that are secreted and bind PDGFRs. All PDGF ligands (A–D) form homodimers, but PDGFA and PDGFB can also form a heterodimer (AB). PDGFA and B are secreted as active ligands, while C and D ligands require cleavage of N-terminal CUB domains to become active. The in vivo proteases responsible for activating C and D ligands have not been definitively identified; however,
PDGF in development
The pattern of PDGF and PDGFR expression in the CNS exhibits important modes of regulation. PDGFA is found expressed in neurons starting on E15 and continues in adult stages while PDGFB is also expressed in neurons but in a more limited manner [20], [21]. There is also evidence that the PDGFB message may be regulated by splicing as two different splice forms, differing in their 5′ untranslated regions (UTRs), are identifiable in developing rat brain [22]. The PDGFA message is also known to have
PDGF in glial tumors
Glial tumors of the CNS include astrocytomas, oligodendrogliomas, and mixed glial tumors, e.g. oligoastrocytomas [31], [32], [33]. Astrocytomas, the most common primary adult CNS tumor—making up to 60% of cases, are composed of tumor cells with features characteristic of astrocytes, supportive cells in the brain that carry out multiple functions. These tumors are categorized into different grades from I to IV based on different histological criteria determined through the World Health
PDGF in mouse models of gliomagenesis
The role of PDGF in tumorigenesis has been validated in many mouse models. Two such models for gliomas have used viral delivery of the PDGF gene into the brains of newborn mice. Delivery of PDGFB by Moloney murine leukemia virus (MMLV) was sufficient to induce malignant tumors [47]. In situ analysis demonstrated co-expression of PDGF and PDGFRα, and thus, capacity for autocrine signaling. In newborn mice, overexpression of PDGFB targeted to neural progenitors induces the formation of
Conclusion
The PDGF signaling pathway is able to perform multiple functions in glial tumorigenesis. Its overexpression in glial tumor samples clearly indicates a tendency for this pathway to be activated in tumor progression. Signaling molecules that could be activated in response to PDGF signals have also been shown to contribute to glial tumor formation. However, the causal link between activation of the PDGF pathway and subsequent signaling components in vivo remains to be explored. Which of these
Acknowledgements
Work in the laboratory is supported by the Serrossi Foundation, Kirby Foundation, NIH grant UO1CA894314-1, and NIH grant RO1 CA099489 to ECH. AHS was supported by NIH MSTP grant GM07739.
References (57)
- et al.
Characterization of heparin and heparan sulfate domains binding to the long splice variant of platelet-derived growth factor a chain
J. Biol. Chem.
(1997) - et al.
Differences in substrate specificities of alpha and beta platelet-derived growth factor (PDGF) receptors. Correlation with their ability to mediate PDGF transforming functions
J. Biol. Chem.
(1993) - et al.
The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions
Mol. Cell
(2001) - et al.
Oncogenic ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes
Mol. Cell
(2003) - et al.
Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation
Cell
(2004) - et al.
Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal
Cell
(1993) - et al.
The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats
Neoplasia
(2005) - et al.
PDGF A-chain gene is expressed by mammalian neurons during development and in maturity
Cell
(1991) - et al.
PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model
Cell
(1991) - et al.
Oligodendrocyte population dynamics and the role of PDGF in vivo
Neuron
(1998)