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Figure 1. Roles of PDGFs/PDGF receptors in tumor biology. Five different PDGFR isoforms interact in a specific manner with three different receptor dimers. PDGFR signaling affects tumor growth through tumor type specific effects on fibroblasts, vascular cells and malignant cells. EMT: Epithelial-to-mesenchymal transition; PDGFR: PDGF receptor.
(Figure omitted. See article PDF.)
PDGF ligands (PDGF-AA, -AB, -BB, -CC and -DD) and their cognate PDGFα- and β-receptors are now well-recognized regulators of tumor biology through their effects on malignant cells, and on other cells of the tumor microenvironment (Figure 1). Clinical relevance has been validated through studies leading to approval of drugs with PDGFR-inhibitory activity [1].
The focus of this review is the potential prognostic relevance of cell-type-specific PDGFR expression. Discussion of these studies is preceded by an overview of the roles of PDGFs and PDGFRs in tumor biology. The review also identifies some emerging studies discussing the potential of PDGFs/PDGFRs as markers for predicting response to treatment. Complementary in-depth discussions of other aspects of the molecular oncology of this growth factor system, and detailed information about PDGFR inhibitors, are presented in other recent reviews [1-3].
PDGFs & PDGFRs in tumor biology
PDGFRs are important regulatory proteins for mesenchymal cells, such as fibroblasts, pericytes, mesangial cells and smooth muscle cells. As such they are also emerging as key regulators of mesenchymal cells of the tumor microenvironment of many common malignancies, such as cancer of the breast, colon and prostate.
In other types of malignancies PDGFR-signaling appears to be directly involved in the growth of the malignant cells as suggested by mutational activation of PDGFs or PDGFRs, or through upregulation of ligand or receptor expression. Examples that are discussed below include glioblastoma multiforme (GBM) [4,5], gastrointestinal stromal tumors (GISTs) [6,7] and dermatofibrosarcoma protuberans (DFSP) [8,9]. Upregulation or overexpression of PDGFs or PDGFRs, of less well-defined functional significance, has also been reported in malignant cells of other tumor types [10,11].
It is predicated that continued exploration of the prognostic, response-predictive and therapeutic targeting potential of PDGFs/PDGFRs will benefit from careful consideration of the cell-type-specific roles of PDGFR signaling in different tumors. The following discussion of PDGFs/PDGFRs in tumor biology is therefore deliberately organized in a manner that separately considers the distinct roles of PDGFR signaling in different cell...