PDGF receptors as cancer drug targets.

Introduction Ever since the discovery 20 years ago that the transforming retroviral v-sis oncogene is derived from the platelet-derived growth factor (PDGF) B chain gene, PDGF signaling has been an interesting target for cancer treatment. In addition to its role in autocrine growth stimulation of tumor cells, PDGF has also been suggested to regulate tumor stroma fibroblasts and tumor angiogenesis (Figure 1). The occurrence of clinically useful PDGF receptor antagonists, like Glivec (STI571/Gleevec), now allows for an evaluation of the importance of PDGF receptor signaling in malignancies (Buchdunger et al, 1996; Capdeville et al., 2002). This review summarizes the biology of PDGF and discusses the role of PDGF receptor expression in different tumor compartments. Two sets of recent findings are particularly emphasized: the first set demonstrates clinical responses to PDGF antagonists in autocrine settings, and the second set presents beneficial effects of targeting PDGF receptors in the tumor stroma in animal models. Cell biological and physiological functions of PDGF Four PDGF polypeptide chains have been identified, which make up five dimeric PDGF isoforms: PDGF-AA,-AB,-BB,-CC, and-DD (Heldin et al., 2002). The isoforms exert their cellular effects through tyrosine kinase α-and β-receptors (Figure 1). All PDGF isoforms, except PDGF-DD, induce PDGF α-receptor dimerization, whereas PDGF-BB and-DD activate PDGF β-receptor dimers. In addition, all isoforms except PDGF-AA activate both receptor types in cells coexpressing the α-and β-receptors. Ligand-induced receptor dimerization causes receptor autophosphorylation, whereafter intracellular signaling pathways are activated by recruitment of SH2 domain-containing signaling molecules (e.g., c-Src, phospholipase C-γ, phos-phatidyl-inositol-3′-kinase and the Grb2/Sos complex) to specific phosphorylated tyrosine residues. Activation of these pathways ultimately induces various cellular responses, including cell proliferation, survival, and migration. Targeting of the genes for PDGF-A and B chains, and for the two receptors, has provided a detailed understanding of the physiological functions of PDGF during development (Betsholtz et al., 2001). Processes driven by the PDGF β-receptor include pericyte recruitment to capillaries, development of smooth muscle cells in vessels, and development of mesangial cells in the kidney. Activation of PDGF α-receptors by PDGF-AA is required for formation of alveolar smooth muscle cells, hair follicle development , proper villus formation in the gut, and oligodendrocyte development. In the adult, PDGF receptor signaling contributes to wound healing through stimulation of, e.g., fibroblasts, smooth muscle cells, and different inflammatory cells. PDGF β-receptors also regulate the interstitial fluid pressure (IFP) and thus potentially control transport from the vasculature into the extracellular compartment …