Gastrointestinal stromal tumours, glioblastomas and dermatofirbosarcoma protuberans are all cancers that, to varying extents, share a common genetic aberration: increased expression or mutations in platelet-derived growth factor (PDGF) or its receptor (PDGFR). Although cancers fitting this description are rare, studies have shown solid tumors in general to be stimulated by the PDGF activity of surrounding stromal cells. Taken together, this makes PDGF signaling a target of interest in cancer therapeutics. In a recent review in Cell Communication & Signaling by Carl-Henrik Heldin, Chairman of the Board of the Nobel Foundation, from the Ludwig Institute for Cancer Research, Sweden, the role of the PDGF pathway in cancer and how it could be targeted is explored. Here Heldin explains more about the importance of PDGF signaling in cancer and its potential application in cancer treatment.
What led to your interest in PDGF signaling in cancer?
When I started as a graduate student during the 1970s, very little was known about mechanisms that control cell growth or about mechanisms that convert a normal cell to a malignant cell. My supervisors Bengt Westermark and Åke Wasteson, thought that we may learn about mechanisms of tumorigenesis by elucidating mechanisms whereby growth factors control cell growth. They had observed that platelets contain high growth promoting activity for certain cell types, and my task was to purify the responsible factor (which we now call PDGF).
What are PDGF isoforms and their normal function?
There are four PDGF polypeptide chains (A, B, C and D) that assemble into homodimers and into the AB heterodimer. They act via binding to two structurally related tyrosine kinase receptors (alpha and beta).
How did it first become apparent that the PDGF signaling pathway might be a target for tumor treatment?
The first solid evidence for the transforming activity of PDGF came from the discovery by us and others that the PDGF B-chains are homologous to the transforming protein p28sis of simian sarcoma virus, which had been found to give brain tumors in marmoset monkeys. In fact, the sis protein transforms by causing autocrine stimulation by a PDGF-like factor.
How does targeting the PDGF pathway inhibit tumor growth, and what advantages could this have over existing treatments?
There are some rather rare tumor types in which the PDGF or PDGF receptor genes are mutated. Patients with these tumors often benefit from treatment with PDGF signaling antagonists. In addition, many normal cells of the tumor stroma respond to PDGF, and targeting these cells with PDGF antagonists may also give a treatment benefit.
Are certain types of tumors likely to be more responsive than others? If so, why?
Yes, the tumors that are driven by mutations in PDGF or PDGF receptor genes are likely to be more responsive than other tumors. In addition, given the trophic relationship between tumor cells and stromal cells in solid tumors, patients with such tumors may also benefit from treatment with PDGF antagonists, although this remains to be studied further.
How is additionally targeting tumor stromal cells more beneficial than targeting tumor cells alone?
It has turned out that treatment of tumors with specific signal transduction inhibitors after some time gives rise to resistance mechanisms, i.e. the tumor cells learn how to avoid the effect of the inhibitor. It has therefore become apparent that efficient treatment of tumors requires combinations of drugs. Given the trophic relationship between tumor cells and stromal cells, it is possible that simultaneous treatment with inhibitors targeting the tumor cells and inhibitors targeting the stromal cells may enhance the treatment effect.
What impact do you think PDGF targeted tumor treatment might have on tumor-related mortality in the next 20 years?
This is very difficult to predict. The tumor types that are driven by mutations in PDGF and PDGF receptor genes are rather rare so the overall impact of PDGF signaling inhibitors may not be so high in terms of the number of tumor patients saved. If combination treatment of patients with solid tumors with PDGF antagonists in order to target the stromal compartment will turn out to be beneficial, the importance of PDGF inhibitors in tumor treatment may be higher, but this remains to be seen.