The platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) families of receptor tyrosine kinases (RTKs) are evolutionarily related cell-surface receptors which regulate physiological and pathological angiogenesis. Neuropilins (NRPs) are transmembrane glycoproteins which function as co-receptors for VEGFR to mediate vascular development and angiogenesis. RTK signalling has a long established role in tumour-cell biology and downstream cellular effects of RTK activation, such as, sustained cell proliferation and invasion are known hallmarks of cancer. NRPs are also up-regulated in tumour cell lines and clinical specimens, and a major focus of NRP research has been to understand the role of NRPs in cancer, which to date has largely been attributed to NRPs contribution to VEGFR activation. Emerging evidence for NRPs in regulating the activation of adhesion molecules, growth factors and RTKs (other than VEGFR) illustrate that NRP has a much broader role in cancer. In cell types including smooth muscle cells, stem cells and tumour cells, there is now evidence that NRP-1 regulates PDGFR activation and signalling. Identification of the molecules that regulate PDGFR signalling will advance the understanding of tumour cell biology and contribute to the development of targeted therapies.To date, few studies have evaluated the role of NRP-1/PDGFR signalling in cancer. The objective of this study was therefore, to elucidate the cellular mechanisms of NRP-1/PDGFR signalling, and to investigate how this cellular crosstalk modulates PDGFR-stimulated signalling, survival and migration of tumour cells. A subset of mesenchymal tumour cell lines that expressed NRP-1 and PDGFR-alpha and/or PDGFR-β and were identified to investigate NRP-1/PDGFR crosstalk. In these cell lines, NRP-1 could associate with PDGFR-alpha and PDGFR-β independent of PDGF growth factor stimulation. NRP-1 did not regulate PDGF-stimulated phosphorylation of PDGFR-alpha or PDGFR-β yet, in a subset of the cell lines, NRP-1 contributed to the activation of the MAPK-ERK and PI3K pathways. NRP-1 did not regulate PDGF-stimulated cell proliferation, yet NRP-1 knockdown attenuated PDGF-stimulated cell migration in certain cell lines. Together, this study has provided evidence of NRP-1/ PDGFR crosstalk, which affects the migratory potential of a subset of mesenchymal tumour cells. In these cell lines, NRP-1 knockdown does not inhibit the overall phosphorylation of PDGFR, yet does have subtle effects on specific downstream PDGFR pathways.
|Date of Award||31 Dec 2013|
- The University of Manchester
|Supervisor||Catherine Kielty (Supervisor)|