Abstract
The platelet-derived growth factor (PDGF) signalling pathway has been reported to play an important role in human cancers by modulating autocrine and paracrine processes such as tumour growth, metastasis and angiogenesis. Several clinical trials document the benefits of targeting this pathway; however, in cervical cancer the role of PDGF signalling in still unclear. In this study, we used siRNA against PDGF beta (PDGFBB) to investigate the cellular and molecular mechanisms of PDGFBB signalling in Ca Ski and HeLa cervical cancer cells. Our results show that PDGFBB inhibition in Ca Ski cells led to rapid alterations of the transcriptional pattern of 579 genes, genes that are known to have antagonistic roles in regulating tumour progression. Concomitantly, with the lack of significant effects on cervical cancer cells proliferation, apoptosis, migration or invasion, these findings suggests that cervical cancer cells shift between compensatory signalling pathways to maintain their behaviour. The observed autocrine effects were limited to cervical cancer cells ability to adhere to an endothelial cell (EC) monolayer. However, by inhibiting PDGFBB on cervical cells, we achieved reduced proliferation of ECs in co-culture settings and cellular aggregation in conditioned media. Because of lack of PDGF receptor expression on ECs, we believe that these effects are a result of indirect PDGFBB paracrine signalling mechanisms. Our results shed some light into the understanding of PDGFBB signalling mechanism in cervical cancer cells, which could be further exploited for the development of synergistic anti-tumour and anti-angiogenic therapeutic strategies.
Highlights
platelet-derived growth factor (PDGF) family consists of four structurally related peptides that link through disulfide bonds to form homo and heterodimers, among which, the PDGF beta (PDGFBB) is described to be the most pluripotent form as it interacts to all PDGF receptors (PDGFRs)
When treated with pazopanib, a small molecule drug that targets VEGF, PDGF and c-Kit pathways, an improved progression-free survival was achieved [7]. These findings suggest that when PDGF signalling is turned off, alternative growth pathways may become activated as a resistance mechanism [10]; further in-depth mechanistic studies are required to understand how PDGFBB regulates the tumour signalling cascades in the development and progression of cancer
Using small interfering RNAs, a classical investigative method for functional genomics studies, we explored the molecular mechanisms and functions of PDGFBB signalling in the two main types of cervical cancer: squamous cells carcinoma represented by Ca Ski cell line and adenocarcinoma represented by HeLa cell line
Summary
Cervical cancer is the second cause of mortality in women, and one of the most aggressive gynaecological diseases [1], this aggressiveness being mainly caused by the favourable environment for rapidly. Processes such as autocrine stimulation of tumour cell growth have been showed to be activated by PDGF/PDGF receptors (PDGFRs) signalling [4]. When treated with pazopanib, a small molecule drug that targets VEGF, PDGF and c-Kit pathways, an improved progression-free survival was achieved [7]. These findings suggest that when PDGF signalling is turned off, alternative growth pathways may become activated as a resistance mechanism [10]; further in-depth mechanistic studies are required to understand how PDGFBB regulates the tumour signalling cascades in the development and progression of cancer. By inhibiting PDGFBB expression in cervical cancer cells, we induced paracrine effects on endothelial cells (ECs) in co-culture and conditioned media systems, effects that seem to be mediated indirectly, through a shift in expression of several extracellular molecules
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