Abstract
The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets. In vitro and in vivo analyses revealed that podoplanin-mediated EMT resulted in increased invasiveness and extravasation of tumour cells. Treatment of mice with a TGF-β-neutralizing antibody statistically suppressed podoplanin-mediated distant metastasis in vivo, suggesting that podoplanin promoted haematogenous metastasis in part by releasing TGF-β from platelets that was essential for EMT of tumour cells. Therefore, our findings suggested that blocking the TGF-β signalling pathway might be a promising strategy for suppressing podoplanin-mediated haematogenous metastasis in vivo.
Highlights
The tumour microenvironment is critical for various characteristics of tumour malignancies
We found that the morphology of UM-UC-5 and H226 cells, which appeared as clustered colonies in culture dishes, changed to a dispersed configuration after exposure to supernatants of tumour cell-platelet reactants (Fig. 1d)
Changes observed in these epithelial-mesenchymal transition (EMT) markers in H226 cells exposed to the supernatants of tumour cell-platelet reactants were subtler than those observed in UM-UC-5 cells
Summary
The tumour microenvironment is critical for various characteristics of tumour malignancies. Several factors secreted from the alpha-granules of activated platelets including transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) enhance the motility of both tumour and vascular endothelial cells as well as the growth of tumour cells at secondary sites[10,11,12] These factors released from platelets might contribute to tumour malignancy and are potential targets for the prevention of metastasis. Given that the forced expression of wild-type but not mutant podoplanin lacking platelet-aggregating ability led to the acquisition of metastatic ability of non-metastatic Chinese hamster ovary (CHO) cells and enhanced the rate of tumour arrest in the lung, the platelet aggregation-inducing activity of podoplanin was suggested to be directly linked to its ability to facilitate metastasis formation[32]. We here investigated the role of podoplanin-mediated platelet aggregation in tumour invasiveness and extravasation
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