A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis

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.

Platelet-derived nanomedicine targets cancer

“…VEGF was one of the most upregulated genes in CNS leukemic cells. Similar findings were recently reported in Blood by Kato et al, 4 who also confirmed the increased expression of VEGF in ALL cells isolated from the CSF of patients with CNS leukemia. These observations complement a previous report of high levels of VEGF in the CSF from patients with CNS leukemia.…”

“…6 VEGF may also promote the survival of cancer and leukemic cells. ) and the apoptosis observed by Kato et al in CNS leukemic cells after treatment with bevacizumab, 4 it is likely that VEGF supports the survival of ALL cells in the hypoxic growth inhibitory environment in the subarachnoid compartment. Indeed, this may be its more important function in CNS leukemia.…”

“…The findings contained in this study have repercussions in the understanding of cancer pathogenesis and its relationship to platelets. While there is strong evidence that platelets contribute to the promotion of cancer, [2][3][4][5] their microparticles appear to counteract platelets by downregulating tumor cell genes and inhibiting tumor growth. The role of platelet microparticles, however, requires internalization by tumor cells and thus strictly implies that microparticles accumulate in the tumor environment.…”

“…2 Platelet transforming growth factor b, for instance, enhances cancer cell proliferation and plays an important part in metastasis. 3,4 Moreover, platelets in circulation shield tumors from their elimination by the immune system and contribute to arrest in endothelium, a process necessary for formation of secondary lesions. 2,5 On activation, platelets shed submicron extracellular vesicles from the plasma membrane, known as microparticles (also called microvesicles).…”

Platelet “first responders” in wound response, cancer, and metastasis

“…Platelet C-type LECtin-like receptor (CLEC-2/Aggrus) is another platelet receptor that initiates platelet activation through molecular multimerization [66,41,62,67,68]. CLEC-2 binds to mucin glycoprotein podoplanin [69–71].…”