Abstract
Podoplanin/Aggrus, known as a platelet aggregation-inducing factor, is frequently overexpressed in lung squamous cell carcinomas (LSCC) and glioblastomas among other tumours, and its expression has been reported to be correlated with poor prognosis. However, the contribution of podoplanin to malignant progression has been elusive. Here we demonstrate that in podoplanin-positive LSCC cells, their growth was abrogated by podoplanin knockout in vivo but not in vitro. Conversely, ectopic expression of podoplanin promoted cell growth in vivo and facilitated intratumoral platelet activation. Consistently, LSCC cells evoked podoplanin-mediated platelet aggregation (PMPA), and the releasates from platelets during PMPA promoted the growth of LSCC cells in vitro. Phospho-receptor-tyrosine-kinase array analysis revealed that epidermal growth factor receptor (EGFR) phosphorylation of LSCC cells was responsible for the growth promotion induced by platelet releasates. Treatment with an antiplatelet agent or podoplanin-neutralizing antibody depressed the growth of an LSCC tumour xenograft via suppression of EGFR phosphorylation. These results suggested that podoplanin in LSCC enhanced cell growth by inducing PMPA in vivo and contributed to malignant progression.
Highlights
A platelet is anucleate blood cell derived from megakaryocytes in bone marrow and has a significant role in hemostasis, angiogenesis, vascular integrity, and wound healing[1]
It has been shown to be expressed in circulating tumour cells[21], in tumour-initiating cells[22] and on the leading edge of tumour cells[23, 24], and its high expression correlated with poor prognosis in patients with glioblastoma and lung squamous cell carcinoma (LSCC)[25, 26]
Activating mutations in epidermal growth factor (EGF) Receptor (EGFR) are almost not detected in LSCC patients, it has been reported that EGFR-TKI therapy was effective for some LSCC patients; EGFR-TKI, erlotinib, and gefitinib have been approved as therapeutic agents for LSCC patients[33, 34]
Summary
A platelet is anucleate blood cell derived from megakaryocytes in bone marrow and has a significant role in hemostasis, angiogenesis, vascular integrity, and wound healing[1]. It has been shown to be expressed in circulating tumour cells[21], in tumour-initiating cells[22] and on the leading edge of tumour cells[23, 24], and its high expression correlated with poor prognosis in patients with glioblastoma and lung squamous cell carcinoma (LSCC)[25, 26] It is involved in tumour progression[27, 28]; a detailed mechanism explaining its role in tumour progression has not been elucidated. Administration of antiplatelet agent or podoplanin-neutralizing antibody suppressed the growth of LSCC tumour xenografts by inhibiting EGFR phosphorylation in vivo These results revealed for the first time a novel mechanism that podoplanin in LSCC contributed to tumour progression in vivo
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