Podoplanin enhances lung cancer cell growth in vivo by inducing platelet aggregation

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.

Functional significance of the platelet immune receptors GPVI and CLEC-2

“…In mouse models, podoplanin promotes tumor growth, epithelial-mesenchymal transition (EMT), invasion, and metastasis (50,139,142). Many of these actions are mediated through platelet CLEC-2, including tumor progression, metastasis, and cancer-induced thrombosis (143)(144)(145)(146). The podoplanin/CLEC-2 axis promotes an immunosuppressed microenvironment, facilitating spread and growth of the cancer (131 and thrombo-inflammation identify both receptors as targets for development of a new class of antithrombotic drugs.…”

Podoplanin: An emerging cancer biomarker and therapeutic target

“…In addition to TGFβ signaling, some lung squamous cell carcinoma cells (eg PC‐10) also implicate EGFR activation by platelet‐derived growth factors induced by PDPN binding. This effect is suppressed by the administration of PDPN antibodies or the EGFR kinase blocker ertlotinib along with suppression of PC‐10 tumor growth in vitro and in xenograft mouse models …”

A safety study of newly generated anti-podoplanin-neutralizing antibody in cynomolgus monkey (Macaca fascicularis)

“…Using a mouse xenograft model, Chang et al [ 17 ] synthesized 2CP, a small compound that specifically binds to CLEC-2 and inhibits podoplanin-induced platelet aggregation in tumor cells without affecting normal hemostasis. Moreover, soluble factors such as PDGF or TGF-β secreted from podoplanin-activated platelets have been shown to induce the growth of some tumors [ 18 , 19 ]. The blocking podoplanin–CLEC-2 interaction by neutralizing antibody contributes to suppress the tumor cell growth [ 11 ].…”