C‐type lectin‐like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor‐bearing mice

Abstract

Background C-type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism.

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism

“…demonstrated that CLEC‐2‐deficiency in mice was protective against thrombosis and hematogenous metastasis. Thrombus formation in tumor vessels was significantly inhibited in CLEC‐2‐depleted mice bearing podoplanin‐expressing B16F10 melanoma cells . Payne et al .…”

“…Podoplanin is a sialomucin‐like glycoprotein and has the ability to induce platelet aggregation via interacting with the C‐type lectin‐like receptor (CLEC)‐2 on platelets . Recent experimental studies using mouse models confirmed the important role of podoplanin in the pathophysiology of VTE . Based on these observations, podoplanin‐induced platelet aggregation might be a major driver of brain tumor‐associated VTE.…”

Platelet-Derived TGF-β Induces Tissue Factor Expression via the Smad3 Pathway in Osteosarcoma Cells

“…MMP2, FcgRIIa, and ADP are involved in the direct activation of platelets by tumor cells . The mechanism of platelet CLEC‐2 activation by tumor podoplanin was recently analyzed, and CLEC‐2 deficiency was found to inhibit tumor metastasis . Similarly, in osteosarcoma, mouse platelets are activated by osteosarcoma cells, and PDGF from activated platelets promotes tumor growth .…”

Cancer‐associated prothrombotic pathways: leucocytosis, but not thrombocytosis, correlates with venous thromboembolism in women with ovarian cancer

“…1,2 Some pathways are distinctive of a particular cancer. For example, the expression of circulating microparticle-associated tissue factor increases the thrombotic risk predominantly in pancreatic cancer 3,4 ; or the expression of podoplanin, a ligand for C-type lectin receptor type 2 on platelets, in glioblastoma multiforme, 5 or the cell surface expression of long-chain polyphosphates on tumour-derived prosteasomes in prostate cancer, which activate coagulation in a factor XII-dependent manner. 6 Tumours may also indirectly promote thrombosis through the induction of thrombocytosis or leucocytosis, both of which are part of some published thrombotic risk score.…”