The fibrinolysis inhibitor α₂-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer

Abstract

Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin’s role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α₂-antiplasmin with VEGF-D in a mouse tumour model. We show that α₂-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previous clinicopathological observations correlating fibrinolytic components with cancer metastasis.

Keywords:

• Cancer
• lymphatic remodelling
• metastasis
• plasmin
• protease
• VEGF-D

Acknowledgements

This work was supported by grants and fellowships from the National Health and Medical Research Council of Australia (to MGA and SAS) and the Operational Infrastructure Support Program of the Victorian Government.

Disclosure statement

M.G.A. and S.A.S. are shareholders in Opthea Ltd. and are Inventors on patents assigned to Vegenics Ltd.

Additional information

Funding

This work was supported by grants and fellowships from the National Health and Medical Research Council of Australia (to MGA and SAS) and the Operational Infrastructure Support Program of the Victorian Government.