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

Sophie Paquet-Fifield, Sally Roufail, You Fang Zhang, Trifina Sofian, David J. Byrne, Paul B. Coughlin, Stephen B. Fox, Steven A Stacker, Marc G Achen

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)61-75
Number of pages15
JournalGrowth Factors
Volume35
Issue number2-3
DOIs
Publication statusPublished - 11 Jul 2017

Keywords

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

Cite this

Paquet-Fifield, Sophie ; Roufail, Sally ; Zhang, You Fang ; Sofian, Trifina ; Byrne, David J. ; Coughlin, Paul B. ; Fox, Stephen B. ; Stacker, Steven A ; Achen, Marc G. / The fibrinolysis inhibitor α2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer. In: Growth Factors. 2017 ; Vol. 35, No. 2-3. pp. 61-75.
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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",
author = "Sophie Paquet-Fifield and Sally Roufail and Zhang, {You Fang} and Trifina Sofian and Byrne, {David J.} and Coughlin, {Paul B.} and Fox, {Stephen B.} and Stacker, {Steven A} and Achen, {Marc G}",
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Paquet-Fifield, S, Roufail, S, Zhang, YF, Sofian, T, Byrne, DJ, Coughlin, PB, Fox, SB, Stacker, SA & Achen, MG 2017, 'The fibrinolysis inhibitor α2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer' Growth Factors, vol. 35, no. 2-3, pp. 61-75. https://doi.org/10.1080/08977194.2017.1349765

The fibrinolysis inhibitor α2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer. / Paquet-Fifield, Sophie; Roufail, Sally; Zhang, You Fang; Sofian, Trifina; Byrne, David J.; Coughlin, Paul B.; Fox, Stephen B.; Stacker, Steven A; Achen, Marc G.

In: Growth Factors, Vol. 35, No. 2-3, 11.07.2017, p. 61-75.

Research output: Contribution to journalArticleResearchpeer-review

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