title: Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner.
abstract: Rearrangement of the skin during wound healing depends on plasmin and plasminogen, which serve to degrade fibrin depositions in the provisional matrix and thereby facilitate keratinocyte migration. In the current study, we investigated whether plasmin and plasminogen likewise played a role during the development of skin cancer. To test this, we set up a chemically induced skin tumor model in a cohort of mice and found that skin tumor growth in Plg(-/-) male mice was reduced by 52% compared with wild-type controls. Histological analyses suggested that the growth-restricting effect of plasminogen deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted by superimposing heterozygous fibrinogen deficiency on Plg(-/-) mice. Tumors derived from these Fib(-/+);Plg(-/-) mice displayed a significantly decreased level of tumor thrombosis compared with Plg(-/-) mice. In summary, these data indicate that plasmin-driven fibrinolysis facilitates tumor growth by maintaining patency of the tumor vasculature.
authors: Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. ahald@finsenlab.dk
authors: Andreas
authors: A
authors: Hald
authors: Hanne
authors: H
authors: Eickhardt
authors: Rasmus Baadsgaard
authors: RB
authors: Maerkedahl
authors: Christina Winther
authors: CW
authors: Feldborg
authors: Kristoffer Lihme
authors: KL
authors: Egerod
authors: Lars Henning
authors: LH
authors: Engelholm
authors: Ole Didrik
authors: OD
authors: Laerum
authors: Leif Røge
authors: LR
authors: Lund
authors: Birgitte
authors: B
authors: Rønø
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000235:genetics / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D005342:Fibrinolysis / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D010052:Ovariectomy; D012737:Sex Factors; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D013927:Thrombosis / Q000378:metabolism
chemical_list: D007797:Laminin; D005337:Fibrin; D005340:Fibrinogen; D005341:Fibrinolysin