TY - JOUR
T1 - Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner
AU - Hald, Andreas
AU - Eickhardt, Hanne
AU - Maerkedahl, Rasmus Baadsgaard
AU - Feldborg, Christina Winther
AU - Egerod, Kristoffer Lihme
AU - Engelholm, Lars Henning
AU - Laerum, Ole Didrik
AU - Lund, Leif Røge
AU - Rønø, Birgitte
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
U2 - 10.1096/fj.12-208025
DO - 10.1096/fj.12-208025
M3 - Journal article
C2 - 22815383
SN - 0892-6638
VL - 26
SP - 4445
EP - 4457
JO - F A S E B Journal
JF - F A S E B Journal
IS - 11
ER -
