TY - JOUR
T1 - Enhanced cell-associated plasminogen activator pathway but not coagulation pathway activity contributes to motility in metastatic breast cancer cells
AU - Carter, J. C.
AU - Campbell, R. A.
AU - Gibbons, J. A.
AU - Gramling, M. W.
AU - Wolberg, A. S.
AU - Church, F. C.
PY - 2010/6
Y1 - 2010/6
N2 - Background: Activation of tumor cell-associated coagulation and plasminogen activator pathways occurs in malignant disease processes, including breast cancer, and may promote metastatic activity. Objectives/Methods: To compare the coagulation and plasminogen activator pathways of normal and metastatic cells, we examined two cell lines from the MCF-10 family of breast cells: near-normal immortalized MCF-10A cells, and metastatic MCF-10CA1 cells. Results: MCF-10CA1 cell motility was significantly increased as compared with that of MCF-10A cells. The two cell types supported similar rates of factor Xa generation, plasma thrombin generation, and fibrin formation. MCF-10A cells produced a stable fibrin network, whereas MCF-10CA1 cells lysed the surrounding fibrin network within 24 h of network formation. Importantly, fibrin located proximal to (within 10 μm) the MCF-10CA1 cell surface lysed substantially faster than fibrin located 100 μm from the surface. MCF-10CA1 cells supported significantly increased plasmin generation rates as compared with MCF-10A cells, providing a mechanism for the increased fibrinolytic activity of these cells towards the fibrin network. Metastatic MCF-10CA1 cells had increased expression (mRNA and protein) levels of urokinase plasminogen activator (u-PA) and decreased levels of plasminogen activator inhibitor-1 as compared with MCF-10A cells. Blocking u-PA activity with the active site-directed protease inhibitor amiloride substantially decreased MCF-10CA1 cell motility. Phosphorylated Akt levels were elevated in MCF-10CA1 cells, which partially explains the increased u-PA expression. Conclusions: These results suggest that the tumor-associated plasminogen activator pathway, not the coagulation pathway, is a key distinguishing feature between metastatic MCF10-CA1 cells and normal MCF-10A cells.
AB - Background: Activation of tumor cell-associated coagulation and plasminogen activator pathways occurs in malignant disease processes, including breast cancer, and may promote metastatic activity. Objectives/Methods: To compare the coagulation and plasminogen activator pathways of normal and metastatic cells, we examined two cell lines from the MCF-10 family of breast cells: near-normal immortalized MCF-10A cells, and metastatic MCF-10CA1 cells. Results: MCF-10CA1 cell motility was significantly increased as compared with that of MCF-10A cells. The two cell types supported similar rates of factor Xa generation, plasma thrombin generation, and fibrin formation. MCF-10A cells produced a stable fibrin network, whereas MCF-10CA1 cells lysed the surrounding fibrin network within 24 h of network formation. Importantly, fibrin located proximal to (within 10 μm) the MCF-10CA1 cell surface lysed substantially faster than fibrin located 100 μm from the surface. MCF-10CA1 cells supported significantly increased plasmin generation rates as compared with MCF-10A cells, providing a mechanism for the increased fibrinolytic activity of these cells towards the fibrin network. Metastatic MCF-10CA1 cells had increased expression (mRNA and protein) levels of urokinase plasminogen activator (u-PA) and decreased levels of plasminogen activator inhibitor-1 as compared with MCF-10A cells. Blocking u-PA activity with the active site-directed protease inhibitor amiloride substantially decreased MCF-10CA1 cell motility. Phosphorylated Akt levels were elevated in MCF-10CA1 cells, which partially explains the increased u-PA expression. Conclusions: These results suggest that the tumor-associated plasminogen activator pathway, not the coagulation pathway, is a key distinguishing feature between metastatic MCF10-CA1 cells and normal MCF-10A cells.
KW - Breast cancer
KW - Cell motility
KW - Plasminogen activator inhibitor-1
KW - Thrombin
KW - Urokinase
UR - http://www.scopus.com/inward/record.url?scp=77954511710&partnerID=8YFLogxK
U2 - 10.1111/j.1538-7836.2010.03825.x
DO - 10.1111/j.1538-7836.2010.03825.x
M3 - Article
C2 - 20180817
AN - SCOPUS:77954511710
SN - 1538-7933
VL - 8
SP - 1323
EP - 1332
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 6
ER -