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Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2003-03-0881.
Submitted March 24, 2003
Accepted June 13, 2003
Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency
Joseph S Palumbo, Kathryn E Talmage, Hong Liu, Christine M La Jeunesse, David P Witte, and Jay L Degen*
Division of Hematology/Oncology, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH, USA
Division of Developmental Biology, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH, USA
Division of Pathology, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH, USA
* Corresponding author; email: degenjl{at}chmcc.org.
The growth of Lewis lung carcinoma (LLC) was sustained in plasminogen-deficient mice when transplanted into the dorsal skin, but dramatically suppressed in another anatomical location, the footpad. This unanticipated negative effect of plasminogen deficiency on footpad tumor growth was entirely relieved by superimposing a deficit in fibrinogen. This finding was not simply an unusual feature of LLC tumors; T241 fibrosarcoma growth in the footpad was also restricted by plasminogen deficiency in a fibrinogen-dependent manner. The probable mechanistic basis for suppression of tumor growth was revealed through transmission electron microscopy studies of tumor tissues. Occlusive microvascular thrombi were commonplace within footpad tumors from plasminogen-deficient mice, whereas no such lesions were observed within either dorsal skin tumors from plasminogen-deficient mice or footpad tumors from mice that also lacked fibrinogen. The data infer that tumor growth in the footpad of plasminogen-deficient mice is compromised as a function of the formation and persistence of vaso-occlusive thrombi that limit tumor blood supply. These studies indicate that both plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their relative importance is dependent on tumor microenvironment. Furthermore, these studies suggest that one target of plasmin(ogen) relevant to tumor progression in vivo is intravascular fibrin.
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