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Blood, 15 October 2003, Vol. 102, No. 8, pp. 2819-2827.
Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2003-03-0881.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

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

From the Divisions of Hematology/Oncology, Developmental Biology, and Pathology, Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH.

The growth of Lewis lung carcinoma (LLC) was sustained in plasminogen-deficient mice when transplanted into the dorsal skin but was dramatically suppressed in another anatomic 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 plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their relative importance is dependent on the 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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