ACTIVATION OF COAGULATION AND ANGIOGENESIS IN CANCER - IMMUNOHISTOCHEMICAL LOCALIZATION IN-SITU OF CLOTTING PROTEINS AND VASCULAR ENDOTHELIAL GROWTH-FACTOR IN HUMAN CANCER

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a character istic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response, Although the pathogenesis of tumor-associated fibrin deposition is no t entirely clear, several tumor procoagulants have been described as l ikely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME), In a previous study of a variety of huma n tumors we have shown that tissue factor (TF) is the major procoagula nt, However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not es tablished, In addition, recent evidence has implicated TF in the regul ation of the synthesis of the pro-angiogenic factor vascular endotheli al growth factor (VEGF) by tumor cells, In the current study we used i n situ techniques to determine the cellular localization of XLF, TF, V EGF, and an alternative tumor procoagulant, so-called cancer procoagul ant (CP), a cysteine protease that activates clotting factor X. In lun g cancer we have found XLF localized predominantly to the surface of t umor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distribu ted with TF at the interface of the tumor and host cells, Cancer proco agulant was localized to tumor cells in several cases but not in conju nction with the deposition of XLF, TF and VEGF were co-localized in bo th lung cancer and breast cancer cells by in situ hybridization and im munohistochemical staining, Furthermore, a strong relationship was fou nd between the synthesis of TF and VEGF levels in human breast cancer cell lines (r(2) = 0.84; P < 0.0001). Taken together, these data are c onsistent with a highly complex interaction between tumor cells, macro phages, and endothelial cells in the TME leading to fibrin formation a nd tumor angiogenesis.