Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.
Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.
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发表时间：
1998-02
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通讯作者：
M. Shoji;W. Hancock;W. Hancock;W. Hancock;Keisuke Abe;Keisuke Abe;Cornelia Micko;Cornelia Micko
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作者：
M. Shoji;W. Hancock;W. Hancock;W. Hancock;Keisuke Abe;Keisuke Abe;Cornelia Micko;Cornelia Micko
凝血酶催化的交联纤维蛋白（XLF）形成是许多人类和实验肿瘤的特征性组织病理学发现，被认为在局部宿主防御反应中很重要。尽管肿瘤相关纤维蛋白沉积的发病机制尚不完全清楚，但一些肿瘤促凝剂可能是肿瘤微环境（TME）中凝血酶（和XLF）生成的主要刺激物。在先前对多种人类肿瘤的研究中，我们已经表明组织因子（TF）是主要的促凝剂。然而，肿瘤细胞TF和宿主细胞TF（如巨噬细胞来源）在TME中对纤维蛋白沉积的相对贡献尚未确定。此外，最近的证据表明，TF参与肿瘤细胞合成促血管生成因子血管内皮生长因子（VEGF）的调节。在目前的研究中，我们使用原位技术来确定XLF、TF、VEGF和另一种肿瘤促凝剂的细胞定位，即所谓的癌症促凝剂（CP），一种激活凝血因子x的半胱氨酸蛋白酶。在肺癌中，我们发现XLF主要定位于肿瘤相关巨噬细胞表面。肿瘤间质区部分内皮细胞和血管周围成纤维细胞与肿瘤和宿主细胞交界处的TF共分布。在一些病例中，促凝剂定位于肿瘤细胞，但与XLF的沉积无关。原位杂交和免疫组化染色显示TF和VEGF在肺癌和乳腺癌细胞中共定位。此外，在人乳腺癌细胞系中，TF的合成与VEGF水平之间存在很强的相关性（r2 = 0.84; P < 0.0001）。综上所述，这些数据与TME中肿瘤细胞、巨噬细胞和内皮细胞之间高度复杂的相互作用一致，导致纤维蛋白形成和肿瘤血管生成。
Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic 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 not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.