Maillard Catherine, Jost Maud, Rømer Maria Unni, Brunner Nils, Houard Xavier, Lejeune Annabelle, Munaut Carine, Bajou Khalid, Melen Laurence, Dano Keld, Carmeliet Peter, Fusenig Norbert E, Foidart Jean Michel, Noel Agnès
Laboratory of Tumor and Development Biology, CRCE, CBIG, University of Liège, Tour de Pathologie (B23), Sart Tilman, Liège B-4000, Belgium.
Neoplasia. 2005 Jan;7(1):57-66. doi: 10.1593/neo.04406.
Angiogenesis and tumor expansion are associated with extracellular matrix remodeling and involve various proteases such as the plasminogen (Plg)/plasminogen activator (PA) system. Recently, several experimental data have implicated the plasminogen activator inhibitor-1 (PAI-1) in tumor angiogenesis in murine systems. However, little is known about PAI-1 functions in human skin carcinoma progression. By generating immunodeficient mice (in Rag-1-/- or nude background) deleted for PAI-1 gene (PAI-1-/-), we have evaluated the impact of host PAI-1 deficiency on the tumorigenicity of two malignant human skin keratinocyte cell lines HaCaT II-4 and HaCaT A5-RT3 forming low-grade and high-grade carcinomas, respectively. When using the surface transplantation model, angiogenesis and tumor invasion of these two cell lines are strongly reduced in PAI-1-deficient mice as compared to the wild-type control animals. After subcutaneous injection in PAI-1-/- mice, the tumor incidence is reduced for HaCaT II-4 cells, but not for those formed by HaCaT A5-RT3 cells. These data indicate that PAI-1 produced by host cells is an important contributor to earlier stages of human skin carcinoma progression. It exerts its tumor-promoting effect in a tumor stage-dependent manner, but PAI-1 deficiency is not sufficient to prevent neoplastic growth of aggressive tumors of the human skin.
血管生成和肿瘤扩展与细胞外基质重塑相关，并涉及多种蛋白酶，如纤溶酶原（Plg）/纤溶酶原激活物（PA）系统。最近，一些实验数据表明纤溶酶原激活物抑制剂-1（PAI-1）在小鼠系统的肿瘤血管生成中发挥作用。然而，关于PAI-1在人类皮肤癌进展中的功能尚知之甚少。通过构建缺失PAI-1基因（PAI-1-/-）的免疫缺陷小鼠（Rag-1-/-或裸鼠背景），我们评估了宿主PAI-1缺乏对两种分别形成低级别和高级别癌的恶性人类皮肤角质形成细胞系HaCaT II-4和HaCaT A5-RT3致瘤性的影响。在使用表面移植模型时，与野生型对照动物相比，PAI-1缺陷小鼠中这两种细胞系的血管生成和肿瘤侵袭均显著降低。在PAI-1-/-小鼠皮下注射后，HaCaT II-4细胞的肿瘤发生率降低，但HaCaT A5-RT3细胞形成的肿瘤发生率未降低。这些数据表明宿主细胞产生的PAI-1是人类皮肤癌进展早期阶段的重要促成因素。它以肿瘤阶段依赖性方式发挥其促肿瘤作用，但PAI-1缺乏不足以阻止人类皮肤侵袭性肿瘤的肿瘤生长。
