Billottet Clotilde, Janji Bassam, Thiery Jean-Paul, Jouanneau Jacqueline
Laboratory of Cell Morphogenesis and Tumor Progression, UMR 144 CNRS, Institut Curie, Section de recherche, 26 rue d'Ulm, 75248 Paris, cedex 05, France.
Oncogene. 2002 Nov 21;21(53):8128-39. doi: 10.1038/sj.onc.1205935.
FGF-1 and FGF-2 are pleiotropic growth factors for many cell types, operating through the activation of specific transmembrane FGF receptors (FGFRs). The role of these factors in tumor progression was investigated, with specific discrimination between their autocrine and non autocrine cellular activity. The rat bladder carcinoma NBT-II cells were engineered to produce FGF-1 or 18 kDa FGF-2 in the presence or absence of their specific receptor. Non-autocrine cells that produced FGF-1 or FGF-2 but lacked FGFRs were epithelial and reminiscent of the parental NBT-II cells. Whilst autocrine cells, which both constitutively produced and secreted the growth factor and expressed FGFRs, had a highly invasive mesenchymal phenotype. Correspondingly, the autocrine cells were highly tumorigenic in vivo compared to the parental and non-autocrine cells, which correlated with the increased production of uPAR and active uPA and increased in vitro invasive potential. Although all cells produced VEGF, only tumors derived from cells that produced FGF-1 or FGF-2 were highly vascularized, suggesting that these two growth factors could be involved in the angiogenic process by activating host endothelial cells. As a result of activation of the FGFR in autocrine cells, changes in cell morphology and an increase in the invasive and tumorigenic properties were observed, however no in vitro or in vivo differential functions between FGF-1 and FGF-2 could be identified in this system. In conclusion, our data demonstrates that rapid tumor development is not dependent upon increased tumor vascularization, suggesting that 'basal' angiogenesis, probably mediated by VEGF, is sufficient to support tumor growth.
成纤维细胞生长因子-1（FGF-1）和成纤维细胞生长因子-2（FGF-2）是针对多种细胞类型的多效性生长因子，通过激活特定的跨膜成纤维细胞生长因子受体（FGFRs）发挥作用。研究了这些因子在肿瘤进展中的作用，并对其自分泌和非自分泌细胞活性进行了明确区分。对大鼠膀胱癌NBT-II细胞进行改造，使其在有或没有其特异性受体的情况下产生FGF-1或18 kDa FGF-2。产生FGF-1或FGF-2但缺乏FGFRs的非自分泌细胞呈上皮样，类似于亲代NBT-II细胞。而自分泌细胞既能组成性产生并分泌生长因子，又能表达FGFRs，具有高度侵袭性的间充质表型。相应地，与亲代细胞和非自分泌细胞相比，自分泌细胞在体内具有高度致瘤性，这与尿激酶型纤溶酶原激活物受体（uPAR）和活性尿激酶型纤溶酶原激活物（uPA）的产生增加以及体外侵袭潜力增加相关。尽管所有细胞都产生血管内皮生长因子（VEGF），但只有源自产生FGF-1或FGF-2的细胞的肿瘤具有高度血管化，这表明这两种生长因子可能通过激活宿主内皮细胞参与血管生成过程。由于自分泌细胞中FGFR的激活，观察到细胞形态发生变化，侵袭性和致瘤性特性增加，然而在该系统中未发现FGF-1和FGF-2在体外或体内的差异功能。总之，我们的数据表明，肿瘤的快速发展并不依赖于肿瘤血管化的增加，这表明可能由VEGF介导的“基础”血管生成足以支持肿瘤生长。
