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In vivo and in vitro characterization of bone-marrow derived fibroblast recruited into cancer induced stroma.

招募到癌症诱导基质中的骨髓来源成纤维细胞的体内和体外表征。

基本信息

批准号：
17590366
负责人：
ISHII Genichiro
金额：
$ 2.3万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Fibroblasts, which are a major component of cancer-induced stroma, can have a significant impact on the progression of adjacent malignant epithelia. To characterize fibroblasts recruited into cancer-induced stroma, we examined the recruitment efficiency of 9 human fibroblast cell lines into experimental tumors generated in immunodeficient mice. Green fluorescence protein (GFP)-labeled fibroblast cell lines and human pancreatic cancer cell line Capan-1 were injected i.p. at different sites ; the GFP-labeled cells within xenografts were then analyzed. KM104GFP (bone marrow) and VA-13GFP (lung) were selectively recruited into cancer stroma more efficiently than the other cell lines. KM104GFP cells did not affect tumor volume ; however, VA-13GFP cells increased tumor volume by about 2-fold. After 5 cyclic in vivo passages of KM104GFP in Capan-1, we selected a subpopulation with an 8.4-fold higher recruitment efficiency (KM104GFP-5G) compared to parental KM104GFP. KM104GFP-5G also exhibited higher chemotaxis and chemoinvasion activity compared to KM104GFP in response to cancer-released chemoattractant(s). Oligonucleotide microarray analysis identified 8 genes with >3-fold upregulation and 6 genes with >3-fold downregulation in KM104GFP-5G. Immunohistochemistry confirmed that fibroblasts recruited into pancreatic cancer stroma strongly expressed carbonic anhydrase IX and keratin-8, whose transcripts were upregulated in KM104GFP-5G by oligonucleotide microarray analysis, whereas their expression in fibroblasts within noncancerous pancreatic stroma were under the detection level. Our results indicate that fibroblast recruitment is not selective with respect to organ origin and that particular fibroblast subpopulations with specific phenotypic characteristics could be recruited efficiently into cancer-induced stroma.

成纤维细胞是癌症诱导的基质的主要成分，可对邻近恶性上皮的进展具有显著影响。为了表征招募到癌症诱导的基质中的成纤维细胞，我们检查了9种人成纤维细胞系在免疫缺陷小鼠中产生的实验肿瘤中的招募效率。在不同部位腹膜内注射绿色荧光蛋白（GFP）标记的成纤维细胞系和人胰腺癌细胞系Capan-1;然后分析异种移植物内的GFP标记细胞。KM 104 GFP（骨髓）和VA-13 GFP（肺）比其他细胞系更有效地选择性募集到癌症基质中。KM 104 GFP细胞不影响肿瘤体积;然而，VA-13 GFP细胞使肿瘤体积增加约2倍。在Capan-1中5次循环的KM 104 GFP体内传代后，我们选择了与亲本KM 104 GFP相比具有8.4倍更高募集效率的亚群（KM 104 GFP-5G）。与KM 104 GFP相比，KM 104 GFP-5G还表现出更高的趋化性和化学侵袭活性，以响应癌症释放的化学引诱物。寡核苷酸微阵列分析鉴定了在KM 104 GFP-5G中具有>3倍上调的8个基因和具有>3倍下调的6个基因。免疫组化证实，招募到胰腺癌间质中的成纤维细胞强烈表达碳酸酐酶IX和角蛋白-8，其转录物通过寡核苷酸微阵列分析在KM 104 GFP-5G中上调，而它们在非癌胰腺间质中的成纤维细胞中的表达低于检测水平。我们的研究结果表明，成纤维细胞的招聘是没有选择性的器官来源和特定的成纤维细胞亚群具有特定的表型特征，可以有效地招募到癌症诱导的基质。