Analysis of molecular mechanisms of basement membrane destruction in the process of lung cancer cell invasion

肺癌细胞侵袭过程中基底膜破坏的分子机制分析

• 批准号: 13670166
• 负责人: AKASHI Takumi
• 金额: $ 1.34万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670166/
• 关键词: lung cancer; adnocarcinoma; invasion; basement membrane; cytokine; cancer stromal interactin; マトリゲル; cDNAアレイ

In the process of lung cancer invasion to the neighboring extracellular matrix, basement membrane is quite often disrupted. For the explanation of this, in addition to the inhibition of cancer cell invasion, we hypothesized that basement membrane sequester the cytokine diffusion secreted by the cancer cells and stimulating the growth of fibroblasts which promote the invasive natures of cancer cells.We showed that lung cancer cell lines stimulated growth of fetal lung fibroblasts. bFGF and PDGF were the one of the growth stimulators in the cancer cell conditioned media. Basement membrane matrix significantly sequestered the diffusion of bFGF by the affinity binding to the heparin sulfate. bFGF were stored in the basement membrane matrix at higher concentration and the possibility of its release secondary to the basement membrane destruction.In the other hand, basement membrane matrix inhibit the invasive growth of HGF-dependent invasion of A549 cells. By the cDNA array method, we examined the change of gene expression pattern of A549 cells in the existence of basement membrane matrix. We found that expression of 50 genes, including EF(elongation factor)1a1, EF1a2, EF1d,were significantly suppressed in the existence of basement membrane matrix. EF(elongation factor)1a1, EF1a2, EF1d were known to bind to f-actin and possibly regulate the celuular motility. Our results suggest that basement membrane inhibits the invasive nature of cancer cells via the suppression of elongation factor genes.

在肺癌侵袭邻近细胞外基质的过程中，基底膜常常被破坏。为了解释这一点，除了抑制癌细胞的侵袭，我们假设基底膜隔离癌细胞分泌的细胞因子扩散，并刺激成纤维细胞的生长，从而促进癌细胞的侵袭性。我们发现，肺癌细胞系刺激胎肺成纤维细胞的生长。bFGF和PDGF是癌细胞条件培养液中的生长刺激因子之一。基底膜基质通过与硫酸肝素的亲和结合显著地隔离了bFGF的扩散。bFGF以较高浓度储存在基底膜基质中，其释放的可能性继发于基底膜的破坏，另一方面，基底膜基质抑制了A549细胞的侵袭性生长。应用cDNA芯片技术，研究了A549细胞在基底膜基质存在下基因表达谱的变化。结果发现，在基底膜基质存在下，包括EF（elongation factor）1a1、EF 1a2、EF 1d在内的50个基因的表达受到明显抑制。EF（elongation factor）1a1、EF 1a2、EF 1d与肌动蛋白结合，可能参与细胞运动的调节。我们的研究结果表明，基底膜通过抑制延伸因子基因抑制癌细胞的侵袭性。

项目成果

明石 巧 他: "肺癌細胞の線維芽細胞増殖刺激に与える基底膜物質の影響"日本病理学会誌. 91. 263 (2002)

Takumi Akashi 等人：“基底膜物质对刺激肺癌细胞成纤维细胞增殖的影响”日本病理学会杂志 91. 263 (2002)。