Analysis of gene expressions involved in cancer-host cells cross talk at the invasion front of nonsmall cell lung cancer

最近有人提出，癌细胞通过与宿主细胞的串扰，为其侵袭创造适宜的微环境。为阐明非小细胞肺癌(NSCLC)侵袭前沿癌细胞-宿主细胞间相互作用的相关基因或分子，采用基因芯片技术分析了1176个非小细胞肺癌(NSCLC)侵袭前沿组织中癌相关基因的表达谱。121个基因，包括细胞周期蛋白D1、c-myc、胰岛素样生长因子、Rho相关GTP结合蛋白、层粘连蛋白受体、DNA聚合酶、β-连环蛋白、WNT 8B、延伸因子α-1在非小细胞肺癌组织中普遍过表达。与低期腺癌相比，膜型基质金属蛋白酶1(MT1-MMPs)、MMP3、p21-rac1、血管内皮生长因子(VEGF)、Jagge-1、Jagge-2、Noch-4、c-fos相关抗原等10个基因在鳞癌和高期腺癌中均有高表达，而Ezrin(Villin 2)和巨噬细胞抑制因子(MTC)-1基因则相反。利用TaqMann-Probe实时荧光定量RT-PCR方法验证了上述结果。提示Rac-1/MT1-MMP组、Jagge-1组、-2/Noch-4组、P53/MIC-1组可能积极参与肺癌与宿主细胞之间的相互作用，或积极或消极地为肺癌细胞的侵袭创造适宜的微环境。我们还建立了激光捕获显微切割/实时RT-PCR方法，以便更详细地分析非小细胞肺癌侵袭前沿的基因表达。此外，利用FDG-和MIBI-PET成功地尝试了体内非小细胞肺癌组织中基因表达的功能性和非侵入性检测方法。本研究结果可能有助于评估非小细胞肺癌的生物学特性，并为肺癌患者制定适当的治疗方案。

It is recently proposed that cancer cells make microenvironment suitable for their invasion through cross talk with host cells. To elucidate genes or molecules involved in the cancer cell-host cell cross talk at the invasion front of nonsmall cell lung cancer (NSCLC), mRNA profilings of 1176 cancer-related genes at the invasion front tissues of NSCLCs of various progressions were analyzed by cDNA macroarray system (Cancer array 1.2, Clontech). 121 genes, including cyclin D1, c-myc, insulin-like growth factor, rho-associated GTP binding proteins, laminin receptor, DNA polymerases, beta-catenin, wnt 8B, elongation factor alpha-1, were commonly overexpressed in NSCLC tissues. Ten genes, such as membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-3, p21-rac1, vascular endothelial growth factor (VEGF), jagged-1, jagged-2, notch-4, c-fos related antigen, were overexpressed both in squamous cell carcinomas and high stage-adenocarcinomas compared with low stage-adenocarcinomas, while ezrin (villin 2) and macrophage inhibitory cytokine (MTC)-1 genes did the opposite. These results were confirmed by real time RT-PCR using TaqMann-probe method. These data suggested that rac-1/MT1-MMP, jagged-1, -2/ notch-4, p53 / MIC-1 groups may actively involved in the cross talk between lung cancer and host cells and works either positively or negatively to make appropriate microenvironment for invasion of the lung cancer cells. We have also established laser-captured microdissection / real time RT-PCR method in order to analyze gene expressions more in detail at the invasion front of NSCLCs. Furthermore, functional and non-invasive examination methods of gene expressions in NSCLC tissues in vivo were tried successfully using FDG- and MIBI-PET. Present results may contribute to estimate biological features of NSCLCs and establish adequate therapy for lung cancer patients.