Sanz-Pamplona Rebeca, Berenguer Antoni, Cordero David, Molleví David G, Crous-Bou Marta, Sole Xavier, Paré-Brunet Laia, Guino Elisabet, Salazar Ramón, Santos Cristina, de Oca Javier, Sanjuan Xavier, Rodriguez-Moranta Francisco, Moreno Victor
Unit of Biomarkers and Susceptibility, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
Mol Cancer. 2014 Mar 5;13:46. doi: 10.1186/1476-4598-13-46.
A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient's gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response.
A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software).
Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue.
The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.
结直肠肿瘤并非生长在身体局限部位的孤立实体。患者的肠道环境构成了肿瘤演变的框架，这种关系促进并包含了肿瘤与炎症、血管形成、营养以及肠道微生物群组成之间复杂而紧密的关联。肿瘤对环境的影响既可能促进抗肿瘤反应，也可能促进促肿瘤反应。
本研究纳入了98对来自结直肠癌（CRC）患者的相邻黏膜和肿瘤组织以及50份来自健康供体的结肠黏膜（共246个样本）。从每个样本中提取的RNA在Affymetrix芯片人类基因组U219上进行杂交。通过系统生物学方法，利用转录调控网络（ARACNe算法）和蛋白质-蛋白质相互作用网络（BIANA软件）推断基因之间的功能关系。
我们在此报告一项转录组分析，揭示了一些在CRC患者相邻黏膜中被激活但在健康供体黏膜中未被激活的基因。对这些基因的功能分析表明，相邻黏膜的这种活跃反应与肿瘤的存在有关。利用转录和蛋白质相互作用网络进一步阐明正常肠道对肿瘤的这种反应，揭示了肿瘤分泌的蛋白质与相邻结肠组织中激活的受体之间的相互作用；反之亦然。值得注意的是，Slit蛋白家族在肿瘤中激活ROBO受体，而肿瘤分泌的蛋白质转导细胞信号最终在相邻组织中激活AP-1。
系统水平的方法为结直肠癌发生的微生态提供了新的见解。破坏这种复杂的细胞间通讯分子网络和促炎微环境可能是CRC患者的治疗靶点。
