Varghese Sheelu, Burness Monika, Xu Hui, Beresnev Tatiana, Pingpank James, Alexander H Richard
Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore 21201, USA.
Ann Surg Oncol. 2007 Dec;14(12):3460-71. doi: 10.1245/s10434-007-9557-7. Epub 2007 Sep 25.
Generally, colorectal and high-grade appendiceal cancers are treated similarly; treatment approach is primarily based on tumor histology and stage of disease. Patients with adenocarcinoma of the lower gastrointestinal tract frequently experience diffuse metastases isolated to liver or peritoneum and have a poor survival. Identification of novel molecular pathways in metastases from these patients may identify novel targets and prognostic factors.
Microarray analyses of 20 metastatic tumors from patients with colorectal adenocarcinoma isolated to liver or peritoneum and eight high-grade appendiceal adenocarcinoma metastatic to peritoneum were performed using oligonucleotide microarray.
In an unsupervised hierarchical cluster analysis of 2-fold upregulated or downregulated genes, there was a clear site-specific segregation of liver versus peritoneal metastases. Genes primarily involved in metastasis, angiogenesis, cell cycle regulation, cell proliferation, and cell adhesion were distinctly altered between these two metastatic sites. Among the metastasis genes, the average expression levels of LI-cadherin, ALCAM, CD2, and CD14 were significantly higher in both metastatic sites. TIMP1 was overexpressed in both sites where as TIMP-2, IGF-1, and HIF-1alpha were upregulated only in peritoneal metastases demonstrating the potential benefit of metastasis site-specific treatments. Subsets of genes significantly associated with poor survival were defined, a RET proto-oncogene interacting gene, GOLGA5, was highly predictive for survival in patients with colorectal adenocarcinoma.
These results demonstrate that liver and peritoneal metastases of lower GI adenocarcinoma have distinct gene expression patterns; these distinctions may help in the development of therapies based on site of metastases.
一般而言，结直肠癌和高级别阑尾癌的治疗方法相似；治疗方案主要基于肿瘤组织学和疾病分期。下消化道腺癌患者常出现孤立于肝脏或腹膜的弥漫性转移，且生存率较低。鉴定这些患者转移灶中的新分子途径可能会发现新的靶点和预后因素。
使用寡核苷酸微阵列对20例孤立于肝脏或腹膜的结直肠腺癌患者的转移瘤以及8例转移至腹膜的高级别阑尾腺癌进行微阵列分析。
在对上调或下调2倍的基因进行无监督层次聚类分析时，肝脏转移灶和腹膜转移灶存在明显的部位特异性分离。在这两个转移部位之间，主要参与转移、血管生成、细胞周期调控、细胞增殖和细胞黏附的基因有明显改变。在转移相关基因中，LI-钙黏蛋白、活化白细胞黏附分子（ALCAM）、CD2和CD14在两个转移部位的平均表达水平均显著更高。金属蛋白酶组织抑制因子1（TIMP1）在两个部位均过表达，而TIMP-2、胰岛素样生长因子1（IGF-1）和缺氧诱导因子1α（HIF-1α）仅在腹膜转移灶中上调，这表明转移部位特异性治疗具有潜在益处。定义了与不良生存显著相关的基因子集，一种RET原癌基因相互作用基因高尔基体5（GOLGA5）对结直肠腺癌患者的生存具有高度预测性。
这些结果表明，下消化道腺癌的肝脏转移灶和腹膜转移灶具有不同的基因表达模式；这些差异可能有助于开发基于转移部位的治疗方法。
