Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors
Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors
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DOI：
10.1007/s10585-009-9295-2
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Mariadason, John M.
中科院分区：
文献类型：
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作者：
Ganepola, Ganepola A. P.;Mazziotta, Robert M.;Mariadason, John M.
本研究的目的是通过表征原发性和转移性结肠癌之间的基因表达差异来深入了解转移过程的生物学基础。最近的研究表明，在结肠肿瘤的转移过程中，很少有新的突变发生[j]., Proc natalacadsci USA, 105(11): 4283-4288, 2008]。然而，在原发性和转移性结肠癌之间发生的表观遗传和转录变化的程度仍然未知。我们使用Affymetrix微阵列来评估宏观解剖的原发性和转移性结肠肿瘤之间基因表达谱的异同。出乎意料的是，我们发现与原发肿瘤相比，结肠肿瘤肝转移中许多细胞增殖标志物的表达降低。这一发现通过福尔马林固定石蜡包埋（FFPE）切片中Ki67和Cyclin D1的免疫组化染色，以及在FFPE匹配的肿瘤和转移组织样本的独立队列中得到验证。这些结果表明原发性和转移性结肠肿瘤之间存在显著的转录差异，并表明转移性病变的增殖率低于原发性肿瘤。这些发现可能有助于解释原发性和转移性病变之间反应率的差异，并表明转移性组织中基于表达的生物标志物的测量将是了解转移性肿瘤对治疗干预反应基础的最重要信息。
The objective of this study was to gain insights into the biological basis of the metastatic process by characterizing the gene expression differences between primary and metastatic colon cancers. Recent studies have demonstrated that few new mutational changes are acquired during the metastatic progression of colon tumors [Jones et al., Proc Natl Acad Sci USA 105 (11): 4283-4288, 2008]. However, the extent to which epigenetic and transcriptional changes occur between primary and metastatic colon cancer remains unknown. We approached these issues using Affymetrix microarrays to assess the similarities and differences in gene expression profiles between macro-dissected primary and metastatic colon tumors. Unexpectedly, we found that expression of a number of cell proliferation markers were reduced in the liver metastases of colon tumors when compared to primary tumors. This finding was validated by immunohistochemical staining of Ki67 and Cyclin D1 in Formalin-Fixed Paraffin-Embedded (FFPE) section of the same samples, and in an independent cohort of FFPE matched tumor and metastatic tissue samples. These results indicate that significant transcriptional differences exist between primary and metastatic colon tumors, and demonstrate that metastatic lesions have a lower proliferative rate compared to primary tumors. These findings may have implications for interpreting differences in response rates between primary and metastatic lesions and suggest that measurement of expression-based biomarkers in metastatic tissue will be most informative for understanding the basis of response of metastatic tumors to therapeutic intervention.