Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors

Abstract

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.

Novel Drug Candidates for the Treatment of Metastatic Colorectal Cancer through Global Inverse Gene-Expression Profiling

“…As opposed to previous studies that have used healthy versus diseased states (29), we rather chose to compare nonmetastatic tumors versus metastatic primary tumors and metastases, to define a gene signature of metastatic potential rather than a general cancer signature. Several groups have studied the gene-expression differences between primary and metastatic colon cancers to explain the molecular basis of the metastatic process and predict clinical outcomes (25,(30)(31)(32). In this study, we decided to employ the reproducible gene-expression signature from (25) that emerged as a consensus from two independent comparisons of Dukes' stage D versus stage A colorectal cancers (Supplementary Table S3; for details see Materials and Methods).…”

Complexity of cancer: A surgeon's perspective

“…It shows that metastasis is a highly inefficient system due to many factors which are important during the first twenty four hour period when the cell is adhering to a new micro environment. In our study of colorectal metastasis to the liver [1], we have identified a reduced proliferative role in the metastasic tumor compared to the primary. Here, cancer cell autophagy plays a role in the immediate survival of the cell in a totally foreign environment after its dislocation from the primary site.…”

Transcriptional silencing of N-Myc downstream-regulated gene 1 (NDRG1) in metastatic colon cancer cell line SW620

“…Accompanying this was the lower proliferation in SW620 and the NDRG1-siRNA-treated SW480. Interestingly, it was reported recently that a global survey of colon cancers revealed that metastatic colon cancers have reduced proliferation compared to primary tumors [22]. The study showed that cell cycle gene expression along with Ki67 staining was decreased in metastatic tumors compared to primary tumors.…”