Abstract
BackgroundThough peritoneal carcinomatosis reflects a late stage of colorectal cancer (CRC), only few patients present with synchronous or metachronous liver metastases alongside their peritoneal carcinomatosis. It is hypothesized that this phenomenon may be causally linked to molecular characteristics of the primary CRC. This study used miRNA profiling of primary CRC tissue either metastasized to the liver, to the peritoneum or not metastasized at all thus to identify miRNAs potentially associated with defining the site of metastatic spread in CRC.MethodsTissue of the primary tumor stemming from CRC patients diagnosed for either liver metastasis (LM; n = 10) or peritoneal carcinomatosis (PER; n = 10) was analyzed in this study. Advanced CRC cases without metastasis (M0; n = 3) were also included thus to select on those miRNAs most potentially associated with determining metastatic spread in general. miRNA profiling of 754 different miRNAs was performed in each group. MiRNAs being either differentially expressed comparing PER and LM or even triple differentially expressed (PER vs. LM vs. M0) were identified. Differentially expressed miRNAs were further validated by in silico and functional analysis.ResultsComparative analysis identified 41 miRNAs to be differentially expressed comparing primary tumors metastasized to the liver as opposed to those spread to the peritoneum. A set of 31 miRNAs was significantly induced in primary tumors that spread to the peritoneum (PER), while the remaining 10 miRNAs were found to be repressed. Out of these 41 miRNAs a number of 25 miRNAs was triple-differentially expressed (i.e. differentially expressed comparing LM vs. PER vs. M0). The latter underwent in silico analysis. Finally, we demonstrated that miR-31 down-regulated c-MET in DLD-1 colon cancer cells.ConclusionsThis study demonstrates that CRC primary tumors spread to the peritoneum vs. metastasized to the liver display significantly different miRNA profiles. Larger patient cohorts will be needed to validate whether determination of e.g. miR-31 may aid to predict the course of disease and whether this may help to create individualized follow up or treatment protocols. To determine whether certain miRNAs may be involved in regulating the metastatic potential of CRC, functional studies will be essential.
Highlights
Though peritoneal carcinomatosis reflects a late stage of colorectal cancer (CRC), only few patients present with synchronous or metachronous liver metastases alongside their peritoneal carcinomatosis
The current study sample (n = 23) was characterized as follows: 10 patients diagnosed for CRC metastasized to the liver either at initial diagnosis or during follow up without peritoneal carcinomatosis, 10 patients diagnosed for CRC spread to the peritoneum either at initial diagnosis or during follow up without liver metastasis and three CRC patients without metastasis formation during follow up period
Age, grade, UICC stage and pN-Stage were not significantly different when cases with peritoneal carcinomatosis and cases diagnosed for liver metastasis were compared
Summary
Though peritoneal carcinomatosis reflects a late stage of colorectal cancer (CRC), only few patients present with synchronous or metachronous liver metastases alongside their peritoneal carcinomatosis. Liver metastases account for about one third of all distant metastasis locations in CRC [3] Another common site of distant spread is the peritoneum and about one out of four patients develops peritoneal carcinomatosis during the course of disease [4]. Our recent work highlighted that stem cell features of the primary tumor may direct the way of metastasis [5, 7] Those CRCs that will spread to the liver display a prominent cancer stem cell-like immuno-phenotype while those which will metastasize to the peritoneum do not. We hypothesized that that primary CRC cases developing solely PC but no hematogenous metastases lack the stem cell features needed for dissemination [5]
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