Abstract
BackgroundMetastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Here, we investigate the geographic expression pattern of MACC1 in colorectal adenocarcinoma and tumor buds in correlation with clinicopathological and molecular features for improvement of survival prognosis.MethodsWe performed geographic MACC1 expression analysis in tumor center, invasive front and tumor buds on whole tissue sections of 187 well-characterized CRCs by immunohistochemistry. MACC1 expression in each geographic zone was analyzed with Mismatch repair (MMR)-status, BRAF/KRAS-mutations and CpG-island methylation.ResultsMACC1 was significantly overexpressed in tumor tissue as compared to normal mucosa (p < 0.001). Within colorectal adenocarcinomas, a significant increase of MACC1 from tumor center to front (p = 0.0012) was detected. MACC1 was highly overexpressed in 55% tumor budding cells. Independent of geographic location, MACC1 predicted advanced pT and pN-stages, high grade tumor budding, venous and lymphatic invasion (p < 0.05). High MACC1 expression at the invasive front was decisive for prediction of metastasis (p = 0.0223) and poor survival (p = 0.0217). The geographic pattern of MACC1 did not correlate with MMR-status, BRAF/KRAS-mutations or CpG-island methylation.ConclusionMACC1 is differentially expressed in CRC. At the invasive front, MACC1 expression predicts best aggressive clinicopathological features, tumor budding, metastasis formation and poor survival outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1150-z) contains supplementary material, which is available to authorized users.
Highlights
Metastasis of colorectal cancer (CRC) is directly linked to patient survival
Patients with strong Metastasis Associated in Colon Cancer 1 (MACC1) expression in the tumor center frequently presented with locally advanced pT3/4 tumors (p = 0.0288) as compared to MACC1 negative cases [Table 1]
MACC1 expression in the tumor center was highly correlated with presence of high-grade tumor budding
Summary
Metastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Since current clinical and histopathological classifications and molecular markers are not sufficient for prediction of metastasis, the development of biomarkers for the early and precise identification of patients at high-risk for metastasis at early stages of the disease is of utmost importance. MACC1 drives proliferation, migration, invasion, wound healing and dissemination and regulates genes transcriptionally important for metastasis, e.g. the receptor tyrosine kinase MET. It is crucially involved in fundamental biological processes, e.g. apoptosis and epithelial-mesenchymal transition (EMT), via pathways such as the HGF/MET/MACC1 axis. In several xenograft mouse models, MACC1 induces tumor progression and metastasis [3,4]
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