Prognostic biomarkers for metastatic colorectal cancer

In colorectal cancer (CRC) distant metastases essentially determine the overall survival and prognosis. Biomarkers that correlate with the presence of distant metastases are therefore of great clinical importance for risk stratification and clinical treatment decisions. As part of the habilitation project various prognostic biomarkers were analyzed and correlated with the occurrence of distant metastases and different patterns of distant spread in CRC. It could be demonstrated that CRC with microsatellite instability (MSI), as detected by a loss of hMLH1 protein expression, have a very low risk of distant metastases. In contrast, microsatellite stable (MSS) CRC (with positive hMLH1 expression) with concurrent activation of the Wnt-beta catenin signaling pathway and strong expression of the cancer stem cell marker CD133, exhibit a very high risk for liver metastases. From these observations a two-step immunohistochemical algorithm based on three immunohistochemical stains could be derived, allowing CRC to be classified according to the risk of distant metastases. Further studies demonstrated that a deregulation of the Wnt-beta catenin signaling pathway and the expression of cancer stem cell markers, such as CD133 and CD44 correlated with hematogenous metastasis to the liver but not with peritoneal carcinomatosis or hematogenous metastasis to the central nervous system (CNS). Finally, in CRC patients with CNS metastases, increased rates of mutations in the mitogen-activated protein kinases (MAPK) pathway (KRAS and BRAF mutations) in combination with a low beta catenin expression could be detected. It can be concluded from these results that for CRC with different patterns of distant spread alternative molecular mechanisms must play a role.