Diagnostic value of syndecan-4 protein expression in colorectal cancer

Abstract

The prognosis of patients with colorectal cancer (CRC) is highly dependent on the disease stage at diagnosis. Therefore, it is crucial to study molecules involved in the progression of colorectal cancer tumorigenesis and to shed light on their potential use as targetable proteins in diagnostics and therapy. As syndecan-4 (SDC4) is a transmembrane proteoglycan with important functions in cell adhesion, migration, cytoskeleton organization, and gene expression through the binding of extracellular matrix molecules, it might play a role in local tumor cell invasion. To clarify its impact on the progression of CRC, we analyzed 177 patients for SDC4 expression in colon carcinoma tissue, lymph node and liver metastasis under consideration of specific morphological features and cellular elements of CRC. Highly upregulated SDC4 was particularly expressed at the tumor invasion front. Expression was strongest in tumor cell buds appearing as membranous expression polarized to peritumoral stromal cells. Increased SDC4 expression directed to the tumor-stromal- or tumor-endothelial-interface was also confirmed for metastasis and angioinvasive tumor cell clusters. Furthermore, strong immunoreactivity of SDC4 in fibroblasts and macrophages being in contact with invasive tumor cells suggests a cooperation between the different types of cells in tumor progression at the cell-matrix interface and a role for SDC4 in tumor cells attached to the extracellular matrix. Overexpression of SDC4 in tumor cells at the invasion front was significantly associated with progressive pathological features and inversely related to disease-free and overall survival. Therefore, overexpression of SDC4 may be a predictor for poor prognosis in patients with CRC and might prove useful in clinical practice, thus identifying patients with potential disease progression. Further investigations will have to reveal the functional role of SDC4 in tumor cell buds, fibroblasts and macrophages at the tumor stromal interface to confirm that SDC4 might also be a possible therapeutic target for the treatment of patients with advanced CRC.

Keywords: Colorectal cancer; Invasion; Syndecan; Tumor budding.