Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

Abstract

Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes.The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients' plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P < 0.0001) and all disease stages (P < 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P ‫؍‬ 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients' risk for metastasis. Gastrointestinal cancers, such as colon, rectal, and gastric cancers, belong to the malignancies with the highest incidences and mortalities worldwide. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. 1,2 To date, primary colorectal carcinomas cannot be sufficiently distinguished with respect to clinical outcome parameters, such as local recurrence and metastasis, by means of conventional clinical and histopathological/immunhistochemical examination. The tumor-node-metastasis (TNM) classification represents the main tool for identifying prognostic differences among patients with early-stage colorectal cancer. 3 This is also true for gastric cancer, currently evaluated by histological staging as well. 4 Therefore, early detection of tumors and metastasis is critical for improving treatment strategies and patient outcomes. There is a clear need for development of molecular markers and of simple tests that can clinically be used for detection, prognostication, and therapy monitoring of cancer. A noninvasive blood test for the early identification of high-risk cancer patients is therefore of special interest. Circulating nucleic acids and, in particular, cell-free mRNA can be detected in plasma and permit plasma-based expression profiling. 5-9 It was recently reported that extracellular plasma RNA from colon cancer pa...

Underlying Mechanisms for Distant Metastasis - Molecular Biology

“…For cancer patients, high mRNA and protein levels of S100A4 have shown to correlate with decreased overall and disease-free survival. Overexpression is correlated with aggressive tumor growth and formation of metastasis [88][89][90][91]. S100A4 is a transcriptional target of β-catenin [88].…”

“…Overexpression is correlated with aggressive tumor growth and formation of metastasis [88][89][90][91]. S100A4 is a transcriptional target of β-catenin [88]. It is located in the cytoplasm, the nucleus, and the extracellular space.…”

S100A4 Protein in Inflammatory Bowel Disease: Results of a Single Centre Prospective Study

“…On the basis of the available literature, where S100A4 was investigated either in the serum (51 studies; two of them in a relation to a gastroenterology disorderliver fibrosis and cirrhosis (44,45)) or in plasma samples (26 studies; two of them were accomplished in gastric and colorectal cancer (46,47)), we decided to investigate serum S100A4. All individuals enrolled into our study including all healthy controls and all IBD patients were investigated in the same manner.…”

S100A4 expression and prognosis of gastric cancer: a meta-analysis

“…In China, there are approximately 160,000 deaths from gastric cancer annually (Chen et al, 2004). A number of studies have reported the relationship between S100A4 expression and the prognosis of gastric cancer (Yonemura et al, 2000;Yu et al, 2006;Huang et al, 2008;Wang et al, 2010;Feng et al, 2011;Stein et al, 2011;Zhao et al, 2013;Li et al, 2013) However, the association of S100A4 with gastric prognosis remains unclear.…”

“…Subsequent studies identified 16 members of this family, based on amino acid sequence homology and similar structural properties (Schafer and Heizmann, 1996). S100A4 is highly expressed in many cancers (Kikuchi et al, 2006;Ai et al, 2008;Kwak et al, 2010) and its presence predicts a poor outcome, such as in pancreatic cancer, (Ai et al 2008), colorectal cancer (Kwak et al, 2010), ovarian carcinoma (Kikuchi et al, 2006), bladder carcinoma (Yao et al 2007), esophageal carcinoma (Ji et al, 2004), and gastric carcinoma (Yonemura et al, 2000;Yu et al, 2006;Huang et al, 2008;Feng et al, 2011;Wang et al, 2010;Stein et al, 2011;Zhao et al, 2013;Li et al, 2013). However, the prognostic value of S100A4 in patients with gastric cancer is still controversial.…”