Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population‐based series and a randomized phase III study on adjuvant chemotherapy

Abstract

Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis‐promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population‐representative cohort and a randomized phase III study on adjuvant 5‐fluorouracil/levamisole. Sensitivity to treatment with 5‐fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse‐free (P < 0.001 and P = 0.010) and overall survival (P = 0.046 and P = 0.006) in univariate analysis. In multivariate analysis, nuclear S100A4 was a predictor of poor relapse‐free survival in the consecutive series (P = 0.002; HR 1.9), but not in the randomized study. Sensitivity to treatment with 5‐fluorouracil was not affected by S100A4 expression in in vitro cell culture assays, and there was no indication from subgroup analyses in the randomized study that S100A4 expression was associated with increased benefit of adjuvant treatment with 5‐fluorouracil/levamisole. The present study confirms that nuclear S100A4 expression is a negative prognostic biomarker in colorectal cancer, but the clinical utility in selection of patients for adjuvant fluoropyrimidine‐based chemotherapy is limited.

Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer

“…Optimization of the antibody concentration was performed (dilutions from 1:250 to 1:2000) and a dilution of 1:500 (from a stock solution of 0.9 mg/ml) was chosen, which is similar to a parallel study in colorectal cancer (CRC) [32]. The staining procedure was done according to the EnVision™ FLEX+ (mouse; Dako, Agilent Technologies, Glostrup, Denmark) protocol (described in [33]).…”

S100A4 in cancer progression and metastasis: A systematic review

“…S100A4 protein was shown to be at the proximity of cyclin B1 and localized in the area corresponding to the centrosomes in mitotic cells before chromosome segregation [ 100 ]. On the contrary, nuclear S100A4 protein could be a negative prognostic biomarker in CRC patients with stage II/III [ 101 ]. Recently, a non-invasive, plasma-based method to detect S100A4 mRNA in the blood circulation provided a novel biomarker with a high sensitivity and specificity for diagnosis, prognosis, and monitoring of treatment responses of CRC patients [ 102 ].…”

Erlotinib induces the human non–small‐cell lung cancer cells apoptosis via activating ROS‐dependent JNK pathways

“…It has been confirmed that induced oxidant stress can be a potential effective strategy selectively toxic toward cancer cells exerted by many chemotherapeutic drugs. Thus, ROS has been recognized as an important target for the development of anticancer drugs .…”