Prognostic significance of calcium-binding protein S100A4 in colorectal cancer

Gongoll, Silvia; Peters, Gerrit; Mengel, M.; Piso, Pompiliu; Klempnauer, Jürgen; Kreipe, Hans; Wasielewski, Reinhard von

doi:10.1053/gast.2002.36606

Cited by 127 publications

(123 citation statements)

References 22 publications

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“…In humans, an increase in S100A4 expression has been correlated with aggressiveness and worse prognosis for patients with different types of carcinoma, including colorectal, gallbladder, pancreas, bladder, gastric, breast, non-small cell lung, and prostate cancers. [11][12][13][14][15][16][17][18] The exact mechanism for the metastasis-promoting activity by S100A4 is poorly understood. S100A4 may influence growth regulation, remodeling of the extracellular matrix, angiogenesis, cell detachment, and cell motility.…”

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confidence: 99%

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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Expression of various S100 genes has been associated with clinically aggressive subtypes in a variety of different cancers. We hypothesized that S100A4 would be overexpressed in endometrial carcinoma compared to benign endometrium. Quantitative real-time RT-PCR (qRT-PCR) was used to quantify the mRNA level of S100A4 in benign endometrium (n ¼ 19), endometrioid adenocarcinoma (n ¼ 87), and non-endometrioid tumors (n ¼ 21). Immunohistochemistry was used to verify the results of qRT-PCR and to assess protein localization. Possible mechanisms of S100A4 gene regulation were also examined. S100A4 was overexpressed in the grade 3 endometrioid tumors, uterine papillary serous carcinoma, and uterine malignant mixed mü llerian tumor. Expression in grade 1 and grade 2 endometrioid tumors was comparable to that of normal endometrium, which was quite low. Expression was significantly higher in stage III and IV tumors compared with stage I. By immunohistochemistry, S100A4 was expressed in the tumor cell cytoplasm of poorly differentiated tumors, but was not detected in normal endometrial glandular epithelium. In benign endometrium, S100A4 expression was confined to stromal cells. S100A4 was not regulated by estrogen or progesterone, and its expression in tumors was not significantly correlated to estrogen receptor or progesterone receptor content. However, methylation of the S100A4 gene was detected in benign endometrium and grade 1 tumors with low S100A4 expression. In contrast, grade 3 endometrioid tumors with high S100A4 mRNA and protein expression showed no methylation of the gene. These methylation results were verified in endometrial cancer cell lines with differential baseline levels of S100A4 protein. These results suggest that hypomethylation is an important mechanism of regulating the expression of the S100A4 gene. These results support the emerging concept that hypomethylation may play a role in the upregulation of genes during later stages of tumorigenesis. Keywords: endometrial cancer; S100A gene family; S100A4; methylation Endometrial carcinoma is the most common malignant neoplasm of the female genital tract and the fourth most frequently diagnosed cancer in women, following cancers of the breast, lung, and colon. 1 On the basis of histological and clinical features, endometrial carcinoma has been classified into two types. 2-4 Type I tumors (approximately 80% of all endometrial carcinomas) are typically low-grade (grade 1 or grade 2) endometrioid adenocarcinoma, most of which are confined to the uterus and have a favorable prognosis. Type II tumors (approximately 20%) are comprised of uterine papillary serous carcinoma, malignant mixed mü llerian tumors, and clear cell carcinoma. The nature of high-grade (grade 3) endometrioid adenocarcinoma is more controversial, as a subset may behave more like the Type II tumors. Type II cancers are associated with extrauterine spread and carry a high mortality rate. Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid ...

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Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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“…Additionally, S100A4 was one of only 25 genes found upregulated in three different mammary cancer stem cell expression signatures (Gupta et al, 2009). Numerous other reports on clinical material from breast (Ismail et al, 2008;Lee et al, 2004), bladder (Matsumoto et al, 2007), colorectal (Flatmark et al, 2003;Gongoll et al, 2002), melanoma and several other types of cancer (Garrett et al, 2006) have confirmed the association between S100A4 expression, and a more severe prognosis. Collectively these findings suggest S100A4 as a major determinant of breast cancer progression.…”

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confidence: 69%

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S1004 induced significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development by, in concert with TGFα, activating MMP-3, thereby increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.

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“…The percentage of S100A4‐positive tumors in previous studies in CRC has varied considerably due to different scoring algorithms and cutoffs, patient selection, and technical reasons (e.g., antibodies used and TMAs vs. whole sections). Here, we used a cutoff for strong staining of 66%, which is similar to the two other large series where TMAs were employed 7, 9. Gongoll and coworkers used 50% as a cutoff, but did not evaluate cytoplasmic and nuclear staining separately, whereas Kho et al.…”

Section: Discussionmentioning

confidence: 99%

“…In CRC, S100A4 is overexpressed compared to normal mucosa and adenomas, and higher expression has been observed in liver metastases than in primary tumors 4, 5. Several studies have shown that S100A4 is a strong predictor of poor survival in patients undergoing curatively intended surgery 6, 7, 8, 9, 10, 11, 12. The protein is localized in the nucleus and the cytoplasm, and nuclear expression seems to be the best prognostic parameter 6, 13.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Prognostic significance of calcium-binding protein S100A4 in colorectal cancer

Cited by 127 publications

References 22 publications

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

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

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