The Metastasis-Associated Gene S100A4 Is a Novel Target of β-catenin/T-cell Factor Signaling in Colon Cancer

Stein, Ulrike; Arlt, Franziska; Walther, Wolfgang; Smith, Janice; Waldman, Todd; Harris, Erik; Mertins, Susan D.; Heizmann, Claus W.; Allard, David; Birchmeier, Walter; Schlag, Peter M.; Shoemaker, Robert H.

doi:10.1053/j.gastro.2006.08.041

Cited by 196 publications

(206 citation statements)

References 46 publications

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“…This finding is confirmed by former studies analyzing S100A4 mRNA levels in solid tissues of colon cancer patients. 29,45 We and others determined an independence of S100A4 mRNA expression determined in colon tumor tissues of stages I, II, and III.…”

Section: Discussionmentioning

confidence: 96%

“…This finding was also revealed by earlier studies performed with colon cancer tissues. 29,45 In addition, S100A4 mRNA expression is of prognostic value for the development of metachronous distant metastases when determined in tissues of the nonmetastasized primary tumor. 29 However, only three of all newly diagnosed 64 nonmetastasized primary tumors, with blood samples taken at the day of the first diagnosis, have so far developed distant metastases metachronously.…”

Section: Discussionmentioning

confidence: 99%

“…29,45 In addition, S100A4 mRNA expression is of prognostic value for the development of metachronous distant metastases when determined in tissues of the nonmetastasized primary tumor. 29 However, only three of all newly diagnosed 64 nonmetastasized primary tumors, with blood samples taken at the day of the first diagnosis, have so far developed distant metastases metachronously. Therefore, the prognostic impact of S100A4 transcripts in plasma for the individual metachronous metastasis risk for patients newly diagnosed with a primary tumor only cannot be so far.…”

Section: Discussionmentioning

confidence: 99%

“…[31][32][33][34] We demonstrated previously that S100A4 transcripts, when quantitatively determined in the nonmetastasized primary tumor, have potential value for prognosis of metastasis formation in colon cancer patients. 29 Here we provide, for the first time, a reliable and simple plasma-based assay for transcript quantification of the metastasis-promoting gene S100A4. We demonstrate its applicability and diagnostic value for newly diagnosed or already treated patients with colorectal and gastric cancer.…”

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confidence: 99%

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

Stein

Burock

Herrmann

et al. 2011

The Journal of Molecular Diagnostics

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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...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Stein

Burock

Herrmann

et al. 2011

The Journal of Molecular Diagnostics

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“…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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Clinical relevance of circulating MACC1 and S100A4 transcripts for ovarian cancer

et al. 2019

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Metastasis‐associated in colon cancer 1 ( MACC 1) and S100 calcium‐binding protein A4 (S100A4) are prominent inducers of tumor progression and metastasis. For the first time, we systematically tracked circulating serum levels of MACC 1 and S100A4 transcripts in the course of surgery and chemotherapy and analyzed their clinical relevance for ovarian cancer. MACC 1 and S100A4 transcripts were quantified in a total of 318 serum samples from 79 ovarian cancer patients by RT ‐ qPCR and digital droplet PCR , respectively. MACC 1 and S100A4 transcripts were significantly elevated in serum of ovarian cancer patients, compared to healthy controls ( P = 0.024; P < 0.001). At primary diagnosis, high levels of MACC 1 or S100A4 correlated with advanced FIGO stage ( P = 0.042; P = 0.008), predicted suboptimal debulking surgery and indicated shorter progression‐free survival ( PFS ; P = 0.003; P = 0.001) and overall survival ( OS ; P = 0.001; P = 0.002). This is the first study in ovarian cancer to propose circulating MACC 1 and S100A4 transcripts as potential liquid biopsy markers.

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The Metastasis-Associated Gene S100A4 Is a Novel Target of β-catenin/T-cell Factor Signaling in Colon Cancer

Cited by 196 publications

References 46 publications

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

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

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

Clinical relevance of circulating MACC1 and S100A4 transcripts for ovarian cancer

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