S100A4 (p9Ka) protein in colon carcinoma and liver metastases: association with carcinoma cells and T-lymphocytes

Abstract

The presence of the EF-hand-calcium-binding protein S100A4 in the carcinoma cells of the primary tumour is associated with a shorter survival time of a group of breast cancer patients. In colon cancer, primary tumours as well as metastases to the liver can be studied. Here we show, using quantitative PCR applied to RNA from 24 normal colon, four liver tissues, 24 colon carcinoma specimens, and 24 livers containing colonic carcinoma metastases, that the level of S100A4 mRNA was significantly higher in the carcinomas compared to normal specimens (Mann-Whitney U-test, P=0.05), and in liver metastases compared to carcinoma specimens (P=0.039). The latter comparison included seven liver metastases and their matched primary carcinomas (P50.001) from the same patient. In situ hybridization and immunocytochemistry techniques have localized S100A4 to both carcinoma cells and lymphocytes in the malignant specimens. The percentage of specimens stained for S100A4 in the epithelial cells is significantly higher for those isolated from carcinomas and metastases than from the corresponding normal tissue, and from metastases than from corresponding carcinoma (Fisher Exact text, P50.0016, P=0.04, respectively). In most specimens, S100A4 is present in clusters of T lymphocytes and this distribution is also found in the lymphoid, uninflamed appendix. Keywords: p9Ka; S100A4; T-lymphocytes; colon carcinoma; metastasisThe EF-hand-containing protein, S100A4 (p9Ka) is closely linked with the ability of mammary tumour cells to metastasize in experimental model systems. Transfection of the gene for rat (Davies et al, 1993) or human (Lloyd et al, 1998) S100A4 into benign rat mammary cells, and the expression of S100A4 protein at an elevated level leads to the expression of a metastatic phenotype. Similar results have been obtained by over-expressing the mouse S100A4 in human MCF-7 cells (Grigorian et al, 1999). Mice, transgenic for the S100A4 gene, which over express S100A4, show no phenotype, but when these mice are mated with mice bearing, as an expressed transgene, an activated oncogene, such as c-erbB-2, which produces benign mammary tumours, offspring which express both the onco-transgene and the S100A4 transgene, exhibit tumours which also metastasize to the lungs (Davies et al, 1996). A similar result was obtained when transgenic mice bearing the mouse S100A4 transgene were mated with a strain of mice which yielded MMTV-induced mammary tumours (Ambartsumian et al, 1996).In a study of 349 patients with breast cancer, the presence of immunocytochemically-detectable S100A4 in the primary tumours is associated with their early demise when followed up for 19 years Rudland et al, 2000). This result suggests a direct link, at least in this group of patients, between the presence of S100A4 in the carcinoma cells of the primary tumour and the process of metastasis, since it is commonly believed that breast cancer patients die of metastatic spread to sites other than that of the lymph nodes. Thus it is important to establish whether the cell...

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

“…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.…”

“…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.…”

Organ-derived dendritic cells have differential effects on alloreactive T cells

“…by guest www.bloodjournal.org From dendritic cells, they have many similarities with respect to their effect on T cells. We found 2 genes previously implicated in liver homing, Cxcr6 49 and S100a4, 52 to be induced by liver-derived dendritic cells. Surprisingly, many granzymes were also up-regulated in the liver compared with spleen.…”

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

“…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.…”