The role of S100a4 ( Mts1 ) in Apc - and Smad4-driven tumour onset and progression

• Published in: European journal of cancer (1990) 2016-11, Vol.68, p.114-124
• Main Authors: Atlasi, Yaser, Noori, Rubina, Marolin, Ivana, Franken, Patrick, Brandao, Joana, Biermann, Katharina, Collini, Paola, Grigorian, Mariam, Lukanidin, Eugene, Ambartsumian, Noona, Fodde, Riccardo
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Animals; Apc; Carcinogenesis - genetics; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Desmoids; Fibromatosis, Aggressive - genetics; Gene Knock-In Techniques; Hematology, Oncology and Palliative Medicine; Humans; Intestinal Neoplasms - genetics; Mice; Mice, Knockout; Mts1; Mutation; Proto-Oncogene Proteins p21(ras) - genetics; S100 Calcium-Binding Protein A4 - genetics; S100 Calcium-Binding Protein A4 - metabolism; S100a4; Smad4; Smad4 Protein - genetics
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2016.09.012

Abstract Introduction S100a4 is a calcium-binding protein belonging to the family of S100-proteins, highly expressed in different stromal cell types. S100A4 has been reported as a prognostic marker in colorectal cancer in association with tumour progression and metastasis. Methods In this study, we analysed the in vivo role of S100a4 in intestinal tumour initiation and progression using different transgenic and knockout mouse models. Results We found that genetic ablation or overexpression of S100a4 in both Apc- and Smad4-mutant mice do not affect tumour initiation in the intestinal tract. In contrast, S100a4 epithelial overexpression in Apc 1638N/+ /KRAS V12G mice increases the dissemination of intestinal tumour cells to the liver, in agreement with its role in tumour metastasis. Moreover, we report a novel role for S100a4 in desmoid formation where S100a4 deficiency results in a significant reduction of the tumour burden characteristic of the Apc 1638N model. In agreement with these results, S100a4 appears to be co-expressed together with mesenchymal stem cell (MSC) markers in desmoid tumours from Apc 1638N/+ mice, as well as from sporadic and hereditary human desmoids. Conclusion Our data provide the first report on the in vivo role of S100a4 in intestinal tumourigenesis and describe a new role for S100a4 in the aetiology of desmoids formation.