Snail levels control the migration mechanism of mesenchymal tumor cells

Abstract

Abstract. Cancer cells use two major types of movement:Mesenchymal, which is typical of cells of mesenchymal origin and depends on matrix metalloproteinase (MMP) activity, and amoeboid, which is characteristic of cells with a rounded shape and relies on the activity of Rho-associated kinase (ROCK). The present authors previously demonstrated that, during neoplastic transformation, telomerase-immortalized human fibroblasts (cen3tel cells) acquired a ROCK-dependent/MMP independent mechanism of invasion, mediated by the downregulation of the ROCK cellular inhibitor Round (Rnd)3/RhoE. In the present study, cen3tel transformation was also demonstrated to be paralleled by downregulation of Snail, a major determinant of the mesenchymal movement. To test whether Snail levels could determine the type of movement adopted by mesenchymal tumor cells, Snail was ectopically expressed in tumorigenic cells. It was observed that ectopic Snail did not increase the levels of typical mesenchymal markers, but induced cells to adopt an MMP-dependent mechanism of invasion. In cells expressing ectopic Snail, invasion became sensitive to the MMP inhibitor Ro 28-2653 and insensitive to the ROCK inhibitor Y27632, suggesting that, once induced by Snail, the mesenchymal movement prevails over the amoeboid one. Snail-expressing cells had a more aggressive behavior in vivo, and exhibited increased tumor growth rate and metastatic ability. These results confirm the high plasticity of cancer cells, which can adopt different types of movement in response to changes in the expression of specific genes. Furthermore, the present findings indicate that Rnd3 and Snail are possible regulators of the type of invasion mechanism adopted by mesenchymal tumor cells.

An X-ray shielded irradiation assay reveals EMT transcription factors control pluripotent adult stem cell migration in vivo in planarians

“…Enhanced Snail gene expression has been reported in several cancer types, including ovarian carcinoma (Davidson et al, 2012), breast tumors (Blanco et al, 2002;Elloul et al, 2005), gastric cancers (Peng et al, 2014;Rosivatz et al, 2002), hepatocellular carcinomas (Miyoshi et al, 2005;Sugimachi et al, 2003), colon cancers (Pálmer et al, 2004) and synovial sarcomas (Saito et al, 2004). Overexpression or downregulation of Snail has been shown to modulate invasiveness and metastasis in in vitro cancer cell culture studies (Adhikary et al, 2014;Belgiovine et al, 2016;Fan et al, 2012;Horvay et al, 2015;Sharili et al, 2013;Smith et al, 2014;Villarejo et al, 2015). Similarly, zeb-1 overactivity has also been implicated in tumorigenesis.…”

Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells

“…In the present study, cen3tel cells at ~1,000 population doublings (PDs) after telomerase immortalization were used. These cells are tumorigenic and metastatic in nude mice and carry a mutation in the TP53 codon 161, which has been used to confirm the identity of the cen3tel cells used in the present study (30,35).…”

Cellular response to glutamine and/or glucose deprivation in in�vitro transformed human fibroblasts

“…Cells and cell culture. The cen3tel cells used in this study belong to the cen3tel cellular system, which was developed from telomerase-immortalized fibroblasts that gradually underwent transformation during propagation in culture (13)(14)(15)(16)(18)(19)(20). Cen3tel cells underwent approximately 1,000 population doublings after telomerase immortalization.…”