title: Snail levels control the migration mechanism of mesenchymal tumor cells.
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 behaviorin 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.
authors.affiliation: Institute of Molecular Genetics, National Research Council, I-27100 Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Belgiovine
authors.affiliation: Institute of Molecular Genetics, National Research Council, I-27100 Pavia, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Chiesa
authors.affiliation: Institute of Molecular Genetics, National Research Council, I-27100 Pavia, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Chiodi
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, I-20156 Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, I-24126 Bergamo, Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Bonezzi
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, I-24126 Bergamo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, I-20156 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Institute of Molecular Genetics, National Research Council, I-27100 Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mondello
keywords: MMP; ROCK; Rnd3/RhoE; Snail; amoeboid movement; mesenchymal movement