Snail levels control the migration mechanism of mesenchymal tumor cells

Belgiovine,Cristina; Chiesa,Giulio; Chiodi,Ilaria; Frapolli,Roberta; Bonezzi,Katiuscia; Taraboletti,Giulia; D'incalci,Maurizio; Mondello,Chiara

doi:10.3892/ol.2016.4642

Snail levels control the migration mechanism of mesenchymal tumor cells

Authors:
- Cristina Belgiovine
- Giulio Chiesa
- Ilaria Chiodi
- Roberta Frapolli
- Katiuscia Bonezzi
- Giulia Taraboletti
- Maurizio D'incalci
- Chiara Mondello
View Affiliations

Affiliations: Institute of Molecular Genetics, National Research Council, I‑27100 Pavia, Italy, Department of Oncology, Mario Negri Institute for Pharmacological Research, I‑20156 Milan, Italy, Department of Oncology, Mario Negri Institute for Pharmacological Research, I‑24126 Bergamo, Italy
Published online on: May 30, 2016 https://doi.org/10.3892/ol.2016.4642
Pages: 767-771

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Sahai E: Mechanisms of cancer cell invasion. Curr Opin Genet Dev. 15:87–96. 2005. View Article : Google Scholar : PubMed/NCBI
2	Friedl P and Wolf K: Plasticity of cell migration: A multiscale tuning model. J Cell Biol. 188:11–19. 2010. View Article : Google Scholar : PubMed/NCBI
3	Rath N and Olson MF: Rho-associated kinases in tumorigenesis: Re-considering ROCK inhibition for cancer therapy. EMBO Rep. 13:900–908. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kaufhold S and Bonavida B: Central role of Snail1 in the regulation of EMT and resistance in cancer: A target for therapeutic intervention. J Exp Clin Cancer Res. 33:622014. View Article : Google Scholar : PubMed/NCBI
6	Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB and Friedl P: Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol. 160:267–277. 2003. View Article : Google Scholar : PubMed/NCBI
7	Carragher NO, Walker SM, Scott Carragher LA, Harris F, Sawyer TK, Brunton VG, Ozanne BW and Frame MC: Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: A link to integrin function. Oncogene. 25:5726–5740. 2006. View Article : Google Scholar : PubMed/NCBI
8	Gadea G, de Toledo M, Anguille C and Roux P: Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol. 178:23–30. 2007. View Article : Google Scholar : PubMed/NCBI
9	Berton S, Belletti B, Wolf K, Canzonieri V, Lovat F, Vecchione A, Colombatti A, Friedl P and Baldassarre G: The tumor suppressor functions of p27(kip1) include control of mesenchymal/amoeboid transition. Mol Cell Biol. 29:5031–5045. 2009. View Article : Google Scholar : PubMed/NCBI
10	Parri M, Taddei ML, Bianchini F, Calorini L and Chiarugi P: EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res. 69:2072–2081. 2009. View Article : Google Scholar : PubMed/NCBI
11	Belgiovine C, Frapolli R, Bonezzi K, Chiodi I, Favero F, Mello-Grand M, Dei Tos AP, Giulotto E, Taraboletti G, D'Incalci M and Mondello C: Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells. PLoS One. 5:e141542010. View Article : Google Scholar : PubMed/NCBI
12	Ostano P, Bione S, Belgiovine C, Chiodi I, Ghimenti C, Scovassi AI, Chiorino G and Mondello C: Cross-analysis of gene and miRNA genome-wide expression profiles in human fibroblasts at different stages of transformation. OMICS. 16:24–36. 2012. View Article : Google Scholar : PubMed/NCBI
13	Mondello C, Chiesa M, Rebuzzini P, Zongaro S, Verri A, Colombo T, Giulotto E, D'incalci M, Franceschi C and Nuzzo F: Karyotype instability and anchorage-independent growth in telomerase-immortalized fibroblasts from two centenarian individuals. Biochem Biophys Res Commun. 308:914–921. 2003. View Article : Google Scholar : PubMed/NCBI
14	Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M and Hung MC: Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 6:931–940. 2004. View Article : Google Scholar : PubMed/NCBI
15	Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, Double JA, Everitt J, Farningham DA, Glennie MJ, et al: Committee of the National Cancer Research Institute: Guidelines for the welfare and use of animals in cancer research. Br J Cancer. 102:1555–1577. 2010. View Article : Google Scholar : PubMed/NCBI
16	Belgiovine C, Chiodi I and Mondello C: Relocalization of cell adhesion molecules during neoplastic transformation of human fibroblasts. Int J Oncol. 39:1199–1204. 2011.PubMed/NCBI
17	Rowe RG, Li XY, Hu Y, Saunders TL, Virtanen I, de Garcia Herreros A, Becker KF, Ingvarsen S, Engelholm LH, Bommer GT, et al: Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J Cell Biol. 184:399–408. 2009. View Article : Google Scholar : PubMed/NCBI
18	Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K and Miyazaki K: Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 92:252–258. 2005.PubMed/NCBI
19	Ota I, Li XY, Hu Y and Weiss SJ: Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci USA. 106:20318–20323. 2009. View Article : Google Scholar : PubMed/NCBI
20	Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L and Yang J: Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 19:372–386. 2011. View Article : Google Scholar : PubMed/NCBI
21	Taddei ML, Giannoni E, Morandi A, Ippolito L, Ramazzotti M, Callari M, Gandellini P and Chiarugi P: Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells. Cell Commun Signal. 12:242014. View Article : Google Scholar : PubMed/NCBI