title: Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells.
abstract: BACKGROUND
  Mesenchymal and amoeboid movements are two important mechanisms adopted by cancer cells to invade the surrounding environment. Mesenchymal movement depends on extracellular matrix protease activity, amoeboid movement on the RhoA-dependent kinase ROCK. Cancer cells can switch from one mechanism to the other in response to different stimuli, limiting the efficacy of antimetastatic therapies.
  
  
  RESULTS
  We investigated the acquisition and molecular regulation of the invasion capacity of neoplastically transformed human fibroblasts, which were able to induce sarcomas and metastases when injected into immunocompromised mice. We found that neoplastic transformation was associated with a change in cell morphology (from fibroblastic to polygonal), a reorganization of the actin cytoskeleton, a decrease in the expression of several matrix metalloproteases and increases in cell motility and invasiveness. In a three-dimensional environment, sarcomagenic cells showed a spherical morphology with cortical actin rings, suggesting a switch from mesenchymal to amoeboid movement. Accordingly, cell invasion decreased after treatment with the ROCK inhibitor Y27632, but not with the matrix protease inhibitor Ro 28-2653. The increased invasiveness of tumorigenic cells was associated with reduced expression of Rnd3 (also known as RhoE), a cellular inhibitor of ROCK. Indeed, ectopic Rnd3 expression reduced their invasive ability in vitro and their metastatic potential in vivo.
  
  
  CONCLUSIONS
  These results indicate that, during neoplastic transformation, cells of mesenchymal origin can switch from a mesenchymal mode of movement to an amoeboid one. In addition, they point to Rnd3 as a possible regulator of mesenchymal tumor cell invasion and to ROCK as a potential therapeutic target for sarcomas.
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (CNR), Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Belgiovine
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Bonezzi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Chiodi
authors.forename: Francesco
authors.initials: F
authors.lastname: Favero
authors.forename: Maurizia
authors.initials: M
authors.lastname: Mello-Grand
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
authors.forename: Elena
authors.initials: E
authors.lastname: Giulotto
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Chiara
authors.initials: C
authors.lastname: Mondello
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics; D048430:Cell Shape / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020782:Matrix Metalloproteinases; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins