Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells

TY - JOUR

T1 - Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells

AU - Belgiovine, Cristina

AU - Frapolli, Roberta

AU - Bonezzi, Katiuscia

AU - Chiodi, Ilaria

AU - Favero, Francesco

AU - Mello-Grand, Maurizia

AU - Dei Tos, Angelo P

AU - Giulotto, Elena

AU - Taraboletti, Giulia

AU - D'Incalci, Maurizio

AU - Mondello, Chiara

PY - 2010/11/30

Y1 - 2010/11/30

N2 - 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.METHODOLOGY AND PRINCIPAL FINDINGS: 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.

AB - 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.METHODOLOGY AND PRINCIPAL FINDINGS: 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.

KW - Animals

KW - Blotting, Western

KW - Cell Line, Transformed

KW - Cell Movement/genetics

KW - Cell Shape/genetics

KW - Female

KW - Fibroblasts/metabolism

KW - Gene Expression

KW - Gene Expression Profiling

KW - Humans

KW - Matrix Metalloproteinases/genetics

KW - Mesoderm/metabolism

KW - Mice

KW - Mice, Nude

KW - Mice, SCID

KW - NIH 3T3 Cells

KW - Neoplasm Invasiveness

KW - Neoplasm Metastasis

KW - Neoplasms, Experimental/genetics

KW - Oligonucleotide Array Sequence Analysis

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - rho GTP-Binding Proteins/genetics

U2 - 10.1371/journal.pone.0014154

DO - 10.1371/journal.pone.0014154

M3 - Journal article

C2 - 21209796

SN - 1932-6203

VL - 5

SP - e14154

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 11

ER -