Abstract
BackgroundMesenchymal 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 FindingsWe 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.ConclusionsThese 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.
Highlights
Neoplastic transformation is a gradual process, during which cells acquire successive mutations, which mainly cause the loss of proliferation control, the ability to divide indefinitely and invade other tissues
They point to Rnd3 as a possible regulator of mesenchymal tumor cell invasion and to ROCK as a potential therapeutic target for sarcomas
Histological analysis revealed that the tumors developed by cen3tel cells at the first and second tumorigenic phases were pleomorphic sarcomas (Fig. 1B and C), those developed by phase III cen3tel cells showed a hemangiopericytoma-like vascular pattern, similar to human poorly differentiated, round-cell synovial sarcoma (Fig. 1D)
Summary
Neoplastic transformation is a gradual process, during which cells acquire successive mutations, which mainly cause the loss of proliferation control, the ability to divide indefinitely and invade other tissues. Different molecular mechanisms are responsible for the acquisition of a migratory and invasive phenotype, such as changes in signal transduction pathways involving tyrosine kinases, changes in cytoskeletal organization and in cell adhesion. The RhoA/ROCK and Rac signalling pathways are required for respectively amoeboid and mesenchymal movements, which are the main types of movements adopted by tumor cells [5,6]. The mesenchymal movement is typical of cells displaying an elongated morphology in a 3D environment; it requires integrin attachment to the extracellular matrix, formation of focal contacts and pericellular proteolysis. 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
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