Rac and Rho GTPases in cancer cell motility control

Matteo Parri,Paola Chiarugi

doi:10.1186/1478-811x-8-23

Matteo Parri, Paola Chiarugi

Open Access

https://doi.org/10.1186/1478-811x-8-23

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Abstract

Rho GTPases represent a family of small GTP-binding proteins involved in cell cytoskeleton organization, migration, transcription, and proliferation. A common theme of these processes is a dynamic reorganization of actin cytoskeleton which has now emerged as a major switch control mainly carried out by Rho and Rac GTPase subfamilies, playing an acknowledged role in adaptation of cell motility to the microenvironment. Cells exhibit three distinct modes of migration when invading the 3 D environment. Collective motility leads to movement of cohorts of cells which maintain the adherens junctions and move by photolytic degradation of matrix barriers. Single cell mesenchymal-type movement is characterized by an elongated cellular shape and again requires extracellular proteolysis and integrin engagement. In addition it depends on Rac1-mediated cell polarization and lamellipodia formation. Conversely, in amoeboid movement cells have a rounded morphology, the movement is independent from proteases but requires high Rho GTPase to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible and several moving cells, including tumor cells, show an high degree of plasticity in motility styles shifting ad hoc between mesenchymal or amoeboid movements. This review will focus on the role of Rac and Rho small GTPases in cell motility and in the complex relationship driving the reciprocal control between Rac and Rho granting for the opportunistic motile behaviour of aggressive cancer cells. In addition we analyse the role of these GTPases in cancer progression and metastatic dissemination.

Highlights

Rho GTPases represent a family of small GTP-binding proteins involved in cell cytoskeleton organization, migration, transcription, and proliferation
The exchange of GDP to GTP and the activation of Rho GTPases is catalyzed by guanine nucleotide exchange factors (GEFs), which act downstream of numerous growth factor receptors, integrins, cytokine receptors, and cadherins
Metastasis is a multistage process needing a strong adaptability of cells to the different microenvironments within primary tumors, in the extracellular matrix (ECM), in blood or lymphatic streams and in the metastatic niche

Summary

Conclusions

Metastasis is a multistage process needing a strong adaptability of cells to the different microenvironments within primary tumors, in the ECM, in blood or lymphatic streams and in the metastatic niche. The combined treatments aimed at blocking simultaneously both modes of migration strongly inhibit the opportunistic behaviour of cancer cells, thereby limiting their invasive potential. These data indicate that the winning strategy to combat successful metastatic diffusion of aggressive cancer cells is either a combinatory treatment targeting both invasive styles, or the identification of single molecular targets driving the ability of cancer cells to adapt to environmental changes, i. The identification of the molecular mediators of plasticity in cell motility is still at its infancy, but it will be surely the challenge to really target the opportunistic motility of cancer cells [69]

20. Werner E

24. Hall A

Findings

55. Friedl P