Rac and Rho GTPases in cancer cell motility control

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.

Figure 1

Cell migration in 3 D matrix. See text for detailed explanation of motility steps.

Figure 2

Reciprocal regulation between Rho and Rac during mesenchymal or amoeboid motility styles. ROS act as a balance for Rac-1/RhoA antagonism. Indeed Rac-1, which drives oriented mesenchymal motility, leading edge protrusion and lamellipodia formation, is a key molecular player of regulated intracellular ROS sources. Rho activation is responsible for amoeboid motility, a non-oriented movement which enables the cell to squeeze between gaps of ECM instead of proteolytically degrade it. Hence, upon Rac activation oxidation/inactivation of the LMW-PTP which normally activate the Rho regulator p190Rho-GTPase, leads to RhoA down-regulation. Conversely, low ROS intracellular content lead to RhoA activation, through LMWPTP activation and p190RhoGAP dephosphorylation/inactivation. Activated RhoA is able to inhibit Rac-1 through the ARHGAP2 (also named chimerin-2), while Rac1 activates WAVE2 which in turn inhibits RhoA.

Figure 3

Involvement of Rho proteins at different stages of tumor progression. A) Maintenance of normal epithelial cell polarity. B) Benign tumors: once a tumor is initiated, Rho proteins can contribute to tumor development by stimulating dedifferentiation, growth and loss of cell polarity. C) Locally invasive tumors: Rho proteins can contribute to tumor development by altering cell-cell and cell-matrix adhesion, Rho proteins allow tumor cells to become invasive. D) Metastasis to distant site: Rho and ROCK are required for tumor cells to cross endothelial cell layers. RhoC promotes expression of angiogenic factors, leading to an increase in vascularization of the tumor.