Multifaceted Role of Rho Proteins in Angiogenesis

Breast and Ovarian Cancer Risk Evaluation Program, University of Michigan Comprehensive Cancer Center, 7217 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0948, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 4.53). 11/2005; 10(4):291-8. DOI: 10.1007/s10911-006-9002-8
Source: PubMed


The Rho family of GTPases is part of the Ras superfamily. The Rho, Rac, and Cdc42 members of the family are present in mammalian cells and have been the subject of attention of researchers due to their vast spectrum of functions. Rac 1, Cdc42, and RhoA are well-known for their role in the regulation of the actin cytoskeleton in promoting the formation of lamellipodia, filopodia, and stress fibers, respectively. The Rho proteins also participate in the control of cell growth, motility, cell-cell adhesions, morphogenesis, cytoskeletal dynamics, and cellular trafficking. The mechanisms for eliciting these functions have become clearer during the last decade. Concordant with their roles in multiple processes of cellular control, the Rho proteins have been shown to be involved in tumor growth, progression, metastasis, and now angiogenesis.

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    • "The specific functions of RhoB have not been described in detail yet, but experimental studies have shown that RhoB is down-regulated in human tumours and that its expression is inversely related to tumour progression [15]. In addition, it was found that Cdc42 is involved in increased cellular motility via participation in the filopodia formation process [16]. "
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    ABSTRACT: Purpose. The aim of this study was to examine the expression of ERM (ezrin, moesin) and Rho (RhoA, RhoB and Cdc42) proteins in breast cancer (BC) patients and to investigate the relationship between the sub-cellular localisation of these proteins and clinicopathological characteristics and patient survival. Methods. The expression and specific sub-cellular distribution of the ERM/Rho proteins was analysed by immunohistochemistry in a homogeneous group of 85 stage II ductal BC patients with a follow-up of 15 years. Results. Enhanced immunoreactivity of all analysed proteins was found to be associated with the presence of lymph node metastases (ezrin, P=0.047, moesin, P=0.038, RhoA, P=0.024, RhoB, P=0.004 and Cdc42, P=0.047). Nuclear localisation of ezrin was found to correlate with the presence of lymph nodes metastases (P=0.004) and with histological de-differentiation (P=0.015). In contrast, we found that the nuclear topography of RhoA and Cdc42, and the perinuclear localisation of RhoB, were strongly associated with a lack of nodal metastases (P=0.008, P=0.048, P=0.001, respectively), whereas a decreased reactivity of RhoA in the stromal compartment of BC tumours was associated with the presence of lymph node metastases (P=0.011). No relationship was observed between ERM/Rho protein expression and oestrogen receptor (ER), progesterone receptor (PgR) or HER-2 reactivity in the BC cells. Also, ERM/Rho protein expression did not predict patient survival, but RhoB over-expression in the stromal compartment of the tumours was found to be associated with a better prognosis (P=0.0106). Conclusions. The ERM/Rho immunoprofile and the assessment of its specific sub-cellular localisation may be instrumental for the prediction of lymph node metastases in ductal BC patients.
    Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2013; 36(3). DOI:10.1007/s13402-013-0125-9 · 4.17 Impact Factor
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    • "The Rho family of GTPases, viz., Rac1, cdc42, and RhoA, play an important role in actin cytoskeleton regulation of lamellipodia and filopodia formation, thus controlling cell adhesion, motility, and growth [48,49]. Rac activation is dependent on the interaction of uPAR with Vn followed by protrusive activity and lamellipodia formation [10]. "
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    ABSTRACT: The angiogenic potential of a cell requires dynamic reorganization of the cytoskeletal architecture that involves the interaction of urokinase-type plasminogen activator receptor (uPAR) with the extracellular matrix. This study focuses on the effect of uPAR deficiency (uPAR-/-) on angiogenic function and associated cytoskeletal organization. Utilizing murine endothelial cells, it was observed that adhesion, migration, proliferation, and capillary tube formation were altered in uPAR-/- cells compared to wild-type (WT) cells. On a vitronectin (Vn) matrix, uPAR-/- cells acquired a "fried egg" morphology characterized by circular actin organization and lack of lamellipodia formation. The up-regulation of β1 integrin, FAK(P-Tyr925), and paxillin (P-Tyr118), and decreased Rac1 activation, suggested increased focal adhesions, but delayed focal adhesion turnover in uPAR-/- cells. This accounted for the enhanced adhesion, but attenuated migration, on Vn. VEGF-enriched Matrigel implants from uPAR-/- mice demonstrated a lack of mature vessel formation compared to WT mice. Collectively, these results indicate that a uPAR deficiency leads to decreased angiogenic functions of endothelial cells.
    Vascular Cell 05/2011; 3(1):10. DOI:10.1186/2045-824X-3-10
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    • "Some reports indicate that RhoA, RhoC and their downstream target ROCK are needed for cancer cell extravasation [130]. Interestingly, RhoC can induce the production of angiogenic factors in breast cancer, and this could help promote entry into blood vessels and thereby metastasis dissemination [105]. Unlike RhoA and RhoC, RhoB is often downregulated in human tumors and its expression inversely correlates with tumor aggressiveness. "
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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.
    Cell Communication and Signaling 09/2010; 8(1):23. DOI:10.1186/1478-811X-8-23 · 3.38 Impact Factor
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