Oncogene (2008) 27, 6970–6980 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW Polarity proteins in migration and invasion S Etienne-Manneville Cell polarity and migration group, Institut Pasteur and CNRS URA 2582, Paris cedex 15, France Cancer is the result of the deregulation of cell prolifera- et al., 1997). In epidermal multilayered epithelium, cells tion and cell migration. In advanced tumors, cells invade that undergo differentiation migrate perpendicularly to the surrounding tissue and eventually form metastases. the basal layer of the epithelium toward the surface of This is particularly evident in carcinomas in which the skin (Kosterand Roop, 2007). In both cases, the epithelial cells have undergone epithelial–mesenchymal directionality of migration is essential for the main- transition. Increased cell migration often correlates with tenance of a functional epithelium. Moreover, intact a weakening of intercellular interactions. Junctions cell–cell contacts maintain the epithelial structure and between neighboring epithelial cells are required to promote coordinated cell migration. Although many of establish and maintain baso-apical polarity, suggesting the molecular mechanisms underlying cell migration are that not only loss of cell–cell adhesion but also common to both normaland tumorcells, tumorcell alteration of cell polarity is involved during invasion. migration is noncoordinated and randomly oriented. Accordingly, perturbation of cell polarity is an important Tumor cells migrate as groups with no clear organiza- hallmark of advanced invasive tumors. Cell polarity is tion oras isolated single cells (Friedl, 2004; Sahai, 2005). also essential for cell migration. Indeed, a front-rear Tumor cell migration leads to alteration of the polarity axis has first to be generated to allow a cell to epithelium structure, disruption of the basal lamina migrate. Because cells migrate during invasion, cell and finally invasion of the tumorinto the underlying polarity is not completely lost. Instead, polarity is tissue. This transition from a collective to an individual modified. From a nonmigrating baso-apically polarized migration recapitulates the developmental process epithelial phenotype, cells acquire a polarized migrating known as epithelial–mesenchymal transition (EMT) mesenchymal phenotype. The aim of this review is to and serves as a good indicator of tumor progression highlight the molecular relationship between the control of (Friedl and Wolf, 2003; Guarino, 2007). During EMT, cell polarity and the regulation of cell motility during polarized epithelial cells that are tightly connected to oncogenesis. one anotherby intercellularjunctions undergotwo Oncogene (2008) 27, 6970–6980; doi:10.1038/onc.2008.347 major functional changes. First, they dissociate from neighboring cells and second, they acquire the ability to Keywords: Par proteins; epithelial mesenchymal transi- migrate away from the original tissue. The molecular tion (EMT); Rho GTPases; Wnt; Scribble mechanisms by which highly polarized and tightly joined epithelial cells transform into randomly migrat- ing cells are likely to have major functions during tumor development. Introduction The formation of distant tumorigenic foci and metas- Cell polarity is essential in cell migration tasis are the main cause of morbidity and mortality in patients with cancer. Controling tumor cell migration is Cell migration is a fundamentally polarized process. Cell a central issue in cancer treatment. Nevertheless, the polarity during cell migration encompasses several cascade of events leading to cell invasion during tumor aspects (Figure 1). It is important to distinguish random development is still poorly understood. In a normal cell migration, in which cells migrate in all directions in polarized epithelium, cell migration occurs concomi- a noncoordinated manner, from directed (or oriented) tantly to cell differentiation and is required for normal cell migration, in which cells respond to polarizing cues tissue renewal. In the gut epithelium, for instance, cells to migrate in a given direction. In both cases, cell migrate from the base of the epithelial crypt toward the polarity is required to generate a front-rear axis (Ridley top of villi until they are shed into the gut lumen (Potten et al., 2003). The small G-proteins, Cdc42, Rac and Rho, seem to be at the heart of the initial signals leading to the Correspondence: Dr S Etienne-Manneville, Cell polarity and migra- tion group, Institut Pasteur and CNRS URA 2582, 25 rue du Dr polarization of migrating cells (Charest and Firtel, Roux, 74724 Paris cedex 15, France. 2007). They participate in cell migration by regulating E-mail: [email protected] cytoskeletal reorganization, a prerequisite for cell Polarity proteins S Etienne-Manneville 6971 Figure 1 Polarity in migrating cells. In response to a chemotactic gradient, both front-rear polarization (green arrow) and direction sensing (red arrow) must occur to transform a nonpolarized and randomly oriented cell (on the left) into a fully polarized migrating cell (on the right). Front-rear polarization is required for migration per se, but is not sufficient forchemotaxis (lowerdrawing).In this case, cells undergo random migration. Cell orientation following direction sensing is crucial to promote directed (or oriented) migration, but is not sufficient to drive cell migration (upper drawing). Orientation of the nucleus-centrosome axis is a good indicator of cell orientation during directed migration of most cell types including fibroblasts, astrocytes or epithelial cells. Actin-driven protrusions are shown in red, microtubules appear in dark green and centrosome in light green. Straight red lines represent stress fibers and red patches represent focal complexes and focal adhesions. N stands for nucleus. motility (Etienne-Manneville and Hall, 2002; Charest along the chemotactic gradient (Allen et al., 1998). and Firtel, 2007). Importantly, the balance of activities Direction sensing is also strongly perturbed, when of the three proteins must be tightly controlled between Cdc42 is depleted from migrating astrocytes (Etienne- the front and the rear of the cell. A simplistic view is that Manneville and Hall, 2001). In contrast with the Cdc42 and Rac are gradually activated toward the front generation of front-rear polarity, which is essentially edge where they control actin and microtubule rearran- actin dependent, cell orientation is largely dependent on gements to promote protrusive activity, whereas Rho is microtubules (Etienne-Manneville, 2004a; Siegrist and rather active at the rear of the cells where, by inducing Doe, 2007). In a wound-healing assay, centrosome and actomyosin contractility, it controls rear-end retraction Golgi reorientation as well as microtubule network and allows forward movement. The role of Cdc42 is polarization do not occur in the absence of Cdc42 actually dual—it not only participates in the protrusive (Osmani et al., 2006) orfollowing perturbationof activity but it is also directly involved in cell orientation microtubule dynamics (Etienne-Manneville and Hall, during directed migration in response to exogenous 2001). Interestingly, expression of a constitutive active polarity cues, such as chemotactic signals or cell Cdc42 or overexpression of an active Cdc42 GEF wounding (Etienne-Manneville, 2004b). Directed migra- perturbs centrosome orientation and microtubule net- tion implies the precise orientation of the front-rear axis work reorganization. This strongly suggests that not following direction sensing. Direction sensing appears to only the activation of a polarity signaling pathway but be a major and evolutionary conserved function of also its spatially restricted localization are required for Cdc42. In chemotactic macrophages, dominant negative correct cell orientation. Cdc42 leads to random migration. In this case, cells can Whereas inhibiting front-rear polarity totally blocks still form a front-rear axis, but are unable to orient it migration, perturbing direction sensing only leads to Oncogene Polarity proteins S Etienne-Manneville 6972 random migration, during which the direction of the in apicobasal polarity. A growing body of evidence front-rear axis does not need to be determined nor even involves polarity proteins in cell migration. Polarity sustained. Although some tumorcells follow chemotac- proteins are therefore likely to be essential players tic signals, invasion of the surrounding tissue does not, during oncogenesis. in principle, require directed cell migration. This is a Epithelial cell polarity is characterized by the presence major difference with embryogenesis or adult tissue of adherens and tight junctions, which control the renewal where coordinated and directed cell migration is segregation of the plasma membrane in biochemically tightly regulated. In baso-apical polarity, generating a and functionally distinct apical and basolateral do- polarity axis is directly related to its correct orientation mains. A strict separation between these two domains is within the epithelium. This implies that signaling path- essential for an epithelium to function as a barrier. ways are common to both polarization and orientation. Three groups of proteins act together to generate and In contrast, during cell migration, front-rear polariza- maintain baso-apical polarity: (1) the Par complex, that tion and cell orientation are controlled by independent includes Parproteins