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Cell and Tissue Polarity As a Non-Canonical Tumor Suppressor

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Cell and Tissue Polarity As a Non-Canonical Tumor Suppressor Commentary 1141 Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor Minhui Lee1,2 and Valeri Vasioukhin1,3,* 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., C3-168, Seattle, WA 98109, USA 2Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA 3Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA *Author for correspondence (e-mail: [email protected]) Accepted 19 February 2008 Journal of Cell Science 121, 1141-1150 Published by The Company of Biologists 2008 doi:10.1242/jcs.016634 Summary Correct establishment and maintenance of cell polarity is and differentiation of cancer stem cells. Data from in vivo and required for the development and homeostasis of all three-dimensional (3D) cell-culture models demonstrate that metazoans. Cell-polarity mechanisms are responsible not only tissue organization attenuates the phenotypic outcome of for the diversification of cell shapes but also for regulation of oncogenic signaling. We suggest that polarized 3D tissue the asymmetric cell divisions of stem cells that are crucial for organization uses cell-cell and cell-substratum adhesion their correct self-renewal and differentiation. Disruption of cell structures to reinforce and maintain the cell polarity of pre- polarity is a hallmark of cancer. Furthermore, recent evidence cancerous cells. In this model, polarized 3D tissue organization indicates that loss of cell polarity is intimately involved in functions as a non-canonical tumor suppressor that prevents cancer: several crucial cell-polarity proteins are known proto- the manifestation of neoplastic features in mutant cells and, oncogenes or tumor suppressors, basic mechanisms of cell ultimately, suppresses tumor development and progression. polarity are often targeted by oncogenic signaling pathways, and deregulation of asymmetric cell divisions of stem or progenitor cells may be responsible for abnormal self-renewal Key words: Cancer, Cell polarity, Stem cells Introduction structural organization usually accompanies neoplastic The human body consists of billions of cells that exist together as transformation. To understand why cells become disorganized in an intricately organized and mutually supportive community. This solid tumors, it is important to understand the mechanisms that are cell community is a dynamic system that is maintained by a well- responsible for normal tissue organization. Two components are Journal of Cell Science regulated balance between cell proliferation and death. However, required for this function: (1) the establishment and maintenance when this balance is skewed in favor of cell accumulation, the of cell polarity and, (2) spatially organized intercellular adhesion. result is tumor development and, potentially, the death of the entire Much of what is known about the mechanisms of apical-basal cell cell community. Fortunately, cells have evolved many mechanisms polarity (Fig. 2) comes from studies in Drosophila melanogaster to prevent such an unfavorable development. Loss of cell polarity (Bilder, 2004; Wodarz, 2005). Whereas mechanisms of cell polarity and subsequent tissue disorganization is a hallmark of cancer are quite complex, three groups of proteins play a central role in (Fig. 1). Although loss of cell polarity was previously considered the establishment and maintenance of apical-basal cell polarity. a by-product of abnormal cell accumulation, recent evidence The Crumbs-Pals1(Stardust)-Patj and the Par3(Bazooka)-Par6- supports the idea that disruption of cell-polarity mechanisms plays aPKC protein complexes localize to the apical membrane domain a causal role in tumor initiation. This Commentary concentrates on and promote apical-membrane-domain identity (Margolis and the role of cell and tissue polarity mechanisms as potential non- Borg, 2005; Suzuki and Ohno, 2006). Their function is antagonized canonical tumor suppressors. Unlike canonical tumor suppressors by the basolaterally localized Lethal giant larvae (Lgl), Scribble that function autonomously within the cell, higher-order tissue (Scrib) and Discs large (Dlg) proteins, which together promote polarity may function as a non-cell-autonomous tumor suppressor basolateral membrane identity (Bilder, 2004) (Fig. 2). Epistatic that relies on the symbiotic relationship of a community of cells to genetic experiments in Drosophila revealed that the apical aPKC- suppress the malignant phenotype of individual mutant cells in Par3-Par6 protein complex and the basolateral Lgl, Scrib and Dlg order to secure the further survival of the entire community. Here, proteins are involved in a tug-of-war-type interaction in which a we will discuss the evidence implicating cell-polarity mechanisms fine balance between their activities defines the boundary position in cancer development and progression, and discuss the potential and the sizes of the apical and basolateral membrane domains mechanisms responsible for a hypothetical tumor-suppressor (Suzuki and Ohno, 2006). Although the molecular mechanisms of function of three-dimensional (3D) tissue organization. mutual inhibition between the apical Par3-Par6-aPKC complex and the basolateral Lgl, Scrib and Dlg proteins are only beginning to Core mechanisms of cellular polarity and their be understood, an important discovery revealed that aPKC connection to the apical junctional complex phosphorylates and ‘inactivates’ Lgl at the apical membrane Histological analyses of mammalian organisms reveal an domain (Betschinger et al., 2003; Plant et al., 2003). The molecular extraordinarily complex organization of cells in normal organs and basis for the reverse inhibitory interaction by Lgl, Scrib and Dlg is tissues. Focal disruption or complete loss of this high-order unknown, although the basolateral cell-polarity-protein Par1 1142 Journal of Cell Science 121 (8) A Par6 Basement membrane aPKC Par3 P P Lgl B Lgl Par1 Fig. 1. Disruption of cell polarity and tissue disorganization is a hallmark of Dlg Scrib advanced epithelial tumors. (A) Normal simple epithelium comprises a monolayer of individual cells that display distinct apical-basal polarity. Cells are tightly packed and connected to each other by the apical junctional Integrin Integrin complexes (blue), which separate apical (red) and basolateral (green) Integrin Integrin membrane domains. (B) Cells in high-grade epithelial tumors display loss of Basement membrane apical-basal polarity and overall tissue disorganization. Fig. 2. The core mechanisms of apical-basal cell polarity. Cell-polarity phosphorylates and inhibits Par3 by promoting its dissociation complexes that contain the Par3-Par6-aPKC protein complex (and the from the Par6-aPKC complex (Benton and St Johnston, 2003). Crumbs-Pals1-Patj complex; not shown) localize to the apical membrane domain and promote apical membrane identity. The function of Par3-Par6- In epithelial tissues, the apical and basolateral membrane aPKC complex is counteracted by the Dlg, Scrib, Lgl and Par1 proteins that domains are separated by a physical barrier called the apical localize to the basal membrane domain, and promote basolateral-membrane- junctional complex (AJC) (Fig. 2), which is also the most domain identity. aPKC counteracts the activity of basal polarity proteins via significant epithelial cell-cell adhesion structure and comprises direct phosphorylation and ‘inactivation’ of Lgl. Although the mechanisms that are responsible for negative regulation of Par3-Par6-aPKC activity by the tight junctions (TJs) and adherens junctions (AJs) (Hartsock and Dlg, Scrib and Lgl proteins are not well understood, basal Par1 can negatively Nelson, 2007). Whereas TJs are crucial for epithelial barrier regulate the apical polarity complex by phosphorylation and inactivation of function by providing a tight seal between the membranes of the apical Par3. neighboring cells, AJs use the forces that are generated by the actin cytoskeleton to keep the cellular membranes of neighboring cells together (Hartsock and Nelson, 2007; Perez-Moreno and Fuchs, AJCs are the major signaling centers that serve as biosensors of the 2006; Vasioukhin et al., 2000). Cell polarity mechanisms have an external cellular environment and mediate communication between intimate relationship with the AJCs and the activities of the apical the neighboring cells in the normal organism (Lien et al., 2006). and basolateral polarity complexes are required for maintenance of We will now discuss what happens to cell polarity and AJCs in Journal of Cell Science AJCs (Bilder and Perrimon, 2000; Chen and Macara, 2005; cancer. Firestein and Rongo, 2001; Harris and Peifer, 2007; Hutterer et al., 2004; Imai et al., 2006; Rolls et al., 2003; Woods et al., 1997). Core cell-polarity mechanisms and mammalian cancer Changes in activity or expression of core cell-polarity proteins AJCs as a crucial physical link between internal cell in cancer polarity and 3D tissue organization The most convincing evidence that implicates cell-polarity Segregation of the apical and basolateral membrane domains is a pathways in cancer comes from studies in Drosophila. The crucial function of AJCs in the maintenance of internal cell Drosophila polarity proteins Lgl, Dlg and Scrib are potent tumor polarity. However, this is not the only function of AJCs. These suppressors, and the loss of these proteins results in neoplastic structures are indispensable for intercellular
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