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First published online April 3, 2008
doi: 10.1242/10.1242/jcs.016634

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Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor

¹ Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., C3-168, Seattle, WA 98109, USA
² Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA
³ Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA

View larger version (24K): [in this window] [in a new window]   Fig. 1. Disruption of cell polarity and tissue disorganization is a hallmark of 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 complexes (blue), which separate apical (red) and basolateral (green) membrane domains. (B) Cells in high-grade epithelial tumors display loss of apical-basal polarity and overall tissue disorganization.

View larger version (31K): [in this window] [in a new window]   Fig. 2. The core mechanisms of apical-basal cell polarity. Cell-polarity complexes that contain the Par3-Par6-aPKC protein complex (and the Crumbs-Pals1-Patj complex; not shown) localize to the apical membrane domain and promote apical membrane identity. The function of Par3-Par6-aPKC complex is counteracted by the Dlg, Scrib, Lgl and Par1 proteins that localize to the basal membrane domain, and promote basolateral-membrane-domain identity. aPKC counteracts the activity of basal polarity proteins via direct phosphorylation and `inactivation' of Lgl. Although the mechanisms that are responsible for negative regulation of Par3-Par6-aPKC activity by the Dlg, Scrib and Lgl proteins are not well understood, basal Par1 can negatively regulate the apical polarity complex by phosphorylation and inactivation of apical Par3.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Oncogenic and tumor-suppressor signaling pathways target cell-polarity mechanisms. (A) Viral E6 oncogene from human HPV targets Dlg and Scrib proteins for ubiquitin-mediated degradation. (B) Activation of TGFβ signaling results in phosphorylation of Par6, and targeting of the E3 ubiquitin ligase Smurf1 to the AJCs, where Smurf1 destroys RhoA, disrupts the integrity of AJCs and causes EMT. (C) Activation of ErbB2 signaling results in disruption of the apical Par6-Par3-aPKC polarity complex by promoting dissociation between Par3 and Par6-aPKC. This function is crucial for ErbB2-mediated disruption of cell polarity and tissue disorganization. (D) The VHL tumor suppressor interacts with core cell-polarity proteins in two ways. First, VHL ubiquitylates active aPKC and targets it for proteasome-mediated degradation. In addition, interaction between VHL and the Par3-Par6-aPKC polarity complex is necessary for correct orientation of the microtubules and for primary cilia formation. (E) The tumor suppressor PTEN is crucial for apical-basal polarization of epithelial cells. During polarization of epithelial cells PTEN is targeted to the future apical membrane domain, where it generates PtdIns(4,5)P2 (PIP2), which facilitates recruitment of annexin 2 (Anx2), Cdc42 and the apical Par6-Par3-aPKC complex. (F) The tumor suppressor LKB1 controls cell polarity, growth and proliferation by regulating the activities of AMPK and Par1 protein kinases.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Symmetric and asymmetric divisions of stem or progenitor cells. (A) Stem or progenitor cells can divide symmetrically and generate either two stem or progenitor cells (expansion), or two differentiated cells (depletion). Alternatively, a stem or progenitor cell can divide asymmetrically and generate one stem or progenitor cell (self-renewal) and one differentiated cell (differentiation). Asymmetric cell division is the predominant type of stem or progenitor cell division during adult mammalian tissue homeostasis. (B) Mechanisms of normal asymmetric cell division and its potential perturbation in cancer. The stem or progenitor cells occupy specific positions within tissues that are called niches and are defined by the presence of the particular neighboring cells and cell-cell and/or cell-substratum adhesion structures. The mother cell asymmetrically localizes the Par3-Par6-aPKC complex (red) and cell fate determinants (green), and orients the mitotic spindle in such a way that basal cell fate determinants are inherited by only one daughter. Segregation of cell-fate determinants to one daughter assures that this cell acquires a fate different to that of the mother cell. Asymmetric cell division may fail because of an inability to asymmetrically localize cell fate determinants (Drosophila lgl, dlg, scribl, pros, brat and mira mutants), an inability to correctly orient the mitotic spindle (Drosophila pins, mud mutants) or both of these defects (Drosophila polo, aurA mutants).

View larger version (23K): [in this window] [in a new window]   Fig. 5. Maintenance of normal tissue homeostasis and a hypothetical model of the cancer-stem-cell-based origin of tumors. (A) Asymmetric cell divisions of stem and progenitor cells result in the generation of differentiated non-proliferating cells, which often constitute the bulk of the normal tissue. (B) Abnormal asymmetric cell division of stem and progenitor cells might be responsible for the accumulation of cells that fail to withdraw from the cell cycle and continue to divide. In this scenario, both progenitor- and stem-cell populations are collectively known as cancer stem cells.

View larger version (59K): [in this window] [in a new window]   Fig. 6. Hypothetical mechanisms of tissue polarity as a non-cell-autonomous tumor suppressor. (A) In normal tissues, cells use their AJCs to link internal cell-polarity mechanisms (asymmetrically localized cell-polarity proteins) with polarized 3D tissue organization. (B) Pro-tumorigenic changes in the mutant cells might disrupt internal cell-polarity mechanisms (see Fig. 3). If mutant cells express AJC proteins, the normal cell neighbors could use AJCs to maintain polarity and attenuate the malignant phenotype of the mutant cells. In this context, both 3D tissue polarity and AJC proteins have an important tumor-suppression function. (C) When the mutant cell is unable to form AJCs with its neighbors, an alternative 3D-mediated tumor-suppression mechanism may be engaged. Epithelial cells use AJCs as a biosensor of the external cellular microenvironment (Lien et al., 2006). Normal cells will treat the AJC-negative mutant as an empty space and may exfoliate it by an actin-myosin-mediated `purse-string' wound-healing mechanism (Brock et al., 1996; Danjo and Gipson, 1998). Only when the mechanisms describend in B and C both fail will the mutant cells progress and form the tumor.

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