Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 5  |  Page : 80-85

The regulation of cell polarity in the progression of lung cancer


Department of Repiratory Medicine, Shenzhou Hospital Affiliated to Shenyang Medical College, Shenyang 110002, China

Date of Web Publication30-Sep-2013

Correspondence Address:
Li-Ping Chen
Shenzhou Hospital Affiliated to Shenyang Medical College, Shenyang 110002
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.119110

Rights and Permissions
 > Abstract 

Lung cancer is the most frequent malignant disease, since it has often metastasized to distant organs by the time of diagnosis. Epithelial-mesenchymal transition (EMT) is an important process during the progression of lung cancer. Epithelial cells lose the polarity, which contributes to uncontrolled invasion and metastasis of cancer cells. Cell polarity establishment and maintenance depends upon the three complex proteins which are par, crumbs and scribble complexes, of which are reported as tumor suppressors. The cell polarity proteins could interact with cell-cell contact and cell-extracellular matrix contact and cell-intrinsic signaling. These interactions are proved to be involved in lung cancer metastasis. However, our understanding of the mechanisms by which this occurs is poor. In this review, we will discuss the regulatory network of cell polarity in the lung cancer, especially on EMT.

Keywords: Epithelial-mesenchymal transition, cell polarity protein, extracellular matrix, lung cancer


How to cite this article:
Liu Y, Chen LP. The regulation of cell polarity in the progression of lung cancer. J Can Res Ther 2013;9, Suppl S1:80-5

How to cite this URL:
Liu Y, Chen LP. The regulation of cell polarity in the progression of lung cancer. J Can Res Ther [serial online] 2013 [cited 2019 May 22];9:80-5. Available from: http://www.cancerjournal.net/text.asp?2013/9/5/80/119110


 > Introduction Top


Lung cancer is the most frequent malignant disease and the leading cause of death from malignant diseases in the world and its incidence is increasing. The main types of lung cancer are small-cell lung carcinoma, and non-small-cell lung carcinoma (NSCLC). The prognosis of lung cancer is poor, since it has often metastasized to distant organs by the time of diagnosis. Although the primary lung cancer commonly metastasizes to the brain, bones, liver and adrenal glands, secondary cancers are happening with high incidence and can be derived from various sites. [1],[2] However, the first step is overcome surrounding cell.

Tumor cells adhere to extracellular matrix or other cells through cytoskeleton, plasma membrane, proteins. The barrier of cell migration is the extracellular matrix, which were called the basement membrane in epithelial cells, basement membrane compose of proteins and glycoproteins, tumor cell can secrete enzymes including Serine protease and matrix metalloproteinases, which degraded the basement membrane protein. Once went through the basement membrane, tumor cell transferred to the body by direct spread, blood, lymph node or implantation in the body cavity. The mechanism of tumor metastasis including cancer stem cell hypothesis and epithelial-mesenchymal transitions (EMT), [3] Furthermore, EMT occur as key steps during embryonic morphogenesis and are now implicated in the progression of primary tumors toward metastases. [4] Treatment against tumor metastasis has been established mostly in the following directions according to the process of metastasis and invasion: Cancer cell adhesion, basement membrane degradation, cancer cell movement, tumor angiogenesis, cell apoptosis. [5]

Cell polarity is the common features of a variety of different cell types and is necessary for most cell differentiation and function. Cell polarity refers to asymmetry distribution of cytoplasmic fraction in cells, thereby forming a concentration gradient of various cell ingredients, [6] cell polarity also causes presence of asymmetric cell division. [7] Cell polarity has been established an important role in many biological process, such as cell adhesion, junction, migration, cell division and EMT. [8] Epithelial cells exhibit apical/basal polarity and planar cell polarity, defects in polarity result in the tissue disorganization associated with tumorgenesis, development and metastasis. Cell polarity behaviors different in different cell types, especially plays an important role in maintain epithelial cells structure, 80-90% human tumors are epithelial origin, and the loss of cell polarity is a critical step towards malignancy. [9]

The role of cell polarity in tumor metastasis has been developed and has a lot of progress in recently years. In this review, we will discuss the polarity regulation in lung cancer metastasis.


 > Cell Polarity Top


Cell polarity is a conversed process in most cell types and species and is important in maintain tissue integrity and cell morphogenesis and the asymmetry distribution of organelles and protein. [6],[10] The establishment and maintenance of cell polarity is a complicate process interact with many molecular and pathways. Three polarity protein plays a main role: The crumbs complex, the scribble complex and the Par complex. [6] The basolateral domain is thought to be specified by the scribble complex, containing signaling adaptors scribble (Scrb), discs large (Dlg) and lethal giant larvae (Lgl). [11] The apical domain is specified by the crumbs complex, which consists of the transmembrane protein crumbs (Crb) and intracellular signaling adaptors protein associated with lin-7 (PALS1) and Pals1-associated tight junction (PATJ) protein (PALS1-associated tight junction protein) [12] and the Par complex, which assembled by Par3, Par6, atypical protein kinase C (aPKC) and Cdc42. [13] Disorder of three protein complexes has been proved to be involved in tumorgenesis and metastasis. [14]

The establishment of cell polarity can be divided into three processes: Symmetry breaking, either through extrinsic cues or stochastically; establishing spatial organization and self-amplifying; long-rang maintaining the polarized state. [15] These processes involving in the crosstalk between three complex and cell intrinsic and extrinsic factors including adhesive contacts between cells and the extracellular matrix, cytoskeleton network and with many signal pathways and subsequently they form feedback loops. [16]

During the embryonic development, epithelial polarization occurs along two axes, and form apical-basal polarity and planner cell polarity (PCP). Apical-basal polarity is a hallmark of epithelial cells that is essential exocrine, trafficking, absorbing and selective barrier functions between the outside world and the inside of an organism. [17] In epithelia, cells not only acquire apico-basal polarity, but they are also polarized within the epithelial plane. PCP establishment is required for the organization of multicellular structures and tissue remodeling. [18] PCP signaling mechanism consists of two major groups of proteins: The core PCP module and the fat/dachsous system (also called global module). [19],[20] PCP proteins are altered widely in cancer. [21] PCP pathway mediated cell communication is important for organized cell movement. [22]


 > Polarity Proteins Could Crosstalk with Each Other Top


The polarity complex interact with each other in the process of polarity, Par and Crb complex are responsible for the establish of apical domain and scribe is responsible for the establish of basolateral domain, signaling between these three polarity protein complexes is interconnected via interactions between members of the different complexes and might affect each other's function. [23] Lgl l/2 compete with Par3 for binding to Par6/aPKC complex, after binding Lgl can be phosphorylate and released to the basolateral side of cell, this competition binding also form an active Par3/Par6/aPKC complex; [24] Lgl, Par3, and Crb3 can be phosphorylated by aPKC, [25] mutual exclusion between Par and scribble, also between Crb and scribble complex, which exclude scribble complex to the basolaterally localization. Proteins from different complex can bind with each other. Crumbs compete with Par3 in binding to Par6, aPKC is able to bind to both PATJ and crumbs and cause the phosphorylation of crumbs. [26] Par6 also has been shown to interact with Pals1 via its PDZ-domain. Complex crosstalk is clearly exist between three conserved polarity proteins, and might affect each other's function. During lung morphogenesis, Dlg5 is necessary for the apical maintenance of aPKC. [27] However, the mechanism of how the polarity complexes communicate with each other is not well clear.

The three conserved polarity protein have been proved contribute to tumorgenesis. [28] Crumb act as a tumor suppressor though its effects in tight junction (TJ) formation, activates the tumor suppressor salvador/warts/Hippo pathway, control of Notch signaling, [29] Par complex performs oncogenic functions in many tumors. [30] Scribble complex and its role in tumor attract a lot attention recently, its mislocalized and downregulated in many tumors cervical cancer, colon adenocarcinoma, endometrial and prostate cancer. [6] Whether these polarity complex have direct function in tumor metastasis, little research has been done. A recent in vitro study proved that, loss of Par3 promotes metastatic behavior of ErbB2-induced tumor epithelial cells by decreasing cell-cell cohesion. [31] Par3 can be considered as an inhibitor/regulator of breast cancer metastasis. [32] Another research reveals that Par3 expression related to metastasis and low survival rate of hepatocellular carcinoma (HCC), Par3 maybe a potential prognostic biomarker and therapeutic target for HCC. [33] Other studies in Drosophila suggest that decreased expression and changed localization of scribble and loss of Hugl-1 expression had a correlation with lymph node metastasis, but not to the patient's age at onset, distant metastasis. [34],[35] These studies show that polarity proteins contribute to tumor metastasis.


 > Cell Polarity Proteins and the Communication of Cell-Cell Contact or Cell-Extracellular Matrix (ECM) in the Lung Cancer Top


Cell polarity proteins participate in cell-cell contact, ECM contact, which contribute to tumor invasion and metastasis. [21]

Cell-cell contact is important in maintaining physiological function of epithelial cell and tissue integrity. Cell adhesion is the early step of cell-cell contact formation and is mediated by cellular adhesion molecule, which contributes to tumor metastasis. [36] Polarity protein could interplay with cell-cell contact. And Par3 is necessary in the formation of TJs, which are involved in regulation of many signal pathways. [16],[37] Besides, crumbs extracellular domain mediates homophilic crumbs-crumbs interactions at the cell-cell junction. [29] The polarity protein aPKC regulates the asymmetric distribution of adherens junctions (AJs), and then promotes the degradation of microtubule, which contribute to the balance of actin and microtubule. [38] Moreover, in migration cells, Par3 contributes to the proper positioning of centrosome though interaction with LIC2 and the ends of microtubule. [39] And Par3 is critical for the transition in major microtubule organizing center function to membrane. [40] Thus, polarity proteins regulate cell junctions and the cell-cell contact. Moreover, disruption of polarity, by overexpression or loss of polarity proteins, induces defective morphogenesis. [14] Thus, cell polarity pathways seem to be essential for tumor initiation. Loss of polarity proteins can initiate tumorigenesis. [21] Downregulation of scribble is sufficient to induce the initiation of lung tumors. [41] Loss of the polarity proteins can directly deregulate cell adhesion processes, which is consistent with the loss of E-cadherin [42] while the situation thus will disrupt morphogenesis and promote tumorigenesis. [43]

Similarly with the function of E-cadherin in ECM, the polarity proteins also involve in regulation of ECM. In highly fibrotic cancers like lung cancer, it is thought that ECM molecules, including collagen, can initiate signals that promote EMT. [44],[45] The cell-ECM interactions are essential for the orientation of epithelial polarity and therefore lumen formation. Akhtar and Streuli has discovered that β1-integrins are the intermediate proteins. [46] However, β1-integrin functions upstream of Par3 as part of this molecular cascade. [47],[48] Although we are beginning to recognize the importance of ECM in cancer, very little is known about the relationship between the cell polarity machinery and ECM remodeling.

Cell polarity proteins interact with cell-cell contact and cell-ECM contact and have impact on lung cancer metastasis. However, the mechanism is still poor understood. These untapped research areas leave a fertile ground for the investigation of cell polarity in lung cancer metastasis, which will lead to discover novel lung cancer biomarkers or therapeutic targets.


 > Cell Polarity and Cell-Intrinsic Signaling Pathways in Lung Cancer Top


The involvement of Rho GTPases in major aspects of cancer development, including cell polarity, has recently been attracting increasing attention. [49] Of these G-proteins, RhoA, Cdc42 and Rac1, play an important role in cell polarity establishment and maintenance. [50] Cdc42 plays a key role in polariton. Cdc42 randomized within the cell. And when activated as Cdc42-GTP, the molecular would be enriching to the cell membrane where it bands to Par6, providing a mechanism by which the GTPase can control cell polarization. [51] After binding to Cdc42-GTP, Par6 inhibit aPKC. [52] Furthermore, Cdc42 can recruit Par6-aPKC complex to the proper position. In basal cell carcinoma Cdc42 abnormal expression contribute to the adherent mechanism and loss of polarity. [53] In mammalian cells, RhoA infect cell polarity though its regulation of polymerized actin cytoskeleton by ROCK. [54] Rac can serve as a starting point in defining cell polarity. Crumb antagonize Rac1 though inhibiting the positive feedback loop between Rac1 and P13K. [55] Disturbance of balance between crumb and Rac1 will cause the loss of epithelial property. Rac1 also play an important role in epithelial tissue integrity though interact with Par complex mediated signaling. [56] Although Par complex is the most studied in communication with small GTPases, the scribble complexes communication with small GTPases is little known.

Recent research has revealed the non-canonical Wnt/planar cell polarity (PCP) signaling in cancer progression, invasion and metastasis. [57] PCP signaling pathway could transform extracellular polarity signals and subsequently induce intracellular cytoskeleton rearrangements. [58] Wnt ligands could stimulate PCP then signaling is transduced by a core module of conserved proteins that includes the seven-pass transmembrane frizzled (Fzd) receptors, the four-pass transmembrane van-Gogh-like proteins, the cytoplasmic proteins, prickle (Pk) and the adaptor protein disheveled (Dvl), [59] which will recruit GEF to activate RhoA. And then the activated RhoA would regulate ROCK to phosphorylate Par3. [60] Besides, frizzled may recruit aPKC through another polarity protein, PATJ; meanwhile, aPKC is able to phosphorylate and inhibit the frizzled receptor. [61] Scribble seems to promote PCP signaling pathways. [62] However, it is unclear how scribble complex implicates in PCP. The involvement of Wnt signaling pathway in cell polarity indicates that cell polarity plays an important role during the lung cancer progression.

Liver kinase 1 (LKB1), an activator of the AMPK-mTOR pathway, also is involved in cell polarity. [63] LKB1 regulates cell polarity mainly via AMPK/mTOR signaling. [64],[65] Somatic inactivation of LKB1 has been associated with lung cancer. [66] AMPK/mTOR signaling components may establish and control cell polarity via microtubule phosphorylating by (microtubule-associatedprotein). [67] Moreover, MARK kinase activities, well-known to be required in epithelial cell polarity [68] would be also activated through a LKB1 independent manner potentially by TAO1 kinase. [69] The role of LKB1 playing in cell polarity and cell migrate might be essential for lung cancer.

Polarity proteins could interact with Hippo components and thus regulate cell proliferation and apoptosis. [70] Crumb complex can phosphorylate YAP1 and TAZ transcript factor of Hippo signal pathway. [71] Crumb can also bind to Expanded, an apical membrane associated protein known to regulate the Hippo pathway. [72] aPKC and Lgl could control localization and activation of Hippo and Ras association domain family 1A (RASSF 1A) [73] while crumb interacts with Yorkie (YKI) to promote YKI phosphorylation and cytoplasmic retention, which thereby inactivates YKI. [74] Merlin has been reported interact with polarity protein through couple α-catenin to Par3 for the apical positioning of TJ or YKI-Par5. [75] Kibra also assiociate with Par complex location and negatively regulate the aPKC activity. [76]

These signaling pathways are proven to involve in lung cancer pathogeny and metastasis. [77] Small GTPase participate in many cellular process such as cell migration and apoptosis and contribute to lung cancer invasion and metastasis. [78] Wnt signal pathway is important to lung cancer metastasis related events such as adhesion, extracellular matrix degradation and tumor angiogenesis. [79] Tumor restrict factor LKB1, is proved to inhibit the metastasis of lung cancer. [80] Hippo pathway comprises several tumor suppressor protein including Merlin, Lats1/2 and MST1/2 kinases. [81] The crosstalk between cell polarity proteins and these signal pathways don't look very good currently, but the further studies will make the picture more complicated.


 > Cell Polarity and Epigenetic Modifications in the Lung Cancer Top


Epigenetic mechanisms controlling EMT processes are shown in many tumors including lung cancer. [77],[82] The epigenetic regulation including three types of changes: Deoxyribonucleic acid methylation, histone modifications and micro ribonucleic acids, all have been shown to play a key role in controlling EMT and cancer metastasis. For example, SNAI2 and miR-203 negative feedback loop play an important role in EMT and breast cancer invasion in vitro and its lung metastatic colonization in vivo. [83] However, the cell polarity are also involved in this regulation. Overexpression of Numbl, which is related to AJs and cell polarity, [84] relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. [85] Moreover, Numbl overexpression correlated with a reduction in overall patient survival in NSCLC. [85] Furthermore, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration and tumor cell invasiveness. [86] It is indicated that miRNA also could regulate cell polarity in the cancer progression. The more cell polarity related miRNA will be discovered in the lung cancer and a deeper understanding of mechanism will contribute to the development of better diagnosis or treatments for invasive lung cancer.


 > Summary Top


Cell polarity is a conserved cell biology process and interacts with many cell instinct and extrinsic factors, as well as many signal pathways, most of these factors and pathways contribute to cancer. However, we know little about the mechanisms that regulate the dynamic plasticity of cell behavior during the lung cancer progression. Recently, three-dimensional culture systems might provide a powerful tool for cell polarity research for investigating the molecular signals that specify epithelial tissue architecture. [87]

As our understanding of polarity protein complex and their cross increases, the ability to target these processes for therapy will offer new biomarkers in the diagnosis treatment of epithelial malignancy and metastasis.

 
 > References Top

1.Sica GL, Gal AA. Lung cancer staging: Pathology issues. Semin Diagn Pathol 2012;29:116-26.  Back to cited text no. 1
[PUBMED]    
2.Liu J, Zhong X, Li J, Liu B, Guo S, Chen J, et al. Screening and identification of lung cancer metastasis-related genes by suppression subtractive hybridization. Thorac Cancer 2012;3:207-16.  Back to cited text no. 2
    
3.Torzilli PA, Bourne JW, Cigler T, Vincent CT. A new paradigm for mechanobiological mechanisms in tumor metastasis. Semin Cancer Biol 2012;22:385-95.  Back to cited text no. 3
[PUBMED]    
4.Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P, Pachkov M, et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 2013;23:768-83.  Back to cited text no. 4
[PUBMED]    
5.Valastyan S, Weinberg RA. Tumor metastasis: Molecular insights and evolving paradigms. Cell 2011;147:275-92.  Back to cited text no. 5
[PUBMED]    
6.Ellenbroek SI, Iden S, Collard JG. Cell polarity proteins and cancer. Semin Cancer Biol 2012;22:208-15.  Back to cited text no. 6
[PUBMED]    
7.Noatynska A, Gotta M. Cell polarity and asymmetric cell division: The C. elegans early embryo. Essays Biochem 2012;53:1-14.  Back to cited text no. 7
[PUBMED]    
8.Asnacios A, Hamant O. The mechanics behind cell polarity. Trends Cell Biol 2012;22:584-91.  Back to cited text no. 8
[PUBMED]    
9.Bergstralh DT, St Johnston D. Epithelial cell polarity: What flies can teach us about cancer. Essays Biochem 2012;53:129-40.  Back to cited text no. 9
[PUBMED]    
10.Peng Q, Li M, Wang Z, Jiang M, Yan X, Lei S, et al. Polarization of tumor-associated macrophage is associated with tumor vascular normalization by endostatin. Thorac Cancer 2013;4:295-305.  Back to cited text no. 10
    
11.Yamanaka T, Ohno S. Role of Lgl/Dlg/scribble in the regulation of epithelial junction, polarity and growth. Front Biosci 2008;13:6693-707.  Back to cited text no. 11
[PUBMED]    
12.Bazellieres E, Assemat E, Arsanto JP, Le Bivic A, Massey-Harroche D. Crumbs proteins in epithelial morphogenesis. Front Biosci (Landmark Ed) 2009;14:2149-69.  Back to cited text no. 12
[PUBMED]    
13.Macara IG. Parsing the polarity code. Nat Rev Mol Cell Biol 2004;5:220-31.  Back to cited text no. 13
[PUBMED]    
14.Rolli CG, Seufferlein T, Kemkemer R, Spatz JP. Impact of tumor cell cytoskeleton organization on invasiveness and migration: A microchannel-based approach. PLoS One 2010;5:e8726.  Back to cited text no. 14
[PUBMED]    
15.Goehring NW, Grill SW. Cell polarity: Mechanochemical patterning. Trends Cell Biol 2013;23:72-80.  Back to cited text no. 15
[PUBMED]    
16.Bazzoun D, Lelièvre S, Talhouk R. Polarity proteins as regulators of cell junction complexes: Implications for breast cancer. Pharmacol Ther 2013;138:418-27.  Back to cited text no. 16
    
17.Nelson WJ. Remodeling epithelial cell organization: Transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol 2009;1:a000513.  Back to cited text no. 17
[PUBMED]    
18.Muñoz-Soriano V, Belacortu Y, Paricio N. Planar cell polarity signaling in collective cell movements during morphogenesis and disease. Curr Genomics 2012;13:609-22.  Back to cited text no. 18
    
19.Simons M, Mlodzik M. Planar cell polarity signaling: From fly development to human disease. Annu Rev Genet 2008;42:517-40.  Back to cited text no. 19
[PUBMED]    
20.Maung SM, Jenny A. Planar cell polarity in Drosophila. Organogenesis 2011;7:165-79.  Back to cited text no. 20
[PUBMED]    
21.Muthuswamy SK, Xue B. Cell polarity as a regulator of cancer cell behavior plasticity. Annu Rev Cell Dev Biol 2012;28:599-625.  Back to cited text no. 21
[PUBMED]    
22.Zou Y. Does planar cell polarity signaling steer growth cones? Curr Top Dev Biol 2012;101:141-60.  Back to cited text no. 22
[PUBMED]    
23.Chen J, Zhang M. The Par3/Par6/aPKC complex and epithelial cell polarity. Exp Cell Res 2013;319:1357-64.  Back to cited text no. 23
[PUBMED]    
24.Betschinger J, Mechtler K, Knoblich JA. The par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 2003;422:326-30.  Back to cited text no. 24
[PUBMED]    
25.Morais-de-Sá E, Mirouse V, St Johnston D. aPKC phosphorylation of bazooka defines the apical/lateral border in Drosophila epithelial cells. Cell 2010;141:509-23.  Back to cited text no. 25
    
26.Sotillos S, Díaz-Meco MT, Caminero E, Moscat J, Campuzano S. DaPKC-dependent phosphorylation of crumbs is required for epithelial cell polarity in Drosophila. J Cell Biol 2004;166:549-57.  Back to cited text no. 26
    
27.Nechiporuk T, Klezovitch O, Nguyen L, Vasioukhin V. Dlg5 maintains apical aPKC and regulates progenitor differentiation during lung morphogenesis. Dev Biol 2013;377:375-84.  Back to cited text no. 27
[PUBMED]    
28.Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 2011;12:23-38.  Back to cited text no. 28
[PUBMED]    
29.Thompson BJ, Pichaud F, Röper K. Sticking together the crumbs-An unexpected function for an old friend. Nat Rev Mol Cell Biol 2013;14:307-14.  Back to cited text no. 29
    
30.Aranda V, Nolan ME, Muthuswamy SK. Par complex in cancer: A regulator of normal cell polarity joins the dark side. Oncogene 2008;27:6878-87.  Back to cited text no. 30
[PUBMED]    
31.Xue B, Krishnamurthy K, Allred DC, Muthuswamy SK. Loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. Nat Cell Biol 2013;15:189-200.  Back to cited text no. 31
[PUBMED]    
32.McCaffrey LM, Montalbano J, Mihai C, Macara IG. Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. Cancer Cell 2012;22:601-14.  Back to cited text no. 32
[PUBMED]    
33.Jan YJ, Ko BS, Liu TA, Wu YM, Liang SM, Chen SC, et al. Expression of partitioning defective 3 (par-3) for predicting extrahepatic metastasis and survival with hepatocellular carcinoma. Int J Mol Sci 2013;14:1684-97.  Back to cited text no. 33
[PUBMED]    
34.Tsuruga T, Nakagawa S, Watanabe M, Takizawa S, Matsumoto Y, Nagasaka K, et al. Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer. Oncol Res 2007;16:431-5.  Back to cited text no. 34
[PUBMED]    
35.Lampugnani MG. Endothelial cell-to-cell junctions: Adhesion and signaling in physiology and pathology. Cold Spring Harb Perspect Med 2012;2:1-14.  Back to cited text no. 35
    
36.Buda A, Pignatelli M. E-cadherin and the cytoskeletal network in colorectal cancer development and metastasis. Cell Commun Adhes 2011;18:133-43.  Back to cited text no. 36
[PUBMED]    
37.Nelson WJ, Dickinson DJ, Weis WI. Roles of cadherins and catenins in cell-cell adhesion and epithelial cell polarity. Prog Mol Biol Transl Sci 2013;116:3-23.  Back to cited text no. 37
[PUBMED]    
38.Harris TJ, Peifer M. aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. Dev Cell 2007;12:727-38.  Back to cited text no. 38
[PUBMED]    
39.Schmoranzer J, Fawcett JP, Segura M, Tan S, Vallee RB, Pawson T, et al. Par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration. Curr Biol 2009;19:1065-74.  Back to cited text no. 39
[PUBMED]    
40.Hale CM, Chen WC, Khatau SB, Daniels BR, Lee JS, Wirtz D. SMRT analysis of MTOC and nuclear positioning reveals the role of EB1 and LIC1 in single-cell polarization. J Cell Sci 2011;124:4267-85.  Back to cited text no. 40
    
41.Vaira V, Faversani A, Dohi T, Maggioni M, Nosotti M, Tosi D, et al. Aberrant overexpression of the cell polarity module scribble in human cancer. Am J Pathol 2011;178:2478-83.  Back to cited text no. 41
[PUBMED]    
42.Pezzilli R. Serum E-cadherin and hepatocyte growth factor in acute pancreatitis: Exploring time course, and severity assessment. Immunogastroenterology 2013;2:57.  Back to cited text no. 42
    
43.Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 2006;10:437-49.  Back to cited text no. 43
[PUBMED]    
44.Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol 2008;38:95-104.  Back to cited text no. 44
[PUBMED]    
45.Walter L, Harper C, Garg P. Role of matrix metalloproteinases in inflammation/colitis-associated colon cancer. Immunogastroenterology 2013;2:22-8.  Back to cited text no. 45
    
46.Akhtar N, Streuli CH. An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium. Nat Cell Biol 2013;15:17-27.  Back to cited text no. 46
[PUBMED]    
47.Zovein AC, Luque A, Turlo KA, Hofmann JJ, Yee KM, Becker MS, et al. Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism. Dev Cell 2010;18:39-51.  Back to cited text no. 47
[PUBMED]    
48.Willis AL, Sabeh F, Li XY, Weiss SJ. Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. J Microsc 2013;251:250-60.  Back to cited text no. 48
[PUBMED]    
49.Leve F, Morgado-Díaz JA. Rho GTPase signaling in the development of colorectal cancer. J Cell Biochem 2012;113:2549-59.  Back to cited text no. 49
    
50.Iden S, Collard JG. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol 2008;9:846-59.  Back to cited text no. 50
[PUBMED]    
51.Wallace SW, Durgan J, Jin D, Hall A. Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B. Mol Biol Cell 2010;21:2996-3006.  Back to cited text no. 51
[PUBMED]    
52.Tucci MG, Lucarini G, Zizzi A, Rocchetti R, Brancorsini D, Primio RD, et al. Cdc42 is involved in basal cell carcinoma carcinogenesis. Arch Dermatol Res 2013;In press.  Back to cited text no. 52
    
53.Meitinger F, Richter H, Heisel S, Hub B, Seufert W, Pereira G. A safeguard mechanism regulates Rho GTPases to coordinate cytokinesis with the establishment of cell polarity. PLoS Biol 2013;11:e1001495.  Back to cited text no. 53
    
54.Watanabe N, Kato T, Fujita A, Ishizaki T, Narumiya S. Cooperation between mDia1 and ROCK in Rho-induced actin reorganization. Nat Cell Biol 1999;1:136-43.  Back to cited text no. 54
[PUBMED]    
55.Valderrama F, Thevapala S, Ridley AJ. Radixin regulates cell migration and cell-cell adhesion through Rac1. J Cell Sci 2012;125:3310-9.  Back to cited text no. 55
[PUBMED]    
56.Amano M, Nakayama M, Kaibuchi K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton (Hoboken) 2010;67:545-54.  Back to cited text no. 56
    
57.Wang Y. Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy. Mol Cancer Ther 2009;8:2103-9.  Back to cited text no. 57
[PUBMED]    
58.Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012;151:1542-56.  Back to cited text no. 58
[PUBMED]    
59.Gray RS, Roszko I, Solnica-Krezel L. Planar cell polarity: Coordinating morphogenetic cell behaviors with embryonic polarity. Dev Cell 2011;21:120-33.  Back to cited text no. 59
[PUBMED]    
60.Katoh M. WNT/PCP signaling pathway and human cancer (review). Oncol Rep 2005;14:1583-8.  Back to cited text no. 60
[PUBMED]    
61.Djiane A, Yogev S, Mlodzik M. The apical determinants aPKC and dPatj regulate frizzled-dependent planar cell polarity in the Drosophila eye. Cell 2005;121:621-31.  Back to cited text no. 61
[PUBMED]    
62.Viktorinová I, Pismen LM, Aigouy B, Dahmann C. Modelling planar polarity of epithelia: The role of signal relay in collective cell polarization. J R Soc Interface 2011;8:1059-63.  Back to cited text no. 62
    
63.Sebbagh M, Olschwang S, Santoni MJ, Borg JP. The LKB1 complex-AMPK pathway: The tree that hides the forest. Fam Cancer 2011;10:415-24.  Back to cited text no. 63
[PUBMED]    
64.Korsse SE, Peppelenbosch MP, van Veelen W. Targeting LKB1 signaling in cancer. Biochim Biophys Acta 2013;1835:194-210.  Back to cited text no. 64
[PUBMED]    
65.Zhong DS, Sun LI, Dong LX. Molecular mechanisms of LKB1 induced cell cycle arrest. Thorac Cancer 2013;4:229-33.  Back to cited text no. 65
    
66.Xu X, Jin D, Durgan J, Hall A. LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation. Mol Cell Biol 2013;33:2671-82.  Back to cited text no. 66
[PUBMED]    
67.Nakano A, Takashima S. LKB1 and AMP-activated protein kinase: Regulators of cell polarity. Genes Cells 2012;17:737-47.  Back to cited text no. 67
[PUBMED]    
68.Cohen D, Brennwald PJ, Rodriguez-Boulan E, Müsch A. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J Cell Biol 2004;164:717-27.  Back to cited text no. 68
    
69.Kojima Y, Miyoshi H, Clevers HC, Oshima M, Aoki M, Taketo MM. Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling. J Biol Chem 2007;282:23532-40.  Back to cited text no. 69
[PUBMED]    
70.Boggiano JC, Fehon RG. Growth control by committee: Intercellular junctions, cell polarity, and the cytoskeleton regulate hippo signaling. Dev Cell 2012;22:695-702.  Back to cited text no. 70
[PUBMED]    
71.Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 2011;144:782-95.  Back to cited text no. 71
    
72.Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, et al. The apical-basal cell polarity determinant crumbs regulates hippo signaling in Drosophila. Proc Natl Acad Sci U S A 2010;107:15810-5.  Back to cited text no. 72
[PUBMED]    
73.Zhao B, Li L, Guan KL. Hippo signaling at a glance. J Cell Sci 2010;123:4001-6.  Back to cited text no. 73
[PUBMED]    
74.Parsons LM, Grzeschik NA, Allott ML, Richardson HE. Lgl/aPKC and Crb regulate the salvador/warts/hippo pathway. Fly (Austin) 2010;4:288-93.  Back to cited text no. 74
[PUBMED]    
75.Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. Kibra functions as a tumor suppressor protein that regulates hippo signaling in conjunction with merlin and expanded. Dev Cell 2010;18:288-99.  Back to cited text no. 75
[PUBMED]    
76.Lawrence PA, Casal J. The mechanisms of planar cell polarity, growth and the Hippo pathway: Some known unknowns. Dev Biol 2013;377:1-8.  Back to cited text no. 76
[PUBMED]    
77.Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-74.  Back to cited text no. 77
[PUBMED]    
78.Wilson KF, Erickson JW, Antonyak MA, Cerione RA. Rho GTPases and their roles in cancer metabolism. Trends Mol Med 2013;19:74-82.  Back to cited text no. 78
[PUBMED]    
79.Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, et al. Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci U S A 2000;97:12776-81.  Back to cited text no. 79
[PUBMED]    
80.Shah U, Sharpless NE, Hayes DN. LKB1 and lung cancer: More than the usual suspects. Cancer Res 2008;68:3562-5.  Back to cited text no. 80
[PUBMED]    
81.Chen CL, Schroeder MC, Kango-Singh M, Tao C, Halder G. Tumor suppression by cell competition through regulation of the hippo pathway. Proc Natl Acad Sci U S A 2012;109:484-9.  Back to cited text no. 81
[PUBMED]    
82.Kumar R, Xi Y. MicroRNA, epigenetic machinery and lung cancer. Thorac Cancer 2011;2:35-44.  Back to cited text no. 82
    
83.Ding X, Park SI, McCauley LK, Wang CY. Signaling between transforming growth factor β (TGF-β) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem 2013;288:10241-53.  Back to cited text no. 83
[PUBMED]    
84.Rasin MR, Gazula VR, Breunig JJ, Kwan KY, Johnson MB, Liu-Chen S, et al. Numb and numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nat Neurosci 2007;10:819-27.  Back to cited text no. 84
[PUBMED]    
85.Vaira V, Faversani A, Martin NM, Garlick DS, Ferrero S, Nosotti M, et al. Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res 2013;73:2695-705.  Back to cited text no. 85
[PUBMED]    
86.Vaira V, Faversani A, Dohi T, Montorsi M, Augello C, Gatti S, et al. miR-296 regulation of a cell polarity-cell plasticity module controls tumor progression. Oncogene 2012;31:27-38.  Back to cited text no. 86
[PUBMED]    
87.Breslin S, O'Driscoll L. Three-dimensional cell culture: The missing link in drug discovery. Drug Discov Today 2013;18:240-9.  Back to cited text no. 87
[PUBMED]    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Cell Polarity>Polarity Protein...>Cell Polarity Pr...>Cell Polarity an...>Cell Polarity an...>Summary
  In this article
>References

 Article Access Statistics
    Viewed2714    
    Printed89    
    Emailed0    
    PDF Downloaded207    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]