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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
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.119110

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 > 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 2021 Feb 25];9:80-5. Available from: https://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.

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