Epithelial cell polarity: what flies can teach us about cancer

Epithelial cells are polarized along their apical-basal axis. Much of the cellular machinery that goes into establishing and maintaining epithelial cell polarity is evolutionarily conserved. Model organisms, including the fruit fly, Drosophila melanogaster, are thus particularly useful for the study of cell polarity. Work in Drosophila has identified several important components of the polarity machinery and has also established the surprising existence of a secondary cell polarity pathway required only under conditions of energetic stress. This work has important implications for the understanding of human cancer. Most cancers are epithelial in origin, and the loss of cell polarity is a critical step towards malignancy. Thus a better understanding of how polarity is established and maintained in epithelial cells will help us to understand the process of malignant transformation and may lead to improved therapies. In the present chapter we discuss the current understanding of how epithelial cell polarity is regulated and the known associations between polarity factors and cancer.     

Cell polarity in development and cancer

The development of cancer is a multistep process in which the DNA of a single cell accumulates mutations in genes that control essential cellular processes. Loss of cell-cell adhesion and cell polarity is commonly observed in advanced tumours and correlates well with their invasion into adjacent tissues and the formation of metastases. Growing evidence indicates that loss of cell-cell adhesion and cell polarity may also be important in early stages of cancer. The strongest hints in this direction come from studies on tumour suppressor genes in the fruitfly Drosophila melanogaster, which have revealed their importance in the control of apical-basal cell polarity.     

Epithelial polarity in flies: more than just crumbs

The plasma membrane of polarized epithelial cells is composed of different domains, which are associated with specific protein complexes. Recent studies in Drosophila shed new light on the functional interactions of these protein complexes during epithelial differentiation in embryogenesis.     

Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.     

Epigenetic regulation of genes during development： A conserved theme from flies to mammals

Eukaryotic genome is organized in form of chromatin within the nucleus. This organization is important for compaction of DNA as well as for the proper expression of the genes. During early embryonic development, genomic packaging receives variety of signals to eventually set up cell type specific expression patterns of genes. This process of regulated chromatinization leads to "cell type specific epigenomes". The expression states attained during differentiation process need to be maintained subsequently throughout the life of the organism. Epigenetie modifications are responsible for chromatin dependent regulatory mechanism and play a key role in maintenance of the expression state-a process referred to as cellular memory. Another key feature in the packaging of the genome is formation of chro- matin domains that are thought to be structural as well as functional units of the higher order chromatin organization. Boundary elements that function to define such domains set the limits of regulatory elements and that of epigenetie modifications. This connection of epige- netic modification, chromatin structure and genome organization has emerged from several studies. Hox genes are among the best studied in this context and have led to the significant understanding of the epigenetic regulation during development. Here we discuss the evolu- tionarily conserved features of epigenetic mechanisms emerged from studies on homeotic gene clusters.     

Tuberculosis vaccine development; from mouse to man

A tuberculosis (TB) vaccine candidate, Mtb72, was developed following an antigen discovery program involving a combination of expression cloning strategies and evaluation of human immune responses. Adjuvant selection was also performed, resulting in the prioritization of AS02A and AS01B, and an industrial process for vaccine production was developed. Safety, immunogenicity, and protection studies in mice, guinea pigs, rabbits, and monkeys supported the initiation of clinical development of Mtb72f in AS02A.     

Lipotoxicity and the development of heart failure: moving from mouse to man

Intracardiac lipid accumulation can cause heart failure. A study in Journal of Clinical Investigation (Son et?al., 2010) found that cardiac-specific PPARγ overexpression caused heart failure with intracardiac triglyceride accumulation. Overexpressing PPARγ on a PPARα-/- background improved cardiac function, suggesting that specific lipid metabolites and lipid packaging determine cardiac lipotoxicity.     

Hedgehog signal transduction: from flies to vertebrates

The patterning and morphogenesis of multicellular organisms require a complex interplay of inductive signals which control proliferation, growth arrest, and differentiation of different cell types. A number of such signaling molecules have been identified in vertebrates and invertebrates. The molecular dissection of these pathways demonstrated that in vertebrates, mutations or abnormals function of these signaling pathways were often associated with developmental disorders and cancer formation. The Hedgehog (Hh) family of secreted proteins provides a perfect example of such signaling proteins. In the following review, we will not discuss in detail the role of Hh as a morphogen, but rather focus on its signal transduction pathway and its role in various human disorders.     

The stem-cell niche theory: lessons from flies

Stem cells are characterized by their ability to self-renew and to produce numerous differentiated cell types, and are directly responsible for generating and maintaining tissues and organs. This property has long been attributed to the instructive signals that stem cells receive from their microenvironment - the so-called 'stem-cell niche'. Studies of stem cells in the Drosophila gonad have yielded much exciting insight into the structure of the niche and the signalling pathways that it produces to regulate the self-renewal of stem cells. These findings are illuminating our understanding of the self-renewing mechanisms of tissue stem cells in general.     

Establishing cell polarity in development

Polarity is a common feature of many different cell types, including the Caenorhabditis elegans zygote, the Drosophila oocyte and mammalian epithelial cells. The initial establishment of cell polarity depends on asymmetric cues that lead to reorganization of the cytoskeleton and polarized localization of several cortical proteins that act downstream of the polarization cues. The past year revealed that homologs of the C. elegans par (partitioning defective) genes are also essential for establishing polarity in Drosophila and vertebrate cells. There is growing evidence that the proteins encoded by these genes interact with key regulators of both the actin and the microtubule cytoskeletons.     

Insulators and imprinting from flies to mammals

The nuclear factor CTCF has been shown to be necessary for the maintenance of genetic imprinting at the mammalian H19/Igf2 locus. MacDonald and colleagues now report in BMC Biology that the mechanisms responsible for maintaining the imprinted state in Drosophila may be evolutionarily conserved and that CTCF may also play a critical role in this process.     

Design and constraints of the Drosophila segment polarity module: robust spatial patterning emerges from intertwined cell state switches

The Drosophila segment polarity genes constitute the last tier in the segmentation cascade; their job is to maintain the boundaries between parasegments and provide positional "read-outs" within each parasegment for the entire developmental history of the animal. These genes constitute a relatively well-defined network with a relatively well-understood patterning task. In a previous publication (von Dassow et al. 2000. Nature 406:188-192) we showed that a computer model predicts the segment polarity network to be a robust boundary-making device. Here we elaborate those findings. First, we explore the constraints among parameters that govern the network model. Second, we test architectural variants of the core network, and show that the network tolerates a wide variety of adjustments in design. Third, we evaluate several topologically identical models that incorporate more or less molecular detail, finding that more-complex models perform noticeably better than simplified ones. Fourth, we discuss two instances in which the failure of the network model to behave in a life-like fashion highlights mechanistic details that need further experimental investigation. We conclude with an explanation of how the segment polarity network can be understood as an interwoven conspiracy of simple dynamical elements, several bistable switches and a homeostat. The robustness with which the network as a whole maintains a spatial regime of stable cell state emerges from generic dynamical properties of these simple elements.     

Apico-basal polarity complex and cancer

Apico-basal polarity is a cardinal molecular feature of adult eukaryotic epithelial cells and appears to be involved in several key cellular processes including polarized cell migration and maintenance of tissue architecture. Epithelial cell polarity is maintained by three well-conserved polarity complexes, namely, PAR, Crumbs and SCRIB. The location and interaction between the components of these complexes defines distinct structural domains of epithelial cells. Establishment and maintenance of apico-basal polarity is regulated through various conserved cell signalling pathways including TGFβ, Integrin and WNT signalling. Loss of cell polarity is a hallmark for carcinoma, and its underlying molecular mechanism is beginning to emerge from studies on model organisms and cancer cell lines. Moreover, deregulated expression of apico-basal polarity complex components has been reported in human tumours. In this review, we provide an overview of the apico-basal polarity complexes and their regulation, their role in cell migration, and finally their involvement in carcinogenesis.