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Key Points Notch signalling can be either oncogenic or tumour suppressive depending on the tissue and/or cellular context. Notch signalling is tumour suppressive for various solid tumours, including squamous cell carcinoma in several epithelial tissues, subtypes of brain cancer, liver cancer and small-cell lung cancer. Loss of Notch signalling can result in perturbed regulation of cell fate decisions in stem and progenitor cells, resulting in tumour development. Loss of Notch signalling can also lead to stromal remodelling and the generation of a pro-tumorigenic microenvironment that promotes carcinogenesis. In this Review, Nowell and Radtke outline the accumulating evidence that Notch functions as a tumour suppressor in a range of cancers, and present potential mechanisms by which loss of Notch signalling could promote tumorigenesis. The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.

Key Points The highly conserved Notch cell–cell signalling pathway operates in many different contexts across which the consequences can differ widely, despite the fact that the core pathway is very simple. Many different types of regulation contribute to the differing outcomes of Notch signalling, ranging from tissue-level coordination to nuclear governance. The pattern of expression of the ligands (which are transmembrane proteins), receptors and crucial modifying enzymes is one level of regulation that is common to many signalling pathways. However, the one-to-one interaction between ligand and receptor in Notch signalling places extra emphasis on this type of regulation, especially because the ligand and receptor can cis -inhibit one another when present in the same cells. 'Topological' tissue organization and the extent of cell–cell contacts are likely to be of unusual importance in influencing the levels of Notch activation because the ligands are transmembrane proteins. Nuclear context, in the form of cell-type-specific transcription factors and chromatin organization, is a primary level of control in generating qualitatively different outcomes after Notch activation. In addition, the wiring of the gene regulatory networks in the signal-receiving cells contributes to the diversity of responses and to the nature of its crosstalk with other signalling pathways. Together, these regulatory mechanisms make the Notch pathway versatile and able to undertake many different roles. But they are also susceptible to perturbations, and may be a contributory factor in Notch-related diseases. The Notch signalling pathway functions in many processes — from developmental patterning to cell growth and cell death. As the complexity of Notch signalling regulation is being unravelled at the levels of cell-surface ligand–receptor interactions and of gene expression, we are gaining a deeper understanding of how this conserved pathway can lead to such diverse cellular responses. The highly conserved Notch signalling pathway functions in many different developmental and homeostatic processes, which raises the question of how this pathway can achieve such diverse outcomes. With a direct route from the membrane to the nucleus, the Notch pathway has fewer opportunities for regulation than do many other signalling pathways, yet it generates exquisitely patterned structures, including sensory hair cells and branched arterial networks. More confusingly, its activity promotes tissue growth and cancers in some circumstances but cell death and tumour suppression in others. Many different regulatory mechanisms help to shape the activity of the Notch pathway, generating functional outputs that are appropriate for each context. These mechanisms include the receptor–ligand landscape, the tissue topology, the nuclear environment and the connectivity of the regulatory networks.

Key Points Kidney fibrosis, the histological manifestation of functional decline in the kidney, is a reactive process that develops in response to excessive epithelial injury and inflammation In fibrosis, epithelial cells and their vascular capillary bed are lost, while activated myofibroblasts, matrix and inflammatory cells accumulate Tissue injury causes activation of developmental pathways, and several reports have shown that fibrosis is associated with increased expression and activity of Notch, Wnt and Hedgehog (Hh) signalling Although activation of these pathways might be important for regeneration of the damaged organ, excessive stimulation contributes to fibrosis development Notch and Wnt signalling have been shown to have a role in epithelial dedifferentiation; Wnt and Hh signalling can induce myofibroblast transformation and proliferation Decreasing the activity of Notch, Wnt, or Hh signalling could potentially be a new therapeutic strategy to ameliorate the development of chronic kidney disease Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation. Here, Katalin Susztak and colleagues discuss the reactivation of three key developmental signalling pathways — Notch, Wnt and Hedgehog — in response to injury, and describe the roles of these pathways in the development of renal fibrosis. Kidney fibrosis is a common histological manifestation of functional decline in the kidney. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation, leading to myofibroblast activation and an accumulation of extracellular matrix. Here, we describe how three key developmental signalling pathways — Notch, Wnt and Hedgehog (Hh) — are reactivated in response to kidney injury and contribute to the fibrotic response. Although transient activation of these pathways is needed for repair of injured tissue, their sustained activation is thought to promote fibrosis. Excessive Wnt and Notch expression prohibit epithelial differentiation, whereas increased Wnt and Hh expression induce fibroblast proliferation and myofibroblastic transdifferentiation. Notch, Wnt and Hh are fundamentally different signalling pathways, but their choreographed activation seems to be just as important for fibrosis as it is for embryonic kidney development. Decreasing the activity of Notch, Wnt or Hh signalling could potentially provide a new therapeutic strategy to ameliorate the development of fibrosis in chronic kidney disease.

The dependency of the growth of tumors on blood vessels, once considered a doubtful proposition, has become a major avenue of research and drug development. This review discusses the results of recent investigations into tumor angiogenesis and surveys the mechanisms of action of antibodies and drugs that inhibit angiogenesis. The dependency of the growth of tumors on blood vessels has become a major avenue of research and drug development. This review discusses the results of recent investigations into tumor angiogenesis and surveys the mechanisms of action of antibodies and drugs that inhibit angiogenesis. The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman's imaginative hypothesis, 1 but 33 years would elapse before the first drug developed as an inhibitor of angiogenesis was approved by the Food and Drug Administration (FDA). 2 , 3 This approval was based on the survival benefit observed in a randomized phase 3 trial of first-line treatment of metastatic colorectal cancer; in that trial, bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), was combined with conventional chemotherapy. 4 Bevacizumab therapy also increased overall survival in the first-line treatment of . . .

Tenascin C is an extracellular matrix protein previously linked to breast cancer metastasis. Here the authors uncover how tenascin C promotes the fitness of metastasis-initiating cells by sustaining the stem and survival signaling pathways NOTCH and Wnt through specific regulation of Msi1 and Lgr5, respectively. We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell–derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 ( MSI1 ) and leucine-rich repeat–containing G protein–coupled receptor 5 ( LGR5 ). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox ( NANOG ), POU class 5 homeobox 1 ( POU5F1 ), also known as OCT4 , and SRY-box 2 ( SOX2 ). TNC protects MSI1 -dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell–derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notch-signalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notch-signalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.

Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.

The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multifunctionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands.

Key Points A causative role for Notch signalling is well established in T cell acute lymphoblastic leukaemias (T-ALLs), which have activating mutations in the Notch genes resulting in a constitutively active pathway. By contrast, solid tumours, which have ample opportunity to activate the pathway, exhibit inappropriate activation by multiple mechanisms, such as overexpression of ligand or loss of negative regulators of the pathway. The role of Notch signalling in solid tumours is highly dependent on the spatial and temporal context of Notch activation, as well as the status of other signalling pathways in the cells. Notch signalling has opposing roles in tumorigenesis depending on the cell type. Opposite interactions of the Notch pathway have been documented with the WNT and p53 pathways. Although synergy with WNT and antagonism of the p53 pathway directs the oncogenic role of Notch, the opposite is seen in the tumour suppressor context. Notch signalling has a major role in the maintenance and progression of tumours by promoting epithelial to mesenchymal transition (EMT) and angiogenesis. It also confers resistance to radiation and chemotherapeutic agents. The knowledge of the extensive crosstalk of the Notch pathway with other pathways such as the epidermal growth factor receptor (EGFR) pathway could prove useful in developing combinatorial cancer therapies. The Notch family of receptors activate a complex web of cancer-relevant signalling pathways, and activating mutations in NOTCH1 are common drivers of T cell acute lymphoblastic leukaemia (T-ALL). Despite this oncogenic role of NOTCH1 in T-ALL, mutations in Notch genes are rare in solid cancers. This Review discusses the growing evidence that deregulation of Notch signalling can indeed have a major role in the development of various solid tumours, and the oncogenic versus tumour suppressive roles of Notch signalling are highly context dependent. The discovery of Notch in Drosophila melanogaster nearly a century ago opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by Notch signalling. As would be expected with such a pleiotropic pathway, the deregulation of Notch signalling leads to several pathological conditions, including cancer. A role for Notch is well established in haematological malignancies, and more recent studies have provided evidence for the importance of Notch activity in solid tumours. As it is thought to act as an oncogene in some cancers but as a tumour suppressor in others, the role of Notch in solid tumours seems to be highly context dependent.

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.