Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia.

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets.

Potential Therapeutic Applications of N-Cadherin Antagonists and Agonists.

This review focuses on the cell adhesion molecule (CAM), known as neural (N)-cadherin (CDH2). The molecular basis of N-cadherin-mediated intercellular adhesion is discussed, as well as the intracellular signaling pathways regulated by this CAM. N-cadherin antagonists and agonists are then described, and several potential therapeutic applications of these intercellular adhesion modulators are considered.

Novel N-cadherin antagonist causes glioblastoma cell death in a 3D bioprinted co-culture model.

Glioblastoma multiforme (GBM) is a deadly type of brain cancer. There is a need to identify novel therapies for GBM as current treatments only marginally increase survival. Modelling the complexity of cancerous tissues using 3D bioprinted constructs serves as a novel approach for preclinical testing of anticancer drugs.

LCRF-0006, a small molecule mimetic of the N-cadherin antagonist peptide ADH-1, synergistically increases multiple myeloma response to bortezomib.

N-cadherin is a homophilic cell-cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre-clinical studies have shown that the N-cadherin antagonist peptide, ADH-1, increases the permeability of tumor-associated vasculature thereby increasing anti-cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF-0006, that is a mimetic of the classical cadherin His-Ala-Val sequence-containing region of ADH-1.

Non-pathological Chondrogenic Features of Valve Interstitial Cells in Normal Adult Zebrafish.

In the heart, unidirectional blood flow depends on proper heart valve function. As, in mammals, regulatory mechanisms of early heart valve and bone development are shown to contribute to adult heart valve pathologies, we used the animal model zebrafish (ZF, Danio rerio) to investigate the microarchitecture and differentiation of cardiac valve interstitial cells in the transition from juvenile (35 days) to end of adult breeding (2.5 years) stages.

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer.

In many types of solid tumours, the aberrant expression of the cell adhesion molecule N-cadherin is a hallmark of epithelial-to-mesenchymal transition, resulting in the acquisition of an aggressive tumour phenotype. This transition endows tumour cells with the capacity to escape from the confines of the primary tumour and metastasise to secondary sites. In this review, we will discuss how N-cadherin actively promotes the metastatic behaviour of tumour cells, including its involvement in critical signalling pathways which mediate these events.

Advantages and Limitations of Salmon-Gal/Tetrazolium Salt Histochemistry for the Detection of LacZ Reporter Gene Activity in Murine Epithelial Tissue.

The Escherichia coli LacZ gene is a widely used reporter for gene regulation studies in transgenic mice. It encodes bacterial β-galactosidase (Bact β-Gal), which causes insoluble precipitates when exposed to chromogenic homologues of galactose. We and others have recently reported that Bact β-Gal detection with Salmon-Gal (S-Gal) in combination with nitro blue tetrazolium chloride (NBT) is very sensitive and not prone to interference by acidic endogenous β-galactosidases.

Comments on Methods to Suppress Endogenous β-Galactosidase Activity in Mouse Tissues Expressing the LacZ Reporter Gene.

The Escherichia coli LacZ gene (encoding β-galactosidase) is a widely used reporter for gene regulation analysis in transgenic mice. Determination of β-galactosidase activity is classically performed using 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside/ferri-/ferrocyanide (X-Gal/FeCN) histochemistry. Uncertainty about the origin of the β-galactosidase signal is encountered in tissues containing high levels of endogenous β-galactosidase.

A simple method for inducing estrous cycle stage-specific morphological changes in the vaginal epithelium of immature female mice.

The vaginal epithelium of the adult female laboratory rodent changes from mucous secretion to cornification over the course of the estrous cycle. The morphophysiological changes occur with such regularity, accuracy and precision that the specific stage of the estrous cycle in the rat can be determined by inspection of the vaginal opening and/or exfoliative vaginal cytology. However, in the mouse, post-mortem vaginal histology is often required to determine the estrous cycle stage for ensuring the required level of reliability.

Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma.

Elevated expression of the cell adhesion molecule N-cadherin (cadherin 2, type 1, N-cadherin (neuronal); CDH2) is associated with poor prognosis in newly-diagnosed multiple myeloma (MM) patients. In this study, we investigated whether targeting of N-cadherin represents a potential treatment for the ~50% of MM patients with elevated N-cadherin. Initially, we stably knocked-down N-cadherin in the mouse MM plasma cell (PC) line 5TGM1 to assess the functional role of N-cadherin in MM pathogenesis.

N-cadherin antagonists as oncology therapeutics.

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours.

The ductal origin of structural and functional heterogeneity between pancreatic islets.

Islets form in the pancreas after the first endocrine cells have arisen as either single cells or small cell clusters in the epithelial cords. These cords constitute the developing pancreas in one of its earliest recognizable stages. Islet formation begins at the time the cords transform into a branching ductal system, continues while the ductal system expands, and finally stops before the exocrine tissue of ducts and acini reaches its final expansion.

Discovery and development of N-cadherin antagonists.

This article describes over 20 years of research on antagonists of the cell adhesion molecule, N-cadherin. Four types of antagonists are discussed: synthetic linear peptides, synthetic cyclic peptides, non-peptidyl peptidomimetics of the disulfide linked cyclic peptide N-Ac-CHAVC-NH(2) and monoclonal antibodies directed against the N-cadherin ectodomain. The biological activities of these antagonists are also discussed.

Inhibition of N-cadherin retards smooth muscle cell migration and intimal thickening via induction of apoptosis.

Objectives: Inhibition of vascular smooth muscle cell (VSMC) migration is a potential strategy for reducing intimal thickening during in-stent restenosis and vein graft failure. In this study, we examined the effect of disrupting the function of the VSMC adhesion molecule, N-cadherin, using antagonists, neutralizing antibodies, and a dominant negative, on VSMC migration and intimal thickening. Migration was assessed by the scratch-wound assay of human saphenous vein VSMCs and in a human saphenous vein ex vivo organ culture model of intimal thickening.

Cadherins as novel targets for anti-cancer therapy.

The cell adhesion molecules N-, VE- and OB-cadherin have been implicated as regulators of tumor growth and metastasis. We discuss evidence that N- and VE-cadherin play a key role in promoting blood vessel formation and stability, processes which are essential for tumor growth. Secondly, we describe the potential involvement of N- and OB-cadherin in the metastatic process.

Identification of a novel dual E- and N-cadherin antagonist.

E- and N-cadherin are related calcium-dependent cell adhesion molecules that exert an influence over multiple biological and disease processes. Antagonists of these cadherins can therefore be envisaged as therapeutically useful drugs. We have used phage display technology to discover such antagonists.

Identification of a novel N-cadherin antagonist.

The cell adhesion molecule, N-cadherin plays a pivotal role in many biological and disease processes. Drugs that modulate N-cadherin function should therefore be useful therapeutic agents. We have used phage display technology to identify amino acid sequences capable of binding to N-cadherin.

N-cadherin-dependent cell-cell contacts promote human saphenous vein smooth muscle cell survival.

Objective: Vascular smooth muscle cell (VSMC) apoptosis is thought to contribute to atherosclerotic plaque instability. Cadherin mediates calcium-dependent homophilic cell-cell contact. We studied the role of N-cadherin in VSMC apoptosis.

Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signalling.

Cadherins are a family of transmembrane glycoproteins mediating calcium-dependent, homophilic cell-cell adhesion. In addition, these molecules are involved in signaling events, regulating such processes as cell motility, proliferation, and apoptosis. Members of the cadherin subfamily, called either classical or type I cadherins, contain a highly conserved sequence at their homophilic binding site consisting of the three amino acids--histidine-alanine-valine (HAV).

Tight junction peptide antagonists enhance neutrophil trans-endothelial chemotaxis.

Occludin is an integral membrane protein within tight junctions. Previous studies suggest it functions as a sealing element, which promotes barrier in endothelial and epithelial cell layers. Here, we examine the role of occludin in neutrophil chemotaxis, using cyclic occludin peptide antagonists that incorporate a conserved occludin cell adhesion recognition (CAR) sequence.

An alternatively spliced cadherin-11 enhances human breast cancer cell invasion.

Although reduced levels of the epithelial cell adhesion molecule E-cadherin are often associated with poorly differentiated breast cancers, recent studies show that expression of other cadherins such as N-cadherin, P-cadherin, and the mesenchymal cadherin-11 is actually elevated in invasive breast cancers and cell lines. Cadherin-11 is unique among cadherins in that it exists as two alternatively spliced forms that are expressed together in the same cell. We now show that expression of wild-type cadherin-11, with or without coexpression of the COOH-terminal truncated splice variant, promotes epithelial differentiation of the cadherin-negative SKBR3 cell line.

Identification of an occludin cell adhesion recognition sequence.

The molecular mechanisms by which the tight junction integral membrane protein, occludin promotes cell adhesion and establishes an endothelial monolayer permeability barrier have not been elucidated. In particular, the amino acid sequences of the occludin cell adhesion recognition (CAR) sites have not been determined. Here we demonstrate that a cyclic peptide containing the sequence LYHY, which is found in the second extracellular domain of occludins in all mammalian species, inhibits the establishment of endothelial cell barriers in vitro and in vivo.

Plasma membrane components of adherens junctions (Review).

This review focuses on the three known plasma membrane components of adherens junctions: E-cadherin, nectin-2 and vezatin. The structures of these three components are discussed, with particular emphasis on the molecular mechanisms by which E-cadherin and nectin-2 promote cell adhesion.

Expression and localization of P-, K-, and OB-cadherin in the prepubertal rat ovary.

Classical and atypical cadherins mediate calcium-dependent cell adhesion and play an important role in morphogenetic processes. We have shown, previously, N- and E-cadherin expression in the rat ovary. This expression, however, was not associated with specific follicle-restructuring events such as antrum formation and segregation of mural from cumulus granulosa cells suggesting that other cadherins may serve this function.

N-cadherin is involved in axon-oligodendrocyte contact and myelination.

We have analyzed the influence of the calcium-dependent cell adhesion molecule, N-cadherin, on events leading to CNS myelination. Interactions between axons and oligodendrocyte progenitor (OP) cells and the CG4 OP cell line were examined by video-microscopy. OPs cocultured with dorsal root ganglia explants migrated around the culture and formed numerous contacts with axons.