Researchers discovered that E-cadherin allows breast cancer cells to survive and promote metastasis

Researchers at the Johns Hopkins Kimmel Cancer Center discovered that a cell adhesion protein, E-cadherin, allows breast cancer cells to survive as they travel through the body and form new tumors, a process termed metastasis.

Their conclusions, obtained through laboratory experiments and in mouse models, help explain how metastasis works in the most common form of breast cancer, invasive ductal carcinoma.

E-cadherin appears to limit molecular stresses within the cancer cells and allow them to survive long enough to form new tumors.

The finding, published online in the Sept. 4 issue of Nature, could lead to new ways to prevent breast cancers from recurring in patients.

“Previously, researchers thought that it was essential for cancer cells to lose E-cadherin in order to metastasize,” says study leader Andrew Ewald, Ph.D., professor of cell biology and co-director of the Cancer Invasion and Metastasis Program at Johns Hopkins Kimmel Cancer Center.

“This was difficult to reconcile with the fact that breast tumors in patients typically continue to express E-cadherin. Our study was designed to test the role of this protein during metastasis.”

The overwhelming majority of breast and other cancer deaths are caused by metastasis; consequently, preventing metastasis is a crucial cancer research goal, he says.

Scientifically, metastasis is characterized by many separate stages, including when cancer cells invade healthy breast tissue, escape the primary tumor, enter and survive within blood vessels, exit into new organs, then survive and seed a new tumor in a distant organ, such as the lungs.

Cancer cells break free from the primary tumor early in metastasis and much research has focused on how cancer cells stick together at the molecular level, through the protein E-cadherin.

In some cancers, such as a form of breast cancer known as invasive lobular carcinoma, genetic mutations that eliminate E-cadherin appear to be pivotal for metastasis to occur.

However, other types of cancer – such as invasive ductal carcinoma, the most common form of breast cancer, responsible for more than 80 percent of all breast cancer diagnoses – retain this protein or even overexpress it, a discrepancy that scientists couldn’t explain.

To investigate this discrepancy, Ewald and his colleagues tested the role of E-cadherin in three experimental models of invasive ductal carcinoma that represent common subtypes of human breast cancer: luminal, basal, and triple negative breast cancer.

These subtypes have different patterns of gene expression and different average patient outcomes.

First, they tested the role of E-cadherin during cancer invasion. Across all three models, loss of the E-cadherin gene dramatically increased the cancer cells’ ability to invade healthy tissue.

For example, in a mouse model, tumors that made E-cadherin invaded along 6 percent of their tumor borders, while those without E-cadherin invaded along 82 percent of their borders.

However, losing E-cadherin sabotaged every other biological stage of metastasis in all three breast cancer models, in both lab experiments and animal models.

Cells without E-cadherin got lost while migrating and died in large numbers at every step after leaving the primary tumor.

The few that did manage to migrate and survive didn’t proliferate in new organs and rarely formed new tumors, Ewald reports.

“The good news,” he says, “is that our study reveals that the process of metastasis, even in ideal laboratory settings, appears to be exceedingly inefficient.”

Research suggests that about 99 percent of cells that leave primary tumors die and never form new tumors.

The study results suggest that breast cancer cells need adhesive connections to survive and eventually spread and kill patients.

“Our future research aims to understand how to target the survival signals related to E-cadherin and prevent metastases from forming, thereby saving patients’ lives,” Ewald says.

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Cancer metastasis is a leading cause of cancer-related mortality. The metastasis of cancer cells within primary tumours is characterised by localised invasion into the surrounding microenvironment, entry into the vasculature and subsequent spread to permissive distant organs [1, 2]. In many epithelial cancers, metastasis is facilitated by the genetic reprogramming and transitioning of cancer cells from a non-motile, epithelial phenotype into a migratory, mesenchymal-like phenotype, a process known as epithelial-to-mesenchymal transition (EMT) [3, 4]. A common feature of EMT is the loss of epithelial cadherin (E-cadherin) expression and the concomitant up-regulation or de novo expression of neural cadherin (N-cadherin). This so-called “cadherin switch” is associated with increased migratory and invasive behaviour [5, 6] and inferior patient prognosis [7–10]. A major consequence of E-cadherin down-regulation is the loss of stable epithelial cell-cell adhesive junctions, apico-basal cell polarity and epithelial tissue structure, thereby facilitating the release of cancer cells from the primary tumour site [11, 12]. In contrast to the migration-suppressive role of E-cadherin, N-cadherin endows tumour cells with enhanced migratory and invasive capacity, irrespective of E-cadherin expression [13]. Thus, the acquisition of N-cadherin appears to be a critical step in epithelial cancer metastasis and disease progression.

In this review, we will discuss how N-cadherin promotes the metastatic behaviour of tumour cells by directly mediating cell-cell adhesion, and by its involvement in modulating critical signalling pathways implicated in metastatic events. In addition, we will discuss the emerging relevance of N-cadherin in haematological malignancies, namely leukaemias and multiple myeloma. Finally, we will review the emerging evidence that N-cadherin may be a viable therapeutic target to inhibit cancer metastasis and overcome resistance to anti-cancer agents.

Structure and formation of the N-cadherin adhesive complex

N-cadherin is a member of the calcium-dependent adhesion molecule family of classical cadherins which directly mediate homotypic and heterotypic cell-cell adhesion. N-cadherin is a classical type I cadherin consisting of 5 extracellular domains linked to a functional intracellular domain. The engagement between N-cadherin monomers on opposing cells occurs by reciprocal insertion of a tryptophan residue side-chain on its first extracellular domain (EC1) into the hydrophobic pocket of the partner N-cadherin EC1 (trans adhesion). In addition, the stabilisation of N-cadherin-mediated adhesion requires the clustering of adjacent monomers on the surface of the same cell, involving the His-Ala-Val (HAV) motif on EC1 and a recognition sequence on the second extracellular domain (EC2) of the lateral N-cadherin monomer (cis adhesion) [14–16]. The membrane expression and lateral clustering of N-cadherin is dependent upon p120 catenin, which localises N-cadherin at cholesterol-rich microdomains [17, 18]. The initial ligation of N-cadherin extracellular domains triggers the activation of the Rho GTPase family member Rac, which stimulates localised actin filament assembly and the formation of membrane protrusions at points of cell-cell contact [19, 20]. The subsequent activation of the Rho GTPase family member RhoA, at the expense of Rac function, facilitates the maturation of N-cadherin-based cell-cell junctions by triggering the sequestration of β-catenin to the cadherin intracellular domain [21, 22]. β-catenin serves as a critical link to α-catenin which accumulates at nascent cell-cell junctions and suppresses actin branching. In addition, α-catenin facilitates the anchorage of the N-cadherin-catenin complex to the actin cytoskeleton via actin-binding proteins such as cortactin and α-actinin, thereby promoting the maturation of cell-cell contacts [23, 24] (Fig. 1). Notably, the adhesive function of N-cadherin is regulated by post-translational modifications of the N-cadherin-catenin complex. For instance, the stability of the N-cadherin-catenin complex is highly dependent on the phosphorylation status of N-cadherin and the associated catenins, which is regulated by tyrosine kinases, such as Fer and Src, and the tyrosine phosphatase PTP1B [25, 26]. In addition, branched N-glycosylation of N-cadherin EC2 and third extracellular domain regulates N-cadherin-dependent cell adhesion, at least in part, by controlling the lateral clustering of N-cadherin monomers [27].

The functional role of N-cadherin in solid tumour metastasis

N-cadherin expression is spatiotemporally regulated throughout development and adulthood. In development, N-cadherin plays an important role in morphogenetic processes during the formation of cardiac and neural tissues, and is involved in osteogenesis, skeletal myogenesis and maturation of the vasculature [28–32]. In adulthood, N-cadherin is expressed by numerous cell types including neural cells, endothelial cells, stromal cells and osteoblasts, and is integral to synapse function, vascular stability and bone homeostasis [30, 33–36]. While N-cadherin is typically absent or expressed at low levels in normal epithelial cells, the aberrant expression of N-cadherin in epithelial cancer cells is a well-documented feature of epithelial malignancies, such as breast, prostate, urothelial and pancreatic cancer, and is associated with disease progression [37–40]. In a similar manner, the up-regulation of N-cadherin expression is a feature of melanoma progression [41–43]. Whilst the aberrant expression of N-cadherin in epithelial tissues is not considered to be oncogenic, or a promoter of solid tumour growth [44–46], increased expression of N-cadherin in cancer is widely associated with tumour aggressiveness. Indeed, many studies have demonstrated a significant correlation between elevated N-cadherin levels in epithelial, and some non-epithelial solid tumours, and clinicopathologic features such as increased localised tumour invasion and distant metastasis, and inferior patient prognosis [7, 8, 47–81] (Table 1). Multivariate analyses have also identified that elevated N-cadherin expression is independently associated with inferior patient prognosis in several epithelial malignancies including prostate, lung and bladder cancer [8, 55, 56, 60, 62, 63, 67, 72, 78, 80] (Table 1). The aggressive phenotype and inferior prognosis associated with up-regulated N-cadherin expression in solid tumours is also supported by a recent meta-analysis incorporating patients with various epithelial malignancies [82].

Beyond the prognostic implications of aberrant N-cadherin expression, the relationship between N-cadherin and metastasis is not merely associative. Indeed, there is a wealth of evidence that increased N-cadherin expression enhances the migratory and invasive capacity of multiple epithelial cancer cell types in vitro [83–87]. The ability of N-cadherin to promote epithelial tumour metastasis in vivo was initially demonstrated using the MCF-7 breast cancer cell line, following injection into the mammary fat pad of nude mice. In contrast to wild-type cells, MCF-7 cells ectopically expressing N-cadherin formed tumour metastases in several organs including the liver, pancreas and lymph nodes [88]. Similarly, N-cadherin expression in the mammary epithelium in the transgenic MMTV-PyMT murine breast cancer model resulted in a three-fold increase in the number of pulmonary metastatic foci without affecting the onset or growth of the primary tumour [45]. Using an orthotopic mouse model of pancreatic cancer, the over-expression of N-cadherin in BxPC-3 cells increased the formation of disseminated tumour nodules throughout the abdominal cavity and induced the formation of N-cadherin-expressing lung micro-metastases [85]. Consistent with these findings, enforced expression of N-cadherin in androgen-responsive prostate cancer cells promoted invasion of underlying muscle and lymph node metastasis following subcutaneous injection in castrated mice [89]. Notably, N-cadherin also potentiates the invasiveness of melanoma cells. To this end, studies have demonstrated that N-cadherin promotes the capacity of melanoma cells to migrate on monolayers of dermal fibroblasts and undergo trans-endothelial migration in vitro [86, 90, 91]. Moreover, N-cadherin silencing has been shown to attenuate the ability of intravenously injected melanoma cells to extravasate and form lung metastases in immunocompromised mice [92].

To appreciate how N-cadherin, a cell adhesion molecule, may actively promote cancer cell migration, it is important to consider that the N-cadherin-catenin complex mediates both cell-cell adhesion and pro-metastatic cell signalling. Moreover, the adhesive function and migration-related signalling capacity of N-cadherin can occur simultaneously, or as antagonistic events, adding further complexity to its role in cancer metastasis. In the following section, we describe three key mechanisms by which N-cadherin has been shown to actively promote the migratory capacity of tumour cells: facilitation of collective cell migration, augmentation of fibroblast growth factor-receptor (FGFR) signalling and modulation of canonical Wnt signalling.

N-cadherin promotes collective cell migration

The migration of cells as sheets, clusters or strands, a process termed collective cell migration, frequently occurs throughout development and in adulthood. For instance, collective cell migration occurs in embryogenesis, during gastrulation and neural crest cell migration, and in adult tissues, during wound healing and angiogenesis [93, 94]. In addition, collective cell migration facilitates the invasion of epithelial cells through the localised tumour host microenvironment, thereby promoting metastasis [95]. During this process, collectively migrating cells maintain physical interconnectivity, collective cell polarity and co-ordinated cytoskeletal activity, resulting in a ‘leader-follower’-type cellular arrangement. This promotes more efficient directional migration, in response to a chemotactic gradient, than that of an individual migrating cell [93, 96]. Adhesive complexes are integral to the co-ordinated behaviour of collectively migrating cells by mediating adhesion, signal transduction and mechanotransduction between adjacent cells [94, 97]. Notably, studies have demonstrated that N-cadherin expression by epithelial cancer cells promotes their capacity for collective migration. For instance, N-cadherin has been shown to promote the ability of lung or ovarian cancer cells to form aggregates and collectively invade three-dimensional (3D) collagen matrices or penetrate peritoneal mesothelium-like cell layers in vitro [87, 98]. Similarly, studies in transformed canine kidney epithelial cells (MDCK cells) have shown that N-cadherin promotes aggregate formation which allows directional collective cell migration in a 3D collagen matrix. In these cells, deletion of the entire N-cadherin intracellular domain, or the β-catenin binding domain alone, resulted in greater individual cell detachment and migration from cell clusters, highlighting the importance of the N-cadherin-actin cytoskeleton interaction in collective cell migration. Moreover, over-expression of an N-cadherin mutant in which the extracellular domain was fused to the anti-binding domain of α-catenin hindered the movement of follower cells, demonstrating that dynamic N-cadherin-actin linkage is required for efficient collective cell migration [99].

In addition to maintaining multi-cellular aggregates of tumour cells, studies in N-cadherin-expressing non-tumour cells have demonstrated that N-cadherin also promotes collective cell migration by polarising Rho-family GTPase signalling (e.g. Rac1 and cdc42), known to co-ordinate cytoskeletal remodelling in collectively migrating cells [100, 101]. For example, models of arterial smooth muscle wound-healing and neural crest migration have shown that the asymmetric distribution of N-cadherin-mediated cell-cell adhesion at the lateral and posterior aspects of leader cells promotes directional cell alignment and increased cdc42 and Rac1 activity and protrusion formation at the free leading cell edge, resulting in enhanced migration [102, 103]. Mechanistically, studies in mouse embryonic fibroblasts have demonstrated that N-cadherin-adhesive complexes at the rear of cells suppress localised integrin-α5 activity, thereby polarising integrin and Rac activity towards the free leading edge of the cell [104]. Indeed, functional inhibition of N-cadherin in transformed mammary cells has been shown to reduce integrin-α5-dependent cell migration on fibronectin in vitro [105]. In a similar manner, silencing of N-cadherin expression in melanoma cells perturbs α2β1-integrin-dependent collagen matrix invasion in vitro [106]. Reciprocally, integrin signalling at focal adhesions has been shown to regulate the ability of HeLa cells to engage in N-cadherin-based connections and to promote collective cell migration [107]. Given that integrins play an important role in the activation of Rho signalling [108, 109], it is plausible that N-cadherin may polarise Rho-family GTPase signalling via intercommunication with integrins, thereby promoting the collective migration of cancer cells (Fig. 2a).

N-cadherin augments fibroblast growth factor receptor signalling

Functional interaction between the extracellular domains of N-cadherin and receptor-tyrosine kinase FGFRs was first recognised as a mechanism by which N-cadherin promoted axonal outgrowth of rat cerebellar neuronal cells. These studies identified that the fourth extracellular domain of N-cadherin (EC4) trans-activated FGFRs to promote neurite outgrowth independent of FGF ligands, suggesting that N-cadherin can act as a surrogate ligand of FGFRs [33, 110]. The physical interaction of N-cadherin and FGFRs has also been shown in breast and pancreatic cancer cells [111–114]. Evidence that FGFR plays a functional role in N-cadherin-mediated cancer metastasis has been demonstrated in BT-20 and PyMT breast cancer cells, whereby FGFR inhibition reduced the in vitro migratory capacity of N-cadherin-expressing cells, but not N-cadherin-negative cells [45, 84]. In addition, FGF-2 increased the invasiveness of N-cadherin-expressing MCF-7 human breast cancer cells, but not control MCF-7 cells [88]. To this end, it has been shown that N-cadherin potentiates FGF-2-activated FGFR-1 signalling by attenuating ligand-induced FGFR-1 internalisation, thereby stabilising FGFR-1 expression [111, 113]. In turn, the sustained activation of down-stream MEK/ERK signalling results in increased production of the extracellular matrix (ECM)-degrading enzyme matrix metalloproteinase-9 (MMP-9) and enhanced breast cancer cell invasiveness [88, 111]. In addition, the interaction of N-cadherin and FGFR is also likely to promote metastasis by activation of the phosphatidylinositide-3 kinase/Akt (PI3K/Akt) signalling pathway in some cancer cell types. For example, studies suggest that the invasiveness of N-cadherin-expressing ErbB2/Neu breast cancer cells following FGFR activation is mediated by PI3K/Akt signalling. N-cadherin potentiates FGFR-Akt signalling and sensitivity to FGFR inhibition in ErbB2/Neu cells, suggesting the involvement of an N-cadherin-FGFR-PI3K/Akt signalling axis in breast cancer cell invasion [115] (Fig. ​(Fig.2b2b).

Two lines of evidence suggest that N-cadherin-FGFR-1 interactions promote the invasive behaviour in both collectively migrating and individual cancer cells. Firstly, N-cadherin-FGFR-1 interactions have been shown to occur over most of the cell membrane, but are excluded from sites of cell-cell adhesion, suggesting that the interaction is independent of N-cadherin-mediated cellular adhesion [112]. Secondly, blocking antibodies directed at the FGFR-1-interacting domain of N-cadherin (EC4) have been shown to inhibit N-cadherin-mediated migration, but not N-cadherin-mediated aggregation, of human breast cancer cells [116]. Thus, it would appear that N-cadherin-mediated cell-cell adhesion and N-cadherin-mediated cell migration via FGFR-1 are independent and mutually exclusive events. Further studies are warranted to identify whether N-cadherin potentiates FGFR-1 signalling in other epithelial malignancies such as pancreatic cancer.

N-cadherin modulates canonical Wnt signalling

In addition to stabilising cadherin-mediated cell-cell adhesion, β-catenin plays a central role in the canonical Wnt signalling pathway. Canonical Wnt signalling promotes the cytoplasmic accumulation and nuclear translocation of β-catenin, which activates T cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription of genes [117–119] that encode tumour invasion and metastasis-promoting molecules (e.g. MMPs and CD44) [120–126]. It has been proposed that cadherins and the canonical Wnt signalling pathway may compete for the same cellular pool of β-catenin, with cadherins sequestering β-catenin from the nucleus, thereby attenuating Wnt signalling [127, 128]. Indeed, enforced expression of N-cadherin in colon carcinoma cells resulted in the relocation of nuclear β-catenin to the plasma membrane and attenuated LEF-responsive trans-activation [129]. Alternatively, studies suggest that the N-cadherin-β-catenin complex may provide a stable pool of β-catenin available for TCF/LEF-mediated gene transcription in cancer cells [91, 130]. To this end, disruption of N-cadherin-mediated adhesion in leukaemic cells was found to increase TCF/LEF reporter activity [131]. Thus, given β-catenin is essential in the stabilisation of N-cadherin-mediated cellular adhesion (discussed earlier), it is feasible that the ability of N-cadherin to modulate TCF/LEF-mediated gene transcription may play an important role in individual cell migration, at the expense of collective cell migration (Fig. ​(Fig.2c2c).

Trans-endothelial migration is an important process in the haematogenous dissemination of cancer cells to distant sites [132]. Notably, studies suggest that N-cadherin promotes the trans-endothelial migration of cancer cells. To this end, N-cadherin silencing has been shown to reduce the ability of melanoma cells to undergo trans-endothelial migration in vitro [91]. Studies have demonstrated that N-cadherin-mediated melanoma cell adhesion to endothelial cells promotes trans-endothelial migration by modulating canonical Wnt signalling. β-catenin co-localises with N-cadherin during the initial stages of melanoma cell adhesion to endothelial cells; however, during transendothelial migration, the tyrosine kinase Src is activated and subsequently phosphorylates the N-cadherin cytoplasmic domain, thereby dissociating the N-cadherin-β-catenin complex. β-catenin is then translocated to the nucleus of melanoma cells and activates TCF/LEF-mediated gene transcription, resulting in up-regulation of the adhesion molecule CD44 [91, 133]. Studies using epithelial cancer cells suggest that CD44 binding to E-selectin on endothelial cells activates intracellular signalling pathways that lead to disassembly of endothelial junctions, thereby facilitating trans-endothelial migration [134–136]. In line with these studies, CD44 expression in melanoma cells has been shown to promote endothelial gap formation and trans-endothelial migration in vitro [137]. Moreover, N-cadherin knock-down in human melanoma cells reduces extravasation and lung nodule formation following intravenous injection in immuno-compromised mice [92]. Notably, while N-cadherin-expressing tumour cells have been detected in the circulation of patients with various epithelial cancers [59, 68, 76], and CD44 has been shown to promote diapedesis in breast cancer cells [134, 138], a role for N-cadherin in the trans-endothelial migration of epithelial cancer cells has not been directly demonstrated to date.

N-cadherin as a therapeutic target in cancer

As N-cadherin is widely implicated in cancer metastasis, the utility of N-cadherin antagonists as therapeutic drugs is being investigated in the oncology setting. Notably, N-cadherin-targeting agents have been shown to inhibit cell adhesion and to modulate cell signalling. Interestingly, studies have also shown that N-cadherin-targeting agents affect both tumour cells and tumour-associated vasculature. Here, we describe the current repertoire of N-cadherin antagonists that have displayed efficacy as anti-cancer agents in vivo.

Monoclonal antibodies

Several monoclonal antibodies directed against N-cadherin have been investigated for their ability to block N-cadherin-dependent tumour migration and invasion in vitro and metastasis in vivo. The mouse monoclonal antibody, designated GC-4, binds to the EC1 domain of N-cadherin monomers and subsequently blocks N-cadherin-mediated adhesion [36, 167, 177, 178]. GC-4 has been shown to suppress N-cadherin-mediated Akt signalling [61, 166], and inhibit the migration and invasion of melanoma, bladder, ovarian and breast cancer cells in vitro [61, 87, 88, 91]. In addition, pre-treatment of AML cells with GC-4 has been shown to inhibit BM homing of circulating tumour cells in vivo [156]. Thus, as N-cadherin plays a role in trans-endothelial migration and BM homing of circulating tumour cells in melanoma and MM, in addition to AML [91, 156, 167, 173], treatment with GC-4 may by therapeutically relevant in the context of limiting the metastatic dissemination of tumour cells in these cancers. Additionally, GC-4-mediated blocking of N-cadherin engagement between human CD34⁺ CML cells and stromal cells increased tumour cell sensitivity to imatinib, demonstrating a potential therapeutic strategy to overcome tyrosine kinase inhibitor resistance [131]. Two additional monoclonal antibodies, 1H7 (targeting N-cadherin EC1–3) and 2A9 (targeting N-cadherin EC4), have shown efficacy in a subcutaneous xenograft prostate cancer mouse model, whereby both antibodies reduced the growth of established tumours and inhibited localised muscle invasion and distant lymph node metastasis [89].

ADH-1

The lateral clustering of N-cadherin monomers (cis adhesion) is essential in the stabilisation and maturation of nascent N-cadherin-mediated adhesive junctions between neighbouring cells [14, 16]. Peptides containing the classical cadherin motif, HAV, are likely to compete with the HAV motif on N-cadherin EC1 for binding to a recognition sequence on EC2 of an adjacent N-cadherin monomer, thereby inhibiting the lateral clustering of N-cadherin monomers [179]. On the basis that a HAV motif located on FGFR-1 is required for FGF-2 binding [112], it is feasible that peptides containing a HAV motif may also inhibit FGFR signalling. This concept led to the development of ADH-1 (N-Ac-CHAVC-NH₂), a stable cyclic peptide harbouring a HAV motif, which similarly inhibited N-cadherin-dependent function [180]. In vitro, ADH-1 has been shown to induce apoptosis in a range of tumour cell types, and inhibits tumour cell migration at sub-cytotoxic concentrations, with cell sensitivity proportional to relative N-cadherin expression [181–183]. The efficacy of ADH-1 as an anti-cancer agent has been demonstrated in a number of pre-clinical mouse models including pancreatic, breast, colon, ovarian and lung cancer [181, 184]. In addition to inhibiting primary tumour growth, pre-clinical studies also suggest that ADH-1 may inhibit localised tumour invasion and dissemination via the circulation [173, 181]. For example, studies using a mouse model of MM reported that daily ADH-1 treatment commencing immediately prior to, but not after, intravenous inoculation of MM PCs resulted in inhibition of tumour development [173]. Notably, ADH-1 has also been identified as a vascular-disrupting agent, suggesting the compound may have effects on both tumour cells and tumour-associated vasculature [184, 185]. In phase I clinical trials, ADH-1 was shown to have an acceptable toxicity profile with no maximum tolerated dose achieved. ADH-1 treatment was associated with disease control in approximately 25% of patients with advanced chemotherapy-refractory solid tumours, independent of tumour N-cadherin expression status [186, 187].

The therapeutic efficacy of ADH-1 as an anti-cancer agent has been most extensively evaluated in the melanoma setting. Pre-clinical studies suggest that ADH-1 synergistically enhances melanoma tumour response to melphalan [188, 189]. These studies showed that ADH-1 enhances the permeability of tumour vasculature and increases melphalan delivery to the tumour microenvironment, as evidenced by increased formation of melphalan-DNA adducts in tumours. However, the combinatorial effects of ADH-1 and melphalan were not replicated in phase I/II clinical trials [190, 191]. In contrast to other tumour settings, studies have also suggested that ADH-1 may stimulate tumour growth in some mouse models of melanoma [188, 189]. These effects were associated with activation of pro-growth and survival intracellular signalling pathways including Akt signalling and the down-stream mTOR signalling pathway in vitro and in vivo [189]. These data suggest that ADH-1 may act as an N-cadherin agonist in certain tumour contexts. However, to date, ADH-1-mediated activation of tumour cell proliferation and signalling has not been reported in the clinical setting.

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More information: Veena Padmanaban et al. E-cadherin is required for metastasis in multiple models of breast cancer, Nature (2019). DOI: 10.1038/s41586-019-1526-3

Journal information: Nature
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