The role of Notch ligand, Delta-like ligand 4 (DLL4), in cancer angiogenesis—implications for therapy

Brzozowa-Zasada, Marlena

doi:10.1007/s10353-021-00707-x

Cited by 6 publications

(4 citation statements)

References 48 publications

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“…In preclinical cancer models, it has been demonstrated that DLL4-Fc, a recombinant protein that mimics the binding of Delta-like ligand 4 (DLL4), activates Notch signaling and inhibits tumor development [101]. In a study published in 2006, the role of DLL4 in tumor angiogenesis was investigated using preclinical models.…”

Section: Ligand-mimicking Moleculesmentioning

confidence: 99%

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Parambath,

Selvraj,

Venugopal

et al. 2024

IJMS

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The highly conserved Notch pathway, a pillar of juxtacrine signaling, orchestrates intricate intercellular communication, governing diverse developmental and homeostatic processes through a tightly regulated cascade of proteolytic cleavages. This pathway, culminating in the migration of the Notch intracellular domain (NICD) to the nucleus and the subsequent activation of downstream target genes, exerts a profound influence on a plethora of molecular processes, including cell cycle progression, lineage specification, cell–cell adhesion, and fate determination. Accumulating evidence underscores the pivotal role of Notch dysregulation, encompassing both gain and loss-of-function mutations, in the pathogenesis of numerous human diseases. This review delves deep into the multifaceted roles of Notch signaling in cellular dynamics, encompassing proliferation, differentiation, polarity maintenance, epithelial–mesenchymal transition (EMT), tissue regeneration/remodeling, and its intricate interplay with other signaling pathways. We then focus on the emerging landscape of Notch aberrations in gynecological pathologies predisposing individuals to infertility. By highlighting the exquisite conservation of Notch signaling in Drosophila and its power as a model organism, we pave the way for further dissection of disease mechanisms and potential therapeutic interventions through targeted modulation of this master regulatory pathway.

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Section: Ligand-mimicking Moleculesmentioning

confidence: 99%

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Parambath,

Selvraj,

Venugopal

et al. 2024

IJMS

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show abstract

“…Paradoxically, blocking DLL4 inhibits tumour growth by increasing, but not decreasing, vascular density through the formation of vessels that lack blood perfusion and are non-functional 148 . Numerous DLL4-NOTCH1 inhibitors have been tested in preclinical models, including anti-DLL4 antibodies, anti-NOTCH1 antibodies, soluble DLL4-Fc, NOTCH1-Fc decoy, γ-secretase inhibitors and DNA vaccines 149 . However, despite potent antitumour activity, DLL4 inhibitors exhibit broad toxicities in the liver, heart, lung and skin 150 .…”

Section: Hif Inhibitorsmentioning

confidence: 99%

Targeting angiogenesis in oncology, ophthalmology and beyond

Cao

Langer

Ferrara

2023

Nat Rev Drug Discov

113

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Angiogenesis is an essential process in normal development and in adult physiology, but can be disrupted in numerous diseases. The concept of targeting angiogenesis for treating diseases was proposed more than 50 years ago, and the first two drugs targeting vascular endothelial growth factor (VEGF), bevacizumab and pegaptanib, were approved in 2004 for the treatment of cancer and neovascular ophthalmic diseases, respectively. Since then, nearly 20 years of clinical experience with anti-angiogenic drugs (AADs) have demonstrated the importance of this therapeutic modality for these disorders. However, there is a need to improve clinical outcomes by enhancing therapeutic efficacy, overcoming drug resistance, defining surrogate markers, combining with other drugs and developing the next generation of therapeutics. In this Review, we examine emerging new targets, the development of new drugs and challenging issues such as the mode of action of AADs and elucidating mechanisms underlying clinical benefits; we also discuss possible future directions of the field. Nature Reviews Drug Discovery Review articleof the embryonic haemangioblasts that subsequently differentiate into haematopoietic cells and endothelial cells 10 . Genetic deletion of a single allele of the mouse Vegf gene leads to embryonic lethality owing to a loss of haematopoietic cells and blood vessels 2,3 . Therefore, an optimal VEGF level is required for normal embryonic development.VEGF is the key angiogenic factor that contributes to the formation of disorganized and primitive vasculature in various tumour tissues 7,8 (Fig. 1). It stimulates diverse biological processes, many of which are relevant to cancer [11][12][13][14] . Consequently, numerous drugs that block the VEGF signalling pathway have been developed, and they have received US Food and Drug Administration (FDA) approval for the treatment of various cancers (Table 1) as well as for neovascular eye disorders.Today, nearly all clinically approved anti-angiogenic drugs (AADs) for cancer therapy and ophthalmic disorders target the VEGF pathway (Table 1). In 2004, the humanized anti-VEGF monoclonal antibody bevacizumab (Avastin) 15 was approved by the FDA for previously untreated metastatic colorectal cancer (CRC). This approval represented an important milestone for the concept of anti-angiogenic therapy in patients with cancer 16 (Fig. 1). Bevacizumab is still one of the most widely used cancer therapeutics, with 12 FDA approvals for multiple indications 17 . It is also widely used off-label to treat ophthalmic neovascular disorders. Owing to the diverse biological functions of VEGF, drugs that block the VEGF pathway are likely to act through complex mechanisms, including anti-angiogenesis, normalization of tumour vasculature, regression of existing tumour vasculatures, reducing vascular leakage, improving delivery of other anticancer drugs and the alteration of immune functions 18 . Although these various mechanisms could underlie clinical benefits, we define these drugs as AADs in this Review.D...

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“…EV content may activate the proliferative and migratory status of ECs, favoring neo-vessel formation via different mechanisms, including epigenetic ones [ 90 ] ( Figure 2 ). The canonical VEGF (or Notch signaling pathway) was described as being activated by EVs from different tumor types because ECs promoted sprouting and proliferation [ 91 , 92 , 93 , 94 ] ( Figure 2 ). Other metabolic programs have also been proven to influence the migration of ECs [ 16 ].…”

Section: Basic Mechanisms and Epigenetic Role Of Evs In Tumor Vascula...mentioning

confidence: 99%

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage

Schiano

Balbi²,

Nigris

et al. 2023

IJMS

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Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

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The role of Notch ligand, Delta-like ligand 4 (DLL4), in cancer angiogenesis—implications for therapy

Cited by 6 publications

References 48 publications

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions

Targeting angiogenesis in oncology, ophthalmology and beyond

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage

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