Page 44 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology NOTCH3 in CSVD and breast cancer

that the conventional ischemic stroke mechanisms, such as in 1914. NOTCH signalling contributes to a range of
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cardioembolic and lacunar strokes, are roughly the same biological processes in different species, including organ
among patients with and without cancer. Furthermore, development, tissue maintenance, and tissue regeneration.
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previous studies have indicated that atherosclerosis is the Consequently, disrupted NOTCH signalling can lead to
leading cause of ischemic stroke in patients with neoplasia. 1 pathological outcomes. In addition, NOTCH protein and
its homologs, including NOTCH1, NOTCH2, NOTCH3,
The exact mechanisms of CSVD and ischemic stroke in the
context of BC remain vague. Given that vascular risk factors NOTCH4, LIN-12, and glucagon-like peptide 1, have
been detected in genomes across all biological kingdoms,
are widespread among CSVD and/or ischemic stroke patients, signifying the ongoing diversification of the NOTCH
whether both CSVD and BC emerge independently and family. Their length spans from approximately 110 amino
simultaneously, or if BC directly impacts the pathophysiology acids in bacteria to about 4,500 amino acids in animals.
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of CSVD and/or ischemic stroke, remains uncertain. Members of the NOTCH family have evolutionarily
Interestingly, hypercoagulability has been considered the preserved type-1 transmembrane glycoproteins, serving the
primary mechanism behind ischemic stroke in individuals dual role of acting as transmembrane receptors for ligands
with cancer. Tumour cells secrete pro-coagulant molecules, and functioning as transcription factors. To date, there
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including tissue factors and cancer pro-coagulants, such as are four paralogous NOTCH transmembrane receptors
cysteine protease, which enhance the coagulation process. encoded by four distinct genes, namely, NOTCH1 to 4
Furthermore, they release various cytokines, such as tumour were found in mammals.
necrosis factor-alpha, and interleukins (ILs), including IL-1
and IL-6. These molecules function as pro-coagulants Structurally, the human NOTCH family receptor
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through three mechanisms: First, by inducing cells to express comprises an extracellular domain (NOTCH extracellular
tissue factors; second, by impeding the activation of Protein C; domain, NECD), a transmembrane domain, and an
and finally, by causing shedding of vascular endothelial cells, intracellular domain (NOTCH intracellular domain,
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thereby contributing to increased blood viscosity and clot NICD) (Figure 1). The NECD comprises between 29
formation. This constitutes a paraneoplastic phenomenon and 36 epidermal growth factor-like repeats (EGF-like
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that remains poorly understood but is associated with reduced domains), a number that varies depending on the receptor
survival in affected individuals. 57 type, along with a negative regulatory region (NRR). The
NRR consists of three cysteine-rich LIN-12/NOTCH
Numerous studies have attempted to employ laboratory repeats (LNRs) and a heterodimerisation domain. Each
markers to assess coagulation abnormalities. D-dimer EGF-like repeat contains six cysteines, resulting in the
serves as an indicator of an activated coagulation system, formation of three disulphide bonds that contribute to the
including in patients with CSVD. Cancer patients who protein’s three-dimensional structure. Moreover, a recent
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experience strokes tend to have elevated D-dimer levels study detailed that the NICD is comprised of an RBPJκ-
in comparison to stroke patients without cancer. 2,54,57 associated molecule (RAM) domain, a domain with seven
D-dimer is also an independent predictor for CSVD ankyrin repeats (ANK), nuclear localization sequences
and strokes caused by non-conventional mechanisms, (NLS), a transcriptional activation domain (TAD), and a
which are notably linked to cancer in several studies. C-terminal Pro-Glu-Ser-Thr (PEST) domain (Figure 1).
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Moreover, previous studies have reported a greater While NOTCH receptors are largely preserved, they
occurrence of micro-embolisms detected by transcranial exhibit structural variability, particularly in the number of
Doppler inpatients who experienced strokes due to EGF-like repeats, the presence of the TAD domain, and the
cancer, especially in cases involving unconventional stroke length of the segment between the ANK repeats and the
mechanisms. This correlation was notably significant and C-terminal region. 65
aligned with elevated D-dimer levels. Nevertheless, it’s
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important to note that D-dimer is a non-specific marker, 5. NOTCH3 signalling
as it can become elevated in various situations, even in The NOTCH3 gene encodes a receptor of approximately
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cancer patients who do not have a stroke. Hence, new and 2321 amino acids, which dictates the fate of vascular
alternative approaches are needed to further strengthen smooth muscle cells (VSMCs) within the brain’s arterial
the association between CSVD and/or stroke and cancer, network. Activation of the NOTCH (in this case
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specifically BC in this context. NOTCH3) signalling pathway occurs through cellular
interactions with a NOTCH ligand. In mammals, there
4.1. Roles of NOTCH3 in BC and CSVD
are five NOTCH ligands have been reported, such as delta-
The Notch gene received its initial identification during like ligands (DLL) 1, 3, and 4 and jagged (JAG) 1, and 2.
research on irregular notched-wing Drosophila melanogaster Before reaching the cell membrane, the intact NOTCH3

Volume 9 Issue 3 (2025) 36 doi: 10.36922/EJMO025150095