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Tumor Discovery The mechanism of cancer-related cognitive decline

parenchyma. This further promotes the polarization of integrity of the vascular endothelial barrier and induce
the inflammatory neuroglial cells and ultimately causes cognitive impairment [34,35] . In systemic cancers, the EVs
pathological, structural, and biochemical changes of the may affect the cognitive function by activating brain
neurons associated with cognitive function [16,23] . metastasis, which disrupts the BBB integrity, secreting
pro-permeability factors to increase BBB permeability and
2.2. Tumor-derived extracellular vesicles (EV) inducing a peripheral blood immune response that triggers
[36]
EVs are a heterogeneous collection of membrane- brain stress responses .
bound vesicles released by cells that contain bioactive
proteins, nucleic acids, and lipids, and are classified into 2.3. BBB dysfunction
exosomes and exfoliated microvesicles according to their BBB is a barrier structure formed by endothelial cells
biological mechanisms . EVs are involved in a variety interacting with pericytes, astrocytes, neurons, and
[24]
of normal physiological processes such as coagulation, microglia of the neurovascular unit. BBB not only
immune regulation, tissue regeneration, angiogenesis restricts the entry of potential neurotoxic components
and synaptic plasticity, as well as pathological processes and pathogens from the blood into the brain tissue,
such as neurodegeneration and cancer . With respect to but also controls the transport of nutrients and energy
[25]
cancer, EVs are involved in various pathological processes sources required by the CNS and essential molecules in
related to cancer progression, such as inflammatory the blood. In addition, it transports brain metabolites
response, angiogenesis, lymphogenesis, cell migration to the periphery to maintain CNS homeostasis and
and proliferation, immunosuppression, and invasion . It function . Although BBB has a strong regulatory effect,
[37]
[26]
has been established that the initiation, propagation, and it is also very fragile. Disruption of any component of
resolution of the inflammatory responses to CNS injuries/ the structure may induce abnormal neuronal signaling
diseases rely on inflammatory factors and microRNAs and disrupt the synaptic integrity and BBB permeability,
[27]
(miRNAs), both of which are contained in EVs . Animal leading to CNS diseases such as ischemic stroke, AD, brain
experiments have shown that intravenous administration tumors, and systemic inflammation. The most significant
of serum exosomes in the recipient mice from donor mice and common pathogenesis of these diseases is the effect
injected with lipopolysaccharide induced an inflammatory of neuroinflammatory changes on BBB dysfunction
response in the CNS. A series of changes, such as and disease progression [37,38] . As previously discussed,
microglial activation, gliosis, increase of pro-inflammatory inflammatory factors produced by the cancer cells and
factors (IL-6 and TNF-α) and production of inflammatory TME can enter the CNS by disrupting the BBB integrity
miRNA-155, were observed in the recipient mice . or increasing its permeability, subsequently activating
[28]
Additionally, a growing line of evidence shows that EVs glial cells and further initiating the pro-inflammatory
can serve as novel mediators of cellular communication signaling cascade, thus affecting the cognitive function.
during normal development and physiological functions In vitro and in vivo BBB model studies have shown that
of the CNS, as well as normal neuronal regeneration . EVs secreted by breast cancer cells could enter the brain
[29]
Under conditions of nutritional deficiency and oxidative tissue by transcytosis of the vascular endothelial cells
stress, neurons can enhance their own viability by or by disrupting the BBB integrity through CVOs .
[39]
internalizing exosomes released from oligodendrocytes . Dysfunction of the active efflux transport in the BBB can
[30]
Astrocytes release exosomes containing heat shock impair the clearance of toxic substances such as β-amyloid
protein 70, which also promotes neuronal survival . (Aβ). The accumulation of Aβ in the brain tissue can
[31]
The uptake of microglia-derived exosomes by neurons promote pathological changes in tau protein and induce
induces production of sphingosine and enhances or exacerbate cognitive impairment, which is very similar
excitatory neurotransmission , suggesting that both to the pathogenic mechanisms of AD . Furthermore,
[40]
[32]
neurons and supporting cells can participate in cellular persistent angiogenesis and immunosuppression are the
communication by secreting exosomes. Tumor-derived typical features of cancer, and pathological angiogenesis
EVs may be involved in physiological and pathological is associated with abnormal blood flow and dysfunction
processes (synaptic growth and plasticity) by mediating of the BBB . Angiopoietin-2 is an early vascular marker
[41]
the communication between neurons, thereby affecting in glioblastoma multiforme. In addition to regulating
brain activity and cognitive function . CNS tumors, such vascular development, maturation, and immediate
[33]
as glioblastoma, remodels the TME by secreting exosomes vascular response, its overexpression can lead to pericyte
to induce intracellular transfer of tumor-derived long defects, disruption of endothelial cell integrity, and
noncoding RNA SBF2-AS1, or the exosomes secrete pro- interference with the BBB function . Thus, immune
[42]
permeability factors (e.g., semaphorin 3A) that disrupt the inflammatory factors and EVs released by cancer cells

Volume 1 Issue 1 (2022) 3 https://doi.org/10.36922/td.v1i1.46