Contribution of Extracellular Vesicles to Cancer Initiation through Cellular Senescence during Aging

Cellular senescence and the senescence-associated secretory phenotype Cellular senescence is a cellular state characterized by arrest of cell growth, enlarged 1,2 morphology, and changes in chromatin and the secretome. It was originally advocated by Dr. 3,4 Hayflick in 1961 and is well known as the “Hayflick limit.” Cellular senescence can be categorized by external and internal changes. Damage to genomic and telomeric DNA can 5–7 8 trigger the DNA damage response. Senescent cells accumulate mutations in their genome that trigger this DNA damage response, thus activating ataxia telangiectasia mutated (ATM) 9,10 and p53, which initiate and maintain cell growth arrest. Expression of p16INK4a, which has regulatory roles with CDK4 and p53 in cell cycle G1 progression, and Wnt family member 16 11 (WNT16B) is also characteristic of senescent cells and contributes to the maintenance of homeostasis in organisms. These cellular states have been considered tumor suppression 5,12,13 1,14 mechanisms. However, this emerging theory appears paradoxical. Senescent cells secrete many factors into the extracellular environment, which is known as a senescence15,16 associated secretory phenotype (SASP). This SASP includes secretion of many factors, including amphiregulin (AREG), granulocyte-macrophage colony-stimulating factor (GMCSF), C-X-C chemokines (CXCLs), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinases (MMPs), monocyte chemoattractant proteins (MCPs), plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), and extracellular 17,18 vesicles (EVs), that control cell growth, motility, differentiation, and inflammation. In humans, there are tissue-resident senescent cells that contribute to aging and age-related 3,19 diseases through the SASP. These SASP-associated factors facilitate tumor cell invasion Abstract


Introduction Cellular senescence and the senescence-associated secretory phenotype
Cellular senescence is a cellular state characterized by arrest of cell growth, enlarged 1,2 morphology, and changes in chromatin and the secretome.It was originally advocated by Dr.

3,4
Hayflick in 1961 and is well known as the "Hayflick limit."Cellular senescence can be categorized by external and internal changes.Damage to genomic and telomeric DNA can Tominaga N. Cancer Studies.2018, 1:6.
Table 1.Contents and function of EVs from senescence cells or blood samples obtained from age Some studies have detected alterations in EV content by comparing healthy young and aged individuals.Levels of six proteins, TSN1, PODXL, IDHC, PPAP, ACBP, and ANXA5, in EVs 47 isolated from urine were distinct between people aged 25-50 and 50-70 years.The authors mentioned a possibility that these proteins has been implicated in cancer and cancer 50 prognosis.In addition, the EV lipidomic profile also differed in senescent platelets.An aging biomarker, miR-24-3p, was identified by assessing the miRNAs in EVs isolated from saliva 55 from young healthy (median age, 21.0 years) and older volunteers (median age, 66.0 years).Recent studies have shown levels of miR-96/-182/-183, i.e., the miR-183 cluster, increase with age in EVs from the bone marrow interstitial fluid of young (3-4 months) and aged (24-28 53 months) mice.

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Studies have shown EV components differ between diseased and healthy individuals.Ten miRNAs from serum EVs were found to have age-related differences by comparing postmenopausal individuals not undergoing estrogenic hormone replacement therapy to 57 premenopausal individuals.In 2009, it was reported EVs may be potential markers of age-66,67 related macular degeneration pathogenesis.
Therefore, it is clear EVs contents change with age.

EV functions in aging individuals and senescent cells
Studies on the SASP and EVs have raised questions concerning the contribution of EVs to cancer initiation due to alterations in EV profiles during aging.In recent years, it has been found cell senescence mechanisms promote carcinogenesis, which appears to be a "double-20,46 edged sword."As mentioned above, one aspect of the SASP is its anti-cancer function.For 58 example, EV secretion maintains homeostasis by discarding accumulated DNA.An inhibition of EV secretion will be induced the innate immune response, senescence-like cell- neurodegeneration.The authors investigated EVs from concentrated human donor platelets, which were stored for 0 to 5 days.Upregulation of miR-144-3p, miR-486-5p, miR-142-5p, miR-451a, miR-25-3p, miR-145-5p, and let-7f-5p, which contribute to certain agerelated diseases, was observed in EVs from senescent platelets.Recent studies have shown EV-derived miR-183-5p from aged bone marrow reduced stem cell proliferation and inhibited 53 osteogenic differentiation, contributing to stem cell senescence in vitro.
In addition, EVs in fetal bovine and human serum contribute to cell growth and promote 68 survival.Many cell lines, including human U87 glioblastoma, human embryonic kidney 293T, HeLa cervical cancer, human SH-SY5Y neuroblastoma, and mouse N2a neuroblastoma cells, grow in EV-depleted serum.However, this growth is enhanced upon the addition of EVs to the serum.The authors discussed the possibility circulating EVs support cell growth and survival in vivo.Endothelial cell EV-derived miR-214 also promote migration and angiogenesis of neighbor cells by reducing cell senescence through repression of ATM by 69 miR-214 expression in vitro and in vivo.The authors suggested that the senescent cells with reduced miR-214 levels rescue from entering senescence by incorporating miR-214 from neighboring miR-214-producing cells via the exosomal shuttle.As mentioned previously, it is possibility that these entering senescent cell have been accumulated the mutation in the genome.Importantly, the EPH receptor A2 (EphA2), which is found in EVs, promotes cancer 49 cell proliferation and EVs from senescent cells are enriched in EphA2.These EphA2containing EVs bind to ephrin-A1 on the surface of cancer cells and, thus, promote cancer cell proliferation through EphA2/ephrin-A1 reverse signaling.The authors suggested EVs from senescent cells have pro-tumorigenic functions.Furthermore, EVs from senescent cells contain certain disease-related components, such as those associated with atherosclerosis, inflammation, and neurodegeneration.Moreover, EV secretion is upregulated with aging.17 Inflammation has a well-known relationship with cancer initiation.Importantly, the 49,51,70 inflammation-associated EV content increases in the bloodstream with aging.One possible explanation is EVs promote cancer initiation through such changes in their profile with age, such as EV-associated induction of inflammation and the uptake of EVs containing disease-related components.However, it is a juvenile field and there is not sufficient evidence for cancer initiation by EVs secreted from senescent cells.

Prospect
Through the extensive efforts of many researchers, different aspects of cancer malignancy have been associated with cell-derived EVs.Recently, it was revealed senescent cells secrete EVs with a different profile than EVs from non-senescent cells.Furthermore, EVs from senescent cells are associated with age-related diseases, such as inflammation, atherosclerosis, and neurodegeneration, and promotion of cancer cell proliferation.Although it is not clear the contribution of EVs to the cancer initiation, but the traditional hypothesis is [71][72][73][74] inflammation and immune responses contribute to cancer initiation.
Moreover, EVs from senescent cells promote cancer progression by activating cell signaling.We can speculate EV secretion from senescent cells contributes to cancer initiation through aging.However, this area of research has yet to be fully explored.Further studies are needed to determine the effect of age-related alterations in circulating EVs on cancer initiation.

Type The alteration of component Function The alteration of EVs amount Origin of EVs References
57cycle arrest, and/or apoptosis in normal human cells.However, other aspects of the SASP play a role in cancer initiation and disease promotion.It was reported senescent platelets secrete EVs containing miRNAs associated with atherosclerosis, inflammation, and 56