scholarly journals Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

2020 ◽  
Author(s):  
Liu Han ◽  
Qilai Long ◽  
Shenjun Li ◽  
Qixia Xu ◽  
Boyi Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Cancer Resistance ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Age Related ◽  
Lysosomal Acidification

ABSTRACTCellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.

scholarly journals Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

2021 ◽  
Vol 22 (15) ◽  
pp. 7847
Author(s):  
Anthony Fringuello ◽  
Philip D. Tatman ◽  
Tadeusz Wroblewski ◽  
John A. Thompson ◽  
Xiaoli Yu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Interleukin 7 ◽  
Poor Outcomes ◽  
Patient Prognosis ◽  
The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

scholarly journals Impact of Loading Phase, Initial Response and CFH Genotype on the Long-Term Outcome of Treatment for Neovascular Age-Related Macular Degeneration

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e42014 ◽  
Author(s):  
Moreno Menghini ◽  
Barbara Kloeckener-Gruissem ◽  
Johannes Fleischhauer ◽  
Malaika M. Kurz-Levin ◽  
Florian K. P. Sutter ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Initial Response ◽  
Age Related Macular Degeneration ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Age Related

scholarly journals VEGF signaling regulates the fate of obstructed capillaries in mouse cortex

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Patrick Reeson ◽  
Kevin Choi ◽  
Craig E Brown
Keyword(s):  
Critical Factor ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Vegf Signaling ◽  
Capillary Rarefaction ◽  
Age Related ◽  
Mouse Cortex ◽  
Cortical Capillaries ◽  
And Function

Cortical capillaries are prone to obstruction, which over time, could have a major impact on brain angioarchitecture and function. The mechanisms that govern the removal of these obstructions and what long-term fate awaits obstructed capillaries, remains a mystery. We estimate that ~0.12% of mouse cortical capillaries are obstructed each day (lasting >20 min), preferentially in superficial layers and lower order branches. Tracking natural or microsphere-induced obstructions revealed that 75–80% of capillaries recanalized within 24 hr. Remarkably, 30% of all obstructed capillaries were pruned by 21 days, including some that had regained flow. Pruning involved regression of endothelial cells, which was not compensated for by sprouting. Using this information, we predicted capillary loss with aging that closely matched experimental estimates. Genetic knockdown or inhibition of VEGF-R2 signaling was a critical factor in promoting capillary recanalization and minimizing subsequent pruning. Our studies reveal the incidence, mechanism and long-term outcome of capillary obstructions which can also explain age-related capillary rarefaction.

scholarly journals Mesenchymal Stromal Cells for Treatment of Acute Steroid-Refractory Graft Versus Host Disease: Clinical Responses and Long-Term Outcome

Stem Cells ◽  
2015 ◽  
Vol 34 (2) ◽  
pp. 357-366 ◽  
Author(s):  
Felix von Dalowski ◽  
Michael Kramer ◽  
Martin Wermke ◽  
Rebekka Wehner ◽  
Christoph Röllig ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Graft Versus Host Disease ◽  
Stromal Cells ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Host Disease ◽  
Graft Versus Host ◽  
Clinical Responses ◽  
Steroid Refractory
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