Autophagy in stem cell aging Revuelta, Miren; Matheu, Ander
Aging Cell,
October 2017, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Summary
Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. ...Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age‐associated diseases.
The improvement of life quality and medical advances has resulted in increased life expectancy. Despite this, health status commonly worsens in the last years of life. Frailty is an intermediate and ...reversible state that often precedes dependency and therefore, its identification may be essential to prevent dependency. However, there is no consensus on the best tools to identify frailty. In this sense, diverse molecules have been proposed as potential biomarkers. Some investigations pointed to an increased chronic inflammation or inflammaging with frailty, while others did not report such differences. In this work, we evaluated the circulating concentration of the inflammaging markers in adults and older adults (aged over 70 years) by ELISA and Luminex techniques. The Barthel Index was applied for the evaluation of dependency and Timed up-and-go, Gait Speed, Short Physical Performance Battery, Tilburg Frailty Indicator and Gerontopole Frailty Screening Tool were used for the identification of frailty. CRP, TNF-α, IL-6 and albumin concentrations were measured, and we found that elevated inflammation is present in older adults, while no differences with frailty and dependency were reported. Our results were consistent for all the evaluated frailty scales, highlighting the need to reconsider increased inflammation as a biomarker of frailty.
Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) ...is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson's disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.
Breast cancer remains the most prevalent cause of cancer mortality in woman worldwide due to the metastatic process and therapy resistance. Resistance against cancer therapy is partially attributed ...to cancer stem cells (CSCs). These cells arise from epithelial cells undergoing epithelial-to-mesenchymal transition (EMT) and might be responsible for tumor recurrence. In this study, we reported the relevance of miR-155 upregulation in chemoresistant cells associated with EMT. Notably, we found miR-155 induction in exosomes isolated from CSCs and resistant cells, followed by resistant cells' exosome transfer to the recipient sensitive cells. Functionally, miR-155 mimic assay showed an enrichment in miR-155 from exosome concomitant with miR-155 exosome transfer to breast cancer cells. In parallel to these effects, we also observed EMT change in miR-155 transfected cells. The chemoresistance phenotype transfer to sensitive cells and the migration capability was analyzed by MTT and scratch assays and our results suggest that exosomes may intermediate resistance and migration capacity to sensitive cells partly through exosome transfer of miR-155. Taken together, our findings establish the significance of exosome-mediate miR-155 chemoresistance in breast cancer cells, with implications for targeting miR-155 signaling as a possible therapeutic strategy.
Abstract
The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated ...cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma.
SOX9
silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence
in vitro
and tumor growth
in vivo
. Gain of-
SOX9
function showed that high levels of SOX9 promote tumor cell proliferation
in vitro
and
in vivo
. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21
CIP
in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21
CIP
in clinical samples of the different cancers. Moreover, BMI1 re-establishment in
SOX9
-silenced tumor cells restored cell viability and proliferation as well as decreased p21
CIP
in vitro
and tumor growth
in vivo
. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21
CIP
. Our results highlight the relevance of the SOX9-BMI1-p21
CIP
axis in tumor progression, shedding novel opportunities for therapeutic development.
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances ...made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance.
Liquid biopsy represents a minimally invasive procedure that can provide similar information from body fluids to what is usually obtained from a tissue biopsy sample. Its implementation in the ...clinical setting might significantly renew the field of medical oncology, facilitating the introduction of the concepts of precision medicine and patient-tailored therapies. These advances may be useful in the diagnosis of brain tumors that currently require surgery for tissue collection, or to perform genetic tumor profiling for disease classification and guidance of therapy. In this review, we will summarize the most recent advances and putative applications of liquid biopsy in glioblastoma, the most common and malignant adult brain tumor. Moreover, we will discuss the remaining challenges and hurdles in terms of technology and biology for its clinical application.
Targeting Myotonic Dystrophy Type 1 with Metformin García-Puga, Mikel; Saenz-Antoñanzas, Ander; Matheu, Ander ...
International journal of molecular sciences,
03/2022, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional ...clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.
Frailty represents a state of vulnerability and increases the risk of negative health outcomes, which is becoming an important public health problem. Over recent years, multiple independent studies ...have attempted to identify biomarkers that can predict, diagnose, and monitor frailty at the biological level. Among them, several promising candidates have been associated with frailty status including antioxidants and free radicals, and also inflammatory response biomarkers. In this review, we will summarize the more recent advances in this field. Moreover, the identification of scales and measurements to detect and quantify frailty in aged mice, as well as the generation of mouse models, have started to unravel the underlying biological and molecular mechanisms of frailty. We will discuss them here with an emphasis on murine models with overexpression of glucose-6-phosphate dehydrogenase and loss of function of superoxide dismutase and interleukin 10, which reveal that altered oxidative stress and inflammation pathways are involved in the physiopathology of frailty. In summary, we provide the current available evidence, from both human cohorts and experimental animal models, that highlights oxidative damage and inflammation as relevant biomarkers and drivers of frailty.
Primary cilium and glioblastoma Álvarez-Satta, María; Matheu, Ander
Therapeutic Advances in Medical Oncology,
01/2018, Letnik:
10
Book Review, Journal Article
Recenzirano
Odprti dostop
Glioblastoma (GBM) represents the most common, malignant and lethal primary brain tumour in adults. The primary cilium is a highly conserved and dynamic organelle that protrudes from the apical ...surface of virtually every type of mammalian cell. There is increasing evidence that abnormal cilia are involved in cancer progression, since primary cilia regulate cell cycle and signalling transduction. In this review, we summarize the role of primary cilium specifically with regard to GBM, where there is evidence postulating it as a critical mediator of GBM tumorigenesis and progression. This opens the way to the application of cilia-targeted therapies (‘ciliotherapy’) as a new approach in the fight against this devastating tumour.
PDF
