1,721,053 research outputs found
Uncovering metabolism in rhabdomyosarcoma
No full textRhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies
Iron, Oxidative Damage and Ferroptosis in Rhabdomyosarcoma.
No full textRecent data have indicated a fundamental role of iron in mediating a non-apoptotic and non-necrotic oxidative form of programmed cell death termed ferroptosis that requires abundant cytosolic free labile iron to promote membrane lipid peroxidation. Different scavenger molecules and detoxifying enzymes, such as glutathione (GSH) and glutathione peroxidase 4 (GPX4), have been shown to overwhelm or exacerbate ferroptosis depending on their expression magnitude. Ferroptosis is emerging as a potential weapon against tumor growth since it has been shown to potentiate cell death in some malignancies. However, this mechanism has been poorly studied in Rhabdomyosarcoma (RMS), a myogenic tumor affecting childhood and adolescence. One of the main drivers of RMS genesis is the Retrovirus Associated DNA Sequences/Extracellular signal Regulated Kinases (RAS/ERK)signaling pathway, the deliberate activation of which correlates with tumor aggressiveness and oxidative stress levels. Since recent studies have indicated that treatment with oxidative inducers can significantly halt RMS tumor progression, in this review we covered different aspects, ranging from iron metabolism in carcinogenesis and tumor growth, to mechanisms of iron-mediated cell death, to highlight the potential role of ferroptosis in counteracting RMS growth
Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas
No full textSeveral lines of recent evidence have opened a new debate on the mechanisms underlying the genesis of rhabdomyosarcoma, a pediatric soft tissue tumor with a widespread expression of muscle-specific markers. In particular, it is increasingly evident that the loss of skeletal muscle integrity observed in some mouse models of muscular dystrophy can favor rhabdomyosarcoma formation. This is especially true in old age. Here, we review these experimental findings and focus on the main molecular and cellular events that can dictate the tumorigenic process in dystrophic muscle, such as the loss of structural or regulatory proteins with tumor suppressor activity, the impaired DNA damage response due to oxidative stress, the chronic inflammation and the conflicting signals arising within the degenerated muscle niche
Caveolin-1 overexpression in the human embryonal rhabdomyosarcoma RD cells increases tumor growth and metastasis in vivo through a phospho-ERK-dependent signaling pathway
Full text linkCaveolin-1 (Cav-1) represents the principal component of caveolae, flask-shaped invaginations of the plasma membrane controlling different processes like endocytosis, mechanoprotection and signal transduction.
Cav-1 expression and/or function is often dysregulated in cancer, being associated to an increased or decreased tumor cell behavior depending on the cell context. We proposed Cav-1 as a marker of poorly differentiated cells in rhabdomyosarcoma (RMS), a class of childhood soft tissue sarcomas characterized by expression of myogenic markers. In addition, we have further shown that increasing or depleting Cav-1 expression levels in the human embryonal RD cells correlates with an augmented or decreased tumor cell behavior, respectively. In the attempt to further characterize the role of Cav-1 in RMS in vivo, here we demonstrate that injecting subcutaneously Cav-1-overexpressing RD cells in SCID nude mice led to rapid growth of huge RMS tumors in comparison to control mice; in addition, tail vein injection was followed by rapid lung metastasis formation. Ex vitro transplantation of lung metastatic cells followed by re-injection in the tail vein of SCID mice allowed us to isolate two clonal metastatic RD populations (named F1 and F2) characterized by increased ability to disseminate in a shorter time as compared to controls. FACS analyses revealed that both Cav-1 overexpressing RD cells and the metastatic F1-F2 populations exhibited a rapid G1 phase transition, characterized by massive activation of the phosphorylated ERK1/2 pathway. As a result, treatment of these cells with a pharmacological inhibitor of ERK phosphorylation (PD098059) was sufficient to prevent in vitro the increased proliferation and migration associated to the high Cav-1 levels. Overall, these data establish an important connection between the levels of Cav-1 and the activation of the ERK1/2 pathway underlying the augmented cell aggressiveness in RMS cells
Molecular and cellular mechanisms of skeletal muscle atrophy: an update
No full textSkeletal muscle atrophy is defined as a decrease in muscle mass and occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g. growth hormone, insulin-like growth factor 1) and catabolic proteins (e.g. tumor necrosis factor alpha, myostatin), may tip the balance towards muscle-specific protein degradation through activation of the proteasomal and autophagic systems or the apoptotic pathway. Based on the current literature, we present an overview of the molecular and cellular mechanisms that contribute to muscle wasting. We also focus on the multi-facetted therapeutic approach that is currently employed to prevent the development of muscle wasting and to counteract its progression. This approach includes adequate nutritional support, implementation of exercise training and possible pharmacological compounds
Defective myogenic differentiation of human rhabdomyosarcoma cells is characterized by sialidase Neu2 loss of expression.
No full textSialidase Neu2 is a glycohydrolytic enzyme whose tissue distribution has been detected principally in differentiated skeletal muscle. In this study we show that Neu2 expression is absent in different embryonal and alveolar human tumor rhabdomyosarcoma (RMS) cells, which are genetically committed myoblasts characterized by delayed differentiation. Forced myogenic differentiation of an embryonal RMS cell line, as obtained via pharmacological and genetic p38 activation or via follistatin overexpression, was characterized by Neu2 loss of expression despite the significant rise of different muscle-specific markers, suggesting therefore that the defective myogenic program of RMS cells is accompanied by Neu2 suppression
Differentiation of human rhabdomyosarcoma RD cells is regulated by reciprocal, functional interactions between myostatin, p38 and ERK signalling pathways
No full textRhabdomyosarcoma (RMS) includes heterogeneous tumours of mesenchymal derivation which are genetically committed to the myogenic lineage, but fail to complete terminal differentiation. Previous works have reported on deregulated myostatin, p38 and extracellular regulated kinase (ERK) signalling in RMS cell lines; however, the functional link between these pathways and their relative contribution to RMS pathogenesis and/or maintenance of the transformed phenotype in vitro are unclear. Herein we show that the constitutive expression of a dominant-negative form of activin receptor type IIb (dnACTRIIb), which inhibits myostatin signalling, decreased proliferation and promoted differentiation of the human RMS RD cell line. DnACTRIIb-dependent differentiation of RD cells correlated with a reduced SMAD2/3 (small mother against decapentaplegic) and ERK signalling and the activation of p38 pathway. Conversely, the expression of a constitutively activated ALK5 (activin receptor-like kinase) (caALK5) form, activating SMAD3 and ERK pathways, led to further impairment of RD differentiation. Pharmacological blockade of ERK pathway in RD cells was sufficient to replicate the biological phenotype observed in dnACTRIIb-expressing RD cells, and also recovered the differentiation of caALK5-expressing RD cells. Conversely, deliberate activation of p38 signalling mimics the effect of dnActRIIb and overcame the differentiation block in RD cells. These data indicate the existence of a network formed by myostatin/SMAD2/3, ERK and p38 pathways that, when deregulated, might contribute to the pathogenesis of RMS. The components of this network might, therefore, be a valuable target for interventions towards correcting the malignant phenotype of RMS
Caveolin-1 overexpression accelerates tumor growth and metastasis of embryonal rhabdomyosarcoma
Full text linkCaveolin-1 (Cav-1) is a plasma membrane scaffolding protein that was shown to control the ERK pathway in muscle satellite cells. Oncogenic transformation of satellite cells is responsible of the generation of rhabdomyosarcoma (RMS), a soft tissue tumor affecting childhood and adolescence. We previously reported that Cav-1 is a marker of proliferating RMS cell lines and that its overexpression promotes increased malignancy of RMS cells in vitro and in vivo. Here we show that tail vein injection of the human embryonal RD cells with Cav-1 overexpression (RD Cav-1) into NOD/SCID mice resulted in formation of lung metastasis in about 9 weeks as compared to control cells that did not form metastasis. After performing ex vivo transplantation of lung metastases we isolated one cell population, termed lung metastatic RD1, which injected in mice again gave rise to lung metastases in 5 weeks; from these disseminated lungs we were able to isolate the lung metastatic RD2 cell population. All the distinct cell populations, including RD Cav-1 and lung metastatic RD1 and RD2 clones, retained high Cav-1 expression and showed high phosphorylation levels of ERK1/2, which completely prevented their ability to undergo myogenic differentiation. In addition, lung metastatic RD1 and RD2 clones exhibited an increased migration, adhesion and production of angiogenic stimuli in comparison to non-metastatic control RD and RD Cav-1 lines. Taken together, these data suggest a key role of Cav-1 in promoting both local tumor growth and metastasis of RMS through cooperation of the ERK signalling pathway
IGF-I INDUCED HYPERTROPHY OF MYOBLASTS INCREASES CYTOSOLIC SIALIDASE NEU2 THROUGH PI-3 KINASE/AKT/mTOR PATHWAY.
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