Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

• Klíčová slova
• BMP, Bis(monoacylglycerol)phosphate, Breast cancer, Lipidomics, Lysosomal membrane permeabilization, Polyunsaturated fatty acids, Reactive oxygen species,
• MeSH
• fosfáty metabolismus   MeSH
• kyseliny dokosahexaenové * MeSH
• lidé MeSH
• lysofosfolipidy metabolismus   MeSH
• lyzozomy metabolismus   MeSH
• myši MeSH
• nádory prsu * patologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• bis(monoacylglyceryl)phosphate MeSH Prohlížeč
• fosfáty MeSH
• kyseliny dokosahexaenové * MeSH
• lysofosfolipidy MeSH
• reaktivní formy kyslíku MeSH

Impairment of the prominent tumor suppressor p53, well known for its canonical role as the "guardian of the genome", is found in almost half of human cancers. More recently, p53 has been suggested to be a crucial regulator of stemness, orchestrating the differentiation of embryonal and adult stem cells, suppressing reprogramming into induced pluripotent stem cells, or inhibiting cancer stemness (i.e., cancer stem cells, CSCs), which underlies the development of therapy-resistant tumors. This review addresses these noncanonical roles of p53 and their implications in sarcoma initiation and progression. Indeed, dysregulation of p53 family proteins is a common event in sarcomas and is associated with poor survival. Additionally, emerging studies have demonstrated that loss of wild-type p53 activity hinders the terminal differentiation of mesenchymal stem cells and leads to the development of aggressive sarcomas. This review summarizes recent findings on the roles of aberrant p53 in sarcoma development and stemness and further describes therapeutic approaches to restore normal p53 activity as a promising anti-CSC strategy to treat refractory sarcomas.

• Klíčová slova
• Cancer stem cells, Mesenchymal stem cells, Sarcoma, p53, p53-targeted therapy,
• MeSH
• buněčná diferenciace genetika   MeSH
• lidé MeSH
• mezenchymální kmenové buňky metabolismus   patologie   MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory měkkých tkání genetika   patologie   MeSH
• nádory genetika   patologie   MeSH
• sarkom genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• TP53 protein, human MeSH Prohlížeč

Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.

• Klíčová slova
• Cancer predisposition, Fanconi anemia, Fumarate, Metabolic reprogramming, Purinosome, de novo purine biosynthesis,
• MeSH
• buněčné linie MeSH
• chromatografie kapalinová MeSH
• Fanconiho anemie metabolismus   MeSH
• glykolýza MeSH
• lidé MeSH
• metabolické sítě a dráhy * MeSH
• metabolomika metody   MeSH
• oprava DNA MeSH
• oxidativní fosforylace MeSH
• proteomika metody   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR-126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.

• Klíčová slova
• Cancer stroma, Exosomes, Malignant mesothelioma, miR-126, miRNA-based therapy,
• MeSH
• epidermální růstové faktory metabolismus   MeSH
• exozómy metabolismus   MeSH
• fibroblasty metabolismus   MeSH
• karcinogeneze metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• maligní mezoteliom MeSH
• mezibuněčná komunikace fyziologie   MeSH
• mezoteliom metabolismus   MeSH
• mikro RNA metabolismus   MeSH
• nádory plic metabolismus   MeSH
• proteiny vázající vápník metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• EGFL7 protein, human MeSH Prohlížeč
• epidermální růstové faktory MeSH
• mikro RNA MeSH
• MIRN126 microRNA, human MeSH Prohlížeč
• proteiny vázající vápník MeSH
• vaskulární endoteliální růstový faktor A MeSH

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

• Klíčová slova
• Chemotherapeutic and immunostimulant, Immunogenic cell death, Nanomedicine and biomaterials, Nanoparticle and microparticle, Pattern recognition receptor,
• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   terapie   MeSH
• nanomedicína metody   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• protinádorové vakcíny MeSH

TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.

• Klíčová slova
• Anticancer therapy, Carbaldehydic xanthone, p73,
• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buňky HT-29 MeSH
• cisplatina farmakologie   MeSH
• doxorubicin farmakologie   MeSH
• HCT116 buňky MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• neuroblastom farmakoterapie   genetika   metabolismus   patologie   MeSH
• protein p73 genetika   metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce účinky léků   MeSH
• synergismus léků MeSH
• xantony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• cisplatina MeSH
• doxorubicin MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protein p73 MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• TP53 protein, human MeSH Prohlížeč
• TP73 protein, human MeSH Prohlížeč
• xantony MeSH

The transcription factor p73 is homologous to the well-known tumor-suppressor p53. The p73-regulated networks are of significant clinical interest, because they may substitute for impaired p53-regulated networks which are commonly perturbed in cancer. Herein, we aimed to characterize a p73-regulated network that mediates cell migration and restores anti-oncogenic responses in p53-mutant cancer cells. In this study, we demonstrate that p73 regulates a network underlying cell migration, which consists of MIR34A/MIR3158/vimentin/β-catenin/lef1. The p73 isoforms transactivate the miRNA components (MIR34A/MIR3158) of this network, which in turn, downregulate their EMT-related mRNA co-targets (vimentin/β-catenin/lef1) to decrease cell-migration. Modulation of this network, by increasing the level of the novel p73-dependent target MIR3158, was found to induce anti-oncogenic/anti-invasive responses in p53-mutant cancer cells. Taken together, a p73-regulated, MIR3158-containing, network restores anti-invasive phenotypes in p53-mutant cancer cells; this property could be exploited towards the development of anticancer therapeutics.

• Klíčová slova
• Anticancer targeting, Epithelial–mesenchymal transition, MIR3158, MIR34A, p73,
• MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• osteosarkom genetika   MeSH
• pohyb buněk MeSH
• protein p73 genetika   MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mikro RNA MeSH
• protein p73 MeSH

A significant part of current research studies utilizes various cellular models which imply specific antibiotics-containing media as well as antibiotics used for clonal selection or promoter de/activation. With the great success of developing such tools, mitochondria, once originated from bacteria, can be effectively targeted by antibiotics. For that reason, some studies propose antibiotics-targeting of mitochondria as part of anticancer therapy. Here, we have focused on the effects of various classes of antibiotics on mitochondria in cancer and non-cancer cells and demonlow mitochondrial membrane potential, reduced ATP production, altered morphology and lowered respiration rate which altogether suggested mitochondrial dysfunction (MDF). This was in parallel with increased level of reactive oxygen species (ROS) and decreased activity of mitochondrial respiration complexes. However, both survival and repopulation capacity of cancer cells was not significantly affected by the antibiotics, perhaps due to a glycolytic shift or activated autophagy. In turn, simultaneous inhibition of autophagy and treatment with antibiotics largely reduced tumorigenic properties of cancer cells suggesting potential strategy for anticancer therapy.

• Klíčová slova
• Antibiotics, Autophagy, Cancer, Mitochondria, Mitochondrial dysfunction, Mitophagy,
• MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• adenosintrifosfát metabolismus   MeSH
• antibakteriální látky farmakologie   MeSH
• autofagie účinky léků   MeSH
• časové faktory MeSH
• elektronový transportní řetězec metabolismus   MeSH
• energetický metabolismus účinky léků   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• mitofagie účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   genetika   metabolismus   patologie   MeSH
• proliferace buněk účinky léků   MeSH
• proteiny asociované s mikrotubuly genetika   metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• synergismus léků MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-methyladenine MeSH Prohlížeč
• adenin MeSH
• adenosintrifosfát MeSH
• antibakteriální látky MeSH
• elektronový transportní řetězec MeSH
• proteiny asociované s mikrotubuly MeSH
• reaktivní formy kyslíku MeSH

Non-specific chromosomal aberrations (CAs) are microscopically detected in about 1% of lymphocytes drawn from healthy persons. Causes of CAs in general population are not known but they may be related to risk of cancer. In view of the importance of the mitotic checkpoint machinery on maintaining chromosomal integrity we selected 9 variants in main checkpoint related genes (BUB1B, BUB3, MAD2L1, CENPF, ESPL1/separase, NEK2, PTTG1/securin, ZWILCH and ZWINT) for a genotyping study on samples from healthy individuals (N = 330 to 729) whose lymphocytes had an increased number of CAs compared to persons with a low number of CAs. Genetic variation in individual genes played a minor importance, consistent with the high conservation and selection pressure of the checkpoint system. However, gene pairs were significantly associated with CAs: PTTG1-ZWILCH and PTTG1-ZWINT. MAD2L1 and PTTG1 were the most common partners in any of the two-way interactions. The results suggest that interactions at the level of cohesin (PTTG1) and kinetochore function (ZWINT, ZWILCH and MAD2L1) contribute to the frequency of CAs, suggesting that gene variants at different checkpoint functions appeared to be required for the formation of CAs.

• Klíčová slova
• Chromosomal integrity, Cytogenetics, DNA double-stranded break, Spindle checkpoint,
• MeSH
• CDC geny * MeSH
• chromozomální aberace * MeSH
• dvouřetězcové zlomy DNA MeSH
• genetická variace * MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jaderné proteiny genetika   MeSH
• kontrolní body M fáze buněčného cyklu genetika   MeSH
• lidé MeSH
• lymfocyty chemie   patologie   MeSH
• Mad2 protein genetika   MeSH
• modely genetické MeSH
• proteiny buněčného cyklu genetika   MeSH
• sekurin genetika   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• jaderné proteiny MeSH
• Mad2 protein MeSH
• MAD2L1 protein, human MeSH Prohlížeč
• pituitary tumor-transforming protein 1, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• sekurin MeSH
• Zwilch protein, human MeSH Prohlížeč
• ZWINT protein, human MeSH Prohlížeč

PURPOSE: Wilms tumor gene 1 (WT1), a zinc-finger transcription factor essential for testis development and function, along with other genes, was investigated for their role in the pathogenesis of testicular germ cell tumors (TGCT). METHODS: In total, 284 TGCT and 100 control samples were investigated, including qPCR for WT1 expression and BRAF mutation, p53 immunohistochemistry detection, and massively parallel amplicon sequencing. RESULTS: WT1 was significantly (p < 0.0001) under-expressed in TGCT, with an increased ratio of exon 5-lacking isoforms, reaching low levels in chemo-naïve relapsed TGCT patients vs. high levels in chemotherapy-pretreated relapsed patients. BRAF V600E mutation was identified in 1% of patients only. p53 protein was lowly expressed in TGCT metastases compared to the matched primary tumors. Of 9 selected TGCT-linked genes, RAS/BRAF and WT1 mutations were frequent while significant TP53 and KIT variants were not detected (p = 0.0003). CONCLUSIONS: WT1 has been identified as a novel factor involved in TGCT pathogenesis, with a potential prognostic impact. Distinct biologic nature of the two types of relapses occurring in TGCT has been demonstrated. Differential mutation rate of the key TGCT-related genes has been documented.

• Klíčová slova
• KIT, Next generation sequencing, TP53, Testicular germ cell tumors, Wilms tumor gene 1 (WT1),
• MeSH
• down regulace MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• geny ras * MeSH
• germinální a embryonální nádory enzymologie   genetika   patologie   MeSH
• imunohistochemie MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA metody   MeSH
• nádorové biomarkery genetika   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• prospektivní studie MeSH
• proteiny WT1 genetika   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• retrospektivní studie MeSH
• studie proveditelnosti MeSH
• testikulární nádory enzymologie   genetika   patologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorový supresorový protein p53 MeSH
• proteiny WT1 MeSH
• protoonkogenní proteiny B-Raf MeSH
• protoonkogenní proteiny c-kit MeSH
• TP53 protein, human MeSH Prohlížeč
• WT1 protein, human MeSH Prohlížeč