Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology.

• MeSH
• karcinogeneze * patologie   genetika   MeSH
• kur domácí MeSH
• kuřecí embryo MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• nádory patologie   genetika   MeSH
• ptáci MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Fibroblasts are an integral cell type of mammary gland stroma, which plays crucial roles in development, homeostasis, and tumorigenesis of mammary epithelium. Fibroblasts produce and remodel extracellular matrix proteins and secrete a plethora of paracrine signals, which instruct both epithelial and other stromal cells of the mammary gland through mechanisms, which have not been fully understood. To enable deciphering of the intricate fibroblast-epithelial interactions, we developed several 3D co-culture methods. In this chapter, we describe methods for establishment of various types of embedded 3D co-cultures of mammary fibroblasts with mammary epithelial organoids, mammary tumor organoids, or breast cancer spheroids to investigate the role of fibroblasts in mammary epithelial development, morphogenesis, and tumorigenesis. The co-culture types include dispersed, aggregated, and transwell cultures.

• MeSH
• buněčné linie MeSH
• epitel metabolismus   MeSH
• epitelové buňky * MeSH
• fibroblasty metabolismus   MeSH
• karcinogeneze patologie   MeSH
• kokultivační techniky MeSH
• lidé MeSH
• mléčné žlázy zvířat * MeSH
• organoidy MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Východiska: Incidence karcinomu pankreatu (pancreatic ductal adenocarcinoma – PDAC) má zejména v rozvinutých zemích zvyšující se tendenci. V roce 2021 bylo celosvětově diagnostikováno 496 000 nových případů PDAC. Incidence v ČR je jedna z nejvyšších na světě a za rok 2018 bylo zachyceno 2 332 nových pacientů. Vzhledem k absenci symptomů v časných stadiích je přibližně 50 % pacientů vstupně diagnostikováno se vzdálenými metastázemi. Mortalita je nepatrně nižší než incidence a navzdory výrazným pokrokům v onkologickém výzkumu zůstává PDAC stále fatální diagnózou. Zajímavým přístupem, a to nejen u PDAC, je studium mikrobiomu. Ten je definován jako soubor všech mikroorganizmů (mikrobiota, tedy bakterie, houby, viry archea a protozoa) a jejich genomu v určitém prostředí. Za fyziologických podmínek je střevní mikrobiom v symbióze s osídleným organizmem, a udržuje tak rovnováhu metabolizmu, slizniční imunomodulaci a reguluje proces trávení. Při dysregulaci počtu či funkce střevních mikroorganizmů nastává dysbióza. Ta pak vede ke vzniku metabolických a kardiovaskulárních chorob, k poruchám nervového systému, indukci zánětů střeva či kancerogenezi. Mikrobiota mohou indukovat kancerogenezi několika způsoby, a to zejména vyvoláním zánětlivé odpovědi, snížením schopnosti imunitního systému eliminovat poškozené buňky a v neposlední řadě mohou metabolity mikrobů vést k deregulaci genomu osídleného organizmu. Tato deregulace vede k aktivaci proapoptotických a proproliferativních proteinů. Dosavadní výzkum prokazuje, že na rozvoji PDAC se může podílet právě střevní či orální mikrobiom. Jednou z nejvíce studovaných bakterií je Porphyromonas gingivalis. I u dalších bakterií, jako jsou Fusobacteria, Enterobacter, Klebsiella, Prevotella či Rothia, byla prokázána role při vzniku PDAC. Cíl: Cílem tohoto přehledového článku je poukázat na jeden z možných mechanizmů vzniku PDAC. Ten by mohl být ovlivnitelný, což může znamenat snížení incidence a zlepšení prognózy tohoto agresivního onemocnění.

Background: The incidence of pancreatic cancer (pancreatic ductal adenocarcinoma – PDAC) is increasing, especially in developed countries. In 2021, 496,000 new PDAC cases were diagnosed worldwide. In the Czech Republic, the incidence is one of the highest in the world, with 2,332 new PDAC patients diagnosed in 2018. Due to the absence of symptoms in the early stages, approximately 50% of patients are initially diagnosed with distant metastases. Mortality is slightly lower than the incidence count and, despite significant advances in cancer research, PDAC remains a fatal diagnosis. However, microbiome seems to be an interesting approach, and not only in PDAC patients. Microbiome is defined as the set of all microorganisms (microbiota, i.e. bacteria, fungi, viruses, archaea, and protozoa) and their genome in a certain environment. In a physiological setting, the gut microbiome is in symbiosis with the host organism, maintaining the balance of metabolism, mucosal immunomodulation and regulating the digestion process. When dysregulation of the number or function of intestinal microorganisms occurs, dysbiosis is developed. It may lead to metabolic and cardiovascular diseases, nervous system disorders, induction of intestinal inflammation, or carcinogenesis. Microbiota can induce carcinogenesis in multiple ways, such as by activating an inflammatory response, reducing the immune system‘s ability to eliminate damaged cells, and deregulation of the host genome by microbial metabolites. This deregulation may lead to an activation of pro-apoptotic and pro-proliferative proteins. To date, research shows that the gut or oral microbiome may be involved in the development of PDAC. One of the most studied bacteria is Porphyromonas gingivalis. Other bacteria, such as Fusobacteria, Enterobacter, Klebsiella, Prevotella, and Rothia, have also been shown to play a role in PDAC. Purpose: The aim of this review article is to point out one of the possible mechanisms of cancerogenesis in PDAC patients and its therapeutic influence to reduce the incidence and improve the prognosis of this aggressive disease.

• MeSH
• duktální karcinom slinivky břišní * diagnóza   epidemiologie   etiologie   mikrobiologie   MeSH
• dysbióza komplikace   mikrobiologie   patologie   MeSH
• karcinogeneze patologie   MeSH
• lidé MeSH
• mikrobiota * MeSH
• rizikové faktory MeSH
• střevní mikroflóra genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• karcinogeneze * genetika   patologie   MeSH
• lidé MeSH
• mutace MeSH
• nestabilita genomu MeSH
• onkogeny genetika   MeSH
• tumor supresorové geny MeSH
• Check Tag
• lidé MeSH

Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-β1 and TGF-β3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-β1 vs. TGF-β3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-β1 and TGF-β3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-β1/3 treatments. In general, TGF-β1 demonstrated a more potent activation of signaling pathways compared to TGF-β3, whereas TGF-β3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-β signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-β isomers considering inherent fibroblast heterogeneity.

• MeSH
• fibroblasty metabolismus   MeSH
• hojení ran MeSH
• jizva hypertrofická * metabolismus   patologie   MeSH
• karcinogeneze metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• nádorová transformace buněk metabolismus   MeSH
• protein - isoformy metabolismus   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transformující růstový faktor beta1 * farmakologie   metabolismus   MeSH
• transformující růstový faktor beta3 metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

• MeSH
• buněčný převod mechanických signálů MeSH
• chemorezistence MeSH
• karcinogeneze metabolismus   patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• signální proteiny YAP * MeSH
• transkripční koaktivátor s motivem vázajícím se na PDZ metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

RNA editing is one of the most prevalent and abundant forms of post-transcriptional RNA modification observed in normal physiological processes and often aberrant in diseases including cancer. RNA editing changes the sequences of mRNAs, making them different from the source DNA sequence. Edited mRNAs can produce editing-recoded protein isoforms that are functionally different from the corresponding genome-encoded protein isoforms. The major type of RNA editing in mammals occurs by enzymatic deamination of adenosine to inosine (A-to-I) within double-stranded RNAs (dsRNAs) or hairpins in pre-mRNA transcripts. Enzymes that catalyse these processes belong to the adenosine deaminase acting on RNA (ADAR) family. The vast majority of knowledge on the RNA editing landscape relevant to human disease has been acquired using in vitro cancer cell culture models. The limitation of such in vitro models, however, is that the physiological or disease relevance of results obtained is not necessarily obvious. In this review we focus on discussing in vivo occurring RNA editing events that have been identified in human cancer tissue using samples surgically resected or clinically retrieved from patients. We discuss how RNA editing events occurring in tumours in vivo can identify pathological signalling mechanisms relevant to human cancer physiology which is linked to the different stages of cancer progression including initiation, promotion, survival, proliferation, immune escape and metastasis.

• MeSH
• adenosin genetika   MeSH
• dvouvláknová RNA genetika   MeSH
• editace RNA * MeSH
• inosin genetika   MeSH
• karcinogeneze genetika   patologie   MeSH
• lidé MeSH
• nádory genetika   metabolismus   patologie   MeSH
• proteiny vázající RNA genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in MLL-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of MLL-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• histonlysin-N-methyltransferasa genetika   metabolismus   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• leukemie genetika   metabolismus   patologie   MeSH
• lidé MeSH
• myši knockoutované MeSH
• myši MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• protoonkogenní protein MLL genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

S100 proteins are involved in biological events related to colorectal carcinogenesis. Aim of this prospective study was to assess serum concentration of S100A6, A8, A9 and A11 proteins in patients with colorectal neoplasia. Eighty-four subjects were enrolled: 20 controls (average risk population with normal findings on colonoscopy; 7 men, 13 women, age 23-74, mean 55 ± 14), 20 patients with non-advanced colorectal adenoma (non-AA, 10 men, 10 women, age 41-82, mean 62 ± 11), 22 with advanced colorectal adenoma (AA, 15 men, 7 women, age 49-80, mean 64 ± 8) and 22 with colorectal cancer (CRC, 12 men, 10 women, age 49-86, mean 69 ± 10). Peripheral venous blood was obtained. Serum S100 proteins were investigated by enzyme immunoassay technique. Serum S100A6 was significantly lower in CRC (mean 8530 ± 4743 ng/L), p = .035 compared to controls (mean 11308 ± 2968 ng/L). Serum S100A8 was significantly higher in AA (median 11955 ng/L, IQR 2681-34756 ng/L), p = .009 and in CRC (median 27532 ng/L, IQR 6794-35092 ng/L), p < .001 compared to controls (median 2513 ng/L, IQR 2111-4881 ng/L). Serum S100A9 concentrations did not differ between any tested group and controls, p > .05. Serum concentration of S100A11 was significantly lower in non-AA (mean 3.5 ± 2.4 μg/L), p = .004 and in CRC (mean 3.4 ± 2.4 μg/L), p = .002 compared to controls (mean 5.9 ± 2.5 μg/L). Sensitivity and specificity for S100A8 protein in patients with CRC were 94% and 73%; positive predictive value 68% and negative predictive value 95%. Patients with colorectal neoplasia have significantly lower serum S100A6 and S100A11 levels, significantly higher S100A8 and unaltered serum S100A9 levels.

• MeSH
• adenom krev   diagnóza   genetika   patologie   MeSH
• dospělí MeSH
• ELISA MeSH
• exprese genu MeSH
• kalgranulin A krev   genetika   MeSH
• kalgranulin B krev   genetika   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• kolorektální nádory krev   diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   genetika   MeSH
• prospektivní studie MeSH
• protein S100A6 krev   genetika   MeSH
• proteiny buněčného cyklu krev   genetika   MeSH
• proteiny S100 krev   genetika   MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

• MeSH
• astrocyty metabolismus   patologie   MeSH
• biologické modely MeSH
• buněčný rodokmen MeSH
• chromatin metabolismus   MeSH
• embryo savčí metabolismus   MeSH
• epigeneze genetická MeSH
• genetická transkripce MeSH
• gliom genetika   patologie   MeSH
• histony genetika   metabolismus   MeSH
• interneurony metabolismus   MeSH
• karcinogeneze genetika   patologie   MeSH
• lysin metabolismus   MeSH
• mutace genetika   MeSH
• myši inbrední C57BL MeSH
• nádory mozku genetika   patologie   MeSH
• nervové kmenové buňky metabolismus   MeSH
• oligodendroglie metabolismus   MeSH
• přední mozek embryologie   MeSH
• přeprogramování buněk genetika   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• regulace genové exprese u nádorů MeSH
• růstový faktor odvozený z trombocytů - receptor alfa genetika   metabolismus   MeSH
• stupeň nádoru MeSH
• transkriptom genetika   MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH