scholarly journals The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhang-Hua Chen ◽  
Shu-Mei Yan ◽  
Xi-Xi Chen ◽  
Qi Zhang ◽  
Shang-Xin Liu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Clonal Evolution ◽  
Genomic Diversity ◽  
Tumor Evolution ◽  
Low Grade ◽  
Precursor Lesions ◽  
Single Strain ◽  
Normal Tissues ◽  
Wnt Pathways

Abstract Background Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. Methods We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments. Results Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function. Conclusions We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.

scholarly journals Mining the Microbiota of the Neonatal Gastrointestinal Tract for Conjugated Linoleic Acid-Producing Bifidobacteria

2004 ◽  
Vol 70 (8) ◽  
pp. 4635-4641 ◽  
Author(s):  
E. Rosberg-Cody ◽  
R. P. Ross ◽  
S. Hussey ◽  
C. A. Ryan ◽  
B. P. Murphy ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Bifidobacterium Bifidum ◽  
Genomic Diversity ◽  
Gas Liquid Chromatography ◽  
Fecal Material ◽  
Single Strain ◽  
Different Strains

ABSTRACT This study was designed to isolate different strains of the genus Bifidobacterium from the fecal material of neonates and to assess their ability to produce the cis-9, trans-11 conjugated linoleic acid (CLA) isomer from free linoleic acid. Fecal material was collected from 24 neonates aged between 3 days and 2 months in a neonatal unit (Erinville Hospital, Cork, Ireland). A total of 46 isolates from six neonates were confirmed to be Bifidobacterium species based on a combination of the fructose-6-phosphate phosphoketolase assay, RAPD [random(ly) amplified polymorphic DNA] PCR, pulsed-field gel electrophoresis (PFGE), and partial 16S ribosomal DNA sequencing. Interestingly, only 1 of the 11 neonates that had received antibiotic treatment produced bifidobacteria. PFGE after genomic digestion with the restriction enzyme XbaI demonstrated that the bifidobacteria population displayed considerable genomic diversity among the neonates, with each containing between one and five dominant strains, whereas 11 different macro restriction patterns were obtained. In only one case did a single strain appear in two neonates. All genetically distinct strains were then screened for CLA production after 72 h of incubation with 0.5 mg of free linoleic acid ml−1 by using gas-liquid chromatography. The most efficient producers belonged to the species Bifidobacterium breve, of which two different strains converted 29 and 27% of the free linoleic acid to the cis-9, trans-11 isomer per microgram of dry cells, respectively. In addition, a strain of Bifidobacterium bifidum showed a conversion rate of 18%/μg dry cells. The ability of some Bifidobacterium strains to produce CLA could be another human health-promoting property linked to members of the genus, given that this metabolite has demonstrated anticarcinogenic activity in vitro and in vivo.

Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2510-2510
Author(s):  
Gaël Roué ◽  
Mónica López-Guerra ◽  
Pierre Milpied ◽  
Patricia Pérez-Galán ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Mantle Cell ◽  
P53 Status

Abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.

scholarly journals Interleukin 3 is a growth factor for human follicular B cell lymphoma.

1992 ◽  
Vol 175 (2) ◽  
pp. 371-376 ◽  
Author(s):  
C Clayberger ◽  
S Luna-Fineman ◽  
J E Lee ◽  
A Pillai ◽  
M Campbell ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Human Peripheral Blood ◽  
Close Association ◽  
B Cell Lymphoma ◽  
Follicular Cell ◽  
Low Grade ◽  
In Vitro Proliferation ◽  
Interleukin 3

More than one-half of adults with non-Hodgkin's B cell lymphomas present with low-grade follicular lymphomas. These tumor cells are found in close association with follicular T lymphocytes and dendritic cells, suggesting that the surrounding cells may play a role in the support of follicular tumors. Supernatants from activated human peripheral blood lymphocytes were found to promote the in vitro proliferation of follicular tumor cells. This effect was entirely due to interleukin 3 (IL-3), a factor generally thought to cause the growth and differentiation of immature hematopoietic cells. IL-3 receptors were detected on fresh isolates of all primary follicular cell tumors examined. These findings suggest that follicular cell tumors may be dependent in vivo on IL-3 and that therapies directed against IL-3, its receptor, or the T cells that produce it may be effective treatment for follicular lymphoma.

scholarly journals Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
José Manuel García-Heredia ◽  
Daniel Otero-Albiol ◽  
Marco Pérez ◽  
Elena Pérez-Castejón ◽  
Sandra Muñoz-Galván ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Notch Pathway ◽  
Metastatic Potential ◽  
Tumor Evolution ◽  
Neoplastic Cells ◽  
Mesenchymal Transition

Abstract MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.

Progression signature underlies clonal evolution and dissemination of multiple myeloma

Blood ◽  
2020 ◽  
Author(s):  
Yu Jia Shen ◽  
Yuji Mishima ◽  
Jiantao Shi ◽  
Romanos Sklavenitis-Pistofidis ◽  
Robert Allyn Redd ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Cells ◽  
Tracking System ◽  
Clonal Evolution ◽  
Dna Barcode ◽  
Multi Stage ◽  
Relapsed Disease ◽  
Predict Model

Clonal evolution drives tumor progression, dissemination and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multi-stage process requires tumor cells to enter the circulation, extravasate and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (Progression through Evolution and Dissemination of Clonal Tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA-sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient datasets. 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR/Cas9 in PrEDiCT model and were shown to be significantly depleted in distant BM sites indicating their role in MM progression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM.

In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues

2011 ◽  
Vol 69 (3) ◽  
pp. 697-707 ◽  
Author(s):  
Caroline Haglund ◽  
Anna Åleskog ◽  
Peter Nygren ◽  
Joachim Gullbo ◽  
Martin Höglund ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Anticancer Drugs ◽  
Clinical Activity ◽  
In Vitro Evaluation ◽  
Normal Tissues

scholarly journals The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4417-4426 ◽  
Author(s):  
Xavier Leleu ◽  
Xiaoying Jia ◽  
Judith Runnels ◽  
Hai T. Ngo ◽  
Anne-Sophie Moreau ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Akt Pathway ◽  
Low Grade ◽  
Normal Donor ◽  
Down Regulation ◽  
Inhibition Of Proliferation ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. We demonstrate up-regulated Akt activity in WM, and that Akt down-regulation by Akt knockdown and the inhibitor perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro, but not in normal donor peripheral blood and hematopoietic progenitors. Importantly, down-regulation of Akt induced cytotoxicity of WM cells in the bone marrow microenvironment (BMM) context. Perifosine induced significant reduction in WM tumor growth in vivo in a subcutaneous xenograft model through inhibition of Akt phosphorylation and downstream targets. We also demonstrated that Akt pathway down-regulation inhibited migration and adhesion in vitro and homing of WM tumor cells to the BMM in vivo. Proteomic analysis identified other signaling pathways modulated by perifosine, such as activation of ERK MAPK pathway, which induces survival of tumor cells. Interestingly, MEK inhibitor significantly enhanced perifosine-induced cytotoxicity in WM cells. Using Akt knockdown experiments and specific Akt and PI3K inhibitors, we demonstrated that ERK activation is through a direct effect, rather than feedback activation, of perifosine upstream ERK pathway. These results provide understanding of biological effects of Akt pathway in WM and provide the framework for clinical evaluation of perifosine in WM patients.

scholarly journals Changes of heterogeneous cell populations in the Ishikawa cell line during long-term culture: Proposal for an in vitro clonal evolution model of tumor cells

Genomics ◽  
2016 ◽  
Vol 107 (6) ◽  
pp. 259-266 ◽  
Author(s):  
Fumio Kasai ◽  
Noriko Hirayama ◽  
Midori Ozawa ◽  
Masashi Iemura ◽  
Arihiro Kohara
Keyword(s):  
Cell Line ◽  
Tumor Cells ◽  
Clonal Evolution ◽  
Evolution Model ◽  
Cell Populations ◽  
Ishikawa Cell ◽  
Long Term Culture

Glucose metabolism in cancer cells: immunogold localization of hexokinase to the outer mitochondrial membrane

1995 ◽  
Vol 53 ◽  
pp. 1044-1045
Author(s):  
Krishan K. Arora ◽  
Glenn L. Decker ◽  
Peter L. Pedersen
Keyword(s):  
Tumor Cells ◽  
Mitochondrial Membrane ◽  
Present Report ◽  
Large Fraction ◽  
Mitochondrial Fraction ◽  
Immunogold Labeling ◽  
Outer Mitochondrial Membrane ◽  
Immunogold Localization ◽  
Hexokinase Activity ◽  
Normal Tissues

Hexokinase (ATP: D-hexose 6-phophotransferase EC 2.7.1.1) is the first enzyme of the glycolytic pathway which commits glucose to catabolism by catalyzing the phosphorylation of glucose with ATP. Previous studies have shown diat hexokinase activity is markedly elevated in rapidly growing tumor cells exhibiting high glucose catabolic rates. A large fraction (50-80%) of this enzyme activity is bound to the mitochondrial fraction (1,2) where it has preferred access to ATP (3). In contrast,the hexokinase activity of normal tissues is quite low, with one exception being brain which is a glucose-utilizing tissue (4). Biochemical evidence involving rigorous subfractionation studies have revealed striking differences between the subcellular distribution of hexokinase in normal and tumor cells [See review by Arora et al (4)].In the present report, we have utilized immunogold labeling techniques to evaluate die subcellular localization of hexokinase in highly glycolytic AS-30D hepatoma cells and in the tissue of its origin, i.e., rat liver.

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