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  1. Disruption of Smad4 in odontoblasts and dental epithelial cells influences the phenotype of multiple keratocystic odontogenic tumors.

    PubMed

    Jiang, Weipeng; Yang, Guan; Chen, Feng; Yang, Xiao; Li, Tiejun

    2015-07-31

    Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasms with a high recurrence rate. The molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Previous research showed that specific ablation of Smad4 in odontoblasts and dental epithelia resulted in spontaneous KCOTs in mice, and that constitutively activated Hedgehog (Hh) signaling was detected in the cyst epithelia of both Smad4(Co/Co) OC-Cre and Smad4(Co/Co) K5-Cre mice. Here, we ablated Smad4 in mouse odontoblasts and dental epithelia and compared the sizes and numbers of KCOTs. Both the number and size of KCOTs in Smad4(Co/Co) OC-Cre mice were larger than those in Smad4(Co/Co) K5-Cre mice, suggesting that paracrine signals from root odontoblasts play a more important role than those from Hertwig's epithelial root sheath (HERS) cells. PMID:26002469

  2. Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions.

    PubMed

    Chen, Yong; Wang, Hengtong; Zhang, Jiangang; Chen, Ke; Li, Yumin

    2015-01-01

    All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID:26648395

  3. Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions

    PubMed Central

    Chen, Yong; Wang, Hengtong; Zhang, Jiangang; Chen, Ke; Li, Yumin

    2015-01-01

    All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID:26648395

  4. Gut macrophage phenotype is dependent on the tumor microenvironment in colorectal cancer

    PubMed Central

    Norton, Samuel E; Dunn, Elliott T J; McCall, John L; Munro, Fran; Kemp, Roslyn A

    2016-01-01

    In contrast to many cancers, a high infiltration of macrophages in colorectal cancer (CRC) has been associated with improved prognosis for patients. Cytokines and other stimuli from the tumor microenvironment affect monocyte to macrophage maturation and subsequent phenotype and function. Heterogeneous myeloid populations were identified using a novel flow cytometry panel in both tumor and paired non-tumor bowel (NTB) from CRC patients. The frequency of macrophage subsets with a gut-conditioned phenotype was lower in tumor compared with NTB. We used an in vitro system to show that two of the macrophage populations represented pro-inflammatory and anti-inflammatory phenotypes. Conditioned media that contained high levels of interleukin-6 promoted and maintained an anti-inflammatory phenotype in vitro. This study demonstrates the plasticity and heterogeneity of macrophage subtypes in human CRC, and the feasibility of studying complex populations. Ex vivo experiments demonstrate that macrophage subsets are influenced by the tumor microenvironment. PMID:27195119

  5. Tumor morphological evolution: directed migration and gain and loss of the self-metastatic phenotype

    PubMed Central

    2010-01-01

    Background Aside from the stepwise genetic alterations known to underlie cancer cell creation, the microenvironment is known to profoundly influence subsequent tumor development, morphology and metastasis. Invasive cluster formation has been assumed to be dependent on directed migration and a heterogeneous environment - a conclusion derived from complex models of tumor-environment interaction. At the same time, these models have not included the prospect, now supported by a preponderance of evidence, that only a minority of cancer cells may have stem cell capacity. This proves to weigh heavily on the microenvironmental requirements for the display of characteristic tumor growth phenotypes. We show using agent-based modeling that some defining features of tumor growth ascribed to directed migration might also be realized under random migration, and discuss broader implications for cause-and-effect determination in general. Results Considering only the properties of random migration in tumors composed of stem cells and committed cells, we are able to recapitulate a characteristic clustering feature of invasive tumor growth, a property we attribute to "self-metastatic" growth. When the additional influence of directed migrations under chemotactic environments are considered, we find that tumor growth and invasive morphology are supported while the tumor is distant from the source, but are progressively discouraged as the tumor converges about that source. Conclusions We show that invasive clustering can derive from basic kinetic assumptions often neglected in more complex models. While higher-order mechanisms, e.g. directed migration upon chemotactic stimuli, may result in clustering growth morphologies, exclusive attributions of this phenotype to this or other structured microenvironments would be inappropriate, in light of our finding these features are observable in a homogeneous environment. Furthermore, directed migration will result in loss of the invasive

  6. The influence of the microenvironment on the malignant phenotype

    NASA Technical Reports Server (NTRS)

    Park, C. C.; Bissell, M. J.; Barcellos-Hoff, M. H.

    2000-01-01

    Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. As tissue becomes cancerous, there are reciprocal interactions between neoplastic cells, adjacent normal cells such as stroma and endothelium, and their microenvironments. The current dominant paradigm wherein multiple genetic lesions provide both the impetus for, and the Achilles heel of, cancer might be inadequate to understand cancer as a disease process. In the following brief review, we will use selected examples to illustrate the influence of the microenvironment in the evolution of the malignant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions might be derived from focusing on microenvironment and tumor cells interactions.

  7. Chemotherapy of WAP-T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination.

    PubMed

    Jannasch, Katharina; Wegwitz, Florian; Lenfert, Eva; Maenz, Claudia; Deppert, Wolfgang; Alves, Frauke

    2015-07-01

    In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single-dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell-like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas. PMID:25449528

  8. The influence of mammographic density on breast tumor characteristics.

    PubMed

    Eriksson, Louise; Czene, Kamila; Rosenberg, Lena; Humphreys, Keith; Hall, Per

    2012-07-01

    Mammographic density (MD) is a well-established risk factor for breast cancer. Whether MD influences the tumor phenotype remains to be clarified. Previous studies are highly inconsistent and most lack important covariate information. This is a case-only study within a population-based case-control study. Cases were all postmenopausal women, aged 50-74 years, with incident breast cancer, diagnosed 1993-1995, and with no history of previous cancer (n = 2,720). 1,747 women with mammograms and information on tumor characteristics were included in analyses. MD was assessed using a computer-assisted thresholding technique. We used linear, logistic, and multinomial logistic regression, adjusting for possible confounders, to study density and tumor characteristics. PD was only statistically significantly associated with tumor size in our study (regression coefficient 0.031, p = 0.017). The effect of PD on tumor size was greater when mode of detection was excluded from the model (regression coefficient 0.043, p = 0.001). No other associations between PD and the tumor characteristics studied (lymph node metastasis, ER-status, PR-status, grade, and histopathological classification) were observed. In summary, PD was positively associated with tumor size in postmenopausal women. However, the relationship was at least partially confounded by mode of detection. Although there may be a true biological relationship between MD and more highly proliferative tumors, it also seems that part of this relationship is due to masking delaying diagnosis. In conclusion, PD does not seem to be differentially associated with tumor phenotype, except for tumor size, after taking mode of detection into consideration. PMID:22710708

  9. Reproducibility of radiomics for deciphering tumor phenotype with imaging

    PubMed Central

    Zhao, Binsheng; Tan, Yongqiang; Tsai, Wei-Yann; Qi, Jing; Xie, Chuanmiao; Lu, Lin; Schwartz, Lawrence H.

    2016-01-01

    Radiomics (radiogenomics) characterizes tumor phenotypes based on quantitative image features derived from routine radiologic imaging to improve cancer diagnosis, prognosis, prediction and response to therapy. Although radiomic features must be reproducible to qualify as biomarkers for clinical care, little is known about how routine imaging acquisition techniques/parameters affect reproducibility. To begin to fill this knowledge gap, we assessed the reproducibility of a comprehensive, commonly-used set of radiomic features using a unique, same-day repeat computed tomography data set from lung cancer patients. Each scan was reconstructed at 6 imaging settings, varying slice thicknesses (1.25 mm, 2.5 mm and 5 mm) and reconstruction algorithms (sharp, smooth). Reproducibility was assessed using the repeat scans reconstructed at identical imaging setting (6 settings in total). In separate analyses, we explored differences in radiomic features due to different imaging parameters by assessing the agreement of these radiomic features extracted from the repeat scans reconstructed at the same slice thickness but different algorithms (3 settings in total). Our data suggest that radiomic features are reproducible over a wide range of imaging settings. However, smooth and sharp reconstruction algorithms should not be used interchangeably. These findings will raise awareness of the importance of properly setting imaging acquisition parameters in radiomics/radiogenomics research. PMID:27009765

  10. Phenotypic quality influences fertility in Gombe chimpanzees

    PubMed Central

    Jones, James Holland; Wilson, Michael L.; Murray, Carson; Pusey, Anne

    2011-01-01

    Summary Fertility is an important fitness component, but is difficult to measure in slowly reproducing, long-lived animals such as chimpanzees (Pan troglodytes).We measured fertility and the effect of measured covariates on fertility in a 43-year sample of birth intervals of chimpanzees from the Gombe National Park, Tanzania using Cox proportional hazards regression with individual-level random effects.The birth hazard declined with mothers’ age at a rate of 0·84 per year following age at first reproduction. This value is somewhat stronger than previous estimates.Loss of the infant that opened the birth interval increased the birth hazard 134-fold.Birth intervals following the first complete birth interval were shorter than this first interval, while sex of the previous infant had no significant effect.Maternal dominance rank was significant at the P < 0·1 level when coded as high/middle/low but was highly significant when we simply considered high rank vs. others.Individual heterogeneity had a substantial impact on birth interval duration. We interpret this individual effect as a measure of phenotypic quality, controlling for the measured covariates such as dominance rank. This interpretation is supported by the correlation of individual heterogeneity scores with similar independent measures of body mass. PMID:20412347

  11. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment.

    PubMed

    Ishii, Genichiro; Ochiai, Atsushi; Neri, Shinya

    2016-04-01

    Cancer microenvironment is created not only by malignant epithelial cells, but also by several kinds of stromal cells. Since Paget proposed the "seed and soil" hypothesis, the biological importance of the cancer microenvironment has come to be widely accepted. The main compartment of host stromal cells are fibroblasts (Cancer-Associated Fibroblasts; CAFs), which are the main source of the collagen-producing cells. CAFs directly communicate with the cancer cells and other types of stromal cells to acquire a specific biological phenotype. CAFs play important roles in several aspects of the tumor progression process and the chemotherapeutic process. However, CAFs have heterogeneous origins, phenotypes, and functions under these conditions. A crucial challenge is to understand how much of this heterogeneity serves different biological responses to cancer cells. In this review, we highlight the issue of how diverse and heterogeneous functions given by CAFs can exert potent influences on tumor progression and therapeutic response. Furthermore, we also discuss the current advances in the development of novel therapeutic strategies against CAFs. PMID:26278673

  12. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors.

    PubMed

    Coffelt, Seth B; Lewis, Claire E; Naldini, Luigi; Brown, J Martin; Ferrara, Napoleone; De Palma, Michele

    2010-04-01

    It is now established that bone marrow-derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as "bone marrow-derived myeloid cells." Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying-and thus being able to target-this proangiogenic force in tumors. PMID:20167863

  13. Elusive Identities and Overlapping Phenotypes of Proangiogenic Myeloid Cells in Tumors

    PubMed Central

    Coffelt, Seth B.; Lewis, Claire E.; Naldini, Luigi; Brown, J. Martin; Ferrara, Napoleone; De Palma, Michele

    2010-01-01

    It is now established that bone marrow–derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as “bone marrow–derived myeloid cells.” Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying—and thus being able to target—this proangiogenic force in tumors. PMID:20167863

  14. Identification of Intrinsic Imaging Phenotypes for Breast Cancer Tumors: Preliminary Associations with Gene Expression Profiles1

    PubMed Central

    Ashraf, Ahmed Bilal; Daye, Dania; Gavenonis, Sara; Mies, Carolyn; Feldman, Michael; Rosen, Mark; Kontos, Despina

    2015-01-01

    Purpose To present a method for identifying intrinsic imaging phenotypes in breast cancer tumors and to investigate their association with prognostic gene expression profiles. Materials and Methods The authors retrospectively analyzed dynamic contrast material–enhanced (DCE) magnetic resonance (MR) images of the breast in 56 women (mean age, 55.6 years; age range, 37–74 years) diagnosed with estrogen receptor–positive breast cancer between 2005 and 2010. The study was approved by the institutional review board and compliant with HIPAA. The requirement to obtain informed consent was waived. Primary tumors were assayed with a validated gene expression assay that provides a score for the likelihood of recurrence. A multiparametric imaging phenotype vector was extracted for each tumor by using quantitative morphologic, kinetic, and spatial heterogeneity features. Multivariate linear regression was performed to test associations between DCE MR imaging features and recurrence likelihood. To identify intrinsic imaging phenotypes, hierarchical clustering was performed on the extracted feature vectors. Multivariate logistic regression was used to classify tumors at high versus low or medium risk of recurrence. To determine the additional value of intrinsic phenotypes, the phenotype category was tested as an additional variable. Receiver operating characteristic analysis and the area under the receiver operating characteristic curve (Az) were used to assess classification performance. Results There was a moderate correlation (r = 0.71, R2 = 0.50, P < .001) between DCE MR imaging features and the recurrence score. DCE MR imaging features were predictive of recurrence risk as determined by the surrogate assay, with an Az of 0.77 (P < .01). Four dominant imaging phenotypes were detected, with two including only low- and medium-risk tumors. When the phenotype category was used as an additional variable, the Az increased to 0.82 (P < .01). Conclusion Intrinsic imaging

  15. Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells

    PubMed Central

    De Saedeleer, Christophe J.; Copetti, Tamara; Porporato, Paolo E.; Verrax, Julien

    2012-01-01

    Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways. PMID:23082126

  16. Gastric Composite Tumor of Alpha Fetoprotein-Producing Carcinoma/Hepatoid Adenocarcinoma and Endocrine Carcinoma with Reference to Cellular Phenotypes

    PubMed Central

    Suzuki, Akira; Koide, Naohiko; Kitazawa, Masato; Mochizuka, Akiyoshi; Ota, Hiroyoshi; Miyagawa, Shinichi

    2012-01-01

    Alpha-fetoprotein-producing carcinoma (AFPC)/hepatoid adenocarcinoma (HAC) and neuroendocrine carcinoma (NEC) are uncommon in the stomach. Composite tumors consisting of these carcinomas and their histologic phenotypes are not well known. Between 2002 and 2007, to estimate the prevalence of composite tumors consisting of tubular adenocarcinoma, AFPC/HAC and NEC, we reviewed specimens obtained from 294 consecutive patients treated surgically for gastric cancer. We examined histological phenotype of tumors of AFPC or NEC containing the composite tumor by evaluating immunohistochemical expressions of MUC2, MUC5AC, MUC6, CDX2, and SOX2. Immunohistochemically, AFPC/HAC dominantly showed the intestinal or mixed phenotype, and NEC frequently showed the gastric phenotype. In the composite tumor, the tubular and hepatoid components showed the gastric phenotype, and the neuroendocrine component showed the mixed type. The unique composite tumor predominantly showed the gastric phenotype, and the hepatoid and neuroendocrine components were considered to be differentiated from the tubular component. PMID:22482081

  17. Skeletal muscle calcineurin: influence of phenotype adaptation and atrophy

    NASA Technical Reports Server (NTRS)

    Spangenburg, E. E.; Williams, J. H.; Roy, R. R.; Talmadge, R. J.; Spangenberg, E. E. (Principal Investigator)

    2001-01-01

    Calcineurin (CaN) has been implicated as a signaling molecule that can transduce physiological stimuli (e.g., contractile activity) into molecular signals that initiate slow-fiber phenotypic gene expression and muscle growth. To determine the influence of muscle phenotype and atrophy on CaN levels in muscle, the levels of soluble CaN in rat muscles of varying phenotype, as assessed by myosin heavy chain (MHC)-isoform proportions, were determined by Western blotting. CaN levels were significantly greater in the plantaris muscle containing predominantly fast (IIx and IIb) MHC isoforms, compared with the soleus (predominantly type I MHC) or vastus intermedius (VI, contains all 4 adult MHC isoforms). Three months after a complete spinal cord transection (ST), the CaN levels in the VI muscle were significantly reduced, despite a significant increase in fast MHC isoforms. Surprisingly, the levels of CaN in the VI were highly correlated with muscle mass but not MHC isoform proportions in ST and control rats. These data demonstrate that CaN levels in skeletal muscle are highly correlated to muscle mass and that the normal relationship with phenotype is lost after ST.

  18. Glioma Cells in the Tumor Periphery Have a Stem Cell Phenotype

    PubMed Central

    Munthe, Sune; Petterson, Stine Asferg; Dahlrot, Rikke Hedegaard; Poulsen, Frantz Rom; Hansen, Steinbjørn; Kristensen, Bjarne Winther

    2016-01-01

    Gliomas are highly infiltrative tumors incurable with surgery. Although surgery removes the bulk tumor, tumor cells in the periphery are left behind resulting in tumor relapses. The aim of the present study was to characterize the phenotype of tumor cells in the periphery focusing on tumor stemness, proliferation and chemo-resistance. This was investigated in situ in patient glioma tissue as well as in orthotopic glioblastoma xenografts. We identified 26 gliomas having the R132 mutation in Isocitrate DeHydrogenase 1 (mIDH1). A double immunofluorescence approach identifying mIDH1 positive tumor cells and a panel of markers was used. The panel comprised of six stem cell-related markers (CD133, Musashi-1, Bmi-1, Sox-2, Nestin and Glut-3), a proliferation marker (Ki-67) as well as a chemo-resistance marker (MGMT). Computer-based automated classifiers were designed to measure the mIDH1 positive nucleus area-fraction of the chosen markers. Moreover, orthotopic glioblastoma xenografts from five different patient-derived spheroid cultures were obtained and the tumor cells identified by human specific immunohistochemical markers. The results showed that tumor cells in the periphery of patient gliomas expressed stem cell markers, however for most markers at a significantly lower level than in the tumor core. The Ki-67 level was slightly reduced in the periphery, whereas the MGMT level was similar. In orthotopic glioblastoma xenografts all markers showed similar levels in the core and periphery. In conclusion tumor cells in the periphery of patient gliomas have a stem cell phenotype, although it is less pronounced than in the tumor core. Novel therapies aiming at preventing recurrence should therefore take tumor stemness into account. Migrating cells in orthotopic glioblastoma xenografts preserve expression and stem cell markers. The orthotopic model therefore has a promising translational potential. PMID:27171431

  19. Glioma Cells in the Tumor Periphery Have a Stem Cell Phenotype.

    PubMed

    Munthe, Sune; Petterson, Stine Asferg; Dahlrot, Rikke Hedegaard; Poulsen, Frantz Rom; Hansen, Steinbjørn; Kristensen, Bjarne Winther

    2016-01-01

    Gliomas are highly infiltrative tumors incurable with surgery. Although surgery removes the bulk tumor, tumor cells in the periphery are left behind resulting in tumor relapses. The aim of the present study was to characterize the phenotype of tumor cells in the periphery focusing on tumor stemness, proliferation and chemo-resistance. This was investigated in situ in patient glioma tissue as well as in orthotopic glioblastoma xenografts. We identified 26 gliomas having the R132 mutation in Isocitrate DeHydrogenase 1 (mIDH1). A double immunofluorescence approach identifying mIDH1 positive tumor cells and a panel of markers was used. The panel comprised of six stem cell-related markers (CD133, Musashi-1, Bmi-1, Sox-2, Nestin and Glut-3), a proliferation marker (Ki-67) as well as a chemo-resistance marker (MGMT). Computer-based automated classifiers were designed to measure the mIDH1 positive nucleus area-fraction of the chosen markers. Moreover, orthotopic glioblastoma xenografts from five different patient-derived spheroid cultures were obtained and the tumor cells identified by human specific immunohistochemical markers. The results showed that tumor cells in the periphery of patient gliomas expressed stem cell markers, however for most markers at a significantly lower level than in the tumor core. The Ki-67 level was slightly reduced in the periphery, whereas the MGMT level was similar. In orthotopic glioblastoma xenografts all markers showed similar levels in the core and periphery. In conclusion tumor cells in the periphery of patient gliomas have a stem cell phenotype, although it is less pronounced than in the tumor core. Novel therapies aiming at preventing recurrence should therefore take tumor stemness into account. Migrating cells in orthotopic glioblastoma xenografts preserve expression and stem cell markers. The orthotopic model therefore has a promising translational potential. PMID:27171431

  20. Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI)

    PubMed Central

    Kim, Eugene; Zhang, Jiangyang; Hong, Karen; Benoit, Nicole E; Pathak, Arvind P

    2011-01-01

    Abnormal vascular phenotypes have been implicated in neuropathologies ranging from Alzheimer's disease to brain tumors. The development of transgenic mouse models of such diseases has created a crucial need for characterizing the murine neurovasculature. Although histologic techniques are excellent for imaging the microvasculature at submicron resolutions, they offer only limited coverage. It is also challenging to reconstruct the three-dimensional (3D) vasculature and other structures, such as white matter tracts, after tissue sectioning. Here, we describe a novel method for 3D whole-brain mapping of the murine vasculature using magnetic resonance microscopy (μMRI), and its application to a preclinical brain tumor model. The 3D vascular architecture was characterized by six morphologic parameters: vessel length, vessel radius, microvessel density, length per unit volume, fractional blood volume, and tortuosity. Region-of-interest analysis showed significant differences in the vascular phenotype between the tumor and the contralateral brain, as well as between postinoculation day 12 and day 17 tumors. These results unequivocally show the feasibility of using μMRI to characterize the vascular phenotype of brain tumors. Finally, we show that combining these vascular data with coregistered images acquired with diffusion-weighted MRI provides a new tool for investigating the relationship between angiogenesis and concomitant changes in the brain tumor microenvironment. PMID:21386855

  1. High throughput functional genomics: identification of novel genes with tumor suppressor phenotypes.

    PubMed

    Koenig-Hoffmann, Kerstin; Bonin-Debs, Angelika L; Boche, Irene; Gawin, Beate; Gnirke, Andrea; Hergersberg, Christoph; Madeo, Frank; Kazinski, Michael; Klein, Matthias; Korherr, Christian; Link, Dieter; Röhrig, Sascha; Schäfer, Rolf; Brinkmann, Ulrich

    2005-01-20

    We have used a combination of high throughput functional genomics, computerized database mining and expression analyses to discover novel human tumor suppressor genes (TSGs). A genome-wide high throughput cDNA phenotype screen was established to identify genes that induce apoptosis or reduce cell viability. TSGs are expressed in normal tissue and frequently act by reduction of growth of transformed cells or induce apoptosis. In agreement with that and thus serving as platform validation, our pro-apoptotic hits included genes for which tumor suppressing activities were known, such as kangai1 and CD81 antigen. Additional genes that so far have been claimed as putative TSGs or associated with tumor inhibitory activities (prostate differentiation factor, hRAS-like suppressor 3, DPH2L1-like and the metastasis inhibitor Kiss1) were confirmed in their proposed TSG-like phenotype by functionally defining their growth inhibitory or pro-apoptotic function towards cancer cells. Finally, novel genes were identified for which neither association with cell growth nor with apoptosis were previously described. A subset of these genes show characteristics of TSGs because they (i) reduce the growth or induce apoptosis in tumor cells; (ii) show reduced expression in tumor vs. normal tissue; and (iii) are located on chromosomal (LOH-) loci for which cancer-associated deletions are described. The pro-apoptotic phenotype and differential expression of these genes in normal and malignant tissue make them promising target candidates for the diagnosis and therapy of various tumors. PMID:15455385

  2. Single-Cell Electrical Phenotyping Enabling the Classification of Mouse Tumor Samples

    PubMed Central

    Zhao, Yang; Jiang, Mei; Chen, Deyong; Zhao, Xiaoting; Xue, Chengcheng; Hao, Rui; Yue, Wentao; Wang, Junbo; Chen, Jian

    2016-01-01

    Single-cell electrical phenotyping (e.g., specific membrane capacitance (Cm) and cytoplasm conductivity (σp)) has long been regarded as potential label-free biophysical markers in tumor status evaluation. However, previous studies only reported the differentiation of tumor cell lines without classifying real tumor samples using cellular electrical properties. In this study, two types of mouse tumor models were constructed by injecting two types of tumor cell lines (A549 and H1299), respectively. Then tumor portions were retrieved for immunohistochemistry studies and single-cell electrical phenotyping based on home-developed microfluidic platforms. Immunohistochemistry results of tumor samples confirmed the adenocarcinoma and large-cell carcinoma characteristics for A549 and H1299 based tumor samples, respectively. Meanwhile, cellular Cm and σp were characterized as 2.25 ± 0.50 μF/cm2 and 0.96 ± 0.20 S/m for A549 based tumor samples (ncell = 1336, Mouse I, II, III) and 1.76 ± 0.54 μF/cm2 and 1.35 ± 0.28 S/m for H1299 based tumor samples (ncell = 1442, Mouse IV, V, VI). Significant differences in Cm and σp were observed between these two types of tumor samples, validating the feasibility of using Cm and σp for mouse tumor classification. PMID:26766416

  3. Metabolic Imaging: A link between Lactate Dehydrogenase A, Lactate and Tumor Phenotype

    PubMed Central

    Thakur, Sunitha B.; Vider, Jelena; Russell, James; Blasberg, Ronald; Koutcher, Jason A.

    2014-01-01

    Purpose We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design LDH-A expression, lactate concentration, glucose utilization and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels (measured by magnetic resonance spectroscopic imaging (MRSI)) and tumor glucose utilization (measured by [18F] 2-deoxy-2-fluoro-D-glucose positron emission tomography ([18F]FDG-PET)) was assessed in orthotopic breast tumors derived from these cell lines. Results We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate tenfold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less intense hypoxia staining was observed in the larger 67NR tumors, and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions Lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. PMID:21844011

  4. Tumor-Associated Neutrophils Show Phenotypic and Functional Divergence in Human Lung Cancer.

    PubMed

    Saha, Shilpi; Biswas, Subhra K

    2016-07-11

    Studies in murine cancer models have demonstrated the phenotypic and functional divergence of neutrophils; however, their role in pro- or anti-tumor responses in human remains elusive. In this issue of Cancer Cell, Singhal et al. report the existence of specialized subsets of neutrophils in human lung cancer with diverging functions. PMID:27411583

  5. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    SciTech Connect

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege  G.; Helland, Åslaug; Rye, Inga  H.; Borresen-Dale, Anne -Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin  L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  6. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    DOE PAGESBeta

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege  G.; Helland, Åslaug; et al

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatialmore » distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.« less

  7. Tumor-derived CCL-2 and CXCL-8 as possible prognostic markers of breast cancer: correlation with estrogen and progestrone receptor phenotyping.

    PubMed

    Ghoneim, H M; Maher, Sara; Abdel-Aty, Asmaa; Saad, A; Kazem, A; Demian, S R

    2009-01-01

    Prognosis of breast cancer is believed to be a multifactorial process best achieved by complex factors including host and tumor-derived biomarkers together with traditional clinicopathological parameters and tumor histologic markers. The present study aimed at evaluating the prognostic significance of chemokine ligand-2 (CCL-2) and interleukin-8 (CXCL-8) expression in extracts of breast carcinomas through correlation with clinicopathological aspects as well as estrogen receptor (ER) and progesterone receptor (PR) phenotyping. The study was conducted on 30 Egyptian breast cancer patients diagnosed by fine needle aspiration cytology (FNAC) and subjected to modified radical mastectomy. Excised tissues were used to prepare tissue sections and extracts for histopathological and immunohistochemical studies. Expression of CCL-2 and CXCL-8 was determined by enzyme-linked immunosorbent assay (ELISA). 26 patients had invasive ductal carcinoma, grades II and III with metastasis to axillary lymph nodes and ER and PR positive phenotype. Expression of CCL-2 and CXCL-8 was significantly influenced by patient's age, menopausal status, nodal involvement, tumor grade and the ER phenotype. In contrast, it was not affected by either tumor size or PR staining pattern. Both chemokines correlated positively to each other and to tumor grade and negatively to age, menopausal status of patients and ER phenotyping. It is concluded that the angiogenic chemokine CXCL-8 and the macrophage chemoattractant CCL-2 might be useful prognostic markers where their routine follow up might be of importance in assessment of tumor aggressiveness in clinical settings. PMID:22059352

  8. Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype1

    PubMed Central

    Bergström, Sofia Halin; Rudolfsson, Stina H; Bergh, Anders

    2016-01-01

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor–positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone. PMID:26992916

  9. Phenotypes and enviromental factors: their influence in PCOS.

    PubMed

    Diamanti-Kandarakis, Evanthia; Christakou, Charikleia; Marinakis, Evangelos

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals. PMID:22229564

  10. Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier.

    PubMed

    Yokoi, Kenji; Chan, Diana; Kojic, Milos; Milosevic, Miljan; Engler, David; Matsunami, Rise; Tanei, Tomonori; Saito, Yuki; Ferrari, Mauro; Ziemys, Arturas

    2015-11-10

    Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography-mass spectrometry (LC-MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2-3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy. PMID:26409121

  11. IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts

    PubMed Central

    Hamilton, Kathryn E.; Noubissi, Felicite K.; Rustgi, Anil K.

    2013-01-01

    Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc Min/+ mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis. PMID:23764754

  12. Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability

    PubMed Central

    García de Herreros, Antonio

    2014-01-01

    During the last years many articles have reported epithelial-to-mesenchymal transitions (EMT) induced by a myriad of gene products either when added to the cell medium or when transfected. Molecularly the EMT is characterized by the up-regulation of transcriptional factors (EMT-TFs) repressing the epithelial gene E-cadherin, a protein essential for the maintenance of the epithelial phenotype. These EMT-TFs are subjected to a complex regulation involving binary self-stimulatory loops, allowing the possibility of the amplification of input signals. The capability of EMT-TFs to promote an EMT is controlled by E-cadherin that limits the transcription of mesenchymal genes. We discuss here the differences between normal and tumor epithelial cells; in the latter a partial inactivation of E-cadherin function enables extracellular signals to be amplified and induce an EMT. This tumor cell phenotypic instability is exacerbated in cell culture conditions. Therefore, it is likely that many of the gene products reported to control this transition act only in very specific cell tumor cell lines; thus, in cells with an unstable phenotype due to pre-existing alterations in E-cadherin safeguard mechanism. PMID:25566541

  13. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors

    PubMed Central

    Malik, Shivani; Villanova, Lidia; Tanaka, Shinji; Aonuma, Misato; Roy, Nilotpal; Berber, Elisabeth; Pollack, Jonathan R.; Michishita-Kioi, Eriko; Chua, Katrin F.

    2015-01-01

    Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers. PMID:25923013

  14. Rumen microbial communities influence metabolic phenotypes in lambs.

    PubMed

    Morgavi, Diego P; Rathahao-Paris, Estelle; Popova, Milka; Boccard, Julien; Nielsen, Kristian F; Boudra, Hamid

    2015-01-01

    The rumen microbiota is an essential part of ruminants shaping their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult sheep microbiota increased bacterial and archaeal diversity independently of protozoa presence. For archaea, Methanomassiliicoccales displaced Methanosphaera. Notwithstanding, protozoa induced differences in functional traits such as digestibility and significantly shaped bacterial community structure, notably Ruminococcaceae and Lachnospiraceae lower up to 6 folds, Prevotellaceae lower by ~40%, and Clostridiaceae and Veillonellaceae higher up to 10 folds compared to microbiota without protozoa. An orthogonal partial least squares-discriminant analysis of urinary metabolome matched differences in microbiota structure. Discriminant metabolites were mainly involved in amino acids and protein metabolic pathways while a negative interaction was observed between methylotrophic methanogens Methanomassiliicoccales and trimethylamine N-oxide. These results stress the influence of gut microbes on animal phenotype and show the potential of metabolomics for monitoring rumen microbial functions. PMID:26528248

  15. Rumen microbial communities influence metabolic phenotypes in lambs

    PubMed Central

    Morgavi, Diego P.; Rathahao-Paris, Estelle; Popova, Milka; Boccard, Julien; Nielsen, Kristian F.; Boudra, Hamid

    2015-01-01

    The rumen microbiota is an essential part of ruminants shaping their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult sheep microbiota increased bacterial and archaeal diversity independently of protozoa presence. For archaea, Methanomassiliicoccales displaced Methanosphaera. Notwithstanding, protozoa induced differences in functional traits such as digestibility and significantly shaped bacterial community structure, notably Ruminococcaceae and Lachnospiraceae lower up to 6 folds, Prevotellaceae lower by ~40%, and Clostridiaceae and Veillonellaceae higher up to 10 folds compared to microbiota without protozoa. An orthogonal partial least squares-discriminant analysis of urinary metabolome matched differences in microbiota structure. Discriminant metabolites were mainly involved in amino acids and protein metabolic pathways while a negative interaction was observed between methylotrophic methanogens Methanomassiliicoccales and trimethylamine N-oxide. These results stress the influence of gut microbes on animal phenotype and show the potential of metabolomics for monitoring rumen microbial functions. PMID:26528248

  16. SU-E-J-248: Contributions of Tumor and Stroma Phenotyping in Computer-Aided Diagnosis

    SciTech Connect

    Li, H; Lan, L; Sennett, C; Giger, M

    2015-06-15

    Purpose: To gain insight into the role of parenchyma stroma in the characterization of breast tumors by incorporating computerized mammographic parenchyma assessment into breast CADx in the task of distinguishing between malignant and benign lesions. Methods: This study was performed on 182 biopsy-proven breast mass lesions, including 76 benign and 106 malignant lesions. For each full-field digital mammogram (FFDM) case, our quantitative imaging analysis was performed on both the tumor and a region-of-interest (ROI) from the normal contralateral breast. The lesion characterization includes automatic lesion segmentation and feature extraction. Radiographic texture analysis (RTA) was applied on the normal ROIs to assess the mammographic parenchymal patterns of these contralateral normal breasts. Classification performance of both individual computer extracted features and the output from a Bayesian artificial neural network (BANN) were evaluated with a leave-one-lesion-out method using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the figure of merit. Results: Lesion characterization included computer-extracted phenotypes of spiculation, size, shape, and margin. For parenchymal pattern characterization, five texture features were selected, including power law beta, contrast, and edge gradient. Merging of these computer-selected features using BANN classifiers yielded AUC values of 0.79 (SE=0.03) and 0.67 (SE=0.04) in the task of distinguishing between malignant and benign lesions using only tumor phenotypes and texture features from the contralateral breasts, respectively. Incorporation of tumor phenotypes with parenchyma texture features into the BANN yielded improved classification performance with an AUC value of 0.83 (SE=0.03) in the task of differentiating malignant from benign lesions. Conclusion: Combining computerized tumor and parenchyma phenotyping was found to significantly improve breast cancer diagnostic accuracy

  17. Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity

    PubMed Central

    Sedlacek, Abigail L.; Kinner-Bibeau, Lauren B.; Binder, Robert J.

    2016-01-01

    A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91+ antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy. We investigate the role of NK cells in gp96-mediated anti-tumor immune responses given their propensity to lyse tumor cells. We show that gp96-mediated rejection of tumors requires a unique and necessary helper role in NK cells. This helper role occurs during the effector phase of the anti-tumor immune response and is required for T cell and APC function. Gp96 activates NK cells indirectly via APCs to a phenotype distinct from NK cells activated by other mechanisms such as IL-2. While NK cells have both lytic and cytokine producing properties, we show that gp96 selectively activates cytokine production in NK cells, which is important in the HSP anti-tumor immune response, and leaves their cytotoxic capacity unchanged. PMID:27431727

  18. Tumor interstitial fluid promotes malignant phenotypes of lung cancer independently of angiogenesis.

    PubMed

    Li, Hong; Li, Ganggang; Liu, Linxin; Guo, Zhenzhen; Ma, Xiaofang; Cao, Ning; Lin, Haihong; Han, Guang; Duan, Yongjian; Du, Gangjun

    2015-11-01

    Angiogenesis is necessary for cancer progression, but antiangiogenic therapy actually promotes tumor recurrence, progression, and metastasis. This study focused on the contribution of the tumor interstitial fluid (TIF) to lung cancer progression. TIF was isolated and quantified for 10 μg protein/mL. Malignant driver characteristics of TIF were examined by tumor-initiating cells (TIC), self-renewal, epithelial-mesenchymal transition (EMT), autophagy, and apoptosis in vitro. In vivo tumor model was used to investigate the mechanistic roles of TIF in lung cancer progression. In vitro, TIF exhibited distinct malignant driver characteristics, which led to increased numbers of TICs, increased self-renewal and EMT, as well as to decreased autophagy and apoptosis under cell starvation conditions. In vivo, the contribution of TIF was similar, as judged by increased TICs indicated by the cancer stem cell marker Nanog, the proliferation marker proliferating cell nuclear antigen, and the EMT marker N-cadherin; TIF also increased the formation of pulmonary tumors. Interestingly, the blockers of inflammation, Na-K-ATPase, and aldosterone receptor decreased TIF-induced tumor progression but increased angiogenesis. Further, we found that the water content of the tissue was positively correlated with the levels of plasma 5-hydroxyindoleacetic acid or tissue aquaporin-1 but not with CD31. However, vadimezan reduced angiogenesis but promoted TIF-induced tumor progression. Our results suggested that TIF could provide better nutrition to the tumor than angiogenesis and that it could promote the development of malignant phenotypes of lung cancer independently of angiogenesis. PMID:26342025

  19. Exploring the quantitative relationship between metabolism and enzymatic phenotype by physiological modeling of glucose metabolism and lactate oxidation in solid tumors

    NASA Astrophysics Data System (ADS)

    Wang, Qian; Vaupel, Peter; Ziegler, Sibylle I.; Shi, Kuangyu

    2015-03-01

    Molecular imaging using PET or hyperpolarized MRI can characterize tumor phenotypes by assessing the related metabolism of certain substrates. However, the interpretation of the substrate turnover in terms of a pathophysiological understanding is not straightforward and only semiquantitative. The metabolism of imaging probes is influenced by a number of factors, such as the microvascular structure or the expression of key enzymes. This study aims to use computational simulation to investigate the relationship between the metabolism behind molecular imaging and the underlying tumor phenotype. The study focused on the pathways of glucose metabolism and lactate oxidation in order to establish the quantitative relationship between the expression of several transporters (GLUT, MCT1 and MCT4), expression of the enzyme hexokinase (HK), microvasculature and the metabolism of glucose or lactate and the extracellular pH distribution. A computational model for a 2D tumor tissue phantom was constructed and the spatio-temporal evolution of related species (e.g. oxygen, glucose, lactate, protons, bicarbonate ions) was estimated by solving reaction-diffusion equations. The proposed model was tested by the verification of the simulation results using in vivo and in vitro literature data. The influences of different expression levels of GLUT, MCT1, MCT4, HK and microvessel distribution on substrate concentrations were analyzed. The major results are consistent with experimental data (e.g. GLUT is more influential to glycolytic flux than HK; extracellular pH is not correlated with MCT expressions) and provide theoretical interpretation of the co-influence of multiple factors of the tumor microenvironment. This computational simulation may assist the generation of hypotheses to bridge the discrepancy between tumor metabolism and the functions of transporters and enzymes. It has the potential to accelerate the development of multi-modal imaging strategies for assessment of tumor

  20. Prediabetes Phenotype Influences Improvements in Glucose Homeostasis with Resistance Training

    PubMed Central

    Eikenberg, Joshua D.; Savla, Jyoti; Marinik, Elaina L.; Davy, Kevin P.; Pownall, John; Baugh, Mary E.; Flack, Kyle D.; Boshra, Soheir; Winett, Richard A.; Davy, Brenda M.

    2016-01-01

    Purpose To determine if prediabetes phenotype influences improvements in glucose homeostasis with resistance training (RT). Methods Older, overweight individuals with prediabetes (n = 159; aged 60±5 yrs; BMI 33±4 kg/m2) completed a supervised RT program twice per week for 12 weeks. Body weight and composition, strength, fasting plasma glucose, 2-hr oral glucose tolerance, and Matsuda-Defronza estimated insulin sensitivity index (ISI) were assessed before and after the intervention. Participants were categorized according to their baseline prediabetes phenotype as impaired fasting glucose only (IFG) (n = 73), impaired glucose tolerance only (IGT) (n = 21), or combined IFG and IGT (IFG/IGT) (n = 65). Results Chest press and leg press strength increased 27% and 18%, respectively, following the 12-week RT program (both p<0.05). Waist circumference (-1.0%; pre 109.3±10.3 cm, post 108.2±10.6 cm) and body fat (-0.6%; pre 43.7±6.8%, post 43.1±6.8%) declined, and lean body mass (+1.3%; pre 52.0±10.4 kg, post 52.7±10.7 kg) increased following the intervention. Fasting glucose concentrations did not change (p>0.05) following the intervention. However, 2-hr oral glucose tolerance improved in those with IGT (pre 8.94±0.72 mmol/l, post 7.83±1.11 mmol/l, p<0.05) and IFG/IGT (pre 9.66±1.11mmol/l, post 8.60±2.00 mmol/l) but not in those with IFG (pre 6.27±1.28mmol/l, post 6.33± 1.55 mmol/l). There were no significant changes in ISI or glucose area under the curve following the RT program. Conclusions RT without dietary intervention improves 2-hr oral glucose tolerance in individuals with prediabetes. However, the improvements in glucose homeostasis with RT appear limited to those with IGT or combined IFG and IGT. Trial Registration ClinicalTrials.gov: NCT01112709 PMID:26840904

  1. PKCδ maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback.

    PubMed

    Kim, R-K; Suh, Y; Hwang, E; Yoo, K-C; Choi, K-S; An, S; Hwang, S-G; Kim, I-G; Kim, M-J; Lee, H-J; Lee, S-J

    2015-11-12

    The existence of tumor initiating cells (TICs) has been emerged as a good therapeutic target for treatment of glioblastoma that is the most aggressive brain tumor with poor prognosis. However, the molecular mechanisms that regulate the phenotypes of TICs still remain obscure. In this study, we found that PKCδ, among PKC isoforms, is preferentially activated in TICs and acts as a critical regulator for the maintenance of TICs in glioblastoma. By modulating the expression levels or activity of PKCδ, we demonstrated that PKCδ promotes self-renewal and tumorigenic potentials of TICs. Importantly, we found that the activation of PKCδ persists in TICs through an autocrine loop with positive feedback that was driven by PKCδ/STAT3/IL-23/JAK signaling axis. Moreover, for phenotypes of TICs, we showed that PKCδ activates AKT signaling component by phosphorylation specifically on Ser473. Taken together, we proposed that TICs regulate their own population in glioblastoma through an autocrine loop with positive feedback that is driven by PKCδ-dependent secretion of cytokines. PMID:25746003

  2. Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype

    PubMed Central

    Bleau, Anne-Marie; Zandueta, Carolina; Redrado, Miriam; Martínez-Canarias, Susana; Larzábal, Leyre; Montuenga, Luis M.

    2015-01-01

    The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo, despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications. PMID:26318423

  3. Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype.

    PubMed

    Bleau, Anne-Marie; Zandueta, Carolina; Redrado, Miriam; Martínez-Canarias, Susana; Larzábal, Leyre; Montuenga, Luis M; Calvo, Alfonso; Lecanda, Fernando

    2015-09-29

    The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo, despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications. PMID:26318423

  4. Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype.

    PubMed

    Bümming, Per; Nilsson, Ola; Ahlman, Håkan; Welbencer, Anna; Andersson, Mattias K; Sjölund, Katarina; Nilsson, Bengt

    2007-09-01

    Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST. PMID:17914114

  5. Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo12

    PubMed Central

    Tellier, Céline; Desmet, Déborah; Petit, Laurenne; Finet, Laure; Graux, Carlos; Raes, Martine; Feron, Olivier; Michiels, Carine

    2015-01-01

    Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL)-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule–1 (ICAM-1); and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor–κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2), IL-6, CXCL1 (C-X-C motif ligand 1), and macrophage inflammatory protein 2 (murine IL-8 functional homologs) mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia–specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5)low/PTGS2high/ICAM-1high/IL-6high/IL-8high expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the involvement of

  6. Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.

    PubMed

    Riabov, Vladimir; Kim, David; Chhina, Surmeet; Alexander, Richard B; Klyushnenkova, Elena N

    2015-07-01

    Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects. PMID:25893810

  7. Astroblastoma: beside being a tumor entity, an occasional phenotype of astrocytic gliomas?

    PubMed Central

    Mellai, Marta; Piazzi, Angela; Casalone, Cristina; Grifoni, Silvia; Melcarne, Antonio; Annovazzi, Laura; Cassoni, Paola; Denysenko, Tetyana; Valentini, Maria Consuelo; Cistaro, Angelina; Schiffer, Davide

    2015-01-01

    The diagnosis of astroblastoma is based on a typical histological aspect with perivascular distribution of cells sending cytoplasmic extensions to the vessels and vascular hyalinization. These criteria are useful for standardizing the identification of the tumor, but, in spite of this, there are discrepancies in the literature concerning the age distribution and the benign or malignant nature of the tumor. Three cases are discussed in this study: Case 1 was a typical high-grade astroblastoma; Case 2 was an oligodendroglioma at the first intervention and an oligoastrocytoma at the second intervention with typical perivascular arrangements in the astrocytic component; Case 3 was a gemistocytic glioma with malignant features and typical perivascular arrangements. Genetic analysis showed genetic alterations that are typical of gliomas of all malignancy grades. Using the neurosphere assay, neurospheres and adherent cells were found to have developed in Case 1, while adherent cells only developed in Case 2, in line with the stemness potential of the tumors. The cases are discussed in relation to their diagnostic assessment as astroblastoma, and it is hypothesized that the typical perivascular distribution of cells may not indicate a separate and unique tumor entity, but may be a peculiarity that can be acquired by astrocytic gliomas when an unknown cause from the tumor microenvironment influences the relationship between vessels and tumor cells. PMID:25737639

  8. Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes

    PubMed Central

    Zhao, Hua; Heimberger, Amy B.; Lu, Zhimin; Wu, Xifeng; Hodges, Tiffany R.; Song, Renduo; Shen, Jie

    2016-01-01

    Background Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. Methods In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. Results Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. Conclusion Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification. PMID:26967252

  9. Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation.

    PubMed

    Braun, Christian J; Bruno, Peter M; Horlbeck, Max A; Gilbert, Luke A; Weissman, Jonathan S; Hemann, Michael T

    2016-07-01

    Targeted transcriptional regulation is a powerful tool to study genetic mediators of cellular behavior. Here, we show that catalytically dead Cas9 (dCas9) targeted to genomic regions upstream or downstream of the transcription start site allows for specific and sustainable gene-expression level alterations in tumor cells in vitro and in syngeneic immune-competent mouse models. We used this approach for a high-coverage pooled gene-activation screen in vivo and discovered previously unidentified modulators of tumor growth and therapeutic response. Moreover, by using dCas9 linked to an activation domain, we can either enhance or suppress target gene expression simply by changing the genetic location of dCas9 binding relative to the transcription start site. We demonstrate that these directed changes in gene-transcription levels occur with minimal off-target effects. Our findings highlight the use of dCas9-mediated transcriptional regulation as a versatile tool to reproducibly interrogate tumor phenotypes in vivo. PMID:27325776

  10. Host genotype and tumor phenotype of chemokine decoy receptors integrally affect breast cancer relapse

    PubMed Central

    Shao, Zhi-Ming

    2015-01-01

    Purpose Chemokines may play vital roles in breast cancer progression and metastasis. The primary members of chemokine decoy receptors (CDR), DARC and D6, are expressed in breast tumors and lymphatic/hematogenous vessels. CDRs sequestrate the pro-malignant chemokines. We hypothesized that breast cancer patients carrying different levels of CDR expression in tumor and/or in host might have differing clinical outcomes. Methods This prospective observational study measured both expression and germline genotype of DARC and D6 in 463 primary breast cancer patients enrolled between 2004 and 2006. The endpoint was breast cancer relapse-free survival (RFS). Results There was a significant association between the co-expression of CDR (immunohistochemical expression of both DARC and D6) with RFS (hazard ratio [HR] of 0.32, 95% confidence interval [CI] 0.19 to 0.54). Furthermore, the co-genotype of two non-synonymous polymorphisms (with two major alleles of DARC-rs12075 and D6-rs2228468 versus the others) significantly related to relapse. Mechanistically, the variant-alleles of these two polymorphisms significantly decreased by 20–30% of CCL2/CCL5 (CDR ligands) levels relative to their major counterparts. Multivariate analysis highlighted that the co-expression and co-genotype of CDR were independent predictors of RFS, with HR of 0.46 (95% CI 0.27 to 0.80) and 0.56 (95% CI 0.37 to 0.85), respectively. The addition of host CDR genetic information to tumor-based factors (including co-expression of CDR) improved the relapse prediction ability (P = 0.02 of AUC comparison). Conclusion The host genotype and tumor phenotype of CDR integrally affect breast cancer relapse. Host-related factors should be considered for individualized prediction of prognosis. PMID:26314842

  11. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

    PubMed Central

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  12. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

    PubMed

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  13. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

    PubMed Central

    Kokolus, Kathleen M.; Capitano, Maegan L.; Lee, Chen-Ting; Eng, Jason W.-L.; Waight, Jeremy D.; Hylander, Bonnie L.; Sexton, Sandra; Hong, Chi-Chen; Gordon, Christopher J.; Abrams, Scott I.; Repasky, Elizabeth A.

    2013-01-01

    We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20–26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30–31 °C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8+ T lymphocytes and CD8+ T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of cold-stress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response. PMID:24248371

  14. Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.

    PubMed

    Lu, Fanghui; Chen, Ying; Zhao, Chuntao; Wang, Haibo; He, Danyang; Xu, Lingli; Wang, Jincheng; He, Xuelian; Deng, Yaqi; Lu, Ellen E; Liu, Xue; Verma, Ravinder; Bu, Hong; Drissi, Rachid; Fouladi, Maryam; Stemmer-Rachamimov, Anat O; Burns, Dennis; Xin, Mei; Rubin, Joshua B; Bahassi, El Mustapha; Canoll, Peter; Holland, Eric C; Lu, Q Richard

    2016-05-01

    Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs. PMID:27165742

  15. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach

    PubMed Central

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-01-01

    Abstract Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma. A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups. The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUVmax and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUVmax, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors. ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas. PMID:26469915

  16. Tumor type influences the effectiveness of pleurodesis in malignant effusions.

    PubMed

    Bielsa, Silvia; Hernández, Paula; Rodriguez-Panadero, Francisco; Taberner, Teresa; Salud, Antonieta; Porcel, José M

    2011-04-01

    Pleurodesis is commonly indicated for symptom relief in patients with malignant pleural effusions. A number of factors may influence pleurodesis outcome, but whether tumor type is one of them is a matter of debate. This study investigates the impact of tumor type on the efficacy of bedside doxycycline and thoracoscopic talc poudrage pleurodesis in order to determine which patients may benefit most from these procedures. A retrospective study of 138 and 450 doxycycline and talc poudrage pleurodesis procedures, respectively, evaluated their overall successes and failures, according to primary tumor types. In addition, a logistic regression model addressed whether the pleurodesis outcome in different tumor types was influenced by or attributable to pleural tumor burden. In the talc group, patients with lung cancer and mesothelioma had significantly lower complete response rates (63 and 61%, respectively) as compared with breast (77%) and other metastatic effusions (74%, p = 0.012). In the doxycycline group, the data followed the same trend in that complete response rates were lower in patients with lung carcinomas (31%) than in those with breast cancer (54%) or metastases from other primary sites (74%, p = 0.001). The regression analysis showed pleural burden and tumor type as independent predictors of pleurodesis failure in the talc group. The tumor type involving the pleural surfaces influences the success of a pleurodesis, regardless of the sclerosing agent used. Malignant effusions due to mesothelioma and lung cancer are particularly prone to a failed procedure. PMID:21331598

  17. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of cellular diversity for genetic and phenotypic features

    PubMed Central

    Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G.; Helland, Åslaug; Rye, Inga H.; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    SUMMARY Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor subtype-specific and it did not change during treatment in tumors with partial or no response. However, lower pre-treatment genetic diversity was significantly associated with complete pathologic response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution. PMID:24462293

  18. Expression of cell cycle regulator cdk2ap1 suppresses tumor cell phenotype by non-cell autonomous mechanisms

    PubMed Central

    Zolochevska, Olga; Figueiredo, Marxa L.

    2009-01-01

    We evaluated the effect of expressing the cell cycle regulator cdk2ap1 in epithelial or stromal cell compartments to reduce SCC growth in vitro and in vivo. Cell autonomous and/or non-cell autonomous expression of cdk2ap1 reduced tumor growth and invasion and altered cell cycle, adhesion, invasion, angiogenesis, and apoptotic gene expression, as assessed by several in vitro phenotype assays, quantitative real time PCR, and in vivo molecular imaging using a novel three-way xenograft animal model. Our findings suggest that the interactions between cancer cells and fibroblasts that promote abnormal growth can be minimized by expressing cdk2ap1, supporting a novel concept by which tumor/growth suppressor genes can impact tumorigenesis phenotypes from non-cell autonomous interactions within the tumor microenvironment. PMID:19515604

  19. Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence.

    PubMed

    Pust, Alexandra; Kylies, Dominik; Hube-Magg, Claudia; Kluth, Martina; Minner, Sarah; Koop, Christina; Grob, Tobias; Graefen, Markus; Salomon, Georg; Tsourlakis, Maria Christina; Izbicki, Jakob; Wittmer, Corinna; Huland, Hartwig; Simon, Ronald; Wilczak, Waldemar; Sauter, Guido; Steurer, Stefan; Krech, Till; Schlomm, Thorsten; Melling, Nathaniel

    2016-02-01

    Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the

  20. Hybridization in sunfish influences the muscle metabolic phenotype.

    PubMed

    Davies, R; Mathers, K E; Hume, A D; Bremer, K; Wang, Y; Moyes, C D

    2012-01-01

    Hybridization has the potential to exert pleiotropic effects on metabolism. Effects on mitochondrial enzymes may arise through incompatibilities in nuclear- and mitochondrial-encoded subunits of the enzyme complexes of oxidative phosphorylation. We explored the metabolic phenotype of bluegill (Lepomis macrochirus), pumpkinseed (Lepomis gibbosus), and their unidirectional F(1) hybrids (male bluegill × female pumpkinseed). In hybrids, glycolytic enzyme activities were indistinguishable from (aldolase, pyruvate kinase) or intermediate to (lactate dehydrogenase, phosphoglucoisomerase) parentals, but complex IV activities aligned with pumpkinseed, both 30% lower than bluegill. In isolated mitochondria, the specific activities of complexes I, II, and V were indistinguishable between groups. However, both complex III and IV showed indications of depressed activities in hybrid mitochondria, though no effects on mitochondrial state 3 or state 4 respiration were apparent. The patterns in complex IV activities were due to differences in enzyme content rather than enzyme V(max); immunoblots comparing complex IV content with catalytic activity were indistinguishable between groups. The sequence differences in complex IV catalytic subunits (CO1, CO2, CO3) were minor in nature; however, the mtDNA-encoded subunit of complex III (cytochrome b) showed eight differences between bluegill and pumpkinseed, several of which could have structural consequences to the multimeric enzyme, contributing to the depressed complex III catalytic activity in hybrids. PMID:22705483

  1. Phenotypic and measurement influences on heritability estimates in childhood ADHD.

    PubMed

    Freitag, Christine M; Rohde, Luis A; Lempp, Thomas; Romanos, Marcel

    2010-03-01

    Twin studies described a strongly heritable component of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. However, findings varied considerably between studies. In addition, ADHD presents with a high rate of comorbid disorders and associated psychopathology. Therefore, this literature review reports findings from population-based twin studies regarding the influence of subtypes, assessment instruments, rater effects, sex differences, and comorbidity rates on ADHD heritability estimates. In addition, genetic effects on the persistence of ADHD are discussed. By reviewing relevant factors influencing heritability estimates more homogeneous subtypes relevant for molecular genetic studies can be elicited. A systematic search of population-based twin studies in ADHD was performed, using the databases PubMed and PsycInfo. Results of family studies were added in case insufficient or contradictory findings were obtained in twin studies. Heritability estimates were strongly influenced by rater effects and assessment instruments. Inattentive and hyperactive-impulsive symptoms were likely influenced by common as well as specific genetic risk factors. Besides persistent ADHD, ADHD accompanied by symptoms of conduct or antisocial personality disorder might be another strongly genetically determined subtype, however, family environmental risk factors have also been established for this pattern of comorbidity. PMID:20213230

  2. Environmental Influences on the Behavioral Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, Kate; Oliver, Chris

    2006-01-01

    Using observational methods, we examined the social influences on laughing and smiling behavior in children with Angelman syndrome by systematically manipulating aspects of social interaction. Seven boys and 4 girls who were between 4 and 11 years of age and who had a confirmed maternal deletion of chromosome 15q11-q13 completed the study. Each…

  3. Multi-modality imaging of tumor phenotype and response to therapy

    NASA Astrophysics Data System (ADS)

    Nyflot, Matthew J.

    2011-12-01

    Imaging and radiation oncology have historically been closely linked. However, the vast majority of techniques used in the clinic involve anatomical imaging. Biological imaging offers the potential for innovation in the areas of cancer diagnosis and staging, radiotherapy target definition, and treatment response assessment. Some relevant imaging techniques are FDG PET (for imaging cellular metabolism), FLT PET (proliferation), CuATSM PET (hypoxia), and contrast-enhanced CT (vasculature and perfusion). Here, a technique for quantitative spatial correlation of tumor phenotype is presented for FDG PET, FLT PET, and CuATSM PET images. Additionally, multimodality imaging of treatment response with FLT PET, CuATSM, and dynamic contrast-enhanced CT is presented, in a trial of patients receiving an antiangiogenic agent (Avastin) combined with cisplatin and radiotherapy. Results are also presented for translational applications in animal models, including quantitative assessment of proliferative response to cetuximab with FLT PET and quantification of vascular volume with a blood-pool contrast agent (Fenestra). These techniques have clear applications to radiobiological research and optimized treatment strategies, and may eventually be used for personalized therapy for patients.

  4. Phenotypic Diversity in Chondromyxoid Fibroma Reveals Differentiation Pattern of Tumor Mimicking Fetal Cartilage Canals Development

    PubMed Central

    Zustin, Jozef; Akpalo, Hana; Gambarotti, Marco; Priemel, Matthias; Rueger, Johannes M.; Luebke, Andreas M.; Reske, Dennis; Lange, Claudia; Pueschel, Klaus; Lohmann, Christoph; Rüther, Wolfgang; Amling, Michael; Alberghini, Marco

    2010-01-01

    Chondromyxoid fibroma represents a rare benign cartilaginous tumor of young patients occurring in a subcortical metaphyseal location. The histogenesis of chondromyxoid fibroma has not yet been postulated, even though the conventional histology and recent immunohistochemical studies on phenotype of the mesenchymal cells and extracellular matrix components suggested its origin in immature cartilage. Therefore, we wished to compare the morphological pattern of immature cartilage tissue with chondromyxoid fibroma to investigate a possible developmental counterpart of chondromyxoid fibroma. Archival paraffin-embedded tissues from 4 fetal femora and 10 cases of chondromyxoid fibroma were analyzed simultaneously using histochemistry (safranin O) and established immunohistochemical antibodies (CD34, CD163, and smooth muscle actin). Vascularized cartilage canals growing into the fetal cartilage from the perichondrium displayed characteristic glomeruloid structures with central arterioles within the immature mesenchymal stroma and numerous superficial sinusoidal blood vessels accompanied by macrophage infiltration. Similarly, each case of chondromyxoid fibroma demonstrated admixture of two characteristic components: immature fibrous tissue of vascularized stroma with accumulation of macrophages in areas of superficial sinusoidal proliferation, and variable amounts of lobulated chondroid tissue. Based on the observed substantial morphological similarity between the cartilage canals and chondromyxoid fibroma, we suggest that the chondromyxoid fibroma represents a neoplasm originating from or mimicking the fetal cartilage canals within the immature cartilage. PMID:20671262

  5. Tumor and reproductive traits are linked by RNA metabolism genes in the mouse ovary: a transcriptome-phenotype association analysis

    PubMed Central

    2010-01-01

    Background The link between reproductive life history and incidence of ovarian tumors is well known. Periods of reduced ovulations may confer protection against ovarian cancer. Using phenotypic data available for mouse, a possible association between the ovarian transcriptome, reproductive records and spontaneous ovarian tumor rates was investigated in four mouse inbred strains. NIA15k-DNA microarrays were employed to obtain expression profiles of BalbC, C57BL6, FVB and SWR adult ovaries. Results Linear regression analysis with multiple-test control (adjusted p ≤ 0.05) resulted in ovarian tumor frequency (OTF) and number of litters (NL) as the top-correlated among five tested phenotypes. Moreover, nearly one-hundred genes were coincident between these two traits and were decomposed in 76 OTF(–) NL(+) and 20 OTF(+) NL(–) genes, where the plus/minus signs indicate the direction of correlation. Enriched functional categories were RNA-binding/mRNA-processing and protein folding in the OTF(–) NL(+) and the OTF(+) NL(–) subsets, respectively. In contrast, no associations were detected between OTF and litter size (LS), the latter a measure of ovulation events in a single estrous cycle. Conclusion Literature text-mining pointed to post-transcriptional control of ovarian processes including oocyte maturation, folliculogenesis and angiogenesis as possible causal relationships of observed tumor and reproductive phenotypes. We speculate that repetitive cycling instead of repetitive ovulations represent the actual link between ovarian tumorigenesis and reproductive records. PMID:21210965

  6. The Influence of Liver Resection on Intrahepatic Tumor Growth.

    PubMed

    Brandt, Hannes H; Nißler, Valérie; Croner, Roland S

    2016-01-01

    The high incidence of tumor recurrence after resection of metastatic liver lesions remains an unsolved problem. Small tumor cell deposits, which are not detectable by routine clinical imaging, may be stimulated by hepatic regeneration factors after liver resection. It is not entirely clear, however, which factors are crucial for tumor recurrence. The presented mouse model may be useful to explore the mechanisms that play a role in the development of recurrent malignant lesions after liver resection. The model combines the easy-to-perform and reproducible techniques of defined amounts of liver tissue removal and tumor induction (by injection) in mice. The animals were treated with either a single laparotomy, a 30% liver resection, or a 70% liver resection. All animals subsequently received a tumor cell injection into the remaining liver tissue. After two weeks of observation, the livers and tumors were evaluated for size and weight and examined by immunohistochemistry. After a 70% liver resection, the tumor volume and weight were significantly increased compared to a laparotomy alone (p <0.05). In addition, immunohistochemistry (Ki67) showed an increased tumor proliferation rate in the resection group (p <0.05). These findings demonstrate the influence of hepatic regeneration mechanisms on intrahepatic tumor growth. Combined with methods like histological workup or RNA analysis, the described mouse model could serve as foundation for a close examination of different factors involved in tumor growth and metastatic disease recurrence within the liver. A considerable number of variables like the length of postoperative observation, the cell line used for injection or the timing of injection and liver resection offer multiple angles when exploring a specific question in the context of post-hepatectomy metastases. The limitations of this procedure are the authorization to perform the procedure on animals, access to an appropriate animal testing facility and acquisition

  7. Macrophage reprogramming: influence of latex beads with various functional groups on macrophage phenotype and phagocytic uptake in vitro.

    PubMed

    Akilbekova, Dana; Philiph, Rachel; Graham, Austin; Bratlie, Kaitlin M

    2015-01-01

    Macrophages play a crucial role in initiating immune responses with various functions ranging from wound healing to antimicrobial actions. The type of biomaterial is suggested to influence macrophage phenotype. Here, we show that exposing M1- and M2-activated macrophages to polystyrene latex beads bearing different functional groups can alter secretion profiles, providing a possible method for altering the course of the host response. Macrophages were stimulated with either lipopolysaccharide or interleukin (IL) 4 and cultured for 24 h with 10 different latex beads. Proinflammatory cytokines (tumor necrosis factor α, monocyte chemotactic protein 1) and nitrite served as markers for the M1 phenotype and proangiogenic cytokine (IL-10) and arginase activity for M2 cells. The ability of the macrophages to phagocytize Escherichia coli particles and water contact angles of the polymers were also assessed. Different patterns of cytokine expression and phagocytosis activity were induced by the various particles. Particles did not polarize the cells toward one specific phenotype versus another, but rather induced changes in both pro- and anti-inflammatory markers. Our results suggest a dependence of pro- and anti-inflammatory cytokines and phagocytic activities on material type and cytokine stimuli. These data also illustrate how biomaterials can be exploited to alter host responses for drug delivery and tissue engineering applications. PMID:24639060

  8. What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration.

    PubMed

    Ketelaar, M E; Hofstra, E M W; Hayden, M R

    2012-04-01

    As monozygotic (MZ) twins are believed to be genetically identical, discordance for disease phenotype between MZ twins has been used in genetic research to understand the contribution of genetic vs environmental factors in disease development. However, recent studies show that MZ twins can differ both genetically and epigenetically. Screening MZ twins for genetic and/or epigenetic differences could be a useful and novel approach to identify modifying factors influencing phenotypic expression of disease. MZ twins that are phenotypically discordant for monogenic diseases are of special interest. Such occurrences have been described for Huntington's disease, spinocerebellar ataxias, as well as for familial forms of Alzheimer's disease. By comparing MZ twins that are phenotypically discordant, crucial factors influencing the phenotypic expression of the disease could be identified, which may be of relevance for understanding disease pathogenesis and variability in disease phenotype. Overall, understanding the crucial factors in development of a neurodegenerative disorder will have relevance for predictive testing, preventive treatment and could help to identify novel therapeutic targets. PMID:21981075

  9. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

    PubMed Central

    Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie W.; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.; Jung, Keehoon; Snuderl, Matija; Muzikansky, Alona; Stubenrauch, Kay G.; Krieter, Oliver; Wakimoto, Hiroaki; Xu, Lei; Munn, Lance L.; Duda, Dan G.; Fukumura, Dai; Batchelor, Tracy T.; Jain, Rakesh K.

    2016-01-01

    Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth. PMID:27044098

  10. Influence of age, irradiation and humanization on NSG mouse phenotypes

    PubMed Central

    Knibbe-Hollinger, Jaclyn S.; Fields, Natasha R.; Chaudoin, Tammy R; Epstein, Adrian A.; Makarov, Edward; Akhter, Sidra P.; Gorantla, Santhi; Bonasera, Stephen J.; Gendelman, Howard E.; Poluektova, Larisa Y.

    2015-01-01

    ABSTRACT Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization. PMID:26353862

  11. Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.

    PubMed

    Yang, Ju Dong; Sun, Zhifu; Hu, Chunling; Lai, Jinping; Dove, Rebecca; Nakamura, Ikuo; Lee, Ju-Seog; Thorgeirsson, Snorri S; Kang, Koo Jeong; Chu, In-Sun; Roberts, Lewis R

    2011-02-01

    The heparin-degrading endosulfatases sulfatase 1 (SULF1) and sulfatase 2 (SULF2) have opposing effects in hepatocarcinogenesis despite structural similarity. Using mRNA expression arrays, we analyzed the correlations of SULF expression with signaling networks in human hepatocellular carcinomas (HCCs) and the associations of SULF expression with tumor phenotype and patient survival. Data from two mRNA microarray analyses of 139 and 36 HCCs and adjacent tissues were used as training and validation sets. Partek and Metacore software were used to identify SULF correlated genes and their associated signaling pathways. Associations between SULF expression, the hepatoblast subtype of HCC, and survival were examined. Both SULF1 and 2 had strong positive correlations with periostin, IQGAP1, TGFB1, and vimentin and inverse correlations with HNF4A and IQGAP2. Genes correlated with both SULFs were highly associated with the cell adhesion, cytoskeletal remodeling, blood coagulation, TGFB, and Wnt/β-catenin and epithelial mesenchymal transition signaling pathways. Genes uniquely correlated with SULF2 were more associated with neoplastic processes than genes uniquely correlated with SULF1. High SULF expression was associated with the hepatoblast subtype of HCC. There was a bimodal effect of SULF1 expression on prognosis, with patients in the lowest or highest tertile having a worse prognosis than those in the middle tertile. SULFs have complex effects on HCC signaling and patient survival. There are functionally similar associations with cell adhesion, ECM remodeling, TGFB, and WNT pathways, but also unique associations of SULF1 and SULF2. The roles and targeting of the SULFs in cancer require further investigation. PMID:21104785

  12. SPONTANEOUS OCCURRENCE OF A DISTINCTIVE RENAL TUBULE TUMOR PHENOTYPE IN RAT CARCINOGENICITY STUDIES CONDUCTED BY THE NATIONAL TOXICOLOGY PROGRAM (NTP)

    PubMed Central

    Hard, Gordon C; Seely, John Curtis; Kissling, Grace E; Betz, Laura J

    2010-01-01

    The Toxicology Data Management System (TDMS) of the National Toxicology Program, NIEHS, NIH, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound. PMID:18441261

  13. Novel Phenotypic Fluorescent Three-Dimensional Co-Culture Platforms for Recapitulating Tumor in vivo Progression and for Personalized Therapy

    PubMed Central

    Fang, Changge; Man, Yan-Gao; Cuttitta, Frank; Stetler-Stevenson, William; Salomon, David; Mazar, Andrew; Kulesza, Piotr; Rosen, Steve; Avital, Itzhak; Stojadinovic, Alexander; Jewett, Anahid; Jiang, Bin; Mulshine, James

    2013-01-01

    Because three-dimensional (3D) in vitro models are more accurate than 2D cell culture models and faster and cheaper than animal models, they have become a prospective trend in the biomedical and pharmaceutical fields, especially for personalized and targeted therapies. Because appropriate 3D models can be customized to mimic the in vivo microenvironment wherein various cell populations grow within an intricate but well organized extracellular matrix (ECM), they can accurately recapitulate physiological and pathophysiological progressions. The majority of cancers are carcinomas, which originate from epithelial cells, and dynamically interact with non-malignant cells including stromal cells (fibroblasts), vascular cells (endothelial cells and pericytes), immune cells (macrophages and mast cells), and the ECM. Employing a tumor monoclonal colony, tumor xenograft or patient cancer biopsy into an in vivo-like microenvironment, the native signaling pathways, cell-cell and cell-matrix interactions, and cell phenotypes are preserved and our fluorescent phenotypic 3D co-culture platforms can then accurately recapitulate the tumor in vivo scenario including tumor induced angiogenesis, tumor growth, and metastasis. In this paper, we describe a robust and standardized method to co-culture a tumor colony or biopsy with different cell populations, e.g., endothelial cells, immune cells, pericytes, etc. The procedures for recovering cells from the co-culture for molecular analyses, imaging, and analyzing are also described. We selected ECM solubilized extract derived from Engelbreth-Holm-Swam sarcoma cells. Because the 3D co-culture platforms can provide drug chemosensitivity data within 9 days that is equivalent to the results generated from mouse tumor xenograft models in 50 days, the 3D co-culture platforms are more accurate, efficient, and cost-effective and may replace animal models in the near future to predict drug efficacy, personalize therapies, prevent drug resistance

  14. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells

    PubMed Central

    MONZAVI-KARBASSI, BEHJATOLAH; HINE, R. JEAN; STANLEY, JOSEPH S.; RAMANI, VISHNU PRAKASH; CARCEL-TRULLOLS, JAIME; WHITEHEAD, TRACY L.; KELLY, THOMAS; SIEGEL, ERIC R.; ARTAUD, CECILE; SHAAF, SAEID; SAHA, RINKU; JOUSHEGHANY, FARIBA; HENRY-TILLMAN, RONDA; KIEBER-EMMONS, THOMAS

    2012-01-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching β-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional micro-environment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  15. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells.

    PubMed

    Monzavi-Karbassi, Behjatolah; Hine, R Jean; Stanley, Joseph S; Ramani, Vishnu Prakash; Carcel-Trullols, Jaime; Whitehead, Tracy L; Kelly, Thomas; Siegel, Eric R; Artaud, Cecile; Shaaf, Saeid; Saha, Rinku; Jousheghany, Fariba; Henry-Tillman, Ronda; Kieber-Emmons, Thomas

    2010-09-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching beta-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional microenvironment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  16. Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype

    PubMed Central

    Maletzki, Claudia; Huehns, Maja; Knapp, Patrick; Waukosin, Nancy; Klar, Ernst; Prall, Friedrich; Linnebacher, Michael

    2015-01-01

    Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53mut, KRASmut; 3/8 marker methylated; HROC43: APCmut, TP53mut, KRASmut; 4/8 marker methylated; HROC60: APCwt, TP53mut, KRASwt; 4/8 marker methylated; HROC183: APCmut, TP53mut, KRASmut; 6/8 marker methylated). Cell lines were of epithelial origin (EpCAM+) with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan). Of note, most cell lines were sensitive towards “non-classical” CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib). This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo-) therapeutics helps bringing forward the concept of personalized tumor therapy. PMID:26618628

  17. Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.

    PubMed

    Sato, Shingo; Tang, Yuning J; Wei, Qingxia; Hirata, Makoto; Weng, Angela; Han, Ilkyu; Okawa, Atsushi; Takeda, Shu; Whetstone, Heather; Nadesan, Puvindran; Kirsch, David G; Wunder, Jay S; Alman, Benjamin A

    2016-07-26

    The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype. PMID:27425618

  18. Macrophages of M1 phenotype have properties that influence lung cancer cell progression.

    PubMed

    Hedbrant, Alexander; Wijkander, Jonny; Seidal, Tomas; Delbro, Dick; Erlandsson, Ann

    2015-11-01

    Stromal macrophages of different phenotypes can contribute to the expression of proteins that affects metastasis such as urokinase-type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), but knowledge of how essential their contribution is in comparison to the cancer cells in small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) is lacking. The expression of uPA, uPAR, and PAI-1 and of the matrix metalloproteinases (MMP)-2 and MMP-9 were studied in human macrophages of M1 and M2 phenotype and compared to a lung SCC (NCI-H520) and a SCLC (NCI-H69) cell line. Effects of treatment with conditioned media (CM) from M1 and M2 macrophages on the expression of these genes in H520 and H69 cells as well as effects on the cell growth were investigated. In addition, data on the stromal macrophages immunoreactivity of uPAR, MMP-2, and MMP-9 in a few SCC and SCLC biopsies was included. uPAR, MMP-2, and MMP-9 were confirmed in stromal cells including macrophages in the SCC and SCLC biopsies. In vitro, both macrophage phenotypes expressed considerably higher mRNA levels of uPA, uPAR, PAI-1, and MMP-9 compared to the cancer cell lines, and regarding uPAR, the highest level was found in the M1 macrophage phenotype. Furthermore, M1 CM treatment not only induced an upregulation of PAI-1 in both H520 and H69 cells but also inhibited cell growth in both cell lines, giving M1 macrophages both tumor-promoting and tumor-killing potential. PMID:26050228

  19. Trisomic and allelic differences influence phenotypic variability during development of Down syndrome mice.

    PubMed

    Deitz, Samantha L; Roper, Randall J

    2011-12-01

    Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the "Down syndrome critical region" or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS. PMID:21926299

  20. Phenotypic and genotypic convergences are influenced by historical contingency and environment in yeast

    PubMed Central

    NIDELET, Thibault; MARTIN, Juliette; LEGRAND, Judith; DILLMANN, Christine; BOURGAIS, Aurélie; de VIENNE, Dominique; SHERLOCK, Gavin; SICARD, Delphine

    2015-01-01

    Different organisms have independently and recurrently evolved similar phenotypic traits at different points throughout history. This phenotypic convergence may be caused by genotypic convergence and constrained by historical contingency. To investigate how convergence may be driven by selection in a particular environment and constrained by history, we analyzed nine life-history traits and four metabolic traits during an experimental evolution of six yeast strains in four different environments. In each of the environments, the population converged towards a different life-history strategy. However, phenotypic convergence was partly associated with the selection of mutations in genes involved in the same pathway. In a fifth of our evolution experiments, mutations in the same gene, BMH1, were selected, in three out of the six ancestral genotypes. Two types of BMH1 mutation with opposite phenotypic effects on several traits were found. The evolution of most traits, as well as the occurrence of BMH1 mutations, was significantly influenced by the ancestral strain. However, this effect could not be easily predicted from ancestors’ phylogeny or past-selection. All together, our data demonstrate that phenotypic and its underlying genotypic convergence depends on a complex interplay between the evolutionary environment, pleiotropy and the ancestor genetic background but are not straightforwardly predicable. PMID:24164389

  1. Somatostatin Analogs and Tumor Localization Do Not Influence Vitamin D Concentration in Patients with Neuroendocrine Tumors.

    PubMed

    Motylewska, Ewelina; Gawronska, Joanna; Niedziela, Agata; Melen-Mucha, Gabriela; Lawnicka, Hanna; Komorowski, Jan; Swietoslawski, Jacek; Stepien, Henryk

    2016-04-01

    Patients with neuroendocrine tumors (NETs), malignancies of rare but still rising incidence, may be a group at higher risk of vitamin D insufficiency. The gastrointestinal tumor prevalence and somatostatin analog (SSA) therapy may cause vitamin D malabsorption. The aim of this study was to evaluate the serum level of vitamin D in NET patients. A total of 36 NET patients were enrolled into the experimental group and 16 individuals were enrolled into the control group. All patients were further classified into subgroups according to primary tumor localization (gastropancreatic, lung, and other NETs) or therapy (with or without SSA treatment). The concentrations of total 25(OH)D were assayed with Electrochemiluminescence immunoassay (ECLIA). Serum concentration of 25(OH)D in NET patients did not differ significantly from that of the control group. However, the average level of 25(OH)D in both groups met the criteria of vitamin D deficiency. Importantly, SSA therapy did not aggravate vitamin D deficiency. Moreover, the concentration of 25(OH)D in the studied group was not significantly influenced by primary tumor localization, patient age, or season. Vitamin D deficiency is a widespread disorder affecting both NET patients and individuals without other health problems, and SSA and gastrointestinal tumor localization do not exacerbate this condition. PMID:27028957

  2. Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype.

    PubMed

    Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Wang, Yang; Qin, Zhihai; Fu, Yang-Xin; Wang, Shengdian

    2015-05-15

    Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance. PMID:25876763

  3. ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: Study in African-American and Caucasian prostate cancer models

    PubMed Central

    Parray, Aijaz; Siddique, Hifzur R.; Kuriger, Jacquelyn K.; Mishra, Shrawan K.; Rhim, Johng S.; Nelson, Heather H.; Aburatani, Hiroyuki; Konety, Badrinath R.; Koochekpour, Shahriar; Saleem, Mohammad

    2015-01-01

    High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/β-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans. PMID:24752651

  4. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells

    PubMed Central

    Wang, Daisy Dandan; Li, Linda; Lin, Peter Ping

    2015-01-01

    Conventional strategy of anti-EpCAM capture and immunostaining of cytokeratins (CKs) to detect circulating tumor cells (CTCs) is limited by highly heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. In this study, a novel integrated cellular and molecular approach of subtraction enrichment (SE) and immunostaining-FISH (iFISH) was successfully developed. Both large or small size CTCs and circulating tumor microemboli (CTM) in various biofluid samples including cerebrospinal fluid (CSF) of cancer patients and patient-derived-xenograft (PDX) mouse models were efficiently enriched and comprehensively identified and characterized by SE-iFISH. Non-hematopoietic CTCs with heteroploid chromosome 8 were detected in 87–92% of lung, esophageal and gastric cancer patients. Characterization of CTCs performed by CK18-iFISH showed that CK18, the dual epithelial marker and tumor biomarker, was strong positive in only 14% of lung and 24% of esophageal CTCs, respectively. Unlike conventional methodologies restricted only to the large and/or both EpCAM and CK positive CTCs, SE-iFISH enables efficient enrichment and performing in situ phenotypic and karyotypic identification and characterization of the highly heterogeneous CTC subtypes classified by both chromosome ploidy and the expression of various tumor biomarkers. Each CTC subtype may possess distinct clinical significance relative to tumor metastasis, relapse, therapeutic drug sensitivity or resistance, etc. PMID:26267323

  5. Multi-Color Spectral Transcript Analysis (SPECTRA) for Phenotypic Characterization of Tumor Cells

    PubMed Central

    Hsu, Joanne H.; Weier, Jingly F.; Weier, Heinz-Ulrich G.; Ito, Yuko

    2013-01-01

    Many human tumors show significant changes in their signal transduction pathways and, thus, the way the cells interact with their environment. Often caused by chromosomal rearrangements, including gene amplifications, translocations or deletions, the altered levels of gene expression may provide a tumor-specific signature that can be exploited for diagnostic or therapeutic purposes. We investigated the utility of multiplexed fluorescence in situ hybridization (FISH) using non-isotopically labeled cDNA probes detected by Spectral Imaging as a sensitive and rapid procedure to measure tumor-specific gene expression signatures. We used a commercially available system to acquire and analyze multicolor FISH images. Initial investigations used panels of fluorescent calibration standards to evaluate the system. These experiments were followed by hybridization of five-to-six differently labeled cDNA probes, which target the transcripts of tyrosine kinase genes known to be differently expressed in normal cells and tumors of the breast or thyroid gland. The relatively simple, yet efficient, molecular cytogenetic method presented here may find many applications in characterization of solid tumors or disseminated tumor cells. Addressing tumor heterogeneity by means of multi-parameter single cell analyses is expected to enable a wide range of investigations in the areas of tumor stem cells, tumor clonality and disease progression. PMID:24970164

  6. Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors.

    PubMed

    Radkay-Gonzalez, Lisa; Faquin, William; McHugh, Jonathan B; Lewis, James S; Tuluc, Madalina; Seethala, Raja R

    2016-06-01

    This study describes a unique subset of ciliated, human papillomavirus (HPV) related, adenosquamous carcinomas (AsqCA) of the head and neck that in contrast to most AsqCA, often show areas with lower grade cytonuclear features. They are comprised of largely non-keratinizing squamous cell carcinoma components with cystic change, gland formation, mucin production, and cilia in tumor cells. Seven cases of ciliated AsqCA were retrieved. Site distribution was as follows: palatine tonsil-3/7, base of tongue-1/7, and neck (unknown primary site)-3/7. Despite the occasional resemblance to mucoepidermoid carcinoma (MEC), the tumors showed focal keratinizing morphology and atypia, and all tumors were negative for MAML2 rearrangements. Oropharyngeal and neck tumors were uniformly p16 positive and showed punctate staining by in situ hybridization for high risk HPV DNA. There were two distant metastases (lung), and one tumor related death. Thus, ciliated AsqCA are HPV-associated lesions that pose unique pitfalls, closely mimicking MEC and other salivary gland tumors. These tumors add to the list of those which defy the dogma that ciliated epithelium always equates to a benign process. PMID:26411881

  7. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    SciTech Connect

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S. . E-mail: jrhim@cpdr.org

    2006-04-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

  8. Activation of endogenous human stem cell-associated retroviruses (SCARs) and therapy-resistant phenotypes of malignant tumors.

    PubMed

    Glinsky, Gennadi V

    2016-07-01

    Recent reports revealed consistent activation of specific endogenous retroviral elements in human preimplantation embryos and embryonic stem cells. Activity of stem cell associated retroviruses (SCARs) has been implicated in seeding thousands of human-specific regulatory sequences in the hESC genome. Activation of specific SCARs has been demonstrated in patients diagnosed with multiple types of cancer, autoimmune diseases, and neurodegenerative disorders, and appears associated with clinically lethal therapy resistant death-from-cancer phenotypes in a sub-set of cancer patients diagnosed with different types of malignant tumors. A hallmark feature of human-specific SCAR integration sites is deletions of ancestral DNA. Analysis of human-specific genetic loci of SCARs' stemness networks in tumor samples of TCGA cohorts representing 29 cancer types suggests that this approach may facilitate identification of pan-cancer genomic signatures of clinically-lethal disease defined by the presence of somatic non-silent mutations, gene-level copy number changes, and transcripts and proteins' expression of SCAR-regulated host genes. Present analyses indicate that multiple lines of strong circumstantial evidence support the hypothesis that activation of SCARs' networks may play an important role in cancer progression and metastasis, perhaps contributing to the emergence of clinically-lethal therapy-resistant death-from-cancer phenotypes. PMID:27084523

  9. Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice.

    PubMed

    Oh, Young Sun; Kim, Dae Gyu; Kim, Gyuyoup; Choi, Eung-Chil; Kennedy, Brian K; Suh, Yousin; Park, Bum Joon; Kim, Sunghoon

    2010-10-01

    Although AIMP3/p18 is normally associated with the macromolecular tRNA synthetase complex, recent reports have revealed a new role of AIMP3 in tumor suppression. In this study, we generated a transgenic mouse that overexpresses AIMP3 and characterized the associated phenotype in vivo and in vitro. Surprisingly, the AIMP3 transgenic mouse exhibited a progeroid phenotype, and the cells that overexpressed AIMP3 showed accelerated senescence and defects in nuclear morphology. We found that overexpression of AIMP3 resulted in proteasome-dependent degradation of mature lamin A, but not of lamin C, prelamin A, or progerin. The resulting imbalance in the protein levels of lamin A isoforms, namely altered stoichiometry of prelamin A and progerin to lamin A, appeared to be responsible for a phenotype that resembled progeria. An increase in the level of endogenous AIMP3 has been observed in aged human tissues and cells. The findings in this report suggest that AIMP3 is a specific regulator of mature lamin A and imply that enhanced expression of AIMP3 might be a factor driving cellular and/or organismal aging. PMID:20726853

  10. The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Corrêa, Stephany; Binato, Renata; Lemos, Gabriela Ferreira; Herrera, Ana Cristina da Silva do Amaral; Seixas, Teresa Fernandes; Cecchini, Rubens; Abdelhay, Eliana

    2015-02-01

    Overexpression of human epithelial growth factor receptor 2 (HER2) is a poor prognostic factor in breast cancer. HER2 is a transmembrane receptor comprising an extracellular domain (ECD), a single transmembrane domain, and an intracellular domain (ICD) with tyrosine-kinase activity. Receptor dimerization triggers pivotal effector pathways in cancer, such as phosphatidylinositol 3-kinase (PI3K) signaling. Currently, screening of HER2 in breast tumors for prognostic and therapeutic purposes involves immunohistochemical (IHC) phenotyping for the ECD, in which tumors with IHC scores below 2+ are reported as HER2-negative. We used a label-free liquid chromatography-mass spectrometry (LC-MS) proteomic approach to compare plasma samples from patients with HER2-positive breast tumors and patients with HER2-negative tumors. Patients with HER2-negative tumors expressed higher circulating levels of calpain-10 than patients with HER2-positive tumors. Calpains cleave HER2, releasing its ECD and transforming phenotypically positive tumors into phenotypically negative tumors. Therefore, we investigated the expression of the ICD in HER2-negative samples that overexpressed calpain-10. We found that 16% of HER2-negative tumors were positive for HER2-ICD, which was associated with circulating HER2-ECD. HER2 gene amplification was also observed in some HER2-negative tumors. Positive staining for the PI3K pathway was observed in the HER2-negative, ICD-positive tumors, similar to the HER2-positive cohort. Microarray analysis revealed that HER2-negative, ICD-positive samples clustered between HER2-positive tumors and triple-negative tumors. Survival analysis revealed that outcome in women with HER2-negative, ICD-positive tumors was better than in women bearing HER2-negative, ICD-negative (triple negative) tumors but was quite similar to HER2-positive tumors and worse than women with luminal A tumors. Moreover, in vitro analyses revealed that MDA-MB 231, a triple negative cell line

  11. Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model

    PubMed Central

    Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

    2016-01-01

    The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs. PMID:27329570

  12. Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model.

    PubMed

    Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

    2016-01-01

    The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs. PMID:27329570

  13. Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

    PubMed Central

    Villares, Gabriel J.; Zigler, Maya; Dobroff, Andrey S.; Wang, Hua; Song, Renduo; Melnikova, Vladislava O.; Huang, Li; Braeuer, Russell R.; Bar-Eli, Menashe

    2011-01-01

    The thrombin receptor protease activated receptor-1 (PAR-1) is overexpressed in metastatic melanoma cell lines and tumor specimens. Previously, we demonstrated a significant reduction in tumor growth and experimental lung metastasis after PAR-1 silencing via systemic delivery of siRNA encapsulated into nanoliposomes. Gene expression profiling identified a 40-fold increase in expression of Maspin in PAR-1–silenced metastatic melanoma cell lines. Maspin promoter activity was significantly increased after PAR-1 silencing, suggesting that PAR1 negatively regulates Maspin at the transcriptional level. ChIP analyses revealed that PAR-1 decreases binding of Ets-1 and c-Jun transcription factors to the Maspin promoter, both known to activate Maspin transcription. PAR-1 silencing did not affect Ets-1 or c-Jun expression; rather it resulted in increased expression of the chromatin remodeling complex CBP/p300, as well as decreased activity of the CBP/p300 inhibitor p38, resulting in increased binding of Ets-1 and c-Jun to the Maspin promoter and higher Maspin expression. Functionally, Maspin expression reduced the invasive capability of melanoma cells after PAR-1 silencing, which was abrogated after rescuing with PAR-1. Furthermore, tumor growth and experimental lung metastasis was significantly decreased after expressing Maspin in a metastatic melanoma cell line. Moreover, silencing Maspin in PAR-1–silenced cells reverted the inhibition of tumor growth and experimental lung metastasis. Herein, we demonstrate a mechanism by which PAR-1 negatively regulates the expression of the Maspin tumor-suppressor gene in the acquisition of the metastatic melanoma phenotype, thus attributing an alternative function to PAR-1 other than coagulation. PMID:21187389

  14. Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype.

    PubMed

    Villares, Gabriel J; Zigler, Maya; Dobroff, Andrey S; Wang, Hua; Song, Renduo; Melnikova, Vladislava O; Huang, Li; Braeuer, Russell R; Bar-Eli, Menashe

    2011-01-11

    The thrombin receptor protease activated receptor-1 (PAR-1) is overexpressed in metastatic melanoma cell lines and tumor specimens. Previously, we demonstrated a significant reduction in tumor growth and experimental lung metastasis after PAR-1 silencing via systemic delivery of siRNA encapsulated into nanoliposomes. Gene expression profiling identified a 40-fold increase in expression of Maspin in PAR-1-silenced metastatic melanoma cell lines. Maspin promoter activity was significantly increased after PAR-1 silencing, suggesting that PAR1 negatively regulates Maspin at the transcriptional level. ChIP analyses revealed that PAR-1 decreases binding of Ets-1 and c-Jun transcription factors to the Maspin promoter, both known to activate Maspin transcription. PAR-1 silencing did not affect Ets-1 or c-Jun expression; rather it resulted in increased expression of the chromatin remodeling complex CBP/p300, as well as decreased activity of the CBP/p300 inhibitor p38, resulting in increased binding of Ets-1 and c-Jun to the Maspin promoter and higher Maspin expression. Functionally, Maspin expression reduced the invasive capability of melanoma cells after PAR-1 silencing, which was abrogated after rescuing with PAR-1. Furthermore, tumor growth and experimental lung metastasis was significantly decreased after expressing Maspin in a metastatic melanoma cell line. Moreover, silencing Maspin in PAR-1-silenced cells reverted the inhibition of tumor growth and experimental lung metastasis. Herein, we demonstrate a mechanism by which PAR-1 negatively regulates the expression of the Maspin tumor-suppressor gene in the acquisition of the metastatic melanoma phenotype, thus attributing an alternative function to PAR-1 other than coagulation. PMID:21187389

  15. VEGFA, FLT1, KDR and colorectal cancer: assessment of disease risk, tumor molecular phenotype, and survival.

    PubMed

    Slattery, Martha L; Lundgreen, Abbie; Wolff, Roger K

    2014-02-01

    Angiogenesis is essential for tumor progression. Vascular endothelial growth factor (VEGFA) and its receptors 1 (FLT1) and 2 (KDR), have been identified as major mediators of this process. We hypothesized that genetic variation in FLT1 (38 SNPs), KDR (22 SNPS), and VEGFA (11 SNPs) would be associated with colon and rectal cancer development and survival. Data from a case-control study of 1555 colon cancer cases and 1956 controls and 754 rectal cancer cases and 959 controls were used. An adaptive rank truncation product (ARTP), based on 10,000 permutations, was used to determine the statistical significance of the candidate genes and angiogenesis pathway. Based on ARTP results, FLT1 was significantly associated with risk of colon cancer (P(ARTP) = 0.045) and VEGFA was significantly associated with rectal cancer (P(ARTP) = 0.036). After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFA rs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors. FLT1 rs2296189 and rs600640 were associated with CIMP+ rectal tumors and FLT1 rs7983774 was associated with TP53-mutated rectal tumors. Four SNPs in FLT1 were associated with colon cancer survival while three SNPs in KDR were associated with survival after diagnosis with rectal cancer. Aspirin/NSAID use, smoking cigarettes, and BMI modified the associations. These findings suggest the importance of inflammation and angiogenesis in the etiology of colorectal cancer and that genetic and lifestyle factors may be targets for modulating disease risk. PMID:23794399

  16. LCN2 Promoter Methylation Status as Novel Predictive Marker for Microvessel Density and Aggressive Tumor Phenotype in Breast Cancer Patients.

    PubMed

    Meka, Phanni bhushann; Jarjapu, Sarika; Nanchari, Santhoshi Rani; Vishwakarma, Sandeep Kumar; Edathara, Prajitha Mohandas; Gorre, Manjula; Cingeetham, Anuradha; Vuree, Sugunakar; Annamaneni, Sandhya; Dunna, Nageswara Rao; Mukta, Srinivasulu; B, Triveni; Satti, Vishnupriya

    2015-01-01

    LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients. PMID:26163623

  17. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

    SciTech Connect

    Coppé, Jean-Philippe; Patil, Christopher; Rodier, Francis; Sun, Yu; Munoz, Denise; Goldstein, Joshua; Nelson, Peter; Desprez, Pierre-Yves; Campisi, Judith

    2008-10-24

    Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

  18. RNAi phenotypes are influenced by the genetic background of the injected strain

    PubMed Central

    2013-01-01

    Background RNA interference (RNAi) is a powerful tool to study gene function in organisms that are not amenable to classical forward genetics. Hence, together with the ease of comprehensively identifying genes by new generation sequencing, RNAi is expanding the scope of animal species and questions that can be addressed in terms of gene function. In the case of genetic mutants, the genetic background of the strains used is known to influence the phenotype while this has not been described for RNAi experiments. Results Here we show in the red flour beetle Tribolium castaneum that RNAi against Tc-importin α1 leads to different phenotypes depending on the injected strain. We rule out off target effects and show that sequence divergence does not account for this difference. By quantitatively comparing phenotypes elicited by RNAi knockdown of four different genes we show that there is no general difference in RNAi sensitivity between these strains. Finally, we show that in case of Tc-importin α1 the difference depends on the maternal genotype. Conclusions These results show that in RNAi experiments strain specific differences have to be considered and that a proper documentation of the injected strain is required. This is especially important for the increasing number of emerging model organisms that are being functionally investigated using RNAi. In addition, our work shows that RNAi is suitable to systematically identify the differences in the gene regulatory networks present in populations of the same species, which will allow novel insights into the evolution of animal diversity. PMID:23324472

  19. Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer

    PubMed Central

    Capela, Carlos; Dossou, Ange Dodji; Silva-Gomes, Rita; Sopoh, Ghislain Emmanuel; Makoutode, Michel; Menino, João Filipe; Fraga, Alexandra Gabriel; Cunha, Cristina; Carvalho, Agostinho; Rodrigues, Fernando; Pedrosa, Jorge

    2016-01-01

    Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes. PMID:27128681

  20. Neonatal environment exerts a sustained influence on the development of the intestinal microbiota and metabolic phenotype.

    PubMed

    Merrifield, Claire A; Lewis, Marie C; Berger, Bernard; Cloarec, Olivier; Heinzmann, Silke S; Charton, Florence; Krause, Lutz; Levin, Nadine S; Duncker, Swantje; Mercenier, Annick; Holmes, Elaine; Bailey, Mick; Nicholson, Jeremy K

    2016-01-01

    The postnatal environment, including factors such as weaning and acquisition of the gut microbiota, has been causally linked to the development of later immunological diseases such as allergy and autoimmunity, and has also been associated with a predisposition to metabolic disorders. We show that the very early-life environment influences the development of both the gut microbiota and host metabolic phenotype in a porcine model of human infants. Farm piglets were nursed by their mothers for 1 day, before removal to highly controlled, individual isolators where they received formula milk until weaning at 21 days. The experiment was repeated, to create two batches, which differed only in minor environmental fluctuations during the first day. At day 1 after birth, metabolic profiling of serum by (1)H nuclear magnetic resonance spectroscopy demonstrated significant, systemic, inter-batch variation which persisted until weaning. However, the urinary metabolic profiles demonstrated that significant inter-batch effects on 3-hydroxyisovalerate, trimethylamine-N-oxide and mannitol persisted beyond weaning to at least 35 days. Batch effects were linked to significant differences in the composition of colonic microbiota at 35 days, determined by 16 S pyrosequencing. Different weaning diets modulated both the microbiota and metabolic phenotype independently of the persistent batch effects. We demonstrate that the environment during the first day of life influences development of the microbiota and metabolic phenotype and thus should be taken into account when interrogating experimental outcomes. In addition, we suggest that intervention at this early time could provide 'metabolic rescue' for at-risk infants who have undergone aberrant patterns of initial intestinal colonisation. PMID:26066712

  1. Exploiting the Tumor Phenotype Using Biodegradable Submicron Carriers of Chemotherapeutic Drugs

    PubMed Central

    Geary, Sean M.; Salem, Aliasger K.

    2014-01-01

    Tumor tissues possess characteristics that distinguish them from healthy tissues and make them attractive targets for submicron carriers of chemotherapeutic drugs (CTX). CTX are generally administered systemically in free form to cancer patients resulting in unwanted cytotoxic effects and placing limitations on the deliverable CTX dose. In an effort to raise the therapeutic index of CTX there are now liposome-based CTX formulations in clinical use that are more tumor specific than the free form of CTX. However, progression to liposome-based chemotherapy in the clinic has been slow and there have been no approved formulations introduced in the last decade. Alternative carrier systems such as those made from the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA) have been investigated in preclinical settings with promising outcomes. Here we review the principle behind biodegradable submicron carriers as CTX delivery vehicles for solid tumors with a specific focUS on liposomes and PLGA-based carriers, highlighting the strengths and weaknesses of each system. PMID:25271435

  2. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed Central

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-01-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  3. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-08-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  4. Correlation of microscopic phenotype with genotype in a formalin-fixed, paraffin-embedded testicular germ cell tumor with universal DNA amplification, comparative genomic hybridization, and interphase cytogenetics.

    PubMed Central

    Speicher, M. R.; Jauch, A.; Walt, H.; du Manoir, S.; Ried, T.; Jochum, W.; Sulser, T.; Cremer, T.

    1995-01-01

    We present a strategy for the evaluation of numerical copy number changes of DNA segments within a solid tumor genome that allows the correlation of microscopic phenotype with genotype in formalin-fixed, paraffin-embedded tumor material. Cells from a human testicular germ cell tumor and adjacent tissue areas with normal seminiferous tubules were selected separately from microscopically analyzed histological tissue sections, and DNA was extracted from the selected areas. After universal DNA amplification, the amplification products were subjected to comparative genomic hybridization. The results confirmed balanced chromosome copy numbers for the normal tissue area, although the analysis of the tumor tissue area revealed numerous gains and losses of chromosome segments. The comparative genomic hybridization results were used to select DNA probes for interphase cytogenetics on serial sections. We conclude that this technique allows the screening of selected tissue areas for numerical DNA alterations, thus enabling a direct phenotype-genotype comparison. Images Figure 1 Figure 2 Figure 4 PMID:7778673

  5. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types. PMID:26568031

  6. Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers

    PubMed Central

    Gradiser, Marina; Matovinovic Osvatic, Martina; Dilber, Dario; Bilic-Curcic, Ines

    2016-01-01

    The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c–d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors. PMID:26999178

  7. Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers.

    PubMed

    Gradiser, Marina; Matovinovic Osvatic, Martina; Dilber, Dario; Bilic-Curcic, Ines

    2016-01-01

    The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c-d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors. PMID:26999178

  8. Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype.

    PubMed

    McConechy, Melissa K; Färkkilä, Anniina; Horlings, Hugo M; Talhouk, Aline; Unkila-Kallio, Leila; van Meurs, Hannah S; Yang, Winnie; Rozenberg, Nirit; Andersson, Noora; Zaby, Katharina; Bryk, Saara; Bützow, Ralf; Halfwerk, Johannes B G; Hooijer, Gerrit K J; van de Vijver, Marc J; Buist, Marrije R; Kenter, Gemma G; Brucker, Sara Y; Krämer, Bernhard; Staebler, Annette; Bleeker, Maaike C G; Heikinheimo, Markku; Kommoss, Stefan; Blake Gilks, C; Anttonen, Mikko; Huntsman, David G

    2016-11-01

    The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < .001). The misdiagnosed cases accounted for 71.9% of disease-specific deaths within five years. In the population-based cohort, overall survival of MD-AGCT patients was not different from age-matched, population-based controls. Even though 35.2% of all the MD-AGCT patients in our study experienced a relapse, AGCT is usually an indolent disease. The historical, premolecular data underpinning our clinical understanding of AGCT was likely skewed by inclusion of misdiagnosed cases, and future management strategies should reflect the potential for surgical cure and long survival even after relapse. PMID:27297428

  9. Mechanical phenotyping of tumor cells using a microfluidic cell squeezer device

    NASA Astrophysics Data System (ADS)

    Khan, Zeina S.; Kamyabi, Nabiollah; Vanapalli, Siva A.

    2013-03-01

    Studies have indicated that cancer cells have distinct mechanical properties compared to healthy cells. We are investigating the potential of cell mechanics as a biophysical marker for diagnostics and prognosis of cancer. To establish the significance of mechanical properties for cancer diagnostics, a high throughput method is desired. Although techniques such as atomic force microscopy are very precise, they are limited in throughput for cellular mechanical property measurements. To develop a device for high throughput mechanical characterization of tumor cells, we have fabricated a microfludic cell squeezer device that contains narrow micrometer-scale pores. Fluid flow is used to drive cells into these pores mimicking the flow-induced passage of circulating tumor cells through microvasculature. By integrating high speed imaging, the device allows for the simultaneous characterization of five different parameters including the blockage pressure, cell velocity, cell size, elongation and the entry time into squeezer. We have tested a variety of in vitro cell lines, including brain and prostate cancer cell lines, and have found that the entry time is the most sensitive measurement capable of differentiating between cell lines with differing invasiveness.

  10. Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma.

    PubMed

    Zeeberg, Katrine; Cardone, Rosa Angela; Greco, Maria Raffaella; Saccomano, Mara; Nøhr-Nielsen, Asbjørn; Alves, Frauke; Pedersen, Stine Falsig; Reshkin, Stephan Joel

    2016-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis, due to the influence of the tumor stroma, which promotes tumor growth, early invasion and chemoradiation resistance. Efforts to develop models for identifying novel anticancer therapeutic compounds have been hampered by the limited ability of in vitro models to mimic these in vivo tumor-stroma interactions. This has led to the development of various three-dimensional (3D) culture platforms recapitulating the in vivo tumor-stroma crosstalk and designed to better understand basic cancer processes and screen drug action. However, a consensus for different experimental 3D platforms is still missing in PDAC. We compared four PDAC cell lines of different malignancy grown in 2D monolayers to three of the more commonly used 3D techniques (ultralow adhesion concave microwells, Matrigel inclusion and organotypic systems) and to tumors derived from their orthotopic implantation in mice. In these 3D platforms, we observed that cells grow with very different tumor morphologies and the organotypic setting most closely resembles the tumor cytoarchitecture obtained by orthotopically implanting the four cell lines in mice. We then analyzed the molecular and cellular responses of one of these cell lines to epidermal growth factor receptor (EGFR) stimulation with EGF and inhibition with erlotinib and found that only in the 3D platforms, and especially the organotypic, cells: i) responded to EGF by changing the expression of signalling components underlying cell-stroma crosstalk and tissue architecture, growth, invasion and drug resistance (E-cadherin, EGFR, ezrin, β1 integrin, NHERF1 and HIF-1α) similar to those reported in vivo; ii) had stimulated growth and increased erlotinib sensitivity in response to EGF, more faithfully mimicking their known in vivo behaviour. Altogether, these results, indicate the organotypic as the most relevant physiological 3D system to study the

  11. Clarification of the phenotypic characteristics and anti-tumor activity of Hedyotis diffusa.

    PubMed

    Lee, Hong-Zin; Bau, Da-Tian; Kuo, Chao-Lin; Tsai, Ru-Yin; Chen, Yu-Chang; Chang, Yu-Hao

    2011-01-01

    Hedyotis diffusa Willd. (Rubiaceae) is an important folk herb used to prevent and cure hepatitis and liver cancer in Taiwan. For differentiation of H. diffusa from counterfeits, macroscopic and microscopic characters of H. diffusa, H. corymbosa and H. tenelliflora were examined in this study. According to Trypan blue exclusion assay and Western blot analysis, H. diffusa had a significant inhibition of cell growth and induction of cell apoptosis in COLO 205 (colon cancer), Hep 3B (hepatocellular carcinoma) and H460 (lung cancer) cell lines. This study also used high-performance liquid chromatography (HPLC) to determine the quality control of H. diffusa. The HPLC data showed that ursolic and oleanolic acid are the components of the H. diffusa, consisting of approximately 4.66-4.80% and 1.86-1.96%, respectively. Our study also demonstrated that ursolic acid has significant anti-tumor activity in COLO 205, Hep 3B and H460 cancer cells. PMID:21213409

  12. Phenotype of circulating tumor cell: face-off between epithelial and mesenchymal masks.

    PubMed

    Hong, Yupeng; Zhang, Qi

    2016-05-01

    Most patients with cancers died of distant metastasis. It is always difficult to find cancer metastasis in early time, let alone to prevent or cure it. Currently, oncologists place high hopes on circulating tumor cell (CTC), which, compared to current imaging methods, is found more sensitive for early metastasis. Recently, techniques for CTC enrichment and identification are developing quickly. However, there are great challenges in the clinical interpretation of CTC assessments. Increasing studies have shown the heterogeneity of CTCs, which may play different roles in cancer metastasis. Epithelial-mesenchymal transition is not only the main mechanism of the cancer cells invading the circulation system but also a distinguished characteristic of CTCs. Investigators are trying to differentiate specific subgroups of CTCs that are truly responsible for cancer metastasis. Here, we reviewed the current evidences on epithelial-mesenchymal transition of CTCs from perspectives of enrichment methods, biology, and its subgroups. PMID:26758432

  13. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype.

    PubMed

    Marsden, Carolyn G; Jensen, Ryan B; Zagelbaum, Jennifer; Rothenberg, Eli; Morrical, Scott W; Wallace, Susan S; Sweasy, Joann B

    2016-08-01

    The RAD51 protein plays a key role in the homology-directed repair of DNA double-strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance. PMID:27513445

  14. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype

    PubMed Central

    Marsden, Carolyn G.; Jensen, Ryan B.; Zagelbaum, Jennifer; Rothenberg, Eli; Morrical, Scott W.; Wallace, Susan S.; Sweasy, Joann B.

    2016-01-01

    The RAD51 protein plays a key role in the homology-directed repair of DNA double-strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance. PMID:27513445

  15. IFN‐λ3 polymorphism indirectly influences NK cell phenotype and function during acute HCV infection

    PubMed Central

    Depla, Marion; Pelletier, Sandy; Bédard, Nathalie; Brunaud, Camille; Bruneau, Julie

    2016-01-01

    Abstract Introduction Polymorphisms in the type III interferon IFN‐λ3 and the killer cell immunoglobulin‐like receptor (KIR) genes controlling the activity of natural killer (NK) cells can predict spontaneous resolution of acute hepatitis C virus (HCV) infection. We hypothesized that IFN‐λ3 polymorphism may modulate NK cell function during acute HCV. Methods We monitored the plasma levels of type III IFNs in relation to the phenotype and the function of NK cells in a cohort of people who inject drugs (PWID) during acute HCV infection with different outcomes. Results Early acute HCV was associated with high variability in type III IFNs plasma levels and the favorable IFN‐λ3 CC genotype was associated with higher viral loads. Reduced expression of Natural Killer Group Protein 2A (NKG2A) was associated with lower IFN‐λ3 plasma levels and the CC genotype. IFN‐γ production by NK cells was higher in individuals with the CC genotype during acute infection but this did not prevent viral persistence. IFN‐λ3 plasma levels did not correlate with function of NK cells and IFN‐λ3 prestimulation did not affect NK cell activation and function. Conclusions These results suggest that IFN‐λ3 polymorphism indirectly influences NK cell phenotype and function during acute HCV but other factors may act in concert to determine the outcome of the infection. PMID:27621819

  16. Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.

    PubMed

    Mastaglia, Frank L; Needham, Merrilee; Scott, Adrian; James, Ian; Zilko, Paul; Day, Timothy; Kiers, Lynette; Corbett, Alastair; Witt, Campbell S; Allcock, Richard; Laing, Nigel; Garlepp, Michael; Christiansen, Frank T

    2009-11-01

    Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM. PMID:19720533

  17. Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed.

    PubMed

    Lindholm-Perry, A K; Kuehn, L A; Freetly, H C; Snelling, W M

    2015-02-01

    Flight speed is a predictive indicator of cattle temperament and is associated with feed efficiency phenotypes. Genetic markers associated with both traits may assist with selection of calmer animals with improved economic value. A preliminary genome-wide association study determined chromosomal regions on BTA9, and 17 were associated with flight speed. The genes quaking (QKI), glutamate receptor, ionotropic, AMPA 2 (GRIA2) and glycine receptor β (GLRB) were identified in these regions as potential functional candidates. Beef steers (n = 1057) were genotyped with SNPs located within and flanking these genes. One SNP located near QKI and one near GRIA2 were nominally associated with flight speed (P ≤ 0.05) although neither was significant after Bonferroni correction. Several studies have shown a correlation between flight speed and feed intake or gain; therefore, we also analyzed SNPs on BTA6:38-39 Mb known to be associated with average daily gain (ADG) and average daily feed intake (ADFI) for association with flight speed. Several SNPs on BTA6 were associated with flight speed (P ≤ 0.005), and three were significant after Bonferroni correction. These results suggest that the genes tested are unlikely to contribute to flight speed variation for our cattle population, but SNPs on BTA6 associated with ADG and ADFI may influence temperament. Use of these markers to select for economically important feed efficiency phenotypes may produce cattle with more desirable temperaments. PMID:25515066

  18. Does the liposuction method influence the phenotypic characteristic of human adipose-derived stem cells?

    PubMed Central

    Bajek, Anna; Gurtowska, Natalia; Gackowska, Lidia; Kubiszewska, Izabela; Bodnar, Magdalena; Marszałek, Andrzej; Januszewski, Rafał; Michalkiewicz, Jacek; Drewa, Tomasz

    2015-01-01

    Adipose-derived stem cells (ASCs) possess a high differentiation and proliferation potential. However, the phenotypic characterization of ASCs is still difficult. Until now, there is no extensive analysis of ASCs markers depending on different liposuction methods. Therefore, the aim of the present study was to analyse 242 surface markers and determine the differences in the phenotypic pattern between ASCs obtained during mechanical and ultrasound-assisted liposuction. ASCs were isolated from healthy donors, due to mechanical and ultrasound-assisted liposuction and cultured in standard medium to the second passage. Differentiation potential and markers expression was evaluated to confirm the mesenchymal nature of cells. Then, the BD LyoplateTM Human Cell Surface Marker Screening Panel was used. Results shown that both population of ASCs are characterized by high expression of markers specific for ASCs: cluster of differentiation (CD)9, CD10, CD34, CD44, CD49d, CD54, CD55, CD59, CD71 and low expression of CD11a, CD11c and CD144. Moreover, we have noticed significant differences in antigen expression in 58 markers from the 242 studied. Presented study shows for the first time that different liposuction methods are not a significant factor which can influence the expression of human ASCs surface markers. PMID:26182374

  19. Subadult experience influences adult mate choice in an arthropod: Exposed female wolf spiders prefer males of a familiar phenotype

    PubMed Central

    Hebets, Eileen A.

    2003-01-01

    Current sexual selection theory proposes several potential mechanisms driving the evolution of female mating preferences, few of which involve social interactions. Although vertebrate examples of socially influenced mating preferences do exist, the invertebrate examples are virtually nonexistent. Here I demonstrate that the mating preferences of female wolf spiders can be acquired through exposure as subadults to unrelated, sexually active adult males. I first conducted exposure trials during which subadult females of the wolf spider Schizocosa uetzi were allowed to interact with mature males of an experimentally manipulated phenotype (either black or brown forelegs). After maturation, these previously exposed females were paired with a male of either a familiar or unfamiliar manipulated phenotype for mate-choice trials. Subadult females that were exposed to directed courtship by mature males of a particular morphological phenotype were subsequently more likely to mate with a male of a familiar phenotype as adults. Furthermore, females that were exposed as subadults were more likely, as adults, to cannibalize a courting male with an unfamiliar phenotype. Unexposed females did not distinguish between phenotypes in either mate choice or cannibalism frequency. These results suggest a previously uncharacterized mechanism influencing the origin of female mating preferences and ultimately the evolution of male traits: subadult experience. This study also stresses the potential importance of learning and memory on adult mate choice in an arthropod. PMID:14597702

  20. Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment

    PubMed Central

    Liu, Fang-Lan; Mo, En-Pan; Yang, Liu; Du, Jun; Wang, Hong-Sheng; Zhang, Huan; Kurihara, Hiroshi; Xu, Jun; Cai, Shao-Hui

    2016-01-01

    Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. PMID:26716641

  1. Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment.

    PubMed

    Liu, Fang-Lan; Mo, En-Pan; Yang, Liu; Du, Jun; Wang, Hong-Sheng; Zhang, Huan; Kurihara, Hiroshi; Xu, Jun; Cai, Shao-Hui

    2016-01-26

    Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. PMID:26716641

  2. Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: Implications for tumor therapy.

    PubMed

    Farooque, Abdullah; Afrin, Farhat; Adhikari, Jawahar Singh; Dwarakanath, Bilikere Srinivasa Rao

    2016-02-01

    2-Deoxy-d-glucose (2-DG) has been found to enhance the cytotoxicity of ionizing radiation and chemotherapeutic drugs in several tumor cell lines in vitro. Systemic administration of 2-DG together with localized irradiation of the tumor leads to tumor regression and cure (disease free survival), which correlate with the differential levels of anti-tumor immunity observed in Ehrlich ascites tumor (EAT) bearing mice. Macrophages being a major player of the innate immune system, we investigated the activation status of splenic macrophages during radio-sensitization of EAT in mice as well as in peritoneal macrophages ex vivo and macrophagic cell line (Raw 264.7) in vitro. Results suggest that under in vivo conditions, the combined treatment (2-DG+radiation) restores the M1 phenotype in spleen that correlated with the tumor response. However, 2-DG neither induced significant cytotoxicity nor enhanced radiation-induced cell death in peritoneal macrophages and the macrophage cell line (Raw 264.7). Further, increased arborization and enhanced functional status (expression of MHC class II, CD80, CD86 and phagocytosis) were observed after the combined treatment. Besides this activation, the combined treatment also skewed the macrophages towards M1 phenotype as evidenced by the enhanced secretion of IL-12, IL-2, TNF-α and IFN-γ. These observations suggest that 2-DG not only preserves the survival of normal macrophages during irradiation, but also activates macrophages by polarizing towards M1 phenotype, which is known to be tumoricidal in nature. This study for the first time sheds light on a potential antitumor immune activation by 2-DG involving macrophagic stimulation during in vivo radio-sensitization of tumors, besides the other known antitumor effects of this glucose analogue. PMID:26597503

  3. Association between body mass index and mortality for colorectal cancer survivors: overall and by tumor molecular phenotype

    PubMed Central

    Campbell, Peter T.; Newton, Christina C.; Newcomb, Polly A.; Phipps, Amanda I.; Ahnen, Dennis J.; Baron, John A.; Buchanan, Daniel D.; Casey, Graham; Cleary, Sean P.; Cotterchio, Michelle; Farris, Alton B.; Figueiredo, Jane C.; Gallinger, Steven; Green, Roger C.; Haile, Robert W.; Hopper, John L.; Jenkins, Mark A.; Le Marchand, Loïc; Makar, Karen W.; McLaughlin, John R.; Potter, John D.; Renehan, Andrew G.; Sinicrope, Frank A.; Thibodeau, Stephen N.; Ulrich, Cornelia M.; Win, Aung Ko; Lindor, Noralane M.; Limburg, Paul J.

    2015-01-01

    Background Microsatellite instability (MSI) and BRAF-mutation status are associated with colorectal cancer survival whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF-mutation, sex, and other factors. Methods This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Pre-diagnosis BMI was derived from self-reported weight approximately 1-year before diagnosis and height. Tumor MSI and BRAF-mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models. Results In multivariable models, high pre-diagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2, HR = 1.10; 95% CI = 1.06 to 1.15), with similar associations stratified by sex (p-interaction: 0.41), colon vs rectum (p-interaction: 0.86), MSI status (p-interaction: 0.84), and BRAF-mutation status (p-interaction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR: 1.32; p-value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR: 0.86; p-value: 0.29), and approximately the same for MSI-high and obese BMI (HR: 1.00; p-value: 0.98). Conclusions High pre-diagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. PMID:26038390

  4. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    PubMed

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  5. Correlation of tumor-infiltrating lymphocytes to histopathological features and molecular phenotypes in canine mammary carcinoma: A morphologic and immunohistochemical morphometric study.

    PubMed

    Kim, Jong-Hyuk; Chon, Seung-Ki; Im, Keum-Soon; Kim, Na-Hyun; Sur, Jung-Hyang

    2013-04-01

    Abundant lymphocyte infiltration is frequently found in canine malignant mammary tumors, but the pathological features and immunophenotypes associated with the infiltration remain to be elucidated. The aim of the present study was to evaluate the relationship between lymphocyte infiltration, histopathological features, and molecular phenotype in canine mammary carcinoma (MC). The study was done with archived formalin-fixed, paraffin-embedded samples (n = 47) by histologic and immunohistochemical methods. The degree of lymphocyte infiltration was evaluated by morphologic analysis, and the T- and B-cell populations as well as the T/B-cell ratio were evaluated by morphometric analysis; results were compared with the histologic features and molecular phenotypes. The degree of lymphocyte infiltration was significantly higher in MCs with lymphatic invasion than in those without lymphatic invasion (P < 0.0001) and in tumors of high histologic grade compared with those of lower histologic grade (P = 0.045). Morphometric analysis showed a larger amount of T-cells and B-cells in MCs with a higher histologic grade and lymphatic invasion, but the T/B ratio did not change. Lymphocyte infiltration was not associated with histologic type or molecular phenotype, as assessed from the immunohistochemical expression of epidermal growth factor receptor 2, estrogen receptor, cytokeratin 14, and p63. Since intense lymphocyte infiltration was associated with aggressive histologic features, lymphocytes may be important for tumor aggressiveness and greater malignant behavior in the tumor microenvironment. PMID:24082407

  6. Folic-acid metabolism and DNA-repair phenotypes differ between neuroendocrine lung tumors and associate with aggressive subtypes, therapy resistance and outcome

    PubMed Central

    Werner, Robert; Vollbrecht, Claudia; Hager, Thomas; Schmid, Kurt Werner; Wohlschlaeger, Jeremias; Christoph, Daniel Christian

    2016-01-01

    Purpose 25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking. Experimental Design Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair. Results Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS). Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001). Conclusions The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms. PMID:27064343

  7. Nanotopographic Substrates of Poly (Methyl Methacrylate) Do Not Strongly Influence the Osteogenic Phenotype of Mesenchymal Stem Cells In Vitro

    PubMed Central

    Janson, Isaac A.; Kong, Yen P.; Putnam, Andrew J.

    2014-01-01

    The chemical, mechanical, and topographical features of the extracellular matrix (ECM) have all been documented to influence cell adhesion, gene expression, migration, proliferation, and differentiation. Topography plays a key role in the architecture and functionality of various tissues in vivo, thus raising the possibility that topographic cues can be instructive when incorporated into biomaterials for regenerative applications. In the literature, there are discrepancies regarding the potential roles of nanotopography to enhance the osteogenic phenotype of mesenchymal stem cells (MSC). In this study, we used thin film substrates of poly(methyl methacrylate) (PMMA) with nanoscale gratings to investigate the influence of nanotopography on the osteogenic phenotype of MSCs, focusing in particular on their ability to produce mineral similar to native bone. Topography influenced focal adhesion size and MSC alignment, and enhanced MSC proliferation after 14 days of culture. However, the osteogenic phenotype was minimally influenced by surface topography. Specifically, alkaline phosphatase (ALP) expression was not increased on nanotopographic films, nor was calcium deposition improved after 21 days in culture. Ca: P ratios were similar to native mouse bone on films with gratings of 415 nm width and 200 nm depth (G415) and 303 nm width and 190 nm depth (G303). Notably, all surfaces had Ca∶P ratios significantly lower than G415 films. Collectively, these data suggest that, PMMA films with nanogratings are poor drivers of an osteogenic phenotype. PMID:24594848

  8. The Relative Influence of Competition and Prey Defenses on the Phenotypic Structure of Insectivorous Bat Ensembles in Southern Africa

    PubMed Central

    Schoeman, M. Corrie; Jacobs, David S.

    2008-01-01

    Deterministic filters such as competition and prey defences should have a strong influence on the community structure of animals such as insectivorous bats that have life histories characterized by low fecundity, low predation risk, long life expectancy, and stable populations. We investigated the relative influence of these two deterministic filters on the phenotypic structure of insectivorous bat ensembles in southern Africa. We used null models to simulate the random phenotypic patterns expected in the absence of competition or prey defences and analysed the deviations of the observed phenotypic pattern from these expected random patterns. The phenotypic structure at local scales exhibited non-random patterns consistent with both competition and prey defense hypotheses. There was evidence that competition influenced body size distribution across ensembles. Competition also influenced wing and echolocation patterns in ensembles and in functional foraging groups with high species richness or abundance. At the same time, prey defense filters influenced echolocation patterns in two species-poor ensembles. Non-random patterns remained evident even after we removed the influence of body size from wing morphology and echolocation parameters taking phylogeny into account. However, abiotic filters such as geographic distribution ranges of small and large-bodied species, extinction risk, and the physics of flight and sound probably also interacted with biotic filters at local and/or regional scales to influence the community structure of sympatric bats in southern Africa. Future studies should investigate alternative parameters that define bat community structure such as diet and abundance to better determine the influence of competition and prey defences on the structure of insectivorous bat ensembles in southern Africa. PMID:19005563

  9. The Family Context of Autism Spectrum Disorders: Influence on the Behavioral Phenotype and Quality of Life

    PubMed Central

    Smith, Leann E.; Greenberg, Jan; Mailick, Marsha R.

    2013-01-01

    Synopsis In this review, we report the findings from our longitudinal program of research examining the bidirectional influences of the family environment on the behavioral phenotype of autism, and describe a newly developed family psychoeducation program, titled Transitioning Together, designed to reduce family stress, address behavior problems, and improve the overall quality of life of adolescents with autism and their families. In our search for characteristics of the family environment that influence the behavioral phenotype of adolescents and adults with autism, we focus on both positive dimensions of family life, such as warmth and positive remarks that may promote adaptive behavior in individuals with autism, as well as negative dimensions, such as high levels of criticism that may result in an escalation of behavior problems. We find that high levels of maternal warmth and positive remarks are associated with the abatement of behavior problems over time, while high levels of maternal criticism are associated with increasing levels of behavior problems in adolescents and adults with autism. These patterns of relationships have been replicated in a longitudinal study of families of children and adolescents with fragile X syndrome, and are consistent with other studies examining the impact of the family on the behavior of children with developmental disabilities. These findings suggest that the family environment is an important target for interventions not only to reduce family stress but also to improve the behavioral functioning of children, adolescents or adults with ASD. Building upon a well-developed intervention for families of individuals with psychiatric conditions, we report on the development of Transitioning Together, a psychoeducation program targeted to families with adolescents with autism who are approaching high school exit, a difficult transition stage for individuals with autism that is often marked by negative changes in behavior problems

  10. Horizontal transmission of a parasite is influenced by infected host phenotype and density.

    PubMed

    Roberts, K E; Hughes, W O H

    2015-02-01

    Transmission is a key determinant of parasite fitness, and understanding the dynamics of transmission is fundamental to the ecology and evolution of host-parasite interactions. Successful transmission is often reliant on contact between infected individuals and susceptible hosts. The social insects consist of aggregated groups of genetically similar hosts, making them particularly vulnerable to parasite transmission. Here we investigate how the ratio of infected to susceptible individuals impacts parasite transmission, using the honey bee, Apis mellifera and its microsporidian parasite Nosema ceranae. We used 2 types of infected hosts found simultaneously in colonies; sterile female workers and sexual males. We found a higher ratio of infected to susceptible individuals in groups resulted in a greater proportion of susceptibles becoming infected, but this effect was non-linear and interestingly, the ratio also affected the spore production of infected individuals. The transmission level was much greater in an experiment where the infected individuals were drones than in an experiment where they were workers, suggesting drones may act as intracolonial 'superspreaders'. Understanding the subtleties of transmission and how it is influenced by the phenotype of the infected/susceptible individuals is important for understanding pathogen transmission at population level, and for optimum targeting of parasite control strategies. PMID:25111753

  11. Do changing moisture levels during incubation influence phenotypic traits of hatchling snakes (Tropidonophis mairii, Colubridae)?

    PubMed

    Brown, Gregory P; Shine, Richard

    2005-01-01

    Phenotypic traits (e.g., size, strength, speed) of hatchlings in many reptile species are influenced by hydric conditions in the nest. Previous experiments have focused on comparisons between eggs maintained under constant (but different) conditions, but eggs in natural nests frequently experience strong temporal shifts in soil water content during incubation. Keelback snakes (Tropidonophis mairii) in the Australian wet-dry tropics nest over most of the year, so early nests experience decreasing water availability during development, late nests experience increases, and others (midyear) remain stable in this respect. We mimicked these three conditions and incubated 54 eggs (nine from each of six clutches) in a split-clutch design to maintain the same average water content but with differing trajectories through incubation. The experimental treatments significantly affected the total amount of water taken up by the eggs (and thus final egg mass), but incubation periods were unaffected. Hatchling size but not strength showed minor but statistically significant effects of incubation regimes. The ability of keelback eggs to take up excess water whenever it becomes available (either early or late in development) and to retain it even when conditions change buffers embryogenesis effectively (but not completely) against fluctuations in soil water conditions. PMID:15957107

  12. Influence of paternal preconception exposures on their offspring: through epigenetics to phenotype

    PubMed Central

    Day, Jonathan; Savani, Soham; Krempley, Benjamin D; Nguyen, Matthew; Kitlinska, Joanna B

    2016-01-01

    Historically, research into congenital defects has focused on maternal impacts on the fetal genome during gestation and prenatal periods. However, recent findings have sparked interest in epigenetic alterations of paternal genomes and its effects on offspring. This emergent field focuses on how environmental influences can epigenetically alter gene expression and ultimately change the phenotype and behavior of progeny. There are three primary mechanisms implicated in these changes: DNA methylation, histone modification, and miRNA expression. This paper provides a summary and subsequent review of past research, which highlights the significant impact of environmental factors on paternal germ cells during the lifetime of an individual as well as those of future generations. These findings support the existence of transgenerational epigenetic inheritance of paternal experiences. Specifically, we explore epidemiological and laboratory studies that demonstrate possible links between birth defects and paternal age, environmental factors, and alcohol consumption. Ultimately, our review highlights the clinical importance of these factors as well as the necessity for future research in the field. PMID:27335698

  13. Muscarinic signaling influences the patterning and phenotype of cholinergic amacrine cells in the developing chick retina

    PubMed Central

    Stanke, Jennifer J; Lehman, Bret; Fischer, Andy J

    2008-01-01

    Background Many studies in the vertebrate retina have characterized the differentiation of amacrine cells as a homogenous class of neurons, but little is known about the genes and factors that regulate the development of distinct types of amacrine cells. Accordingly, the purpose of this study was to characterize the development of the cholinergic amacrine cells and identify factors that influence their development. Cholinergic amacrine cells in the embryonic chick retina were identified by using antibodies to choline acetyltransferase (ChAT). Results We found that as ChAT-immunoreactive cells differentiate they expressed the homeodomain transcription factors Pax6 and Islet1, and the cell-cycle inhibitor p27kip1. As differentiation proceeds, type-II cholinergic cells, displaced to the ganglion cell layer, transiently expressed high levels of cellular retinoic acid binding protein (CRABP) and neurofilament, while type-I cells in the inner nuclear layer did not. Although there is a 1:1 ratio of type-I to type-II cells in vivo, in dissociated cell cultures the type-I cells (ChAT-positive and CRABP-negative) out-numbered the type-II cells (ChAT and CRABP-positive cells) by 2:1. The relative abundance of type-I to type-II cells was not influenced by Sonic Hedgehog (Shh), but was affected by compounds that act at muscarinic acetylcholine receptors. In addition, the abundance and mosaic patterning of type-II cholinergic amacrine cells is disrupted by interfering with muscarinic signaling. Conclusion We conclude that: (1) during development type-I and type-II cholinergic amacrine cells are not homotypic, (2) the phenotypic differences between these subtypes of cells is controlled by the local microenvironment, and (3) appropriate levels of muscarinic signaling between the cholinergic amacrine cells are required for proper mosaic patterning. PMID:18254959

  14. Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes.

    PubMed

    Huang, Rui-Len; Chao, Chung-Faye; Ding, Dah-Ching; Yu, Cheng-Ping; Chang, Cheng-Chang; Lai, Hung-Chen; Yu, Mu-Hsien; Liu, Hang-Seng; Chu, Tang-Yuan

    2004-09-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal inherited cancer syndrome characterized by germline plus somatic mutations of DNA mismatch repair genes and familial clustering of cancers of colorectum and other visceral organs. So far, to our knowledge, there has been no proof of nonepithelial tumors in association with HNPCC. Here we report on a MSH2 frameshift HNPCC family with a carrier found to have multiple primary tumors, including endometrial hyperplasia, ovarian adenocarcinoma, skin cavernous hemangioma, and skin dermatofibrosarcoma protuberans (DFSP). We studied the replication error (RER) phenotype in noncoding (Bat-26, Bat-25, D2S123, D5S346, and D17S250) and coding (MSH3, MSH6, BAX, and TGFBR2 genes) DNA sequences, and characterized the germline and somatic mutations of the MSH2 gene in the tumors described above and in endometrial carcinomas from two of her affected siblings. RER was observed in an order of hyperplasic endometrium (6/10 markers), ovarian carcinoma (5/10 markers), endometrial carcinomas (4/9 and 3/10), DFSP (2/9 markers), and cavernous hemangioma (2/10 markers). All the tumors showed the same germline mutation of G5-->G6 frameshift at 183-187 and polymorphism of C1168T in a heterozygous pattern. In an endometrial carcinoma, deletion of the second allele of MSH2 was evident. Heterogeneous RER patterns were noted in multiple primary tumors of the same individual and in premalignant and malignant endometrial tumors from different individuals. The study demonstrated the two hits of the hMSH(2) gene as well as intra- and interindividual variations of RER phenotypes in HNPCC. The first characterized nonepithelial tumors in HNPCC seem to carry a limited panel of RER, including a framesift at the (A)(10) tract of TGFBR2. PMID:15350299

  15. Hyperlipoproteinaemia in primary gout: hyperlipoproteinaemic phenotype and influence of alcohol intake and obesity in Japan.

    PubMed Central

    Jiao, S; Kameda, K; Matsuzawa, Y; Tarui, S

    1986-01-01

    Serum lipoprotein profiles were investigated in 108 male patients with primary gout before treatment to elucidate the prevalence of each individual phenotype of coexisting hyperlipoproteinaemia and pathogenic factors responsible for it. The mean serum triglyceride (TG) and total cholesterol (TC) levels in the patients with gout were 2.10 +/- 0.14 mmol/l and 5.26 +/- 0.10 mmol/l (mean +/- SEM) respectively, which were significantly higher (p less than 0.01 and p less than 0.05 respectively) than the levels in age matched controls without gout (1.30 +/- 0.07 mmol/l and 4.77 +/- 0.08 mmol/l respectively). Serum high density lipoprotein cholesterol (HDL-C) values were slightly decreased in patients with gout compared with controls (1.24 +/- 0.08 mmol/l v 1.40 +/- 0.03 mmol/l, p less than 0.05). Hyperlipoproteinaemia was seen in 61 patients (56%), of whom patients with type IIa, IIb, and IV hyperlipoproteinaemia formed 13, 15, and 69% respectively. Thus the prevalence of type IV hyperlipoproteinaemia was high in primary gout as compared with primary hyperlipoproteinaemia with primary hyperlipoproteinaemia (69% v 43%, p less than 0.01). The independent and relative influences of clinical data of the patients upon the concentrations of serum lipids were assessed by stepwise multiple regression analysis. Two major predictors of serum TG level were alcohol intake (p less than 0.01) and serum uric acid level (p less than 0.05). The most significant predictive variable was alcohol intake, but its influence was judged to be small (r2 = 0.067). None of the other variables, including obesity index, had any significant influence. The relationships between any of these variables and serum TC or HDL-C levels were not significant. In addition, serum lipid levels were investigated in patients with neither obesity (defined as 120% or more of ideal body weight) nor a history of alcohol intake. Their serum TG and TC concentrations were also significantly higher than the respective

  16. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

    PubMed Central

    Fredericks, William J.; Sepulveda, Jorge; Lal, Priti; Tomaszewski, John E.; Lin, Ming-Fong; McGarvey, Terry; Rauscher, Frank J; Malkowicz, S. Bruce

    2013-01-01

    Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that

  17. A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity.

    PubMed

    Castoldi, R; Ecker, V; Wiehle, L; Majety, M; Busl-Schuller, R; Asmussen, M; Nopora, A; Jucknischke, U; Osl, F; Kobold, S; Scheuer, W; Venturi, M; Klein, C; Niederfellner, G; Sustmann, C

    2013-12-12

    Simultaneous targeting of epidermal growth factor receptor (EGFR) and Met in cancer therapy is under pre-clinical and clinical evaluation. Here, we report the finding that treatment with EGFR inhibitors of various tumor cells, when stimulated with hepatocyte growth factor (HGF) and EGF, results in transient upregulation of phosphorylated AKT. Furthermore, EGFR inhibition in this setting stimulates a pro-invasive phenotype as assessed in Matrigel-based assays. Simultaneous treatment with AKT and EGFR inhibitors abrogates this invasive growth, hence functionally linking signaling and phenotype. This observation implies that during treatment of tumors a balanced ratio of EGFR and Met inhibition is required. To address this, we designed a bispecific antibody targeting EGFR and Met, which has the advantage of a fixed 2:1 stoichiometry. This bispecific antibody inhibits proliferation in tumor cell cultures and co-cultures with fibroblasts in an additive manner compared with treatment with both single agents. In addition, cell migration assays reveal a higher potency of the bispecific antibody in comparison with the antibodies' combination at low doses. We demonstrate that the bispecific antibody inhibits invasive growth, which is specifically observed with cetuximab. Finally, the bispecific antibody potently inhibits tumor growth in a non-small cell lung cancer xenograft model bearing a strong autocrine HGF-loop. Together, our findings strongly support a combination treatment of EGFR and Met inhibitors and further evaluation of resistance mechanisms to EGFR inhibition in the context of active Met signaling. PMID:23812422

  18. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    SciTech Connect

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A.; Lewis, R.A.; MacCluer, J.W.; Schwartz, P.J.; Locati, E.H.; Tzivoni, D.

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  19. Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes.

    PubMed

    Kovacs, David; Eszlari, Nora; Petschner, Peter; Pap, Dorottya; Vas, Szilvia; Kovacs, Peter; Gonda, Xenia; Bagdy, Gyorgy; Juhasz, Gabriella

    2016-05-01

    Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 × RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype-phenotype relationship in this heterogeneous disorder. PMID:26821321

  20. Influence of Cancer-Associated Endometrial Stromal Cells on Hormone-Driven Endometrial Tumor Growth

    PubMed Central

    Pineda, M. J.; Lu, Z.; Cao, D.

    2016-01-01

    Cancer-associated fibroblasts have been shown to inhibit or stimulate tumor growth depending on stage, grade, and tumor type. It remains unclear, however, the effect of endometrial-cancer-associated fibroblasts on hormone-driven responses in endometrial cancer. In this study, we investigated the effect of normal and cancer-associated stromal cells from patients with and without endometrial cancer on endometrial tumor growth in response to estradiol (E2) and progesterone (P4). Compared to benign endometrial stromal cells, the low-grade and high-grade cancer-associated stromal cells exhibited a blunted hormone response for proliferation as well as IGFBP1 secretion. Additional analysis of the influence of stromal cells on hormone-driven tumor growth was done by mixing stromal cells from benign, low-grade, or high-grade tumors, with Ishikawa cells for subcutaneous tumor formation. The presence of both benign and high-grade cancer-associated stromal cells increased estradiol-driven xenografted tumor growth compared to Ishikawa cells alone. Low-grade cancer-associated stromal cells did not significantly influence hormone-regulated tumor growth. Addition of P4 attenuated tumor growth in Ishikawa + benign or high-grade stromal cells, but not in Ishikawa cells alone or with low-grade stromal cells. Using an angiogenesis focused real-time array TGFA, TGFB2 and TGFBR1 and VEGFC were identified as potential candidates for hormone-influenced growth regulation of tumors in the presence of benign and high-grade stromal cells. In summary, endometrial-cancer-associated cells responded differently to in vitro hormone treatment compared to benign endometrial stromal cells. Additionally, presence of stromal cells differentially influenced hormone-driven xenograft growth in vivo depending on the disease status of the stromal cells. PMID:25976290

  1. Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development

    PubMed Central

    Beheshti, Afshin; Wage, Justin; McDonald, J. Tyson; Lamont, Clare; Peluso, Michael; Hahnfeldt, Philip; Hlatky, Lynn

    2015-01-01

    The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease. PMID:26497558

  2. GATA-4 and FOG-2 Expression in Pediatric Ovarian Sex Cord-Stromal Tumors Replicates Embryonal Gonadal Phenotype: Results from the TREP Project

    PubMed Central

    Virgone, Calogero; Cecchetto, Giovanni; Ferrari, Andrea; Bisogno, Gianni; Donofrio, Vittoria; Boldrini, Renata; Collini, Paola; Dall’Igna, Patrizia; Alaggio, Rita

    2012-01-01

    Aim GATA proteins are a family of zinc finger transcription factors regulating gene expression, differentiation and proliferation in various tissues. The expression of GATA-4 and FOG-2, one of its modulators, was studied in pediatric Sex Cord-Stromal tumors of the ovary, in order to evaluate their potential role as diagnostic markers and prognostic factors. Materials and Methods Clinical and histological data of 15 patients, enrolled into the TREP Project since 2000 were evaluated. When available, immunostaines for FOG-2, GATA-4, α-Inhibin, Vimentin and Pancytokeratin were also analyzed. Results In our series there were 6 Juvenile Granulosa Cell Tumors (JGCT), 6 Sertoli-Leydig Cell Tumors (SLCT), 1 Cellular Fibroma, 1 Theca Cell Tumor and 1 Stromal Sclerosing Tumor (SST). Thirteen patients obtained a complete remission (CR), 1 reached a second CR after the removal of a metachronous tumor and 1 died of disease. Inhibin was detectable in 11/15, Vimentin in 13/15, Pancytokeratin in 6/15, GATA-4 in 5/13 and FOG-2 in 11/15. FOG-2 was highly expressed in 5/6 JGCT, while GATA-4 was weakly detectable only in 1 of the cases. SLCT expressed diffusely FOG-2 (4/6) and GATA-4 (3/5). GATA-4 and FOG-2 were detected in fibroma and thecoma but not in the SST. Conclusions Pediatric granulosa tumors appear to express a FOG-2/GATA-4 phenotype in keeping with primordial ovarian follicles. High expression of GATA-4 does not correlate with aggressive behaviour as seen in adults, but it is probably involved in cell proliferation its absence can be associated with the better outcome of JGCT. SLCTs replicate the phenotype of Sertoli cells during embryogenesis in normal testis. In this group, the lack of expression of FOG-2 in tumors in advanced stages might reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway. In fibroma/thecoma group GATA-4 and FOG-2 point out the abnormal activation of GATA pathway and might be involved in the onset of these tumors. PMID:23029311

  3. Interleukin-6 Induced “Acute” Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics

    PubMed Central

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L.; Yan, Wei; Xu, Lisa X.

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and

  4. The mesenchymal substrate influences the epithelial phenotype in a three-dimensional cell culture.

    PubMed

    Merne, Marina; Syrjänen, Stina

    2003-09-01

    Cell-matrix interactions are thought to influence epithelial structure, growth, and differentiation. Three-dimensional cell cultures were used to study the effects of the composition of the dermal equivalent on the morphology of epithelium grown from HaCaT skin keratinocytes. Three commercial preparations, a basement membrane preparation from a tumor (matrix 1), two preparations consisting of collagen type I and III (matrix 3 and 4) and a noncommercial preparation containing collagen type I (matrix 2) were investigated. The effects of fibroblasts of different origin (vaginal mucosa, oral buccal mucosa, and skin) were investigated in connection with matrix 4. The histomorphology and expression of the proteins PCNA, Ki-67, p53, p21, pankeratin, involucrin, cytokeratin 10 (Ck10), Ck17, Ck19 and collagen type IV were evaluated. Three-dimensional cultures of HaCaT cells gave rise to an epithelium with an immature and hyperproliferative character, showing active proliferation with intense PCNA staining. Both matrix 1 and matrix 2 resulted in an epithelium with budding into the matrix and some degree of layering. These epithelia showed only scattered Ck17 and Ck19 expression but a low terminal differentiation potential as indicated by scattered Ck10 and involucrin staining. The epithelia of cocultures with matrices 3 and 4 were positive for Ck17 and Ck19. However, the epithelium on matrix 3 showed strong expression of the terminal differentiation marker Ck10 and involucrin. This methodological study provides evidence of the importance of standardization of the composition of the matrix to avoid confounding effects on epithelial morphology and protein expression in studies using a three-dimensional epithelial culture model. PMID:12898149

  5. The influence of gene flow and drift on genetic and phenotypic divergence in two species of Zosterops in Vanuatu

    PubMed Central

    Clegg, Sonya M.; Phillimore, Albert B.

    2010-01-01

    Colonization of an archipelago sets the stage for adaptive radiation. However, some archipelagos are home to spectacular radiations, while others have much lower levels of diversification. The amount of gene flow among allopatric populations is one factor proposed to contribute to this variation. In island colonizing birds, selection for reduced dispersal ability is predicted to produce changing patterns of regional population genetic structure as gene flow-dominated systems give way to drift-mediated divergence. If this transition is important in facilitating phenotypic divergence, levels of genetic and phenotypic divergence should be associated. We consider population genetic structure and phenotypic divergence among two co-distributed, congeneric (Genus: Zosterops) bird species inhabiting the Vanuatu archipelago. The more recent colonist, Z. lateralis, exhibits genetic patterns consistent with a strong influence of distance-mediated gene flow. However, complex patterns of asymmetrical gene flow indicate variation in dispersal ability or inclination among populations. The endemic species, Z. flavifrons, shows only a partial transition towards a drift-mediated system, despite a long evolutionary history on the archipelago. We find no strong evidence that gene flow constrains phenotypic divergence in either species, suggesting that levels of inter-island gene flow do not explain the absence of a radiation across this archipelago. PMID:20194170

  6. Expression of the Homeobox Gene HOXA9 in Ovarian Cancer Induces Peritoneal Macrophages to Acquire an M2 Tumor-Promoting Phenotype

    PubMed Central

    Ko, Song Yi; Ladanyi, Andras; Lengyel, Ernst; Naora, Honami

    2015-01-01

    Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8+ tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages. PMID:24332016

  7. Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation

    PubMed Central

    2010-01-01

    Background CpG island methylator phenotype (CIMP), in which multiple genes concordantly methylated, has been demonstrated to be associated with progression, recurrence, as well as overall survival in some types of cancer. Methods We examined the promoter methylation status of seven genes including P16, CDH1, GSTP1, DAPK, XAF1, SOCS1 and SYK in 65 cases of HCC treated with LT by methylation-specific PCR. CIMP+ was defined as having three or more genes that are concordantly methylated. The relationship between CIMP status and clinicopathological parameters, as well as tumor recurrence was further analyzed. Results CIMP+ was more frequent in HCC with AFP > 400 ng/ml than those with AFP ≤ 400 ng/ml (P = 0.017). In addition, patients with CIMP+ were prone to have multiple tumor numbers than those with CIMP- (P = 0.007). Patients with CIMP+ tumors had significantly worse recurrence-free survival (RFS) than patients with CIMP-tumors by Kaplan-Meier estimates (P = 0.004). Multivariate analysis also revealed that CIMP status might be a novel independent prognostic factor of RFS for HCC patients treated with LT (HR: 3.581; 95% CI: 1.473-8.710, P = 0.005). Conclusion Our results suggested that CIMP could serve as a new prognostic biomarker to predict the risk of tumor recurrence in HCC after transplantation. PMID:20678188

  8. Phenotypic Transition as a Survival Strategy of Glioma

    PubMed Central

    ICHIKAWA, Tomotsugu; OTANI, Yoshihiro; KUROZUMI, Kazuhiko; DATE, Isao

    2016-01-01

    Malignant glioma is characterized by rapid proliferation, invasion into surrounding central nervous system tissues, and aberrant vascularization. There is increasing evidence that shows gliomas are more complex than previously thought, as each tumor comprises considerable intratumoral heterogeneity with mixtures of genetically and phenotypically distinct subclones. Heterogeneity within and across tumors is recognized as a critical factor that limits therapeutic progress for malignant glioma. Recent genotyping and expression profiling of gliomas has allowed for the creation of classification schemes that assign tumors to subtypes based on similarity to defined expression signatures. Also, malignant gliomas frequently shift their biological features upon recurrence and progression. The ability of glioma cells to resist adverse conditions such as hypoxia and metabolic stress is necessary for sustained tumor growth and strongly influences tumor behaviors. In general, glioma cells are in one of two phenotypic categories: higher proliferative activity with angiogenesis, or higher migratory activity with attenuated proliferative ability. Further, they switch phenotypic categories depending on the situation. To date, a multidimensional approach has been employed to clarify the mechanisms of phenotypic shift of glioma. Various molecular and signaling pathways are involved in phenotypic shifts of glioma, possibly with crosstalk between them. In this review, we discuss molecular and phenotypic heterogeneity of glioma cells and mechanisms of phenotypic shifts in regard to the glioma proliferation, angiogenesis, and invasion. A better understanding of the molecular mechanisms that underlie phenotypic shifts of glioma may provide new insights into targeted therapeutic strategies. PMID:27169497

  9. Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non-genetic factors.

    PubMed

    Izumi, Kosuke; Hayashi, Daisuke; Grochowski, Christopher M; Kubota, Noriko; Nishi, Eriko; Arakawa, Michiko; Hiroma, Takehiko; Hatata, Tomoko; Ogiso, Yoshifumi; Nakamura, Tomohiko; Falsey, Alexandra M; Hidaka, Eiko; Spinner, Nancy B

    2016-02-01

    Alagille syndrome is a multisystem developmental disorder characterized by bile duct paucity, congenital heart disease, vertebral anomalies, posterior embryotoxon, and characteristic facial features. Alagille syndrome is typically the result of germline mutations in JAG1 or NOTCH2 and is one of several human diseases caused by Notch signaling abnormalities. A wide phenotypic spectrum has been well documented in Alagille syndrome. Therefore, monozygotic twins with Alagille syndrome provide a unique opportunity to evaluate potential phenotypic modifiers such as environmental factors or stochastic effects of gene expression. In this report, we describe an Alagille syndrome monozygotic twin pair with discordant placental and clinical findings. We propose that environmental factors such as prenatal hypoxia may have played a role in determining the phenotypic severity. PMID:26463753

  10. The influence of disease categories on gene candidate predictions from model organism phenotypes

    PubMed Central

    2014-01-01

    Background The molecular etiology is still to be identified for about half of the currently described Mendelian diseases in humans, thereby hindering efforts to find treatments or preventive measures. Advances, such as new sequencing technologies, have led to increasing amounts of data becoming available with which to address the problem of identifying disease genes. Therefore, automated methods are needed that reliably predict disease gene candidates based on available data. We have recently developed Exomiser as a tool for identifying causative variants from exome analysis results by filtering and prioritising using a number of criteria including the phenotype similarity between the disease and mouse mutants involving the gene candidates. Initial investigations revealed a variation in performance for different medical categories of disease, due in part to a varying contribution of the phenotype scoring component. Results In this study, we further analyse the performance of our cross-species phenotype matching algorithm, and examine in more detail the reasons why disease gene filtering based on phenotype data works better for certain disease categories than others. We found that in addition to misleading phenotype alignments between species, some disease categories are still more amenable to automated predictions than others, and that this often ties in with community perceptions on how well the organism works as model. Conclusions In conclusion, our automated disease gene candidate predictions are highly dependent on the organism used for the predictions and the disease category being studied. Future work on computational disease gene prediction using phenotype data would benefit from methods that take into account the disease category and the source of model organism data. PMID:25093073

  11. Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans

    PubMed Central

    Jacobsen, Mette J.; Cirera, Susanna; Kogelman, Lisette J. A.; Bruun, Camilla S.; Mark, Thomas; Jørgensen, Claus B.; Grarup, Niels; Appel, Emil V. R.; Galjatovic, Ehm A. A.; Hansen, Torben; Pedersen, Oluf; Guerin, Maryse; Huby, Thierry; Lesnik, Philipppe; Meuwissen, Theo H. E.; Kadarmideen, Haja N.; Fredholm, Merete

    2015-01-01

    The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that

  12. Cross-talk between Dopachrome Tautomerase and Caveolin-1 Is Melanoma Cell Phenotype-specific and Potentially Involved in Tumor Progression.

    PubMed

    Popa, Ioana L; Milac, Adina L; Sima, Livia E; Alexandru, Petruta R; Pastrama, Florin; Munteanu, Cristian V A; Negroiu, Gabriela

    2016-06-10

    l-Dopachrome tautomerase (l-DCT), also called tyrosinase-related protein-2 (TRP-2), is a melanoma antigen overexpressed in most chemo-/radiotherapeutic stress-resistant tumor clones, and caveolin-1 (CAV1) is a main regulator of numerous signaling processes. A structural and functional relationship between DCT and CAV1 is first presented here in two human amelanotic melanoma cell lines, derived from vertical growth phase (MelJuSo) and metastatic (SKMel28) melanomas. DCT co-localizes at the plasma membrane with CAV1 and Cavin-1, another molecular marker for caveolae in both cell phenotypes. Our novel structural model proposed for the DCT-CAV1 complex, in addition to co-immunoprecipitation and mass spectrometry data, indicates a possible direct interaction between DCT and CAV1. The CAV1 control on DCT gene expression, DCT post-translational processing, and subcellular distribution is cell phenotype-dependent. DCT is a modulator of CAV1 stability and supramolecular assembly in both cell phenotypes. During autocrine stimulation, the expressions of DCT and CAV1 are oppositely regulated; DCT increases while CAV1 decreases. Sub-confluent MelJuSo clones DCT(high)/CAV1(low) are proliferating and acquire fibroblast-like morphology, forming massive, confluent clusters as demonstrated by immunofluorescent staining and TissueFAXS quantitative image cytometry analysis. CAV1 down-regulation directly contributes to the expansion of MelJuSo DCT(high) subtype. CAV1 involved in the perpetuation of cell phenotype-overexpressing anti-stress DCT molecule supports the concept that CAV1 functions as a tumor suppressor in early stages of melanoma. DCT is a regulator of the CAV1-associated structures and is possibly a new molecular player in CAV1-mediated processes in melanoma. PMID:27053106

  13. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  14. Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The measure of flight speed for cattle has been shown to be a predictive indicator of temperament and has also been associated with feed efficiency phenotypes, thus, genetic markers associated with both traits may assist with the selection of animals with calmer disposition and economic value. Chrom...

  15. Diverse Bone Morphogenetic Protein Expression Profiles and Smad Pathway Activation in Different Phenotypes of Experimental Canine Mammary Tumors

    PubMed Central

    Wensman, Helena; Heldin, Nils-Erik; Pejler, Gunnar; Hellmén, Eva

    2009-01-01

    Background BMPs are currently receiving attention for their role in tumorigenesis and tumor progression. Currently, most BMP expression studies are performed on carcinomas, and not much is known about the situation in sarcomas. Methodology/Principal Findings We have investigated the BMP expression profiles and Smad activation in clones from different spontaneous canine mammary tumors. Spindle cell tumor and osteosarcoma clones expressed high levels of BMPs, in particular BMP-2, -4 and -6. Clones from a scirrhous carcinoma expressed much lower BMP levels. The various clones formed different tumor types in nude mice but only clones that expressed high levels of BMP-6 gave bone formation. Phosphorylated Smad-1/5, located in the nucleus, was detected in tumors derived from clones expressing high levels of BMPs, indicating an active BMP signaling pathway and BMP-2 stimulation of mammary tumor cell clones in vitro resulted in activation of the Smad-1/5 pathway. In contrast BMP-2 stimulation did not induce phosphorylation of the non-Smad pathway p38 MAPK. Interestingly, an increased level of the BMP-antagonist chordin-like 1 was detected after BMP stimulation of non-bone forming clones. Conclusions/Significance We conclude that the specific BMP expression repertoire differs substantially between different types of mammary tumors and that BMP-6 expression most probably has a biological role in bone formation of canine mammary tumors. PMID:19771160

  16. Isoforms of Pax5 and co-regulation of T- and B-cells associated genes influence phenotypic traits of ascetic cells causing Dalton's lymphoma.

    PubMed

    Bharti, Brij; Mishra, Rajnikant

    2011-12-01

    The Pax5 and its isoforms influence proliferation of B- and T-cells, during development and oncogenesis but molecular mechanism and host-tumor relationship is not clear. This report describes status of Pax5 isoforms and co-regulation of molecular markers of ascite cells causing Dalton's lymphoma in murine. Higher expressions of Pax5, CD19, CD3, Ras and Raf were observed in DLA cells. The levels of transcripts as well as p53 protein were also higher in DLA cells. The transcript of p53 from DLA cells was a variant of p53 having deletion of 50bp as compared to control. On annotation, it reflects transformation related protein p53 pseudogene mRNA. Lower level of superoxide dismutase (SOD) indicates oxidative stress and higher level of LDH5 in DLA cells reflects hypoxia in cancerous condition. The expression of Pax5d/e isoforms in DLA cells suggests presence of resting B-cells. Thus, isoforms of Pax5 and co-regulation of T- and B-cells associated genes influence phenotypic traits of ascetic cells causing Dalton's lymphoma. PMID:21854813

  17. Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin β3 and TGF-β receptor type II.

    PubMed

    Page, Jonathan M; Merkel, Alyssa R; Ruppender, Nazanin S; Guo, Ruijing; Dadwal, Ushashi C; Cannonier, Shellese A; Basu, Sandip; Guelcher, Scott A; Sterling, Julie A

    2015-09-01

    Cancer patients frequently develop skeletal metastases that significantly impact quality of life. Since bone metastases remain incurable, a clearer understanding of molecular mechanisms regulating skeletal metastases is required to develop new therapeutics that block establishment of tumors in bone. While many studies have suggested that the microenvironment contributes to bone metastases, the factors mediating tumors to progress from a quiescent to a bone-destructive state remain unclear. In this study, we hypothesized that the "soil" of the bone microenvironment, specifically the rigid mineralized extracellular matrix, stimulates the transition of the tumor cells to a bone-destructive phenotype. To test this hypothesis, we synthesized 2D polyurethane (PUR) films with elastic moduli ranging from the basement membrane (70 MPa) to cortical bone (3800 MPa) and measured expression of genes associated with mechanotransduction and bone metastases. We found that expression of Integrin β3 (Iβ3), as well as tumor-produced factors associated with bone destruction (Gli2 and parathyroid hormone related protein (PTHrP)), significantly increased with matrix rigidity, and that blocking Iβ3 reduced Gli2 and PTHrP expression. To identify the mechanism by which Iβ3 regulates Gli2 and PTHrP (both are also known to be regulated by TGF-β), we performed Förster resonance energy transfer (FRET) and immunoprecipitation, which indicated that Iβ3 co-localized with TGF-β Receptor Type II (TGF-β RII) on rigid but not compliant films. Finally, transplantation of tumor cells expressing Iβ3 shRNA into the tibiae of athymic nude mice significantly reduced PTHrP and Gli2 expression, as well as bone destruction, suggesting a crucial role for tumor-produced Iβ3 in disease progression. This study demonstrates that the rigid mineralized bone matrix can alter gene expression and bone destruction in an Iβ3/TGF-β-dependent manner, and suggests that Iβ3 inhibitors are a potential

  18. The chemotherapeutic drug boanmycin induces cell senescence and senescence-associated secretory phenotype factors, thus acquiring the potential to remodel the tumor microenvironment.

    PubMed

    Chen, Peng; Guo, Hua; Chen, Jinliang; Fu, Yujie

    2016-02-01

    Boanmycin hydrochloride, a new antitumor agent, functions similarly to bleomycin, but has a shorter half-life and faster clearance in vivo. Therefore, it is used in clinical studies for lung squamous cell cancer. However, previous studies have shown that besides its antitumor effect, bleomycin also induces the generation of senescence fibroblasts, which secrete senescence-associated secretory phenotype factors that have protumorigenic potential, consequently altering the tumor microenvironment. Hence, it is critical to clarify boanmycin potential in remodeling the tumor microenvironment after the chemotherapy treatment of tumors. Bone is the favorite organ for lung cancer metastasis. Thus, in this study, lung fibroblasts and bone osteoblasts (OBs) were used to reflect the resident stromal cells in the primary lung and bone metastatic microenvironment, respectively. Lung fibroblasts (IMR90) and primary OBs were treated with 6.7 μl/ml boanmycin or bleomycin for 24 h and MTT was monitored from day 1 to day 9; senescence-associated β-galactosidase staining, which indicated the cell senescence, was performed on day 7; and well-established senescence-associated secretory phenotype factor interleukin-6 expression was detected on day 9. MTT data showed that boanmycin inhibited cell proliferation in both IMR90 and OBs. Moreover, senescence-associated β-galactosidase staining showed that in response to boanmycin, there were 90% senescence cells in IMR90 and 95% in OBs. However, in vehicle, there were only 40 or 30% senescence cells, respectively. Furthermore, quantitative PCR data also showed that the interleukin-6 expression was highly induced by boanmycin to six-fold in OBs. Boanmycin treatment for cancer chemotherapy has the remodeling ability to alter the tumor microenvironment and might contribute toward lung cancer relapse and metastasis on long-term treatment. PMID:26460847

  19. Overexpression of Cell Cycle Progression Inhibitor Geminin is Associated with Tumor Stem-Like Phenotype of Triple-Negative Breast Cancer

    PubMed Central

    Di Bonito, Maurizio; Collina, Francesca; Scognamiglio, Giosuè; Cerrone, Margherita; La Mantia, Elvira; Barbato, Antonio; Liguori, Giuseppina; Botti, Gerardo

    2012-01-01

    Purpose Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm. Methods To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triple-negative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification. Results Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p=0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076). Conclusion The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers. PMID:22807933

  20. Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells.

    PubMed

    Sampath, Janardhan; Long, Pandy R; Shepard, Robert L; Xia, Xiaoling; Devanarayan, Viswanath; Sandusky, George E; Perry, William L; Dantzig, Anne H; Williamson, Mark; Rolfe, Mark; Moore, Robert E

    2003-11-01

    Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance. PMID:14578179

  1. Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes.

    PubMed

    Sheehan, Vivien A; Luo, Zhaoyu; Flanagan, Jonathan M; Howard, Thad A; Thompson, Bruce W; Wang, Winfred C; Kutlar, Abdullah; Ware, Russell E

    2013-07-01

    The recently completed BABY HUG trial investigated the safety and efficacy of hydroxyurea in infants with sickle cell anemia (SCA). To investigate the effects of known genetic modifiers, genomic DNA on 190 randomized subjects were analyzed for alpha thalassemia, beta-globin haplotype, polymorphisms affecting endogenous fetal hemoglobin (HbF) levels (XmnI, BCL11A, and HBS1L-MYB), UGT1A1 promoter polymorphisms, and the common G6PD A(-) mutation. At study entry, infants with alpha thalassemia trait had significantly lower mean corpuscular volume, total bilirubin, and absolute reticulocyte count. Beta-globin haplotypes associated with milder disease had significantly higher hemoglobin and %HbF. BCL11A and XmnI polymorphisms had significant effects on baseline HbF, while UGT1A1 promoter polymorphisms significantly influenced baseline serum bilirubin. At study exit, subjects randomized to placebo still exhibited laboratory effects of alpha thalassemia and other modifiers, while those assigned hydroxyurea had treatment effects that exceeded most genetic influences. The pain phenotype was influenced by HbF modifiers in both treatment groups. These data document that genetic polymorphisms do modify laboratory and clinical phenotypes even in very young patients with SCA. The hydroxyurea effects are more potent, however, indicating that treatment criteria should not be limited to certain genetic subsets, and supporting the use of hydroxyurea for all young patients with SCA. PMID:23606168

  2. Telomere length and elevated iron: the influence of phenotype and HFE genotype.

    PubMed

    Mainous, Arch G; Wright, Robert U; Hulihan, Mary M; Twal, Waleed O; McLaren, Christine E; Diaz, Vanessa A; McLaren, Gordon D; Argraves, W Scott; Grant, Althea M

    2013-06-01

    Elevated body iron stores are associated with morbidity and mortality due to oxidative stress. Hereditary hemochromatosis, a common condition caused by HFE gene mutations, can lead to excess iron storage and disease but clinical penetrance of HFE gene mutations is low and many people with elevated iron stores lack HFE mutations. We analyzed data from the Hemochromatosis and Iron Overload Screening Study to assess the relationship among HFE genotype (individuals with either homozygous or compound heterozygous status for C282Y and/or H63D HFE mutations were defined as genotype positive, or G+), elevated iron phenotype (individuals exceeding gender-specific transferrin saturation and serum ferritin threshold levels were considered phenotype positive, or P+), and leukocyte telomere length, a marker of biological aging and cumulative oxidative stress. In unadjusted analyses in comparison to individuals who were G-P-, G+P- were not significantly different (OR 0.74; 95% CI 0.26-2.04), while the G+P+ (OR 2.03; 95% CI 1.15-3.56), and G-P+ (OR 2.24; 95% CI 1.5-3.29) had increased risk of short telomeres (<=25th percentile) rather than long telomeres (>=75th percentile). In analyses adjusting for age, gender, and race/ethnicity, the effect of individuals with elevated iron phenotypes having short telomeres persisted with G+P+ individuals (OR 1.94; 95% CI 1.02-3.72), and G-P+ individuals (OR 2.17; 95% CI 1.39-3.39) being significantly different from the G-P- group. In conclusion, elevated iron phenotype, but not HFE genotype, was associated with shortened telomeres. Further studies will be needed to determine whether telomere length provides a marker for morbidities specifically associated with iron overload. PMID:23512844

  3. Phenotypic Plasticity Influences the Size, Shape and Dynamics of the Geographic Distribution of an Invasive Plant

    PubMed Central

    Pichancourt, Jean-Baptiste; van Klinken, Rieks D.

    2012-01-01

    Phenotypic plasticity has long been suspected to allow invasive species to expand their geographic range across large-scale environmental gradients. We tested this possibility in Australia using a continental scale survey of the invasive tree Parkinsonia aculeata (Fabaceae) in twenty-three sites distributed across four climate regions and three habitat types. Using tree-level responses, we detected a trade-off between seed mass and seed number across the moisture gradient. Individual trees plastically and reversibly produced many small seeds at dry sites or years, and few big seeds at wet sites and years. Bigger seeds were positively correlated with higher seed and seedling survival rates. The trade-off, the relation between seed mass, seed and seedling survival, and other fitness components of the plant life-cycle were integrated within a matrix population model. The model confirms that the plastic response resulted in average fitness benefits across the life-cycle. Plasticity resulted in average fitness being positively maintained at the wet and dry range margins where extinction risks would otherwise have been high (“Jack-of-all-Trades” strategy JT), and fitness being maximized at the species range centre where extinction risks were already low (“Master-of-Some” strategy MS). The resulting hybrid “Jack-and-Master” strategy (JM) broadened the geographic range and amplified average fitness in the range centre. Our study provides the first empirical evidence for a JM species. It also confirms mechanistically the importance of phenotypic plasticity in determining the size, the shape and the dynamic of a species distribution. The JM allows rapid and reversible phenotypic responses to new or changing moisture conditions at different scales, providing the species with definite advantages over genetic adaptation when invading diverse and variable environments. Furthermore, natural selection pressure acting on phenotypic plasticity is predicted to result in

  4. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

    PubMed

    Merker, Vanessa L; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Muzikansky, Alona; Nguyen, Rosa; Mautner, Victor F; Plotkin, Scott R

    2014-06-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis share a predisposition to develop multiple nerve sheath tumors. Previous studies have demonstrated that patients with NF1 and NF2 have reduced quality of life (QOL), but no studies have examined the relationship between whole-body tumor burden and QOL in these patients. We administered a QOL questionnaire (the SF-36) and a visual analog pain scale (VAS) to a previously described cohort of adult neurofibromatosis patients undergoing whole-body MRI. One-sample t-tests were used to compare norm-based SF-36 scores to weighted population means. Spearman correlation coefficients and multiple linear regression analyses controlling for demographic and disease-specific clinical variable were used to relate whole-body tumor volume to QOL scales. Two hundred forty-five patients (142 NF1, 53 NF2, 50 schwannomatosis) completed the study. Subjects showed deficits in selected subscales of the SF-36 compared to adjusted general population means. In bivariate analysis, increased tumor volume was significantly associated with pain in schwannomatosis patients, as measured by the SF-36 bodily pain subscale (rho = -0.287, P = 0.04) and VAS (rho = 0.34, P = 0.02). Regression models for NF2 patients showed a positive relationship between tumor burden and increased pain, as measured by the SF-36 (P = 0.008). Patients with NF1, NF2, and schwannomatosis suffer from reduced QOL, although only pain shows a clear relationship to patient's overall tumor burden. These findings suggest that internal tumor volume is not a primary contributor to QOL and emphasize the need for comprehensive treatment approaches that go beyond tumor-focused therapies such as surgery by including psychosocial interventions. PMID:24664633

  5. Brain metastasis of Wilms tumor with diffuse anaplasia and complex cytogenetic phenotype in a child with neurofibromatosis Type 1.

    PubMed

    Shvartsbeyn, Marianna; Bassani, Luigi; Mikolaenko, Irina; Wisoff, Jeffrey H

    2011-10-01

    The authors report the first case of a Wilms tumor (WT) with diffuse anaplasia metastatic to the brain in a 13-year-old girl with a history of neurofibromatosis Type 1. At presentation, the metastatic tumor had radiological features that suggested a meningioma. Histologically it was characterized by striking anaplasia and features similar to the patient's previously resected WT with diffuse anaplasia. PMID:21961578

  6. The Influence of Frontal Lobe Tumors and Surgical Treatment on Advanced Cognitive Functions.

    PubMed

    Fang, Shengyu; Wang, Yinyan; Jiang, Tao

    2016-07-01

    Brain cognitive functions affect patient quality of life. The frontal lobe plays a crucial role in advanced cognitive functions, including executive function, meta-cognition, decision-making, memory, emotion, and language. Therefore, frontal tumors can lead to serious cognitive impairments. Currently, neurosurgical treatment is the primary method to treat brain tumors; however, the effects of the surgical treatments are difficult to predict or control. The treatment may both resolve the effects of the tumor to improve cognitive function or cause permanent disabilities resulting from damage to healthy functional brain tissue. Previous studies have focused on the influence of frontal lesions and surgical treatments on patient cognitive function. Here, we review cognitive impairment caused by frontal lobe brain tumors. PMID:27072331

  7. INFLUENCE OF ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ON MAMMARY GLAND DEVELOPMENT AND TUMOR SUSCEPTIBILITY

    EPA Science Inventory

    Influence of Endocrine Disrupting Compounds (EDCs) on Mammary Gland Development and Tumor Susceptibility.

    Suzanne E. Fenton1, and Jennifer Rayner1,2

    1 Reproductive Toxicology Division, NHEERL/ORD, U.S. EPA, Research Triangle Park, NC, and 2 Department of Environmen...

  8. A novel miR-451a isomiR, associated with amelanotypic phenotype, acts as a tumor suppressor in melanoma by retarding cell migration and invasion.

    PubMed

    Babapoor, Sankhiros; Fleming, Elizabeth; Wu, Rong; Dadras, Soheil S

    2014-01-01

    miRNAs are key regulatory small non-coding RNAs involved in critical steps of melanoma tumorigenesis; however, the relationship between sequence specific variations at the 5' or 3' termini (isomiR) of a miRNA and cancer phenotype remains unclear. Deep-sequencing and qRT-PCR showed reduced expression of miR-144/451a cluster and most abundant isomiR (miR451a.1) in dysplastic nevi, in-situ and invasive melanomas compared to common nevi and normal skin (n = 101). miRNA in situ hybridization reproducibly confirmed lost miR-451a.1 in melanoma compared to nevus cells or adjacent keratinocytes. Significantly higher expression of miR-451a.1 was associated with amelanotic phenotype in melanomas (n = 47). In contrast, miR-451a was associated with melanotic phenotype, absent pagetoid scatter of intraepidermal melanocytes, superficial spreading histological subtype and tumor inflammation. Sequencing miRNAs from cultured melanocytes with cytoplasmic melanin gradient (light, medium to dark) showed absent miR-451a while revealing other melanin-associated miRNAs, e.g. miR-30b, miR-100 and miR-590 in darkly and let-7a, let-7i and let-7f in lightly to moderately pigmented cultured melanocytes. Ectopic expression of miR-144/451a in melanoma cell lines resulted in markedly higher levels of mature miR-451a.1 than miR451a or miR-144; and significantly retarded cell migration and inhibited invasion in a glucose-sensitive manner. Surprisingly, these effects were not mediated by calcium binding protein 39 (CAB39), a proven miR451a gene target. miR-144/miR-451a cluster is a novel miRNA locus with tumor suppressive activity in melanoma. PMID:25237911

  9. Tumor and Endothelial Cell-Derived Microvesicles Carry Distinct CEACAMs and Influence T-Cell Behavior

    PubMed Central

    Muturi, Harrison T.; Dreesen, Janine D.; Nilewski, Elena; Jastrow, Holger; Giebel, Bernd; Ergun, Suleyman; Singer, Bernhard B.

    2013-01-01

    Normal and malignant cells release a variety of different vesicles into their extracellular environment. The most prominent vesicles are the microvesicles (MVs, 100-1 000 nm in diameter), which are shed of the plasma membrane, and the exosomes (70-120 nm in diameter), derivates of the endosomal system. MVs have been associated with intercellular communication processes and transport numerous proteins, lipids and RNAs. As essential component of immune-escape mechanisms tumor-derived MVs suppress immune responses. Additionally, tumor-derived MVs have been found to promote metastasis, tumor-stroma interactions and angiogenesis. Since members of the carcinoembryonic antigen related cell adhesion molecule (CEACAM)-family have been associated with similar processes, we studied the distribution and function of CEACAMs in MV fractions of different human epithelial tumor cells and of human and murine endothelial cells. Here we demonstrate that in association to their cell surface phenotype, MVs released from different human epithelial tumor cells contain CEACAM1, CEACAM5 and CEACAM6, while human and murine endothelial cells were positive for CEACAM1 only. Furthermore, MVs derived from CEACAM1 transfected CHO cells carried CEACAM1. In terms of their secretion kinetics, we show that MVs are permanently released in low doses, which are extensively increased upon cellular starvation stress. Although CEACAM1 did not transmit signals into MVs it served as ligand for CEACAM expressing cell types. We gained evidence that CEACAM1-positive MVs significantly increase the CD3 and CD3/CD28-induced T-cell proliferation. All together, our data demonstrate that MV-bound forms of CEACAMs play important roles in intercellular communication processes, which can modulate immune response, tumor progression, metastasis and angiogenesis. PMID:24040308

  10. Environmental influences on the Indo–Pacific octocoral Isis hippuris Linnaeus 1758 (Alcyonacea: Isididae): genetic fixation or phenotypic plasticity?

    PubMed Central

    Pochon, Xavier; Watling, Les

    2015-01-01

    As conspicuous modular components of benthic marine habitats, gorgonian (sea fan) octocorals have perplexed taxonomists for centuries through their shear diversity, particularly throughout the Indo–Pacific. Phenotypic incongruence within and between seemingly unitary lineages across contrasting environments can provide the raw material to investigate processes of disruptive selection. Two distinct phenotypes of the Isidid Isis hippuris Linnaeus, 1758 partition between differing reef environments: long-branched bushy colonies on degraded reefs, and short-branched multi/planar colonies on healthy reefs within the Wakatobi Marine National Park (WMNP), Indonesia. Multivariate analyses reveal phenotypic traits between morphotypes were likely integrated primarily at the colony level with increased polyp density and consistently smaller sclerite dimensions at the degraded site. Sediment load and turbidity, hence light availability, primarily influenced phenotypic differences between the two sites. This distinct morphological dissimilarity between the two sites is a reliable indicator of reef health; selection primarily acting on colony morphology, porosity through branching structure, as well as sclerite diversity and size. ITS2 sequence and predicted RNA secondary structure further revealed intraspecific variation between I. hippuris morphotypes relative to such environments (ΦST = 0.7683, P < 0.001). This evidence suggests—but does not confirm—that I. hippuris morphotypes within the WMNP are two separate species; however, to what extent and taxonomic assignment requires further investigation across its full geographic distribution. Incongruence between colonies present in the WMNP with tenuously described Isis alternatives (Isis reticulata Nutting, 1910, Isis minorbrachyblasta Zou, Huang & Wang, 1991), questions the validity of such assignments. Furthermore, phylogenetic analyses confirm early taxonomic suggestion that the characteristic jointed axis of the

  11. An optimized disaggregation method for human lung tumors that preserves the phenotype and function of the immune cells.

    PubMed

    Quatromoni, Jon G; Singhal, Sunil; Bhojnagarwala, Pratik; Hancock, Wayne W; Albelda, Steven M; Eruslanov, Evgeniy

    2015-01-01

    Careful preparation of human tissues is the cornerstone of obtaining accurate data in immunologic studies. Despite the essential importance of tissue processing in tumor immunology and clinical medicine, current methods of tissue disaggregation have not been rigorously tested for data fidelity. Thus, we critically evaluated the current techniques available in the literature that are used to prepare human lung tumors for immunologic studies. We discovered that these approaches are successful at digesting cellular attachments and ECMs; however, these methods frequently alter the immune cell composition and/or expression of surface molecules. We thus developed a novel approach to prepare human lung tumors for immunologic studies by combining gentle mechanical manipulation with an optimized cocktail of enzymes used at low doses. This enzymatic digestion cocktail optimized cell yield and cell viability, retrieved all major tumor-associated cell populations, and maintained the expression of cell-surface markers for lineage definition and in vivo effector functions. To our knowledge, we present the first rigorously tested disaggregation method designed for human lung tumors. PMID:25359999

  12. An optimized disaggregation method for human lung tumors that preserves the phenotype and function of the immune cells

    PubMed Central

    Quatromoni, Jon G.; Singhal, Sunil; Bhojnagarwala, Pratik; Hancock, Wayne W.; Albelda, Steven M.; Eruslanov, Evgeniy

    2015-01-01

    Careful preparation of human tissues is the cornerstone of obtaining accurate data in immunologic studies. Despite the essential importance of tissue processing in tumor immunology and clinical medicine, current methods of tissue disaggregation have not been rigorously tested for data fidelity. Thus, we critically evaluated the current techniques available in the literature that are used to prepare human lung tumors for immunologic studies. We discovered that these approaches are successful at digesting cellular attachments and ECMs; however, these methods frequently alter the immune cell composition and/or expression of surface molecules. We thus developed a novel approach to prepare human lung tumors for immunologic studies by combining gentle mechanical manipulation with an optimized cocktail of enzymes used at low doses. This enzymatic digestion cocktail optimized cell yield and cell viability, retrieved all major tumor-associated cell populations, and maintained the expression of cell-surface markers for lineage definition and in vivo effector functions. To our knowledge, we present the first rigorously tested disaggregation method designed for human lung tumors. PMID:25359999

  13. Role of the tumor suppressor ARF in macrophage polarization: Enhancement of the M2 phenotype in ARF-deficient mice.

    PubMed

    Herranz, Sandra; Través, Paqui G; Luque, Alfonso; Hortelano, Sonsoles

    2012-11-01

    The ARF locus is frequently inactivated in human cancer. The oncosuppressor ARF has indeed been described as a general sensor for different situation of cellular stress. We have previously demonstrated that ARF deficiency severely impairs inflammatory responses in vitro and in vivo, establishing a role for ARF in the regulation of innate immunity. The aim of the present work was to get further insights into the immune functions of ARF and to evaluate its possible contribution to the polarization of macrophages toward the M1 or M2 phenotype. Our results demonstrate that resting Arf(-/-) macrophages express high levels of Ym1 and Fizz-1, two typical markers of alternatively-activated macrophages (M2). Additionally, Arf(-/-) peritoneal macrophages showed an impaired response to lipopolysaccharide (a classical inducer of M1 polaryzation) and a reduced production of pro-inflammatory cytokines/chemokines. Moreover, upon stimulation with interleukin-4 (IL-4), an inducer of the M2 phenotype, well established M2 markers such as Fizz-1, Ym1 and arginase-1 were upregulated in Arf(-/-) as compared with wild type macrophages. Accordingly, the cytokine and chemokine profile associated with the M2 phenotype was significantly overexpressed in Arf(-/-) macrophages responding to IL-4. In addition, multiple pro-angiogenic factors such as VEGF and MMP-9 were also increased. In summary, these results indicate that ARF contributes to the polarization and functional plasticity of macrophages. PMID:23243586

  14. Fc block treatment, dead cells exclusion, and cell aggregates discrimination concur to prevent phenotypical artifacts in the analysis of subpopulations of tumor-infiltrating CD11b(+) myelomonocytic cells.

    PubMed

    Kuonen, Francois; Touvrey, Cedric; Laurent, Julien; Ruegg, Curzio

    2010-11-01

    It is well established that cancer cells can recruit CD11b(+) myeloid cells to promote tumor angiogenesis and tumor growth. Increasing interest has emerged on the identification of subpopulations of tumor-infiltrating CD11b(+) myeloid cells using flow cytometry techniques. In the literature, however, discrepancies exist on the phenotype of these cells (Coffelt et al., Am J Pathol 2010;176:1564-1576). Since flow cytometry analysis requires particular precautions for accurate sample preparation and trustable data acquisition, analysis, and interpretation, some discrepancies might be due to technical reasons rather than biological grounds. We used the syngenic orthotopic 4T1 mammary tumor model in immunocompetent BALB/c mice to analyze and compare the phenotype of CD11b(+) myeloid cells isolated from peripheral blood and from tumors, using six-color flow cytometry. We report here that the nonspecific antibody binding through Fc receptors, the presence of dead cells and cell doublets in tumor-derived samples concur to generate artifacts in the phenotype of tumor-infiltrating CD11b(+) subpopulations. We show that the heterogeneity of tumor-infiltrating CD11b(+) subpopulations analyzed without particular precautions was greatly reduced upon Fc block treatment, dead cells, and cell doublets exclusion. Phenotyping of tumor-infiltrating CD11b(+) cells was particularly sensitive to these parameters compared to circulating CD11b(+) cells. Taken together, our results identify Fc block treatment, dead cells, and cell doublets exclusion as simple but crucial steps for the proper analysis of tumor-infiltrating CD11b(+) cell populations. PMID:20824631

  15. Phenotypic heterogeneity influences the behavior of rat aortic smooth muscle cells in collagen lattice

    SciTech Connect

    Orlandi, Augusto . E-mail: orlandi@uniroma2.it; Ferlosio, Amedeo; Gabbiani, Giulio; Spagnoli, Luigi Giusto; Ehrlich, Paul H.

    2005-12-10

    Phenotypic modulation of vascular smooth muscle cells (SMCs) in atherosclerosis and restenosis involves responses to the surrounding microenvironment. SMCs obtained by enzymatic digestion from tunica media of newborn, young adult (YA) and old rats and from the thickened intima (TI) and underlying media of young adult rat aortas 15 days after ballooning were entrapped in floating populated collagen lattice (PCL). TI-SMCs elongated but were poor at PCL contraction and remodeling and expressed less {alpha}2 integrin compared to other SMCs that appeared more dendritic. During early phases of PCL contraction, SMCs showed a marked decrease in the expression of {alpha}-smooth muscle actin and myosin. SMCs other than TI-SMCs required 7 days to re-express {alpha}-smooth muscle actin and myosin. Only TI-SMCs in PCL were able to divide in 48 h, with a greater proportion in S and G2-M cell cycle phases compared to other SMCs. Anti-{alpha}2 integrin antibody markedly inhibited contraction but not proliferation in YA-SMC-PLCs; anti-{alpha}1 and anti-{alpha}2 integrin antibodies induced a similar slight inhibition in TI-SMC-PCLs. Finally, TI-SMCs rapidly migrated from PCL on plastic reacquiring their epithelioid phenotype. Heterogeneity in proliferation and cytoskeleton as well the capacity to remodel the extracellular matrix are maintained, when SMCs are suspended in PCLs.

  16. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.

    PubMed

    Brancaleoni, V; Balwani, M; Granata, F; Graziadei, G; Missineo, P; Fiorentino, V; Fustinoni, S; Cappellini, M D; Naik, H; Desnick, R J; Di Pierro, E

    2016-01-01

    X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromosomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

  17. Viral proliferation and expression of tumor-related gene in different chicken embryo fibroblasts infected with different tumorigenic phenotypes of avian leukosis virus subgroup J.

    PubMed

    Qu, Yajin; Liu, Litao; Niu, Yujuan; Qu, Yue; Li, Ning; Sun, Wei; Lv, Chuanwei; Wang, Pengfei; Zhang, Guihua; Liu, Sidang

    2016-10-01

    Subgroup J avian leukosis virus (ALV-J) causes a neoplastic disease in infected chickens. The ALV-J strain NX0101, which was isolated from broiler breeders in 2001, mainly induced formation of myeloid cell tumors. However, strain HN10PY01, which was recently isolated from laying hens, mainly induces formation of myeloid cell tumors and hemangioma. To identify the molecular pathological mechanism underlying changes in host susceptibility and tumor classification induced by these two types of ALV-J strains, chicken embryo fibroblasts derived from chickens with different genetic backgrounds (broiler breeders and laying hens) and an immortalized chicken embryo fibroblasts (DF-1) were prepared and infected with strain NX0101 or HN10PY01, respectively. The 50% tissue culture infective dose (TCID50) and levels of ALV group-specific antigen p27 and heat shock protein 70 in the supernatant collected from the ALV-J infected cells were detected. Moreover, mRNA expression levels of tumor-related genes p53, c-myc, and Bcl-2 in ALV-J-infected cells were quantified. The results indicated that the infection of ALV-J could significantly increase mRNA expression levels of p53, c-myc, and Bcl-2 Strain HN10PY01 exhibited a greater influence on the three tumor-related genes in each of the three types of cells when compared with strain NX0101, and the TCID50 and p27 levels in the supernatant collected from HN10PY01-infected cells were higher than those collected from NX0101-infected cells. These results indicate that the infection of the two ALV-J strains influenced the gene expression levels in the infected cells, while the newly isolated strain HN10PY01 showed higher replication ability in cells and induced higher expression levels of tumor-related genes in infected cells. Furthermore, virus titers and expression levels of tumor-related genes and cellular stress responses of cells with different genetic backgrounds when infected with each of the two ALV-J strain were different

  18. Childhood wheezing phenotypes influence asthma, lung function and exhaled nitric oxide fraction in adolescence.

    PubMed

    Duijts, Liesbeth; Granell, Raquel; Sterne, Jonathan A C; Henderson, A John

    2016-02-01

    The objective of this study was to examine the associations of childhood wheezing phenotypes with asthma, lung function and exhaled nitric oxide fraction (FeNO) in adolescence.In a population-based, prospective cohort study of 6841 children, we used latent class analysis to identify wheezing phenotypes during the first 7 years of life. Physician-diagnosed asthma, spirometry and FeNO were assessed at 14-15 years.Compared with never/infrequent wheeze, intermediate-onset and persistent wheeze were consistently strongest associated with higher risk of asthma (risk ratio (95% CI) 10.9 (8.97-13.16) and 9.13 (7.74-10.77), respectively), lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (mean difference in standard deviation units (SDU) (95% CI) -0.34 (-0.54- -0.14) and -0.50 (-0.62- -0.38), respectively), lower forced expiratory flow at 25-75% of FVC (FEF25-75%) (mean difference in SDU (95% CI) -0.30 (-0.49- -0.10) and -0.42 (-0.54- -0.30), respectively) and increased FEV1 bronchodilator reversibility (mean difference in SDU (95% CI) 0.12 (0.02-0.22) and 0.13 (0.06-0.19), respectively). Prolonged early and persistent wheeze were associated with a decline in FEV1/FVC ratio and FEF25-75% between 8-9 and 14-15 years. Intermediate-onset, late-onset and persistent wheeze were associated with higher FeNO ratios (ratio of geometric means (95% CI) 1.90 (1.59-2.29), 1.57 (1.39-1.77) and 1.37 (1.22-1.53), respectively, compared with never/infrequent wheeze).Early-onset wheezing phenotypes persisting after 18 months of age show the strongest associations with asthma, lower lung function, even worsening from mid-childhood, and higher FeNO levels in adolescence. PMID:26647439

  19. Locoregional Tumor Progression After Radiation Therapy Influences Overall Survival in Pediatric Patients With Neuroblastoma

    SciTech Connect

    Pai Panandiker, Atmaram S.; McGregor, Lisa; Krasin, Matthew J.; Wu Shengjie; Xiong Xiaoping; Merchant, Thomas E.

    2010-03-15

    Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. Results: With a median follow-up of 34 months +- 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy.

  20. Tumor

    MedlinePlus

    ... be removed because of their location or harmful effect on the surrounding normal brain tissue. If a tumor is cancer , possible treatments may include: Chemotherapy Radiation Surgery Targeted cancer therapy Biologic therapy Other treatment options

  1. Influence of phenotype conversion of epicardial adipocytes on the coronary atherosclerosis and its potential molecular mechanism

    PubMed Central

    Wang, Jing; Chen, Dong; Cheng, Xun-Min; Zhang, Qi-Gao; Peng, Yong-Ping; Wang, Li-Jun; He, Song-Qing; Gong, Jian-Bin

    2015-01-01

    Objective: To investigate the phenotype conversion of epicardial adipocytes and its potential molecular mechanism during the occurrence and development of coronary atherosclerosis. Methods: A total of 30 health male New Zealand white rabbits were used. In experiment group (n=15), rabbits were fed with high fat food to establish atherosclerosis animal model; rabbits in control group (n=15) were fed with normal food. Results: At week 0, UCP-1 and PPARγ mRNA expressions in EAT and sBAT were significantly higher than in eWAT, and leptin mRNA expression lower than (P<0.05). In experiment group, the mRNA expressions of UCP-1 and PPARγ reduced gradually, but leptin mRNA increased progressively in EAT (P<0.05). UCP-1 expression reduced gradually, the newly generated blood vessels reduced significantly, but leptin and RAM11 increased gradually (P<0.05). The adipocyte volume in EAT increased gradually, but the adipocyte number reduced progressively (P<0.05). The number of mitochondria with multiple crests reduced gradually in EAT; IL-6 reduced the mRNA expressions of UCP-1 and PPARγ in adipocytes of BAT in a dose dependent manner, but it increased the mRNA expressions of leptin and STAT3 (P<0.05). In the presence of IL-6, JSI-124 increased the mRNA expressions of UCP-1 and PPAR-γ in adipocytes of BAT in a dose dependent manner, but it reduced the mRNA expressions of leptin and STAT3 (P<0.05). Conclusion: During the progression of atherosclerosis, there is a phenotype conversion of EAT from BAT to WAT, which further promotes the focal occurrence and development of atherosclerosis; IL-6 may activate JAK-STAT3 pathway to induce this conversion. PMID:26692919

  2. Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype

    PubMed Central

    Gao, Jing; Wang, Dongsheng; Liu, Dan; Liu, Min; Ge, Yehua; Jiang, Minghong; Liu, Yanxin; Zheng, Dexian

    2015-01-01

    Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB–dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients. PMID:26224317

  3. Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

    PubMed

    Maggi, E C; Trillo-Tinoco, J; Struckhoff, A P; Vijayaraghavan, J; Del Valle, L; Crabtree, J S

    2016-01-01

    Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs. PMID:27548814

  4. Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype

    PubMed Central

    Maggi, E C; Trillo-Tinoco, J; Struckhoff, A P; Vijayaraghavan, J; Del Valle, L; Crabtree, J S

    2016-01-01

    Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs. PMID:27548814

  5. The influence of distinct asthma phenotypes on lung function following weight loss in the obese

    PubMed Central

    Chapman, David G.; Irvin, Charles G.; Kaminsky, David A.; Forgione, Patrick M.; Bates, Jason H.T.; Dixon, Anne E.

    2014-01-01

    Background and objective There appears to be two distinct clinical phenotypes of obese patients with asthma – those with early-onset asthma and high serum IgE (TH2-high) and those with late-onset asthma and low serum IgE (TH2-low). The aim of the present study was to determine in the two phenotypes of obese asthma the effect of weight-loss on small airway function. Methods TH2-low (n=8) and TH2-high (n=5) obese asthmatics underwent methacholine challenge before and 12 months following bariatric surgery. Dose response slopes as measures of sensitivity to airway closure and narrowing were measured as maximum %fall FVC and FEV1/FVC, respectively, divided by dose. Resting airway mechanics were measured by forced oscillation technique. Results Weight-loss reduced sensitivity to airway closure in TH2-low but not TH2-high obese asthmatics (pre-post mean change ± 95%CI: 1.8 ± 0.8 doubling doses vs −0.3 ± 1.7 doubling doses, p=0.04). However, there was no effect of weight loss on the sensitivity to airway narrowing in either group (p=0.8, TH2-low: 0.8 ± 1.0 doubling doses, TH2-high: −1.1 ± 2.5 doubling doses). In contrast, respiratory resistance (20Hz) improved in TH2-high but not in TH2-low obese asthmatics (pre-post change median [IQR]: 1.5 [1.3 – 2.8] cmH2O/L/s vs 0.6 [−1.8 – 0.8] cmH2O/L/s, p=0.03). Conclusions TH2-low obese asthmatics appear to be characterised by increased small airway responsiveness and abnormalities in resting airway function that may persist following weight loss. However, this was not the case for TH2-high obese asthmatics, highlighting the complex interplay between IgE status and asthma pathophysiology in obesity. PMID:25138203

  6. The individual and combined influence of ACE and ACTN3 genotypes on muscle phenotypes before and after strength training.

    PubMed

    Erskine, R M; Williams, A G; Jones, D A; Stewart, C E; Degens, H

    2014-08-01

    Alternative measures of muscle size, strength, and power to those used in previous studies could help resolve the controversy surrounding associations between polymorphisms of the angiotensin-I converting enzyme (ACE) and α-actinin-3 (ACTN3) genes and skeletal muscle phenotypes, and the responses to resistance training (RT). To this end, we measured quadriceps femoris muscle volume (Vm), physiological cross-sectional area (PCSA), maximum isometric force (Ft), specific force (Ft per unit PCSA), maximum isoinertial strength (1-RM), and maximum power (Wmax ; n = 40) before and after 9-week knee extension RT in 51 previously untrained young men, who were genotyped for the ACE I/D and ACTN3 R577X polymorphisms. ACTN3 R-allele carriers had greater Vm, 1-RM, and Wmax than XX homozygotes at baseline (all P < 0.05), but responses to RT were independent of ACTN3 genotype (all P > 0.05). Muscle phenotypes were independent of ACE genotype before (all P > 0.05) and after RT (all P > 0.01). However, people with the "optimal" ACE+ACTN3 genotype combination had greater baseline 1-RM and Wmax compared to those with the "suboptimal" profile (both P < 0.0125). We show for the first time that the ACTN3 R577X polymorphism is associated with human Vm and (independently and in combination with the ACE I/D polymorphism) influences 1-RM and Wmax. PMID:23384112

  7. The timing of surgery after neoadjuvant radiotherapy influences tumor dissemination in a preclinical model

    PubMed Central

    Leroi, Natacha; Sounni, Nor Eddine; Van Overmeire, Eva; Blacher, Silvia; Marée, Raphael; Van Ginderachter, Jo; Lallemand, François; Lenaerts, Eric; Coucke, Philippe; Noel, Agnès; Martinive, Philippe

    2015-01-01

    Neoadjuvant radiotherapy (neoRT) used in cancer treatments aims at improving local tumor control and patient overall survival. The neoRT schedule and the timing of the surgical treatment (ST) are empirically based and influenced by the clinician's experience. The current study examines how the sequencing of neoRT and ST affects metastatic dissemination. In a breast carcinoma model, tumors were exposed to different neoRT schedules (2x5Gy or 5x2Gy) followed by surgery at day 4 or 11 post-RT. The impact on the tumor microenvironment and lung metastases was evaluated through immunohistochemical and flow cytometry analyses. After 2x5Gy, early ST (at day 4 post-RT) led to increased size and number of lung metastases as compared to ST performed at day 11. Inversely, after 5x2Gy neoRT, early ST protected the mice against lung metastases. This intriguing relationship between tumor aggressiveness and ST timing could not be explained by differences in classical parameters studied such as hypoxia, vessel density and matrix remodeling. The study of tumor-related inflammation and immunity reveals an increased circulating NK cell percentage following neoRT as compared to non irradiated mice. Then, radiation treatment and surgery were applied to tumor-bearing NOD/SCID mice. In the absence of NK cells, neoRT appears to increase lung metastatic dissemination as compared to non irradiated tumor-bearing mice. Altogether our data demonstrate that the neoRT schedule and the ST timing affect metastasis formation in a pre-clinical model and points out the potential role of NK cells. These findings highlight the importance to cautiously tailor the optimal window for ST following RT. PMID:26440148

  8. Influence of Sex on Suicidal Phenotypes in Affective Disorder Patients with Traumatic Childhood Experiences

    PubMed Central

    Carlberg, Laura; Swoboda, Patrick; Ludwig, Birgit; Koller, Romina; Kapusta, Nestor D.; Aigner, Martin; Haslacher, Helmuth; Schmöger, Michaela; Kasper, Siegfried; Schosser, Alexandra

    2015-01-01

    Objectives In the current study, we aimed to investigate the impact of childhood trauma on suicidal behaviour phenotypes in a group of patients with diagnosed affective disorder (unipolar or bipolar affective disorder). Patients and Methods Patients with and without a history of childhood abuse, measured by Childhood Trauma Questionnaire (CTQ), were assessed to explore risks for suicidal behaviour (including suicide attempt, self-harm and non-suicidal self-injury). The tested sample consisted of 258 patients (111 males and 147 females, in-patients and out-patients at the Department of Psychiatry and Psychotherapy, Medical University of Vienna and University Hospital Tulln, Lower Austria). Psychiatric diagnoses were derived from the SCAN (Schedules for Clinical Assessment in Neuropsychiatry) interview. In addition, patients were administered the Lifetime Parasuicidal Count (LPC), Suicidal Behaviour Questionnaire (SBQ-R), and Viennese Suicide Risk Assessment Scale (VISURIAS) questionnaires. Results In contrast to male suicide attempters, female suicide attempters showed both significantly higher total CTQ scores (p<0.001), and higher CTQ subscores (emotional, physical and sexual abuse, as well as emotional and physical neglect) in comparison to the non-suicidal control group. Besides, females with a history of self-harming behaviour (including suicidal intention) and Non-Suicidal-Self Injury (NSSI) had significantly higher CTQ total scores (p<0.001) than the control group. Conclusion These findings suggest gender differences in suicidal behaviour after being exposed to childhood trauma. PMID:26366559

  9. The Specificity of Targeted Vaccines for APC Surface Molecules Influences the Immune Response Phenotype

    PubMed Central

    Grødeland, Gunnveig; Mjaaland, Siri; Tunheim, Gro; Fredriksen, Agnete B.; Bogen, Bjarne

    2013-01-01

    Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8+/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs. PMID:24244595

  10. Nuances in diet quality and quantity influence phenotypic dimorphism during honey bee (Apis mellifera) caste determination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nutrition intake during the larval stage of holometabolous insect’s influences and fuels growth throughout metamorphosis. In social insects, differences in larval nutrition can regulate a profound reproductive division of labor. Provisioning by nurse bees differs between worker-destined and queen-de...

  11. Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype.

    PubMed

    Azevedo, M; Eriksson, S; Mendes, N; Serpa, J; Figueiredo, C; Resende, L P; Ruvoën-Clouet, N; Haas, R; Borén, T; Le Pendu, J; David, L

    2008-07-01

    Helicobacter pylori (Hp) infects half the world's population and causes diverse gastric lesions, from gastritis to gastric cancer. Our aim was to evaluate the significance of secretor and Lewis status in infection and in vitro adherence by Hp expressing BabA adhesin. We enrolled 304 Hp-infected individuals from Northern Portugal. Gastric biopsies, blood and saliva were collected. Polymerase chain reaction (PCR) and immunofluorescence were used to detect BabA+ Hp in gastric biopsies. In vitro adherence by a BabA expressing Hp strain to gastric biopsies was performed. Secretor status was identified by Ulex, a lectin that recognizes secretor-dependent glycan structures in saliva and in gastric mucosa, and by Lewis(a/b) antibodies, and indirectly by identification of an inactivating mutation in the FUT2 gene (G428A). BabA status of infecting Hp was associated with CagA and VacAs1 (p < 0.05), intercellular localization of Hp (p < 0.01) and the presence of intestinal metaplasia (p < 0.05) and degenerative alterations (p < 0.005) in the biopsies. BabA was associated (p < 0.05) with Ulex staining of gastric biopsies and, although not significantly, to absence of homozygosity for FUT2 G428A inactivating polymorphism. In vitro Hp adherence was higher in cases wild-type or heterozygous for FUT2 G428A mutation (p < 0.0001), cases staining for Ulex (p < 0.0001) and a(-)b+ and a(-)b(-) secretor phenotypes (p < 0.001). In conclusion, BabA+ Hp infection/adhesion is secretor-dependent and associated with the severity of gastric lesions. PMID:18498114

  12. Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

    PubMed Central

    Bresin, Elena; Rurali, Erica; Caprioli, Jessica; Sanchez-Corral, Pilar; Fremeaux-Bacchi, Veronique; Rodriguez de Cordoba, Santiago; Pinto, Sheila; Goodship, Timothy H.J.; Alberti, Marta; Ribes, David; Valoti, Elisabetta; Remuzzi, Giuseppe

    2013-01-01

    Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype–phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%–10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation. PMID:23431077

  13. Molecular cytogenetic anomalies and phenotype alterations in a newly established cell line from Wilms tumor with diffuse anaplasia.

    PubMed

    Faussillon, Marine; Murakami, Ichiro; Bichat, Magalie; Telvi, Louise; Jeanpierre, Cécile; Nezelof, Christian; Jaubert, Francis; Gogusev, Jean

    2008-07-01

    The novel continuous cell line WT-Pe.1 was established in vitro from Wilms tumor with histological features of diffuse anaplasia. The cultures grew as poorly differentiated epithelial-like cells with pleomorphic polygonal shapes and formation of typical monolayers. WT-Pe.1 cells were immunoreactive for cytokeratin, vimentin, laminin, villin, CD10, and CD24 proteins. Conventional cytogenetic analysis by RHG-banding revealed a hypotriploid karyotype with numerous abnormalities including ring chromosomes, double-minutes, homogeneous staining regions, radial structures, dicentrics, and several marker chromosomes. Comparative genomic hybridization analysis revealed DNA copy numbers losses on chromosome segments 1p, 3p, 6q, 9q34.1 approximately q34.3, 11q24 approximately q25, 14q12 approximately qter, 16q, 18q, and 22q11 approximately q13; gain of genomic material was localized on chromosome arms 1q, 4p, 6q, and 7p and the entire chromosome 12. With DNA from the original tumor, copy number losses were detected on chromosomes 1p, 14q, 16q, 17q, and 22q and gains were observed on 1q, 4p, 8q, 12p, 12q, and chromosome 14p. Copy number amplifications of distinct loci were found on 1q21.1 and 4p15.3, as well as an elevated copy number of cyclin D2 (CCND2) and cyclin D associated kinase (CDK4) genes on chromosome 12 (confirmed by fluorescence in situ hybridization). PMID:18558285

  14. MicroRNA 218 Acts as a Tumor Suppressor by Targeting Multiple Cancer Phenotype-associated Genes in Medulloblastoma*

    PubMed Central

    Venkataraman, Sujatha; Birks, Diane K.; Balakrishnan, Ilango; Alimova, Irina; Harris, Peter S.; Patel, Purvi R.; Handler, Michael H.; Dubuc, Adrian; Taylor, Michael D.; Foreman, Nicholas K.; Vibhakar, Rajeev

    2013-01-01

    Aberrant expression of microRNAs has been implicated in many cancers. We recently demonstrated differential expression of several microRNAs in medulloblastoma. In this study, the regulation and function of microRNA 218 (miR-218), which is significantly underexpressed in medulloblastoma, was evaluated. Re-expression of miR-218 resulted in a significant decrease in medulloblastoma cell growth, cell colony formation, cell migration, invasion, and tumor sphere size. We used C17.2 neural stem cells as a model to show that increased miR-218 expression results in increased cell differentiation and also decreased malignant transformation when transfected with the oncogene REST. These results suggest that miR-218 acts as a tumor suppressor in medulloblastoma. MicroRNAs function by down-regulating translation of target mRNAs. Targets are determined by imperfect base pairing of the microRNA to the 3′-UTR of the mRNA. To comprehensively identify actual miR-218 targets, medulloblastoma cells overexpressing miR-218 and control cells were subjected to high throughput sequencing of RNA isolated by cross-linking immunoprecipitation, a technique that identifies the mRNAs bound to the RNA-induced silencing complex component protein Argonaute 2. High throughput sequencing of mRNAs identified 618 genes as targets of miR-218 and included both previously validated targets and many targets not predicted computationally. Additional work further confirmed CDK6, RICTOR, and CTSB (cathepsin B) as targets of miR-218 and examined the functional role of one of these targets, CDK6, in medulloblastoma. PMID:23212916

  15. DNMT3B7 Expression Promotes Tumor Progression to a More Aggressive Phenotype in Breast Cancer Cells

    PubMed Central

    Brambert, Patrick R.; Kelpsch, Daniel J.; Hameed, Rabia; Desai, Charmi V.; Calafiore, Gianfranco; Godley, Lucy A.; Raimondi, Stacey L.

    2015-01-01

    Epigenetic changes, such as DNA methylation, have been shown to promote breast cancer progression. However, the mechanism by which cancer cells acquire and maintain abnormal DNA methylation is not well understood. We have previously identified an aberrant splice form of a DNA methyltransferase, DNMT3B7, expressed in virtually all cancer cell lines but at very low levels in normal cells. Furthermore, aggressive MDA-MB-231 breast cancer cells have been shown to express increased levels of DNMT3B7 compared to poorly invasive MCF-7 cells, indicating that DNMT3B7 may have a role in promoting a more invasive phenotype. Using data gathered from The Cancer Genome Atlas, we show that DNMT3B7 expression is increased in breast cancer patient tissues compared to normal tissue. To determine the mechanism by which DNMT3B7 was functioning in breast cancer cells, two poorly invasive breast cancer cell lines, MCF-7 and T-47D, were stably transfected with a DNMT3B7 expression construct. Expression of DNMT3B7 led to hypermethylation and down-regulation of E-cadherin, altered localization of β-catenin, as well as increased adhesion turnover, cell proliferation, and anchorage-independent growth. The novel results presented in this study suggest a role for DNMT3B7 in the progression of breast cancer to a more aggressive state and the potential for future development of novel therapeutics. PMID:25607950

  16. Influence of brain tumors on the MR spectra of healthy brain tissue.

    PubMed

    Busch, M; Liebenrodt, K; Gottfried, S; Weiland, E; Vollmann, W; Mateiescu, S; Winter, S; Lange, S; Sahinbas, H; Baier, J; van Leeuwen, P; Grönemeyer, D

    2011-01-01

    The neurochemical environment of nontumorous white matter tissue was investigated in 135 single voxel spectra of "healthy" white matter regions of 43 tumor patients and 129 spectra of 52 healthy subjects. Spectra were acquired with short TE and TR values. With the data of tumor patients, it was examined whether differences were caused by the tumor itself or aggressive tumor therapies as confounding factors. Comparing the spectra of both classes, an excellent differentiation was possible based on the metabolite peak of N-acetylaspartate (P ≈ 0) and myoinositol (P < 0.03). The area under curve of the receiver operating characteristic was calculated as 0.86 and 0.62, respectively. With linear discriminant analysis using combinations of integrals, a prediction was possible, whether a spectrum belonged to the patient or the healthy subject class with an overall accuracy above 80%. The confounding factors could be ruled out as source of the differences. The results show strong evidence for an influence of malignant growth on the biochemical environment of nontumorous white matter tissue. Because of the T(1) weighting, the measured differences between both classes were most likely concentration changes interfered by T(1) effects. The underlying processes will be subject of future studies. PMID:20859993

  17. Nuclear β-Catenin Induces an Early Liver Progenitor Phenotype in Hepatocellular Carcinoma and Promotes Tumor Recurrence

    PubMed Central

    Zulehner, Gudrun; Mikula, Mario; Schneller, Doris; van Zijl, Franziska; Huber, Heidemarie; Sieghart, Wolfgang; Grasl-Kraupp, Bettina; Waldhör, Thomas; Peck-Radosavljevic, Markus; Beug, Hartmut; Mikulits, Wolfgang

    2010-01-01

    Transforming growth factor-β cooperates with oncogenic Ras to activate nuclear β-catenin during the epithelial to mesenchymal transition of hepatocytes, a process relevant in the progression of hepatocellular carcinoma (HCC). In this study we investigated the role of β-catenin in the differentiation of murine, oncogene-targeted hepatocytes and in 133 human HCC patients scheduled for orthotopic liver transplantation. Transforming growth factor-β caused dissociation of plasma membrane E-cadherin/β-catenin complexes and accumulation of nuclear β-catenin in Ras-transformed, but otherwise normal hepatocytes in p19ARF−/− mice. Both processes were inhibited by Smad7-mediated disruption of transforming growth factor-β signaling. Overexpression of constitutively active β-catenin resulted in high levels of CK19 and M2-PK, whereas ablation of β-catenin by axin overexpression caused strong expression of CK8 and CK18. Therefore, nuclear β-catenin resulted in dedifferentiation of neoplastic hepatocytes to immature progenitor cells, whereas loss of nuclear β-catenin led to a differentiated HCC phenotype. Poorly differentiated human HCC showed cytoplasmic redistribution or even loss of E-cadherin, suggesting epithelial to mesenchymal transition. Analysis of 133 HCC patient samples revealed that 58.6% of human HCC exhibited strong nuclear β-catenin accumulation, which correlated with clinical features such as vascular invasion and recurrence of disease after orthotopic liver transplantation. These data suggest that activation of β-catenin signaling causes dedifferentiation to malignant, immature hepatocyte progenitors and facilitates recurrence of human HCC after orthotopic liver transplantation. PMID:20008139

  18. Impact of new screening technologies: should we screen and does phenotype influence this decision?

    PubMed

    Bonham, James Robert

    2013-07-01

    The early detection offered by newborn screening for phenylketonuria clearly demonstrates the benefits for patients with inherited metabolic disorders of well organised screening programmes. It is therefore perhaps surprising that 20 years after the introduction of electrospray MS/MS methods to support expanded newborn screening that considerable international variation in practice, not linked to economic factors, exists. It is likely that the commonly used criteria to assess the suitability of a disorder for screening need to be re-appraised as they apply to rare disorders. In addition, national differences in the pattern of policy making may influence the strategy adopted and these different approaches need to be scrutinised more closely. Despite this contextual variation a number of real issues do need to be addressed as the range of conditions included in screening programmes continues to increase. These include the need for well organised outcome studies based upon agreed case definitions and comparable treatment regimens; the need for appropriate information for parents to support them before and during the screening odyssey; an improved understanding of the impact of false positive results and in particular a clearer understanding of the way in which some of the problems resulting from false positive results can be avoided or ameliorated; the challenge offered by mild or atypical screen positive cases and the consequent design of proportionate treatment options. A thorough understanding of the genetic, biochemical and clinical features of screen positive cases supported by effective international outcome studies is required to optimise both screening and treatment strategies. PMID:23508696

  19. Host genetic influence on papillomavirus-induced tumors in the horse.

    PubMed

    Staiger, Elizabeth A; Tseng, Chia T; Miller, Donald; Cassano, Jennifer M; Nasir, Lubna; Garrick, Dorian; Brooks, Samantha A; Antczak, Douglas F

    2016-08-15

    The common equine skin tumors known as sarcoids have been causally associated with infection by bovine papillomavirus (BPV). Additionally, there is evidence for host genetic susceptibility to sarcoids. We investigated the genetic basis of susceptibility to sarcoid tumors on a cohort of 82 affected horses and 270 controls genotyped on a genome-wide platform and two custom panels. A Genome Wide Association Study (GWAS) identified candidate regions on six chromosomes. Bayesian probability analysis of the same dataset verified only the regions on equine chromosomes (ECA) 20 and 22. Fine mapping using custom-produced SNP arrays for ECA20 and ECA22 regions identified two marker loci with high levels of significance: SNP BIEC2-530826 (map position 32,787,619) on ECA20 in an intron of the DQA1 gene in the Major Histocompatibility Complex (MHC) class II region (p = 4.6e-06), and SNP BIEC2-589604 (map position 25,951,536) on ECA22 in a 200 kb region containing four candidate genes: PROCR, EDEM2, EIF6 and MMP24 (p = 2.14e-06). The marker loci yielded odds ratios of 5.05 and 4.02 for ECA20 and ECA22, respectively. Associations between genetic MHC class II variants and papillomavirus-induced tumors have been reported for human papillomavirus and cottontail rabbit papillomavirus infections. This suggests a common mechanism for susceptibility to tumor progression that may involve subversion of the host immune response. This study also identified a genomic region other than MHC that influenced papillomavirus-induced tumor development in the studied population. PMID:27037728

  20. Size matters: How population size influences genotype–phenotype association studies in anonymized data

    PubMed Central

    Denny, Joshua C.; Haines, Jonathan L.; Roden, Dan M.; Malin, Bradley A.

    2014-01-01

    Objective Electronic medical records (EMRs) data is increasingly incorporated into genome-phenome association studies. Investigators hope to share data, but there are concerns it may be “re-identified” through the exploitation of various features, such as combinations of standardized clinical codes. Formal anonymization algorithms (e.g., k-anonymization) can prevent such violations, but prior studies suggest that the size of the population available for anonymization may influence the utility of the resulting data. We systematically investigate this issue using a large-scale biorepository and EMR system through which we evaluate the ability of researchers to learn from anonymized data for genome- phenome association studies under various conditions. Methods We use a k-anonymization strategy to simulate a data protection process (on data sets containing clinical codes) for resources of similar size to those found at nine academic medical institutions within the United States. Following the protection process, we replicate an existing genome-phenome association study and compare the discoveries using the protected data and the original data through the correlation (r2) of the p-values of association significance. Results Our investigation shows that anonymizing an entire dataset with respect to the population from which it is derived yields significantly more utility than small study-specific datasets anonymized unto themselves. When evaluated using the correlation of genome-phenome association strengths on anonymized data versus original data, all nine simulated sites, results from largest-scale anonymizations (population ∼ 100;000) retained better utility to those on smaller sizes (population ∼ 6000—75;000). We observed a general trend of increasing r2 for larger data set sizes: r2 = 0.9481 for small-sized datasets, r2 = 0.9493 for moderately-sized datasets, r2 = 0.9934 for large-sized datasets. Conclusions This research implies that regardless of the

  1. Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: Role of β-catenin/connexin43 association

    SciTech Connect

    Talhouk, Rabih S.; Fares, Mohamed-Bilal; Rahme, Gilbert J.; Hariri, Hanaa H.; Rayess, Tina; Dbouk, Hashem A.; Bazzoun, Dana; Al-Labban, Dania; El-Sabban, Marwan E.

    2013-12-10

    Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures. C-terminus truncated Cx43 did not alter proliferation. Untransfected MCF-7 cells formed spherical aggregates in 3D cultures, and MDA-MB-231 cells formed stellar aggregates. However, MCF-7 cells over-expressing Cx43 formed smaller sized clusters and Cx43 expressing MDA-MB-231 cells lost their stellar morphology. Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced by 60% and 30% respectively. On the other hand, silencing Cx43 in MCF10A cells, nonneoplastic human mammary cell line, increased proliferation in both 2D and 3D cultures, and disrupted acinar morphology. Although Cx43 over-expression did not affect total levels of β-catenin, α-catenin and ZO-2, it decreased nuclear levels of β-catenin in 2D and 3D cultures of MCF-7 cells, and in 3D cultures of MDA-MB-231 cells. Cx43 associated at the membrane with α-catenin, β-catenin and ZO-2 in 2D and 3D cultures of MCF-7 cells, and only in 3D conditions in MDA-MB-231 cells. This study suggests that Cx43 exerts tumor suppressive effects in a context-dependent manner where GJ assembly with α-catenin, β-catenin and ZO-2 may be implicated in reducing growth rate, invasiveness, and, malignant phenotype of 2D and 3D cultures of MCF-7 cells, and 3D cultures of MDA-MB-231 cells, by sequestering β-catenin away from nucleus. - Highlights: • Cx43 over-expressing MCF-7 and MDA-MB-231 were grown in 2D and 3D cultures. • Proliferation and growth morphology were affected in a context dependent manner. • Extravasation ability of both MCF

  2. Influence of fatty acid-free diet on mammary tumor development and growth rate in HER-2/Neu transgenic mice.

    PubMed

    Rossini, Anna; Zanobbio, Laura; Sfondrini, Lucia; Cavalleri, Adalberto; Secreto, Giorgio; Morelli, Daniele; Palazzo, Marco; Sommariva, Michele; Tagliabue, Elda; Rumio, Cristiano; Balsari, Andrea

    2013-01-01

    Numerous investigations have found a relationship between higher risk of cancer and increased intake of fats, while results of clinical studies of fat reduction and breast cancer recurrence have been mixed. A diet completely free of fats cannot be easily administered to humans, but experimental studies in mice can be done to determine whether this extreme condition influences tumor development. Here, we examined the effects of a FA-free diet on mammary tumor development and growth rate in female FVB-neu proto-oncogene transgenic mice that develop spontaneous multifocal mammary tumors after a long latency period. Mice were fed a fatty acid-free diet beginning at 112, 35, and 30 days of age. In all these experiments, tumor appearance was delayed, tumor incidence was reduced and the mean number of palpable mammary tumors per mouse was lower, as compared to standard diet-fed mice. By contrast, tumor growth rate was unaffected in mice fed the fatty acid-free diet. Plasma of mice fed the fatty acid-free diet revealed significantly higher contents of oleic, palmitoleic and 20:3ω9 acids and lower contents of linoleic and palmitic acids. In conclusion, these findings indicate that a FA-free diet reduces tumor incidence and latency but not tumor growth rate, suggesting that a reduction in dietary FAs in humans may have a protective effect on tumorigenesis but not on tumors once they appear. PMID:22689438

  3. Perioperative problems in patients with brainstem tumors and their influence on patient outcome

    PubMed Central

    Bharati, Sachidanand J; Pandia, Mihir Prakash; Rath, Girija Prasad; Bithal, Parmod Kumar; Dash, Hari Hara; Dube, Surya K

    2016-01-01

    Background and Aims: Patients with brainstem tumors have many associated systemic abnormalities and are prone to develop perioperative complications. We studied the problems associated with brainstem tumors and their influence on the postoperative neurological outcome. Material and Methods: Retrospective review of records of patients who underwent surgery for brainstem tumors over a period of 8 years was done. Preoperative variables, perioperative complications and neurological outcome as assessed by Glasgow Outcome Scale at the time of hospital discharge were noted. Association between perioperative factors and the unfavorable neurological outcome was evaluated. Results: Data of 70 patients were retrieved, 7 patients were excluded from the study because of incomplete data and data analysis was carried out for 63 patients. We found that lower cranial nerve palsies (32%) and hydrocephalus (43%) were common preoperatively. Various intraoperative problems encountered were hemodynamic instability (56%), major blood loss requiring blood transfusion (40%) and venous air embolism (11%), and postoperative problems were meningitis (51%), hypokalemia (38%), chest infection (21%), seizure (11%), deterioration of Glasgow Coma Scale (GCS, 11%), hyponatremia (8%), hydrocephalus (6%), respiratory distress (3%) and operatives site hematoma (3%). Fifty-six (89%) patients had favorable outcome at hospital discharge whereas, 7 (11%) had an unfavorable outcome. There was no association between pre- and intra-operative factors and the neurological outcome. Deterioration of GCS, chest infection, and the need for reintubation and tracheostomy were associated with unfavorable neurological outcome. Conclusion: Patients of brainstem tumors are at increased risk of perioperative complications. Some of the postoperative complications were associated with unfavorable neurological outcome. PMID:27275044

  4. Influence of catechol-O-methyltransferase (COMT) genotypes on the prognosis of canine mammary tumors.

    PubMed

    Dias Pereira, P; Lopes, C C; Matos, A J F; Pinto, D; Gärtner, F; Lopes, C; Medeiros, R

    2009-11-01

    Catechol-O-methyltransferase (COMT) is an important enzyme involved in inactivation of catechol estrogens, which are metabolites with carcinogenic properties. Some investigations in human breast cancer associate a genetic polymorphism in the COMT gene (COMT val158met) with an increased risk and poor clinical progression of the disease. In dogs, there are 2 recognized single nucleotide polymorphisms in the COMT gene (COMTG216A and COMTG482A); however, their influence on the outcome of mammary neoplasms has never been investigated. The purpose of this study is to investigate the influence of COMT in the clinical progression of canine mammary tumors, namely in recurrence, metastasis and survival by testing 2 SNPs (G216A and G482A), and 2 genotypes of the COMT gene. A case series was conducted analyzing genomic DNA samples by polymerase chain reaction-restriction fragment length polymorphism from 80 bitches with mammary tumors. Animals were submitted to an active follow-up study for a period of 24 months after surgery. We observed that bitches carrying both genetic variations simultaneously are more likely to develop recurrence of mammary lesions. Our results demonstrate a possible role for COMT genotypes in the outcome of mammary neoplasms in the dog. Identifying a genetic factor predictive of recurrence may be useful in selecting the most effective surgical approach for canine mammary neoplasms. PMID:19605895

  5. Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors.

    PubMed

    Willerding, Linus; Limmer, Simone; Hossann, Martin; Zengerle, Anja; Wachholz, Kirsten; Ten Hagen, Timo L M; Koning, Gerben A; Sroka, Ronald; Lindner, Lars H; Peller, Michael

    2016-01-28

    Systemic chemotherapy of solid tumors could be enhanced by local hyperthermia (HT) in combination with thermosensitive liposomes (TSL) as drug carriers. In such an approach, effective HT of the tumor is considered essential for successful triggering local drug release and targeting of the drug to the tumor. To investigate the effect of HT method on the effectiveness of drug delivery, a novel laser-based HT device designed for the use in magnetic resonance imaging (MRI) was compared systematically with the frequently used cold light lamp and water bath HT. Long circulating phosphatidyldiglycerol-based TSL (DPPG2-TSL) with encapsulated doxorubicin (DOX) were used as drug carrier enabling intravascular drug release. Experiments were performed in male Brown Norway rats with a syngeneic soft tissue sarcoma (BN 175) located on both hind legs. One tumor was heated while the second tumor remained unheated as a reference. Six animals were investigated per HT method. DPPG2-TSL were injected i.v. at a stable tumor temperature above 40°C. Thereafter, temperature was maintained for 60min. Total DOX concentration in plasma, tumor tissue and muscle was determined post therapy by HPLC. Finally, the new laser-based device was tested in a MRI environment at 3T using DPPG2-TSL with encapsulated Gd-based contrast agent. All methods showed effective DOX delivery by TSL with 4.5-23.1ng/mg found in the heated tumors. In contrast, DOX concentration in the non-heated tumors was 0.5±0.1ng/mg. Independent of used HT methods, higher DOX levels were found in the smaller tumors. In comparison water bath induced lowest DOX delivery but still showing fourfold higher DOX concentrations compared to the non-heated tumors. With the laser-based applicator, a 13 fold higher DOX deposition was possible for large tumors and a 15 fold higher for the small tumors, respectively. Temperature gradients in the tumor tissue were higher with the laser and cold light lamp (-0.3°C/mm to -0.5°C/mm) compared to

  6. Vision 20/20: Molecular-guided surgical oncology based upon tumor metabolism or immunologic phenotype: Technological pathways for point of care imaging and intervention

    PubMed Central

    Paulsen, Keith D.; Samkoe, Kimberley S.; Elliott, Jonathan T.; Hasan, Tayyaba; Strong, Theresa V.; Draney, Daniel R.; Feldwisch, Joachim

    2016-01-01

    Surgical guidance with fluorescence has been demonstrated in individual clinical trials for decades, but the scientific and commercial conditions exist today for a dramatic increase in clinical value. In the past decade, increased use of indocyanine green based visualization of vascular flow, biliary function, and tissue perfusion has spawned a robust growth in commercial systems that have near-infrared emission imaging and video display capabilities. This recent history combined with major preclinical innovations in fluorescent-labeled molecular probes, has the potential for a shift in surgical practice toward resection guidance based upon molecular information in addition to conventional visual and palpable cues. Most surgical subspecialties already have treatment management decisions partially based upon the immunohistochemical phenotype of the cancer, as assessed from molecular pathology of the biopsy tissue. This phenotyping can inform the surgical resection process by spatial mapping of these features. Further integration of the diagnostic and therapeutic value of tumor metabolism sensing molecules or immune binding agents directly into the surgical process can help this field mature. Maximal value to the patient would come from identifying the spatial patterns of molecular expression in vivo that are well known to exist. However, as each molecular agent is advanced into trials, the performance of the imaging system can have a critical impact on the success. For example, use of pre-existing commercial imaging systems are not well suited to image receptor targeted fluorophores because of the lower concentrations expected, requiring orders of magnitude more sensitivity. Additionally the imaging system needs the appropriate dynamic range and image processing features to view molecular probes or therapeutics that may have nonspecific uptake or pharmacokinetic issues which lead to limitations in contrast. Imaging systems need to be chosen based upon objective

  7. Vision 20/20: Molecular-guided surgical oncology based upon tumor metabolism or immunologic phenotype: Technological pathways for point of care imaging and intervention.

    PubMed

    Pogue, Brian W; Paulsen, Keith D; Samkoe, Kimberley S; Elliott, Jonathan T; Hasan, Tayyaba; Strong, Theresa V; Draney, Daniel R; Feldwisch, Joachim

    2016-06-01

    Surgical guidance with fluorescence has been demonstrated in individual clinical trials for decades, but the scientific and commercial conditions exist today for a dramatic increase in clinical value. In the past decade, increased use of indocyanine green based visualization of vascular flow, biliary function, and tissue perfusion has spawned a robust growth in commercial systems that have near-infrared emission imaging and video display capabilities. This recent history combined with major preclinical innovations in fluorescent-labeled molecular probes, has the potential for a shift in surgical practice toward resection guidance based upon molecular information in addition to conventional visual and palpable cues. Most surgical subspecialties already have treatment management decisions partially based upon the immunohistochemical phenotype of the cancer, as assessed from molecular pathology of the biopsy tissue. This phenotyping can inform the surgical resection process by spatial mapping of these features. Further integration of the diagnostic and therapeutic value of tumor metabolism sensing molecules or immune binding agents directly into the surgical process can help this field mature. Maximal value to the patient would come from identifying the spatial patterns of molecular expression in vivo that are well known to exist. However, as each molecular agent is advanced into trials, the performance of the imaging system can have a critical impact on the success. For example, use of pre-existing commercial imaging systems are not well suited to image receptor targeted fluorophores because of the lower concentrations expected, requiring orders of magnitude more sensitivity. Additionally the imaging system needs the appropriate dynamic range and image processing features to view molecular probes or therapeutics that may have nonspecific uptake or pharmacokinetic issues which lead to limitations in contrast. Imaging systems need to be chosen based upon objective

  8. Clinical study on the influence of motion and other factors on stereotactic radiotherapy in the treatment of adrenal gland tumor

    PubMed Central

    Wang, Jingsheng; Li, Fengtong; Dong, Yang; Song, Yongchun; Yuan, Zhiyong

    2016-01-01

    Background The aim of this study was to investigate the adrenal tumor motion law and influence factors in the treatment of adrenal gland tumor and provide a reference value basis for determining the planning target volume margins for therapy. Materials and methods The subjects considered in this study were 38 adrenal tumor patients treated with CyberKnife with the placement of 45 gold fiducials. Fiducials were implanted into each adrenal tumor using β-ultrasonic guidance. Motion amplitudes of gold fiducials were measured with a Philips SLS simulator and motion data in the left–right, anterior–posterior, and cranio–caudal directions were obtained. Multiple linear regression models were used to analyze influencing factors. t-Test was used for motion amplitude comparison of different tumor locations along the z-axis. Results The motion distances were 0.1–0.4 cm (0.27±0.07 cm), 0.1–0.5 cm (0.31±0.11 cm), and 0.5–1.2 cm (0.87±0.21 cm) along the x-, y-, and z-axes, respectively. Motion amplitude along the z-axis may be affected by tumor location, but movement along the other axes was not affected by age, height, body mass, location, and size. Conclusion The maximum motion distance was along the z-axis. Therefore, this should be the main consideration when defining the planning target volume safety margin. Due to the proximity of the liver, adrenal gland tumor motion amplitude was smaller on the right than the left. This study analyzed adrenal tumor motion amplitude data to evaluate how motion and other factors influence the treatment of adrenal tumor with a goal of providing a reference for stereotactic radiotherapy boundary determination. PMID:27486331

  9. Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers.

    PubMed

    Wu, Lei; Parton, Anastasia; Lu, Ling; Adams, Mary; Schafer, Peter; Bartlett, J Blake

    2011-01-01

    We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student's t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D-NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit. PMID:20848094

  10. Modulatory influence of Phyllanthus niruri on oxidative stress, antioxidant defense and chemically induced skin tumors.

    PubMed

    Sharma, Priyanka; Parmar, Jyoti; Verma, Preeti; Goyal, Pradeep Kumar

    2011-01-01

    The present study evaluates the modulatory potential of Phyllanthus niruri on chemically induced skin carcinogenesis, and its influence on oxidative stress and the antioxidant defense system. Oral administration of P. niruri extract (PNE), during peri- (Gr. III), post- (Gr. IV), or peri- and post- (Gr. V) initiational stages of 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil–induced papillomagenesis considerably reduced tumor burden to 4.20, 4.00, and 3.33(positive control value 6.20); cumulative number of papillomas to 21, 16, and 10, respectively, (positive control value 62); and incidence of mice bearing papillomas to 50, 40, and 30%, respectively (positive control value 100%), but significantly increased the average latent period to 10.14, 10.62, and 11.60, and inhibition of tumor multiplicity to 66, 74,and 83%, respectively. Enzyme analysis of skin and liver showed a significant (p ≤ 0.05, ≤ 0.01, ≤ 0.001) elevation in antioxidant parameters such as superoxide dismutase, catalase, glutathione, and vitamin C in PNE-treated groups (Gr. III–V) when compared with the carcinogen-treated control (Gr. II). The elevated level of lipid peroxidation in the carcinogen-treated positive control group was significantly (p ≤ 0.05, ≤ 0.01, ≤ 0.001) inhibited by PNE administration. These results indicate that P. niruri extract has potentiality to reduce skin papillomas by enhancing antioxidant defense system. PMID:21609315

  11. Multi-course PDT of malignant tumors: the influence on primary tumor, metastatic spreading and homeostasis of cancer patients

    NASA Astrophysics Data System (ADS)

    Sokolov, Victor V.; Chissov, Valery I.; Yakubovskaya, Raisa I.; Filonenko, E. V.; Sukhin, Garry M.; Nemtsova, E. R.; Belous, T. A.; Zharkova, Natalia N.

    1996-12-01

    The first clinical trials of photodynamic therapy (PDT) of cancer with two photosensitizers, PHOTOHEME and PHOTOSENS, were started in P.A. Hertzen Research Oncological Institute (Moscow, Russia) in 1992 and 1994. Up to now, 208 patients with primary, recurrent and metastatic malignant tumors (469) of skin (34 patients/185 tumors), breast cancer (24/101), head and neck (30/31), trachea and bronchus (31/42), esophagus (35/35), stomach (31/32), rectum (4/4), vagina and uterine cervix (7/8) and bladder (12/31) have been treated by PDT. One-hundred-thirty patients were injected with PHOTOHEME, 64 patients were injected with PHOTOSENS, 14 patients were injected with PHOTOHEME and PHOTOSENS. Totally, 302 courses of treatment were performed: 155 patients had one course and 53 patients were subjected to two to nine PDT sources with intervals from 1 to 18 months. A therapeutic effect of a one-course and multi- course PDT of malignant tumors (respiratory, digestive and urogenital systems) was evaluated clinically, histologically, roentgenologically, sonographically and endoscopically. The biochemical, hematological and immunological investigations were performed for all the patients in dynamics. Results of our study showed that a multi-course PDT method seems to be perspective in treatment of malignant tumors of basic localizations.

  12. Lactobacillus rhamnosus GG supplementation during critical windows of gestation influences immune phenotype in Swiss albino mice offspring.

    PubMed

    Himaja, N; Hemalatha, R; Narendra Babu, K; Shujauddin, M

    2016-03-11

    Probiotic supplementation during critical windows of gestation might have a significant influence on the infant's immune phenotype. Swiss albino mice (F0 generation) aged 31 days were supplemented orally with probiotic Lactobacillus rhamnosus GG (LGG); and the supplementation was continued throughout mating, gestation and lactation. The pups (F1 generation) born to them were separated post weaning and received either the same probiotic supplementation as their mothers or were denied supplementation postnatally. Neutrophil phagocytic ability, splenocyte proliferation, immunoglobulins and cytokines were determined in both F0 and F1 pups. In addition, antibody response against hepatitis-B surface antigen (HBsAg) was determined in F1 pups. Probiotic supplementation had no effect on the neutrophil phagocytic ability and splenocyte proliferation index. The serum immunoglobulin G (IgG) and secretory IgA (s-IgA) among the probiotic supplemented group of F0 generation were significantly (P<0.05) higher compared to the controls. Similarly, the mean concentration of interleukin (IL)-10, IL-17 and interferon gamma (IFN-γ) among F0 probiotic group were significantly higher (P<0.05) compared to the control. Prenatal and postnatal probiotic supplementation in F1 pups led to similar results as F0 dams. Prenatal probiotic supplementation in F1 pups led to significantly (P<0.05) higher serum IgG (55.15±1.35 ng/ml) and intestinal s-IgA (77.9 ± 2.86 ng/mg protein) concentration when compared to the control. Similarly, IFN-γ concentration increased (P<0.05) with prenatal probiotic supplementation compared to the control. However, IL-10 and IL-17 concentrations of prenatal probiotic supplemented F1 pups were comparable to the control. As for the antibody response to HBsAg, prenatal probiotic supplementation led to enhanced HBsAg antibody response (471.4±3.97 U/ml) compared to the control. LGG affected the immune regulation and immune responses favourably in mothers and offspring

  13. Intraoperative Spillage of Favorable Histology Wilms Tumor Cells: Influence of Irradiation and Chemotherapy Regimens on Abdominal Recurrence. A Report From the National Wilms Tumor Study Group

    SciTech Connect

    Kalapurakal, John A.; Li, Sierra M.; Breslow, Norman E.; Beckwith, J. Bruce; Ritchey, Michael L.; Shamberger, Robert C.; Haase, Gerald M.; Thomas, Patrick R.M.; Grundy, Paul; Green, Daniel M.; D'Angio, Giulio J.

    2010-01-15

    Purpose: We undertook this study to determine (1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and (2) the patterns of relapse and outcomes in such patients. Methods and Materials: The influence of RT dose (0, 10, and 20 Gy), RT fields (flank, whole abdomen), and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added doxorubicin (three drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients. Each patient was considered at risk for two types of failure: flank and subdiaphragmatic beyond-flank recurrence, with the correlation between the two outcomes accounted for in the analyses. Results: The crude odds ratio for the risk of recurrence relative to no RT was 0.35 (0.15-0.78) for 10Gy and 0.08 (0.01-0.58) for 20Gy. The odds ratio for the risk of recurrence for doxorubicin to two drugs after adjusting for RT was not significant. For Stage II patients (NWTS-4), the 8-year event rates with and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07) and 90% and 95% for overall survival (p = 0.04). Conclusions: Irradiation (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients reduced relapse-free survival and overall survival, but only the latter was of statistical significance. These data provide a basis for assessing the risks vs. benefits when considering treatment for children with favorable histology Wilms tumor and surgical spillage.

  14. An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector.

    PubMed

    Liu, Guozheng; Dou, Shuping; Rusckowski, Mary; Hnatowich, Donald J

    2008-05-01

    In treating tumors by pretargeting, the antitumor antibody and the cytotoxic effector (e.g., toxins and radioactivity) are separately administered. Therefore, pretargeting is more complicated with many variables. We are conducting studies to understand the influence of each variable using a novel recognition pair of mutually complementary phosphorodiamidate morpholino oligomers (MORF/cMORF). Earlier we developed a semi-empirical model capable of accurately predicting the behavior of a radiolabeled cMORF effector with variations in dosages and timing. We have now extended the model to predict the effector behavior, in particular, its maximum percent tumor accumulation (MPTA) in mice pretargeted with three different MORF-conjugated antibodies (MN14, B72.3, and CC49). The MN14 and the CC49 target different antigens in the same tumor, whereas the CC49 and the B72.3 target the same antigen but with very different tumor accumulation. By comparing the pretargeting results of these three antibodies with our prediction, we confirmed that the MPTA of the radiolabeled cMORF effector in the LS174T tumor is independent of the antibodies. In conclusion, the MPTA cannot be improved through the use of different pretargeting antibodies, although different antibodies may improve the maximum absolute tumor accumulation, the heterogeneity, and/or the tumor-to-normal tissue ratios of the effector. This conclusion will apply equally well to effectors carrying a fluorescent probe, an anticancer agent, or a radioactive imaging agent. PMID:18483292

  15. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model

    PubMed Central

    Brenneman, Mark; Field, Amanda; Yang, Jiandong; Williams, Gretchen; Doros, Leslie; Rossi, Christopher; Schultz, Kris Ann; Rosenberg, Avi; Ivanovich, Jennifer; Turner, Joyce; Gordish-Dressman, Heather; Stewart, Douglas; Yu, Weiying; Harris, Anne; Schoettler, Peter; Goodfellow, Paul; Dehner, Louis; Messinger, Yoav; Hill, D. Ashley

    2015-01-01

    Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,  DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of  DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of  DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing  DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or  de novo germline LOF mutations, most of which truncate the  DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing  DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of  DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in  DICER1-associated  tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. PMID:26925222

  16. The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27.

    PubMed

    d'Almeida, Sènan M; Kauffenstein, Gilles; Roy, Charlotte; Basset, Laetitia; Papargyris, Loukas; Henrion, Daniel; Catros, Véronique; Ifrah, Norbert; Descamps, Philippe; Croue, Anne; Jeannin, Pascale; Grégoire, Marc; Delneste, Yves; Tabiasco, Julie

    2016-07-01

    Tumor-associated macrophages (TAM) are immunosuppressive cells that can massively accumulate in the tumor microenvironment. In patients with ovarian cancer, their density is correlated with poor prognosis. Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14(+) CD163(+) TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14(high) CD163(high) CD39(high) macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163(+) macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages. PMID:27622030

  17. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.

    PubMed Central

    Mulcahy, B.; Waldron-Lynch, F.; McDermott, M. F.; Adams, C.; Amos, C. I.; Zhu, D. K.; Ward, R. H.; Clegg, D. O.; Shanahan, F.; Molloy, M. G.; O'Gara, F.

    1996-01-01

    The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 "shared epitope" (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. PMID:8751869

  18. No-glucose strategy influences posterior cranial fossa tumors' postoperative course: introducing the Glycemic Stress Index.

    PubMed

    Pietrini, Domenico; Di Rocco, Concezio; Di Bartolomeo, Rossella; Conti, Giorgio; Ranelletti, Franco O; De Luca, Daniele; Tosi, Federica; Mensi, Sonia; D'Arrigo, Sonia; Piastra, Marco

    2009-07-01

    In a selected patient population, we evaluated the glycemic response to different infusional policies in the management of posterior cranial fossa tumor (PFT) removal. We analyzed the perioperative course, prospectically collected, of 137 children undergoing 150 surgical procedures. Patients were divided in two groups according to different intraoperative fluids (group A, 2.5% glucose; group B, crystalloids). In group B glycemia remained below 125 mg dl(-1), while group A showed persistently supranormal glycemic plasma values, reaching statistical significance at the end of surgery (P < 0.018). As no perioperative mortality occurred and no differences were found between groups regarding PICU respiratory or infectious complications, PICU length of stay (LOS) was assumed as the main outcome indicator. LOS was not influenced by group A or B inclusion, while a new indicator, namely the Glycemic Stress Index (GSI), representing both glycemic intraoperative change and procedure length, showed significantly different results in the study groups (P = 0.004). Our clinical experience suggests that both intraoperative glucose-free solutions are safe, and GSI can be a useful tool to identify prolonged PICU stay patients. PMID:19199005

  19. Tumor necrosis factor-alpha genetic predisposing factors can influence clinical severity in nephropathia epidemica.

    PubMed

    Maes, Piet; Clement, Jan; Groeneveld, Paul H P; Colson, Paul; Huizinga, Tom W J; Van Ranst, Marc

    2006-01-01

    Severe human infection with Hantavirus is characterized by high fever, cold chills, thrombocytopenia, arterial hypotension, acute renal failure, and/or adult respiratory distress syndrome (ARDS)-like pulmonary involvement, but the clinical course varies greatly between individuals. We investigated whether genetically determined differences in tumor necrosis factor (TNF)-alpha production can influence the severity of Hantavirus disease. We studied a TNF-alpha single-nucleotide promoter polymorphism (SNP) at position -238 (a guanine [G]-to-adenine [A] transition) and ex vivo TNF-alpha production in a recall study of 36 Belgian patients who had a serologically proven form of Puumala virus-induced Hantavirus infection with the kidney as main target organ. In our study, the highest creatinine levels were found in patients with the lowest ex vivo TNF-alpha production. Creatinine levels correlated inversely with TNF-alpha production (R = -0.35, p < 0.05). The number of thrombocytes was significantly lower in patients with the GA-238 genotype (low TNF-alpha producers) compared with patients with the GG-238 genotype. In our study, genetically determined low production of TNF-alpha was associated with some parameters indicating a more severe clinical course of Puumala Hantavirus infection in humans, possibly by impaired activation of TNF-alpha-dependent antiviral mechanisms, which could in turn result in decreased clearance of Hantavirus. PMID:16987073

  20. Mycobacterium avium subsp hominissuis biofilm is composed of distinct phenotypes and influenced by the presence of antimicrobials

    PubMed Central

    McNabe, Molly; Tennant, Rachel; Danelishvili, Lia; Young, Lowell; Bermudez, Luiz E.

    2010-01-01

    Mycobacterium avium subsp hominissuis, hereafter referred to as M. avium, forms biofilm, a property that, in mice, is associated with lung infection via aerosol. As M. avium might co-inhabit the respiratory tract with other pathogens, treatment of the co-pathogen-associated infections, such as in bronchiectasis, would expose M. avium to therapeutic compounds which may have their origin in other organisms sharing the natural environments. Incubation of M. avium with two compounds produced by environmental organisms, streptomycin and tetracycline in vitro at sub-inhibitory concentrations increased biofilm formation in a number of M. avium strains, although exposure to ampicillin, moxifloxacin, rifampin, and TMP/SMX had no effect on biofilm. No selection of genotypically resistant clones was observed. While bacteria incubation in presence of streptomycin upregulates the expression of biofilm-associated genes, the response to the antibiotics had no association with a regulation of a regulator (LysR) linked to the formation of biofilm in M. avium. Biofilms are made of planktonic and sessile bacteria. While planktonic M. avium is susceptible to clarithromycin and ethambutol (clinically used antimicrobials), sessile bacteria are at least 3- to 4-fold more resistant to antibiotics. The sessile phenotype, though, is reversible, and no selection of resistant clones was observed. Mice infected through the airway with both phenotypes were infected with a similar number of bacteria, demonstrating no phenotype advantage. M. avium biofilm formation is enhanced by commonly used compounds and, in the sessile bacterial phenotype, is resistant to clarithromycin and ethambutol, in a reversible manner. PMID:20636426

  1. Inherited and Environmental Influences on a Childhood Co-Occurring Symptom Phenotype: Evidence From an Adoption Study

    PubMed Central

    Roos, Leslie E.; Fisher, Philip A.; Shaw, Daniel S.; Kim, Hyoun K.; Neiderhiser, Jenae M.; Reiss, David; Natsuaki, Misaki N.; Leve, Leslie D.

    2015-01-01

    Risk factors for the childhood development of co-occurring internalizing and externalizing symptoms are not well understood, despite a high prevalence and poor clinical outcomes associated with this co-occurring phenotype. We examined inherited and environmental risk factors for co-occurring symptoms in a sample of children adopted at birth and their birth mothers and adoptive mothers (N = 293). Inherited risk factors (i.e., birth mothers’ processing speed and internalizing symptoms) and environmental risk factors (i.e., adoptive mothers’ processing speed, internalizing symptoms, and uninvolved parenting) were examined as predictors for the development of internalizing-only, externalizing-only, or co-occurring symptoms using structural equation modeling. Results suggested a unique pattern of predictive factors for the co-occurring phenotype, with risk conferred by adoptive mothers’ uninvolved parenting, birth mothers’ slower processing speed, and the birth mothers’ slower processing speed in tandem with adoptive mothers’ higher internalizing symptoms. Additional analyses indicated that when co-occurring-symptom children were incorporated into internalizing and externalizing symptom groups, differential risk factors for externalizing and internalizing symptoms emerged. The findings suggest that spurious results may be found when children with co-occurring symptoms are not examined as a unique phenotypic group. PMID:25851306

  2. Inherited and environmental influences on a childhood co-occurring symptom phenotype: Evidence from an adoption study.

    PubMed

    Roos, Leslie E; Fisher, Philip A; Shaw, Daniel S; Kim, Hyoun K; Neiderhiser, Jenae M; Reiss, David; Natsuaki, Misake N; Leve, Leslie D

    2016-02-01

    Risk factors for the childhood development of co-occurring internalizing and externalizing symptoms are not well understood, despite a high prevalence and poor clinical outcomes associated with this co-occurring phenotype. We examined inherited and environmental risk factors for co-occurring symptoms in a sample of children adopted at birth and their birth mothers and adoptive mothers (N = 293). Inherited risk factors (i.e., birth mothers' processing speed and internalizing symptoms) and environmental risk factors (i.e., adoptive mothers' processing speed, internalizing symptoms, and uninvolved parenting) were examined as predictors for the development of internalizing-only, externalizing-only, or co-occurring symptoms using structural equation modeling. Results suggested a unique pattern of predictive factors for the co-occurring phenotype, with risk conferred by adoptive mothers' uninvolved parenting, birth mothers' slower processing speed, and the birth mothers' slower processing speed in tandem with adoptive mothers' higher internalizing symptoms. Additional analyses indicated that when co-occurring-symptom children were incorporated into internalizing and externalizing symptom groups, differential risk factors for externalizing and internalizing symptoms emerged. The findings suggest that spurious results may be found when children with co-occurring symptoms are not examined as a unique phenotypic group. PMID:25851306

  3. Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence.

    PubMed

    Videla Richardson, Guillermo Agustín; Garcia, Carolina Paola; Roisman, Alejandro; Slavutsky, Irma; Fernandez Espinosa, Damián Darío; Romorini, Leonardo; Miriuka, Santiago Gabriel; Arakaki, Naomi; Martinetto, Horacio; Scassa, María Elida; Sevlever, Gustavo Emilio

    2016-01-01

    Although BMP4-induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC-enriched cell lines (GSC-ECLs) from high-grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC-ECLs' behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC-ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC-ECL. Additionally, treatment of GSC-ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC-ECLs adopted an unexpected smooth muscle-like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies. PMID:25808628

  4. Validation of the Concept of a Common Typical Time of Disease Duration for Hepatocellular Carcinoma Patients Using the Fisher Information Processing of Tumor Imaging Results Combined With Network Phenotyping Strategy Quantification of Individual Patient Clinical Profile Patterns.

    PubMed

    Pančoška, Petr; Skála, Lubomír; Nešetřil, Jaroslav; Carr, Brian I

    2015-08-01

    A primary goal of current clinical cancer research is the identification of prognostic tumor subtypes. It is increasingly clear that tumor growth depends on both internal tumor factors, and factors that are external to the tumor, such as microenvironment. We recently showed that parameter values alone are less important than the patterns of all patient parameters together for the identification of prognostic subtypes and have identified a network phenotyping strategy method to quantitatively describe the dependency of the tumor on the environment, to characterize hepatocellular carcinoma (HCC) subtypes. We have also shown that information about tumor mass together with patterns of other prognostic factors is related to survival. We now use a different patient cohort to validate this prognostic approach. A main finding is our identification of a common time of total disease duration (TDD) for every HCC patient. Clinical prognosis at the time of baseline patient evaluation is then calculable as the difference between TDD and the time from disease onset to diagnosis (T(onset)). We show that the total pattern of all parameter values and the differences in the relationships between this pattern and a reference pattern that, together with the tumor mass, best reflects the patient's prognosis at baseline. Our approach led us to identify 15 different composite HCC subtypes. Our results highlight the nearly identical TDD in all patients, which must therefore be a characteristic of the HCC disease, as opposed to the variable quantity of T(onset), which is impacted by multiple macro- and micro-environmental factors. PMID:26320070

  5. Augmenting tumor uptake of Tc-99m monoclonal antibodies (MAbs) with biological response modifiers: Influence of interferon

    SciTech Connect

    Li, J.; Thakur, M.L.; Wilder, S.

    1994-05-01

    Following the evaluation of radiolabeled MAbs for scintigraphic imaging or therapy, low tumor uptake emerged as one of the most prominent problems. The aim of this investigation was to examine the influence of interferon (IFN)-{alpha}2b in augmenting uptake of Tc-99m labeled antimelanoma MAb 31.3 in nude mice bearing experimental human melanoma. MAb was labeled with Tc-99m by our ascorbic acid mediated reduction technique, analyzed and 20 {mu}g containing 40-120 {mu}Ci Tc-99m were administered i.v., 1 hr following i.m. or i.v. administration of 10K, 20K, or 100K i.u. IFN-{alpha}2b. Animals receiving 0.9% saline similarly served as controls. 4 and 24 hrs later, animals were sacrificed, imaged, and dissected for tissue distribution studies. Tumor blood flow was measured before and after administration of IFN by color Doppler imaging technique, intratumoral temperature was recorded using thermocouples, and tumor histology was performed to visualize tumor lymphocytic infiltration. Although no excessive lymphocytic infiltration was seen within 72 hr post-injection of IFN, and only a modest increase in tumor temperature was noted, a significant increase in blood flow was observed within 45 min. as differentiated by amplitudes at peak systolic and end diastolic cardiac cycles. The best tumor uptake enhancement was noted at 24 hr following i.m. administration of 20K i.u. IFN and measured greater than 300% of the control value (7.2{plus_minus}1.2%/g vs. 2.2{plus_minus}1.4%/g). IFN-{alpha}2b enhances tumor blood flow in experimental tumors and significantly augments the uptake of radiolabeled MAbs.

  6. Influence of autologous dendritic cells on cytokine-induced killer cell proliferation, cell phenotype and antitumor activity in vitro

    PubMed Central

    Cao, Jingsong; Chen, Cong; Wang, Yuhuan; Chen, Xuecheng; Chen, Zeying; Luo, Xiaoling

    2016-01-01

    Dendritic cell (DCs) are essential antigen processing and presentation cells that play a key role in the immune response. In this study, DCs were co-cultured with cytokine-induced killer cells (DC-CIKs) in vitro to detect changes in cell proliferation, cell phenotype and cell cytotoxicity. The results revealed that the DCs were suitable for co-culture with CIKs at day 7, and that cell quantity of DC-CIKs was lower than that of CIKs until day 11, but it was significantly improved to 1.17-fold that of CIKs at day 13. Flow cytometry was used to detect the cell phenotype of CIKs and DC-CIKs. Compared with CIKs at day 13, the percentage of CD3+, CD3+CD4+, CD3+CD8+ and CD3+CD56+ T cells in DC-CIKs was significantly improved 1.02, 1.79, 1.26 and 2.44-fold, respectively. In addition, trypan blue staining analysis demonstrated that the cell viability of CIKs and DC-CIKs was 96% and 98%, respectively. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis verified that CIK and DC-CIK cytotoxicity in Hela cells was 58% and 80%, respectively, with a significant difference. Taken together, our results indicate that the cell proliferation, cell phenotype and antitumor activity of CIKs were all enhanced following co-culture with DCs in vitro. These results are likely to be useful for DC-CIK application in antitumor therapies. PMID:27602134

  7. Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

    PubMed

    Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

    2015-02-01

    The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients. PMID:24801760

  8. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis

    SciTech Connect

    Mulcahy, B.; Waldron-Lynch, F.; Adams, C.; O`Gara, F.

    1996-09-01

    The major histocompatibility complex class H1 tumor necrosis factor-tymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3 % not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 {open_quotes}shared epitope{close_quotes} (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, BS, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. 50 refs., 1 fig., 1 tab.

  9. Phenotypic differences in a cryptic predator: factors influencing morphological variation in the terciopelo Bothrops asper (Garman, 1884; Serpentes: Viperidae).

    PubMed

    Saldarriaga-Córdoba, Mónica María; Sasa, Mahmood; Pardo, Rodrigo; Méndez, Marco Antonio

    2009-12-01

    The terciopelo Bothrops asper, is a cryptic lancehead pitviper widely distributed in humid environments of Middle America and the north-western portion of South America. Throughout its extensive distribution range, the terciopelo exhibits great morphological variation in external characters, a situation that has complicated its proper separation from other related species. In this paper, we analyzed the phenotypic variation of B. asper based in a sample of 514 specimens from nine distinct physiographic regions. Univariate and multivariate analyses demonstrated great phenotypic differentiation among most pre-established groups, and the pattern is fairly congruent between sexes. However, no correspondence was observed between morphological variation and molecular divergence, inferred from mDNA sequences, between individuals representing the physiographical regions under study. Geographic variation in the number of interrictals, ventral scales, subcaudal scales and dorsal blotches was positively correlated with latitude and number of dry months, but inversely related with precipitation. However, other variables do not exhibit such an effect. The observed relationships between scale counts and environmental variables are explained in terms of selective pressures to improve water balance along the distributional range of the species. PMID:19505490

  10. The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.

    PubMed

    Schultz, Matthew J; Holdbrooks, Andrew T; Chakraborty, Asmi; Grizzle, William E; Landen, Charles N; Buchsbaum, Donald J; Conner, Michael G; Arend, Rebecca C; Yoon, Karina J; Klug, Christopher A; Bullard, Daniel C; Kesterson, Robert A; Oliver, Patsy G; O'Connor, Amber K; Yoder, Bradley K; Bellis, Susan L

    2016-07-01

    The glycosyltransferase ST6Gal-I, which adds α2-6-linked sialic acids to substrate glycoproteins, has been implicated in carcinogenesis; however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors, and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal-I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for α2-6 sialylation grew as spheroids, while cells lacking α2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I-expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Finally, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively, this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state. Cancer Res; 76(13); 3978-88. ©2016 AACR. PMID:27216178

  11. NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

    PubMed Central

    Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Sparatore, Bianca; Gonzalez, Segundo; Olive, Daniel; Bottino, Cristina

    2016-01-01

    Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue. PMID:27294158

  12. Matrix molecule influence on chondrocyte phenotype and proteoglycan 4 expression by alginate-embedded zonal chondrocytes and mesenchymal stem cells.

    PubMed

    Coates, Emily E; Riggin, Corinne N; Fisher, John P

    2012-12-01

    Articular cartilage resists load and provides frictionless movement at joint surfaces. The tissue is organized into the superficial, middle, deep, and calcified zones throughout its depth, each which serve distinct functions. Proteoglycan 4 (PRG4), found in the superficial zone, is a critical component of the joint's lubricating mechanisms. Maintenance of both the chondrocyte and zonal chondrocyte phenotype remain challenges for in vitro culture and tissue engineering. Here we investigate the expression of PRG4 mRNA and protein by primary bovine superficial zone chondrocytes, middle/deep zone chondrocytes, and mesenchymal stem cells encapsulated in alginate hydrogels with hyaluronic acid (HA) and chondroitin sulfate (CS) additives. Chondrogenic phenotype and differentiation markers are evaluated by mRNA expression, histochemical, and immunohistochemical staining. Results show middle/deep cells express no measurable PRG4 mRNA by day 7. In contrast, superficial zone cells express elevated PRG4 mRNA throughout culture time. This expression can be significantly enhanced up to 15-fold by addition of both HA and CS to scaffolds. Conversely, PRG4 mRNA expression is downregulated (up to 5-fold) by CS and HA in differentiating MSCs, possibly due to build up of entrapped protein. HA and CS demonstrate favorable effects on chondrogenesis by upregulating transcription factor Sox9 mRNA (up to 4.6-fold) and downregulating type I collagen mRNA (up to 18-fold). Results highlight the important relationship between matrix components and expression of critical lubricating proteins in an engineered cartilage scaffold. PMID:22674584

  13. NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

    PubMed Central

    Daemen, Kerstin; Keil, Jana; Stevanovic-Meyer, Maja; Lehner, Frank; Haller, Hermann; Blume, Cornelia; Falk, Christine S.

    2015-01-01

    To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56dim NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-γ, TNF-α, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-γ production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients. PMID:26147651

  14. Tumor stroma-derived factors skew monocyte to dendritic cell differentiation toward a suppressive CD14+ PD-L1+ phenotype in prostate cancer

    PubMed Central

    Spary, Lisa K; Salimu, Josephine; Webber, Jason P; Clayton, Aled; Mason, Malcolm D; Tabi, Zsuzsanna

    2014-01-01

    Tumor-associated stromal myofibroblasts are essential for the progression and metastatic spread of solid tumors. Corresponding myeloid cell infiltration into primary tumors is a negative prognostic factor in some malignancies. The aim of this study was to define the exact role of stromal myofibroblasts and stromal factors in early prostate carcinoma (PCa) regulating monocyte infiltration and differentiation into dendritic cells (DCs). Epithelial and stromal primary cultures were generated from PCa biopsies and their purity confirmed. Stromal cells produced significantly more of the (C–C) motif chemokine ligand 2 (CCL2), interleukin 6 (IL-6) and transforming growth factor β (TGFβ) than epithelial cells. Monocyte chemoattraction was predominantly due to stromal-derived factors, mainly CCL2. DCs generated in the presence of stromal (but not epithelial) factors upregulated CD209, but failed to downregulate the monocyte marker CD14 in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Monocytes exposed to stromal factors did not produce detectable amounts of IL-10, however, upon lipopolysaccharide stimulation, stromal factor generated dendritic cells (sDC) produced significantly more IL-10 and less IL-12 than their conventional DC counterparts. sDC failed to cross-present tumor-antigen to CD8+ T cells and suppressed T-cell proliferation. Most importantly, sDC expressed significantly elevated levels of programmed cell death ligand-1 (PD-L1) in a primarily STAT3 and IL-6-dependent manner. In parallel with our findings in vitro, tumor-infiltrating CD14+ cells in situ were found to express both PD-L1 and CD209, and a higher percentage of tumor-associated CD3+ T cells expressed programmed cell death-1 (PD-1) molecules compared to T cells in blood. These results demonstrate a hitherto undescribed, fundamental contribution of tumor-associated stromal myofibroblasts to the development of an immunosuppressive microenvironment in early PCa. PMID

  15. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors

    PubMed Central

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-01-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. PMID:26212113

  16. Influence of Murine Mesenchymal Stem Cells on Proliferation, Phenotype, Vitality, and Cytotoxicity of Murine Cytokine-Induced Killer Cells in Coculture

    PubMed Central

    Stolzing, Alexandra

    2014-01-01

    Stimulating lymphocytes with Ifn-γ, anti-CD3, and interleukin-2 promotes the proliferation of a cell population coexpressing T-lymphocyte surface antigens such as CD3, CD8a, and CD25 as well as natural killer cell markers such as NK1.1, CD49, and CD69. These cells, referred to as cytokine-induced killer cells (CIKs), display cytotoxic activity against tumour cells, even without prior antigen presentation, and offer a new cell-based approach to the treatment of malignant diseases. Because CIKs are limited in vivo, strategies to optimize in vitro culture yield are required. In the last 10 years, mesenchymal stem cells (MSCs) have gathered considerable attention. Aside from their uses in tissue engineering and as support in haematopoietic stem cell transplantations, MSCs show notable immunomodulatory characteristics, providing further possibilities for therapeutic applications. In this study, we investigated the influence of murine MSCs on proliferation, phenotype, vitality, and cytotoxicity of murine CIKs in a coculture system. We found that CIKs in coculture proliferated within 7 days, with an average growth factor of 18.84, whereas controls grew with an average factor of 3.7 in the same period. Furthermore, higher vitality was noted in cocultured CIKs than in controls. Cell phenotype was unaffected by coculture with MSCs and, notably, coculture did not impact cytotoxicity against the tumour cells analysed. The findings suggest that cell–cell contact is primarily responsible for these effects. Humoral interactions play only a minor role. Furthermore, no phenotypical MSCs were detected after coculture for 4 h, suggesting the occurrence of immune reactions between CIKs and MSCs. Further investigations with DiD-labelled MSCs revealed that the observed disappearance of MSCs appears not to be due to differentiation processes. PMID:24516591

  17. Influence of nuclear interactions in body tissues on tumor dose in carbon-ion radiotherapy

    SciTech Connect

    Inaniwa, T. Kanematsu, N.; Tsuji, H.; Kamada, T.

    2015-12-15

    Purpose: In carbon-ion radiotherapy treatment planning, the planar integrated dose (PID) measured in water is applied to the patient dose calculation with density scaling using the stopping power ratio. Since body tissues are chemically different from water, this dose calculation can be subject to errors, particularly due to differences in inelastic nuclear interactions. In recent studies, the authors proposed and validated a PID correction method for these errors. In the present study, the authors used this correction method to assess the influence of these nuclear interactions in body tissues on tumor dose in various clinical cases. Methods: Using 10–20 cases each of prostate, head and neck (HN), bone and soft tissue (BS), lung, liver, pancreas, and uterine neoplasms, the authors first used treatment plans for carbon-ion radiotherapy without nuclear interaction correction to derive uncorrected dose distributions. The authors then compared these distributions with recalculated distributions using the nuclear interaction correction (corrected dose distributions). Results: Median (25%/75% quartiles) differences between the target mean uncorrected doses and corrected doses were 0.2% (0.1%/0.2%), 0.0% (0.0%/0.0%), −0.3% (−0.4%/−0.2%), −0.1% (−0.2%/−0.1%), −0.1% (−0.2%/0.0%), −0.4% (−0.5%/−0.1%), and −0.3% (−0.4%/0.0%) for the prostate, HN, BS, lung, liver, pancreas, and uterine cases, respectively. The largest difference of −1.6% in target mean and −2.5% at maximum were observed in a uterine case. Conclusions: For most clinical cases, dose calculation errors due to the water nonequivalence of the tissues in nuclear interactions would be marginal compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response. In some extreme cases, however, these errors can be substantial. Accordingly, this correction method should be routinely applied to treatment planning in clinical practice.

  18. Cancer-associated adipocytes promotes breast tumor radioresistance

    SciTech Connect

    Bochet, Ludivine; Meulle, Aline; Imbert, Sandrine; Salles, Bernard; Valet, Philippe; Muller, Catherine

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  19. Do cage effects influence tumor incidence? An examination of laboratory animal carcinogenicity studies utilizing Fischer 344 rats.

    PubMed

    Haseman, J K

    1988-08-01

    Approximately 125 carcinogenicity studies in Fischer 344 rats conducted by the National Toxicology Program (NTP) were examined to determine the frequency with which cage effects were associated with observed carcinogenic responses. All studies involving groups of 50 rats housed five per cage and showing evidence of chemically-related carcinogenicity were considered. For each of these experiments, two statistical analyses were carried out for each dosed and control group: (i) a test to determine whether or not the occurrence of tumors clustered within cages; and (ii) an evaluation to determine whether or not tumor incidences differed significantly between differing cage shelf levels. These analyses showed that the numbers of statistically significant (P less than 0.05 or P less than 0.01) effects were consistent with the number expected by chance alone. Thus, cage-related factors appeared to have little or no impact upon tumor incidence in these particular studies. Experimental design protocols now used by the NTP (which include random assignment of animals to cages; random assignment of columns of cages to dosed and control groups; and periodic rotation of cage location) further reduce the likelihood that factors associated with the housing of the animals could influence tumor incidence in current studies. PMID:3183292

  20. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    SciTech Connect

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E. )

    1990-09-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.

  1. Frailty phenotypes in the elderly based on cluster analysis: a longitudinal study of two Danish cohorts. Evidence for a genetic influence on frailty.

    PubMed

    Dato, Serena; Montesanto, Alberto; Lagani, Vincenzo; Jeune, Bernard; Christensen, Kaare; Passarino, Giuseppe

    2012-06-01

    Frailty is a physiological state characterized by the deregulation of multiple physiologic systems of an aging organism determining the loss of homeostatic capacity, which exposes the elderly to disability, diseases, and finally death. An operative definition of frailty, useful for the classification of the individual quality of aging, is needed. On the other hand, the documented heterogeneity in the quality of aging among different geographic areas suggests the necessity for a frailty classification approach providing population-specific results. Moreover, the contribution of the individual genetic background on the frailty status is still questioned. We investigated the applicability of a cluster analysis approach based on specific geriatric parameters, previously set up and validated in a southern Italian population, to two large longitudinal Danish samples. In both cohorts, we identified groups of subjects homogeneous for their frailty status and characterized by different survival patterns. A subsequent survival analysis availing of Accelerated Failure Time models allowed us to formulate an operative index able to correlate classification variables with survival probability. From these models, we quantified the differential effect of various parameters on survival, and we estimated the heritability of the frailty phenotype by exploiting the twin pairs in our sample. These data suggest the presence of a genetic influence on the frailty variability and indicate that cluster analysis can define specific frailty phenotypes in each population. PMID:21567248

  2. Linking individual phenotype to density-dependent population growth: the influence of body size on the population dynamics of malaria vectors

    PubMed Central

    Russell, Tanya L.; Lwetoijera, Dickson W.; Knols, Bart G. J.; Takken, Willem; Killeen, Gerry F.; Ferguson, Heather M.

    2011-01-01

    Understanding the endogenous factors that drive the population dynamics of malaria mosquitoes will facilitate more accurate predictions about vector control effectiveness and our ability to destabilize the growth of either low- or high-density insect populations. We assessed whether variation in phenotypic traits predict the dynamics of Anopheles gambiae sensu lato mosquitoes, the most important vectors of human malaria. Anopheles gambiae dynamics were monitored over a six-month period of seasonal growth and decline. The population exhibited density-dependent feedback, with the carrying capacity being modified by rainfall (97% wAICc support). The individual phenotypic expression of the maternal (p = 0.0001) and current (p = 0.040) body size positively influenced population growth. Our field-based evidence uniquely demonstrates that individual fitness can have population-level impacts and, furthermore, can mitigate the impact of exogenous drivers (e.g. rainfall) in species whose reproduction depends upon it. Once frontline interventions have suppressed mosquito densities, attempts to eliminate malaria with supplementary vector control tools may be attenuated by increased population growth and individual fitness. PMID:21389034

  3. The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema.

    PubMed

    Hasegawa, Yuzo; Iuchi, Toshihiko; Sakaida, Tsukasa; Yokoi, Sana; Kawasaki, Koichiro

    2016-09-01

    The development of perifocal edema and tumor bed cyst has been reported after implantation of biodegradable carmustine wafers for the treatment of malignant gliomas. We retrospectively evaluated these changes in a series of patients; 19 consecutive patients with malignant glioma who received carmustine wafer implantation at our hospital from January 2013 through July 2013, and 28 patients who underwent surgery prior to our institution's initiation of carmustine wafer implantation, as historical controls. The volume of the tumor bed cyst and perifocal edema was calculated on MRI acquired at four time points: ⩽72hours after surgery for baseline, and at 1-4, 5-8, and 9-12weeks after surgery. The volume of the tumor bed cyst in the wafer group increased significantly relative to the control group at all time points (p=0.04). Opening of the ventricle was inversely correlated with enlargement of the tumor bed cyst in the wafer group (p=0.04). The change in the volume of perifocal edema in the wafer group was not significantly different (p=0.48), but exhibited a considerable increase in patients with anaplastic oligodendroglioma relative to glioblastoma patients in the wafer group (p=0.01). We demonstrated significant enlargement of the tumor bed cyst volume after carmustine wafer implantation, as well as the development of marked perifocal edema in patients with anaplastic oligodendroglioma. PMID:27430412

  4. The influence of myeloid-derived suppressor cells on angiogenesis and tumor growth after cancer surgery.

    PubMed

    Wang, Jun; Su, Xiaosan; Yang, Liu; Qiao, Fei; Fang, Yu; Yu, Lu; Yang, Qian; Wang, Yiyin; Yin, Yanfeng; Chen, Rui; Hong, Zhipeng

    2016-06-01

    While myeloid-derived suppressor cells (MDSCs) have been reported to participate in the promotion of angiogenesis and tumor growth, little is known about their presence and function during perioperative period. Here, we demonstrated that human MDSCs expressing CD11b(+), CD33(+) and HLA-DR(-) significantly increased in lung cancer patients after thoracotomy. CD11b(+) CD33(+) HLA-DR(-) MDSCs isolated 24 hr after surgery from lung cancer patients were more efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation in allograft tumor model. In addition, CD11b(+) CD33(+) HLA-DR(-) MDSCs produced high levels of MMP-9. Using an experimental lung metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and Gr-1(+) CD11b(+) MDSCs at postoperative period were enhanced in proportion to the degree of surgical manipulation. We also examined that syngeneic bone marrow mesenchymal stem cells (BMSCs) significantly inhibited the induction and proliferation of Gr-1(+) CD11b(+) MDSCs and further prevented lung metastasis formation in the mice undergoing laparotomy. Taken together, our results suggest that postoperatively induced MDSCs were qualified with potent proangiogenic and tumor-promotive ability and this cell population should be considered as a target for preventing postoperative tumor metastasis. PMID:26756887

  5. Exclusive Association of p53 Mutation with Super-High Methylation of Tumor Suppressor Genes in the p53 Pathway in a Unique Gastric Cancer Phenotype

    PubMed Central

    Ema, Akira; Katada, Natsuya; Kikuchi, Shiro; Watanabe, Masahiko

    2015-01-01

    Background A comprehensive search for DNA methylated genes identified candidate tumor suppressor genes that have been proven to be involved in the apoptotic process of the p53 pathway. In this study, we investigated p53 mutation in relation to such epigenetic alteration in primary gastric cancer. Methods The methylation profiles of the 3 genes: PGP9.5, NMDAR2B, and CCNA1, which are involved in the p53 tumor suppressor pathway in combination with p53 mutation were examined in 163 primary gastric cancers. The effect of epigenetic reversion in combination with chemotherapeutic drugs on apoptosis was also assessed according to the tumor p53 mutation status. Results p53 gene mutations were found in 44 primary gastric tumors (27%), and super-high methylation of any of the 3 genes was only found in cases with wild type p53. Higher p53 pathway aberration was found in cases with male gender (p = 0.003), intestinal type (p = 0.005), and non-infiltrating type (p = 0.001). The p53 pathway aberration group exhibited less recurrence in lymph nodes, distant organs, and peritoneum than the p53 non-aberration group. In the NUGC4 gastric cancer cell line (p53 wild type), epigenetic treatment augmented apoptosis by chemotherapeutic drugs, partially through p53 transcription activity. On the other hand, in the KATO III cancer cell line (p53 mutant), epigenetic treatment alone induced robust apoptosis, with no trans-activation of p53. Conclusion In gastric cancer, p53 relevant and non-relevant pathways exist, and tumors with either pathway type exhibited unique clinical features. Epigenetic treatments can induce apoptosis partially through p53 activation, however their apoptotic effects may be explained largely by mechanism other than through p53 pathways. PMID:26447864

  6. The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Kuštrimović, Nataša; Mitić, Katarina; Vujić, Vesna; Aleksić, Iva; Radojević, Katarina; Leposavić, Gordana

    2013-11-01

    The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2(high) cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity. PMID

  7. A case-control study of borderline ovarian tumors: the influence of perineal exposure to talc.

    PubMed

    Harlow, B L; Weiss, N S

    1989-08-01

    The authors interviewed 116 female residents of western Washington State with serous and mucinous borderline ovarian tumors diagnosed between 1980 and 1985 and questioned them on their use of hygienic powders. A sample of 158 control women from the same counties were identified through random digit dialing and were interviewed as well. Neither the perineal application of baby powder nor the perineal application of cornstarch was associated with an appreciably altered risk of borderline ovarian tumors. However, women who used deodorizing powders alone or in combination with other talc-containing powders had 2.8 times the risk (95% confidence interval 1.1-11.7) of women who had not had perineal exposure to powder. These results suggest that future studies of ovarian tumors in relation to the application of talc-containing powders should consider ascertaining the specific type(s) of powder used. PMID:2750733

  8. Accelerated Partial Breast Irradiation through Brachytherapy for Ductal Carcinoma in situ: Factors Influencing Utilization and Risks of Second Breast Tumors

    PubMed Central

    Liu, Ying; Schloemann, Derek T.; Lian, Min; Colditz, Graham A.

    2015-01-01

    Purpose To examine influencing factors and outcomes of accelerated partial breast irradiation through brachytherapy (APBIb) versus whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). Patients and Methods From the Surveillance Epidemiology and End Results program, we identified 40749 women who were diagnosed with first primary DCIS between 2002 and 2011 and treated with breast conserving surgery (BCS) and radiotherapy. A multi-level logistic regression analysis was performed to estimate odds ratios of APBIb use. Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression. Results Overall, 2212 (4.5%) of 40749 women (the whole cohort) received APBIb. Factors associated with the increased use of APBIb included older age, non-Hispanic white race/ethnicity, smaller tumor size, hormone receptor positivity, comedo subtypes and urban residence. During the 46-month follow-up, 74 (0.8%) and 131 (1.4%) of 9165 propensity score-matched patients developed IBTs and CBTs, respectively. Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR, 1.74; 95% CI, 1.06 to 2.85) but not CBTs (OR, 0.91; 95% CI, 0.59 to 1.41). Conclusion This population-based study suggests that APBIb use for DCIS was influenced by patient and tumor characteristics as well as urbanization of residence. We observed a moderately increased IBT risk associated with APBIb versus WBI, suggesting that APBIb should be used with caution for DCIS before data from randomized controlled trials with long-term followups are available. PMID:25893591

  9. Influence of blood pressure profile on frailty phenotype in community-dwelling elders in Brazil - FIBRA study.

    PubMed

    Fattori, A; Santimaria, M R; Alves, R M A; Guariento, M E; Neri, A L

    2013-01-01

    Frailty is a clinical condition associated with pathological aging and biological vulnerability. In the spectrum of events related to frailty, aging of the cardiocirculatory system and abnormalities in arterial blood pressure (BP) partly explain the changes in tissue perfusion and, potentially, the decrease in physiological reserves. This study investigated the relationship between BP levels, systemic arterial hypertension (SAH) and the frailty phenotype by analyzing frailty criteria in a cross-sectional model into the FIBRA network, a populational sample of community-dwelling elders in Southeastern Brazil. Study participants with ≥65 years were selected by probabilistic sampling of residents in the urban area of the municipality of Campinas (n=900). Considering frailty as a whole and the difference between genders, there was a greater proportion of frail or pre-frail individuals among women than men. Analysis of individual frailty criteria showed that weight loss and fatigue were more common among women (18.3% vs. 12.5%, p=0.034 and 22.5% vs. 11.9%, p<0.001, respectively). Comparison of individuals with or without SAH failed to reveal any differences related to frailty criteria. Nevertheless, averages of diastolic blood pressure (DBP) and mean arterial blood pressure values were lower among elderly individuals with reduced grip strength, physical activity and the frailty classification as a whole (OR 0.986, IC 0.975-0.997) (for every 1 mmHg reduction in MBP values, the likelihood of being frail increased 1.4%). Our findings corroborate the relationship between BP values and frailty in the elderly and contribute to an understanding of the pathophysiological mechanisms of the syndrome. PMID:22939428

  10. The influence of abiotic stress and phenotypic plasticity on the distribution of invasive Alternanthera philoxeroides along a riparian zone

    NASA Astrophysics Data System (ADS)

    Pan, Xiaoyun; Geng, Yupeng; Zhang, Wenju; Li, Bo; Chen, Jiakuan

    2006-11-01

    Relatively few studies have compared invasibility and species invasiveness among microhabitats within communities, synchronously. We surveyed the abundance and performance of non-native Alternanthera philoxeroides (Mart.) Griseb. (alligator weed), its co-occurring native congener, Alternanthera sessilis (L.) DC. (sessile joyweed), and other species in a wetland community along a riparian zone in southeast China to test the hypotheses that: i) degree of invasion differs between different types of microhabitats within the community; and ii) microhabitat types that differ in invasibility also differ in soil resource availability or in sediment characteristics likely to affect resource availability; iii) phenotypic plasticity of A. philoxeroides may play a key role in its adaptation to diverse habitats as can be concluded from its extremely low genetic diversity in China. The study riparian zone comprises different types of microhabitats including wet abandoned field, swamp, marsh dunes and gravel dunes. Consistent with these hypotheses, cover of A. philoxeroides was high in abandoned fields (73 ± 2.9%) and swamps (94 ± 1.3%), which had high soil nutrients and water availability. On the contrary, cover of native A. sessilis was relatively high in marsh dunes and grave dunes, which had coarse gravel surfaces, low soil nutrients and low water availability. A. philoxeroides showed greater morphological plasticity in response to habitat variation. In abiotically harsh habitats, stems had limited growth, and were prostrate with weak adventitious roots at nodes, forming thin, scattered patches. In the two richer habitats, the highly branched plants spread over the water or soil surface, supporting dense stronger leaf-bearing stems which grew vertically. The growth pattern of A. sessilis among microhabitats did not exhibit significant variations. These results suggest that morphological plasticity and microhabitat types with high soil resources may facilitate invasions of A

  11. Influence of the lpr environment on the lymph node cell phenotypes in C57BL/6 nubg and nulpr chimeras.

    PubMed Central

    Tiberghien, F; Ceredig, R; Loor, F

    1994-01-01

    Mice homozygous for the lpr gene show a marked lymphoproliferative syndrome. Most T cells which accumulate in their lymphoid organs belong to a fairly unusual subpopulation. Although being CD44+ T cells expressing neither CD4 nor CD8, they are CD3 T-cell receptor (TCR) alpha beta positive and express both Thy-1 and B220, the B-cell form of the CD45 marker. To support engraftment and development of transferred lpr lymphomyeloid cells, athymic recipients must be genetically lpr. While nude/beige (nubg) recipients do not allow the development of any lymphoproliferative syndrome, this is variable in nude/lpr (nulpr) recipients, and the genotypic origin of the proliferating lymphocytes in nulpr recipients is unclear. In this study, the surface phenotype of lymph node cells from nulpr recipients of lpr grafts ([lpr-->nulpr] chimeras) was analysed by flow cytometry, and compared with various chimeras and parental (donor and recipient) strains as controls. Abnormal cells of the lpr type were not detectable either in [lpr-->nubg] chimeras or in [wild-->nubg] controls. Absence of lpr cells was also seen in neonatal lpr thymus-grafted nubg mice engrafted previously with lpr haematopoietic cells. In contrast, a substantial emergence of double-positive B220+ Thy-1+ cells occurred in [lpr-->nulpr] chimeras, together with high levels of CD4+ cells, a substantial fraction of which might express B220. Finally, in thymus-grafted nulpr mice, the levels of B220+ Thy-1+ cells were as high as in lpr mice and there was again an expansion of CD4+ (potentially B220+) cells. Abnormality of the nulpr haemopoietic environment was also shown by the low percentages of T cells, particularly CD8+ cells, in short-lived [wild-->nulpr] chimeras. Taken together, our results underline the differences between the nubg and nulpr environments. PMID:7875735

  12. Nectar robbery by a hermit hummingbird: association to floral phenotype and its influence on flowers and network structure.

    PubMed

    Maruyama, Pietro Kiyoshi; Vizentin-Bugoni, Jeferson; Dalsgaard, Bo; Sazima, Ivan; Sazima, Marlies

    2015-07-01

    Interactions between flowers and their visitors span the spectrum from mutualism to antagonism. The literature is rich in studies focusing on mutualism, but nectar robbery has mostly been investigated using phytocentric approaches focused on only a few plant species. To fill this gap, we studied the interactions between a nectar-robbing hermit hummingbird, Phaethornis ruber, and the array of flowers it visits. First, based on a literature review of the interactions involving P. ruber, we characterized the association of floral larceny to floral phenotype. We then experimentally examined the effects of nectar robbing on nectar standing crop and number of visits of the pollinators to the flowers of Canna paniculata. Finally, we asked whether the incorporation of illegitimate interactions into the analysis affects plant-hummingbird network structure. We identified 97 plant species visited by P. ruber and found that P. ruber engaged in floral larceny in almost 30% of these species. Nectar robbery was especially common in flowers with longer corolla. In terms of the effect on C. paniculata, the depletion of nectar due to robbery by P. ruber was associated with decreased visitation rates of legitimate pollinators. At the community level, the inclusion of the illegitimate visits of P. ruber resulted in modifications of how modules within the network were organized, notably giving rise to a new module consisting of P. ruber and mostly robbed flowers. However, although illegitimate visits constituted approximately 9% of all interactions in the network, changes in nestedness, modularity, and network-level specialization were minor. Our results indicate that although a flower robber may have a strong effect on the pollination of a particular plant species, the inclusion of its illegitimate interactions has limited capacity to change overall network structure. PMID:25740333

  13. Macrophage phenotypes in atherosclerosis.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Staels, Bart

    2014-11-01

    Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype. PMID:25319333

  14. LncRNA GAS5 is a critical regulator of metastasis phenotype of melanoma cells and inhibits tumor growth in vivo

    PubMed Central

    Chen, Long; Yang, Huixin; Xiao, Yanbin; Tang, Xiaoxia; Li, Yuqian; Han, Qiaoqiao; Fu, Junping; Yang, Yuye; Zhu, Yuechun

    2016-01-01

    The present study intended to demonstrate the effects of long noncoding RNA growth arrest-specific transcript 5 (GAS5) on the migration and invasion of melanoma cells. We first detected the expression of GAS5 among four kinds of melanoma cell lines, followed by constructing GAS5-knocked down and overexpressed stable cells. Next, we evaluated the effects of GAS5 on cell migration and invasion using wound healing and gelatin zymography assays. Finally, melanoma cells with different GAS5 expression were injected into nude mice, and the tumor volumes were recorded and tumor tissues were analyzed after sacrificing the mice. This study systematically examined the function of GAS5 in mediating melanoma metastasis and revealed that GAS5 plays an anticancer role in melanoma via regulating gelatinase A and B, both in vitro and in vivo. PMID:27445498

  15. Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype

    PubMed Central

    Bonet, Caroline; Bonazzi, Vanessa F; Allegra, Marylin; Giuliano, Sandy; Bille, Karine; Bahadoran, Philippe; Giacchero, Damien; Lacour, Jean Philippe; Boyle, Glen M; Hayward, Nicholas F

    2013-01-01

    Here, we showed that the secretome of senescent melanoma cells drives basal melanoma cells towards a mesenchymal phenotype, with characteristic of stems illustrated by increased level of the prototype genes FN1, SNAIL, OCT4 and NANOG. This molecular reprogramming leads to an increase in the low-MITF and slow-growing cell population endowed with melanoma-initiating cell features. The secretome of senescent melanoma cells induces a panel of 52 genes, involved in cell movement and cell/cell interaction, among which AXL and ALDH1A3 have been implicated in melanoma development. We found that the secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. Collectively, the findings provide insights into how the secretome of melanoma cells entering senescence upon chemotherapy treatments increases the tumorigenicity of naïve melanoma cells by inducing, through STAT3 activation, a melanoma-initiating cell phenotype that could favor chemotherapy resistance and relapse. PMID:24344100

  16. Conceptual and Data-based Investigation of Genetic Influences and Brain Asymmetry: A Twin Study of Multiple Structural Phenotypes

    PubMed Central

    Eyler, Lisa T.; Vuoksimaa, Eero; Panizzon, Matthew S.; Fennema-Notestine, Christine; Neale, Michael C.; Chen, Chi-Hua; Jak, Amy; Franz, Carol E.; Lyons, Michael J.; Thompson, Wesley K.; Spoon, Kelly M.; Fischl, Bruce; Dale, Anders M.; Kremen, William S.

    2014-01-01

    Right–left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neuro-developmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals (130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins) from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Inter-hemispheric genetic correlations were high and significant; in only two subcortical regions (pallidum and accumbens) did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left–right size differences? There was no evidence that variation in asymmetry (i.e., the size difference) of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing left–right, we view the present results as consistent with previous findings. PMID:24283492

  17. Influence of WR 2721 on the efficacy of radiotherapy and chemotherapy of murine tumors

    SciTech Connect

    Clement, J.J.; Johnson, R.K.

    1982-03-01

    The effect of WR2721 on the response of tumors to radiation, antineoplastic alkylating drugs, and DNA binding agents was evaluated and compared to the degree of normal tissue protection provided by WR 2721 against these agents. WR 2721 administered to mice bearing P388 leukemia or Lewis lung carcinoma was found to reduce the radiosensitivity of the leukemia and lung tumor by dose modifying factors of 1.4 and 1.3, respectively. WR 2721 protected bone marow, intestine, and skin from radiation by factors of 1.9. 1.4 and 1.8. WR 2721 protected mice from the lethality of cyclophosphamide by a factor of only 1.2 whereas protection from melphalan toxicity was more dramatic with a dose modifying factor of 1.6. In chemotherapy studies of established M5076 ovarian tumor, the combination of WR 2721 plus cyclophosphamide was equivalent in activity to cyclophosphamide alone. WR 2721 did not modify the antitumor activity of melphalan in early Lewis lung carcinoma did not decrease the antileukemic effects of this agent by a factor of 2.6 indicating tumor protection greater than host protection in the leukemia. The antitumor activity of the DNA binding agents etoposide (VP16-213) and mitoxantrone against systemic P388 leukemia was not diminished by WR 2721, while a substantial increase in host toxicity was noted for the combinations. The protective effects of WR 2721 against radiation and drug damage were, therefore, not entirely selective for normal tissues. In some cases the degree of tumor protection can be similar to, or greater than, normal tissue protection.

  18. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity.

    PubMed

    Hargadon, Kristian M

    2016-01-01

    TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1's contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed. PMID:27589814

  19. Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner

    PubMed Central

    Pérez-Torras, S; Vidal-Pla, A; Cano-Soldado, P; Huber-Ruano, I; Mazo, A; Pastor-Anglada, M

    2013-01-01

    Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs have specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP-ribose) polymerase hyperactivation and cell death and reduced cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. Moreover, this study also shows that restoration of hCNT1 expression is able to reduce tumor growth in a mouse model of pancreatic adenocarcinoma. These data predict a novel role for a NT protein, hCNT1, which appears to be independent of its role as mediator of nucleoside uptake by cells. Thereby, hCNT1 fits the profile of a transceptor in a substrate translocation-independent manner and is likely to be relevant to tumor biology. PMID:23722537

  20. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study

    PubMed Central

    Hamroun, Dalil; Varet, Hugo; Fabbro, Marianne; Rougier, Felix; Amarof, Khadija; Arne Bes, Marie-Christine; Bedat-Millet, Anne-Laure; Behin, Anthony; Bellance, Remi; Bouhour, Françoise; Boutte, Celia; Boyer, François; Campana-Salort, Emmanuelle; Chapon, Françoise; Cintas, Pascal; Desnuelle, Claude; Deschamps, Romain; Drouin-Garraud, Valerie; Ferrer, Xavier; Gervais-Bernard, Helene; Ghorab, Karima; Laforet, Pascal; Magot, Armelle; Magy, Laurent; Menard, Dominique; Minot, Marie-Christine; Nadaj-Pakleza, Aleksandra; Pellieux, Sybille; Pereon, Yann; Preudhomme, Marguerite; Pouget, Jean; Sacconi, Sabrina; Sole, Guilhem; Stojkovich, Tanya; Tiffreau, Vincent; Urtizberea, Andoni; Vial, Christophe; Zagnoli, Fabien; Caranhac, Gilbert; Bourlier, Claude; Riviere, Gerard; Geille, Alain; Gherardi, Romain K.; Eymard, Bruno; Puymirat, Jack; Katsahian, Sandrine; Bassez, Guillaume

    2016-01-01

    Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials. PMID:26849574

  1. Influence of Pulmonary Nodules on Chest Computed Tomography and Risk of Recurrence in Stage IV Wilms Tumor

    SciTech Connect

    Kirkland, Robert S.; Nanda, Ronica H.; Alazraki, Adina; Esiashvili, Natia

    2015-06-01

    Purpose: Chest computed tomography (CT) is currently accepted as the main modality for initial disease staging and response assessment in Wilms tumor (WT). However, there is great variability in the number and size of lung metastases at the time of diagnosis and after induction chemotherapy. There is a lack of clinical evidence as to how this variability in tumor burden affects choice of therapy and disease outcome. This study sought to evaluate a previously proposed lung metastases risk stratification system based on CT findings and clinical outcomes in stage IV WT patients. Methods and Materials: Thirty-five pediatric patients with a diagnosis of stage IV WT with evaluable pre- and postdiagnosis CT scans between 1997 and 2012 were included in the analysis. Patients were divided into low-, intermediate-, and high-risk categories based on the size and number of pulmonary metastases before and after 6 weeks of chemotherapy. Association of the lung risk groups with lung recurrence-free survival and overall survival at each time point was analyzed with relevant covariates. Results: Risk group distribution both at diagnosis and after induction chemotherapy was not influenced by tumor histology. Initial risk grouping suggested an association with disease-free survival at 5 years (P=.074); however, the most significant correlation was with postinduction chemotherapy disease status (P=.027). In patients with an intermediate or high burden of disease after 6 weeks of chemotherapy, despite receiving whole-lung and boost irradiation, survival outcomes were poorer. Conclusions: Pulmonary tumor burden in stage IV WT on chest CT can predict disease outcome. Patients with intermediate- or low-risk disease, especially after induction therapy, have a higher risk for recurrence. After prospective validation, this method may become a valuable tool in adaptation of therapy to improve outcome.

  2. Noble metal nanoparticle-induced oxidative stress modulates tumor associated macrophages (TAMs) from an M2 to M1 phenotype: An in vitro approach.

    PubMed

    Pal, Ramkrishna; Chakraborty, Biswajit; Nath, Anupam; Singh, Leichombam Mohindro; Ali, Mohammed; Rahman, Dewan Shahidur; Ghosh, Sujit Kumar; Basu, Abhishek; Bhattacharya, Sudin; Baral, Rathindranath; Sengupta, Mahuya

    2016-09-01

    Diagnosis of cancer and photothermal therapy using optoelectronic properties of noble metal nanoparticles (NPs) has established a new therapeutic approach for treating cancer. Here we address the intrinsic properties of noble metal NPs (gold and silver) as well as the mechanism of their potential antitumor activity. For this, the study addresses the functional characterization of tumor associated macrophages (TAMs) isolated from murine fibrosarcoma induced by a chemical carcinogen, 3-methylcholanthrene (MCA). We have previously shown antitumor activity of both gold nanoparticles (AuNPs) and silver nanoparticle (AgNPs) in vivo in a murine fibrosarcoma model. In the present study, it has been seen that AuNPs and AgNPs modulate the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, suppressing the antioxidant system of cells (TAMs). Moreover, the antioxidant-mimetic action of these NPs maintain the ROS and RNS levels in TAMs which act as second messengers to activate the proinflammatory signaling cascades. Thus, while there is a downregulation of tumor necrosis factor-α (TNF-α) and Interleukin-10 (IL-10) in the TAMs, the proinflammatory cytokine Interleukin-12 (IL-12) is upregulated resulting in a polarization of TAMs from M2 (anti-inflammatory) to M1 (pro-inflammatory) nature. PMID:27344639

  3. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry.

    PubMed

    Peña, L; Gama, A; Goldschmidt, M H; Abadie, J; Benazzi, C; Castagnaro, M; Díez, L; Gärtner, F; Hellmén, E; Kiupel, M; Millán, Y; Miller, M A; Nguyen, F; Poli, A; Sarli, G; Zappulli, V; de las Mulas, J Martín

    2014-01-01

    Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms. PMID:24227007

  4. Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype.

    PubMed

    Heerema-McKenney, Amy; Wijnaendts, Liliane C D; Pulliam, Joseph F; Lopez-Terrada, Dolores; McKenney, Jesse K; Zhu, Shirley; Montgomery, Kelli; Mitchell, Janet; Marinelli, Robert J; Hart, Augustinus A M; van de Rijn, Matt; Linn, Sabine C

    2008-10-01

    The pathologic classification of rhabdomyosarcoma (RMS) into embryonal or alveolar subtype is an important prognostic factor guiding the therapeutic protocol chosen for an individual patient. Unfortunately, this classification is not always straightforward, and the diagnostic criteria are controversial in a subset of cases. Ancillary studies are used to aid in the classification, but their potential use as independent prognostic factors is rarely studied. The aim of this study is to identify immunohistochemical markers of potential prognostic significance in pediatric RMS and to correlate their expression with PAX-3/FKHR and PAX-7/FKHR fusion status. A single tissue microarray containing 71 paraffin-embedded pediatric RMSs was immunostained with antibodies against p53, bcl-2, Ki-67, CD44, myogenin, and MyoD1. The tissue microarray and whole paraffin blocks were studied for PAX-3/FKHR and PAX-7/FKHR gene fusions by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. Clinical follow-up data were available for each patient. Immunohistochemical staining results and translocation status were correlated with recurrence-free interval (RFI) and overall survival (OS) using the Kaplan-Meier method, the log-rank test, and Cox proportional hazard regression. The minimum clinical follow-up interval was 24 months (median follow-up=57 mo). On univariable analysis, immunohistochemical expression of myogenin, bcl-2, and identification of a gene fusion were associated with decreased 5-year RFI and 10-year OS (myogenin RFI P=0.0028, OS P=0.0021; bcl-2 RFI P=0.037, OS P=0.032; gene fusion RFI P=0.0001, OS P=0.0058). After adjustment for Intergroup Rhabdomyosarcoma Study-TNM stage, tumor site, age, tumor histology, and translocation status by multivariable analysis, only myogenin retained an independent association with RFI (P=0.034) and OS (P=0.0069). In this retrospective analysis, diffuse immunohistochemical reactivity for myogenin in RMS

  5. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment

    PubMed Central

    Chanmee, Theerawut; Ontong, Pawared; Konno, Kenjiro; Itano, Naoki

    2014-01-01

    During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy. PMID:25125485

  6. Tumor-associated macrophages as major players in the tumor microenvironment.

    PubMed

    Chanmee, Theerawut; Ontong, Pawared; Konno, Kenjiro; Itano, Naoki

    2014-01-01

    During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy. PMID:25125485

  7. Routine Clinical-Pathologic Correlation of Pigmented Skin Tumors Can Influence Patient Management

    PubMed Central

    Longo, Caterina; Piana, Simonetta; Lallas, Aimilios; Moscarella, Elvira; Lombardi, Mara; Raucci, Margherita; Pellacani, Giovanni; Argenziano, Giuseppe

    2015-01-01

    Background Several studies have demonstrated the benefit of integrating clinical with pathologic information, to obtain a confident diagnosis for melanocytic tumors. However, all those studies were conducted retrospectively and no data are currently available about the role of a clinical-pathologic correlation approach on a daily basis in clinical practice. Aim of the Study In our study, we evaluated the impact of a routine clinical-pathologic correlation approach for difficult skin tumors seen over 3 years in a tertiary referral center. Results Interestingly, a re-appraisal was requested for 158 out of 2015 (7.7%) excised lesions because clinical-pathologic correlation was missing. Of note, in 0.6% of them (13 out of 2045) the first histologic diagnosis was revised in the light of clinical information that assisted the Pathologist to re-evaluate the histopathologic findings that might be bland or inconspicuous per se. Conclusion In conclusion, our study demonstrated that an integrated approach involving clinicians and pathologists allows improving management of selected patients by shifting from a simply disease-focused management (melanoma versus nevus) to a patient-centered approach. PMID:26325678

  8. Influence of Anti-Mouse Interferon Serum on the Growth and Metastasis of Tumor Cells Persistently Infected with Virus and of Human Prostatic Tumors in Athymic Nude Mice

    NASA Astrophysics Data System (ADS)

    Reid, Lola M.; Minato, Nagahiro; Gresser, Ion; Holland, John; Kadish, Anna; Bloom, Barry R.

    1981-02-01

    Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF--NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.

  9. Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma.

    PubMed

    Prakash, Hridayesh; Klug, Felix; Nadella, Vinod; Mazumdar, Varadendra; Schmitz-Winnenthal, Hubertus; Umansky, Liudmila

    2016-03-01

    Tumor infiltrating iNOS+ macrophages under the influence of immunosuppressive tumor microenvironment gets polarized to tumor-promoting and immunosuppressive macrophages, known as tumor-associated macrophages (TAM). Their recruitment and increased density in the plethora of tumors has been associated with poor prognosis in cancer patients. Therefore, retuning of TAM to M1 phenotype would be a key for effective immunotherapy. Radiotherapy has been a potential non-invasive strategy to improve cancer immunotherapy and tumor immune rejection. Irradiation of late-stage tumor-bearing Rip1-Tag5 mice twice with 2 Gy dose resulted in profound changes in the inflammatory tumor micromilieu, characterized by induction of M1-associated effecter cytokines as well as reduction in protumorigenic and M2-associated effecter cytokines. Similarly, in vitro irradiation of macrophages with 2 Gy dose-induced expression of iNOS, NO, NFκBpp65, pSTAT3 and proinflammatory cytokines secretion while downregulating p38MAPK which are involved in iNOS translation and acquisition of an M1-like phenotype. Enhancement of various M2 effecter cytokines and angiogenic reprogramming in iNOs+ macrophage depleted tumors and their subsequent reduction by 2 Gy dose in Rip1-Tag5 transgenic mice furthermore demonstrated a critical role of peritumoral macrophages in the course of gamma irradiation mediated M1 retuning of insulinoma. PMID:26785731

  10. Suppression of Wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming

    PubMed Central

    Simmen, Rosalia C.M.

    2013-01-01

    Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. In this study, we investigated whether early exposure to blueberry (BB) via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein (CAS, control) or blueberry-supplemented (CAS + 3%BB) diets throughout pregnancy and lactation. Offspring were weaned to CAS and mammary tumor development was followed until age 8 months. Tumor incidence and latency were similar for both groups; however, tumor weight at killing and tumor volume within 2 weeks of initial detection were lower (by 50 and 60%, respectively) in offspring of BB- versus control-fed dams. Dietary BB exposure beginning at weaning did not alter mammary tumor parameters. Tumors from maternal BB-exposed offspring showed higher tumor suppressor (Pten and Cdh1) and lower proproliferative (Ccnd1), anti-apoptotic (Bcl2) and proangiogenic (Figf, Flt1 and Ephb4) transcript levels, and displayed attenuated microvessel density. Expression of Pten and Cdh1 genes was also higher in mammary tissues of maternal BB-exposed offspring. Mammary tissues and tumors of maternal BB-exposed offspring showed increased chromatin-modifying enzyme Dnmt1 and Ezh2 transcript levels. Body weight, serum insulin and serum leptin/adiponectin ratio were lower for maternal BB-exposed than control tumor-bearing offspring. Tumor weights and serum insulin were positively correlated. Results suggest that dietary influences on the maternal environment contribute to key developmental programs in the mammary gland to modify breast cancer outcome in adult progeny. PMID:23144318

  11. Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

    PubMed Central

    Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette; Borup, Rehannah; Broholm, Helle; Kjær, Andreas; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése

    2014-01-01

    Background Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. Methods Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice. Results By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control. Conclusion Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies. PMID

  12. Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma.

    PubMed

    Taylor, Nicholas J; Thomas, Nancy E; Anton-Culver, Hoda; Armstrong, Bruce K; Begg, Colin B; Busam, Klaus J; Cust, Anne E; Dwyer, Terence; From, Lynn; Gallagher, Richard P; Gruber, Stephen B; Nishri, Diane E; Orlow, Irene; Rosso, Stefano; Venn, Alison J; Zanetti, Roberto; Berwick, Marianne; Kanetsky, Peter A

    2016-09-15

    Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. PMID:27101944

  13. Influence of random daughter exposure rate, unattachment fraction, and disequilibrium on occurrence of lung tumors

    SciTech Connect

    Cross, F.T.; Palmer, R.F.; Dagle, G.E.; Busch, R.H.; Buschbom, R.L.

    1983-10-01

    Groups of male, specific-pathogen-free (SPF), Wistar rats were exposed to several concentrations of radon daughters and uranium ore dust to clarify the roles of exposure rate, unattached RaA daughters, and the degree of radon daughter disequilibrium, in the development of respiratory system disease. Modeled, human-dosimetric data indicate that the dose to sensitive tissues of the respiratory tract increases with increasing radon-daughter unattachment fraction and degree of disequilibrium. Experimental verification of these dose-effect relationships is needed to protect the health of workers and of the public exposed to radon-daughter environments. Data bearing on these relationships as well as updated results of experiments designed to test the role of radon-daughter exposure rate on lung-tumor incidence are reported. 13 references, 3 tables.

  14. Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

    PubMed Central

    Gupta, Shilpi; Kumar, Prabhat; Kaur, Harsimrut; Sharma, Nishi; Saluja, Daman; Bharti, Alok C.; Das, Bhudev C.

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID:26581505

  15. Turmeric enhancing anti-tumor effect of Rhizoma paridis saponins by influencing their metabolic profiling in tumors of H22 hepatocarcinoma mice.

    PubMed

    Man, Shuli; Chai, Hongyan; Qiu, Peiyu; Liu, Zhen; Fan, Wei; Wang, Jiaming; Gao, Wenyuan

    2015-12-01

    Rhizoma Paridis saponins combined with turmeric (RT) showed well anti-hepatocarcinoma activities in our previous research. The aim of this study was to investigate the progression of the biochemical response to RT and capture metabolic variations during intragastric administration of their compatibility. In the experiment, histopathological examination and (1)H NMR method were developed and validated for the metabolic profiling of RT intervention in H22 tumor growth. Data were analyzed with principal components analysis (PCA) and partial least-squares discrimination analysis (PLS-DA). As a result, Rhizoma paridis saponins (RPS) or RT induced inflammatory cell infiltration in tumors. RT also mediated the tumor microenvironment to promote anti-tumor immunity of mice. RT significantly inhibited tumor growth rate through suppressing levels of amino acids containing alanine, asparagine, glutamine, putrescine, and sarcosine, lipid compounds, and carbohydrates like myo-inositol and arabinose in the tumor tissues. In conclusion, these results uncovered unexpectedly poor nutritional conditions in the RT-treated tumor tissues whose effect was stronger than RPS's. Therefore, RT could be a novel anticancer agent that targets on cancer metabolism through starving tumors reducing viability of cancer cells. PMID:26471217

  16. Cathepsin S-mediated autophagic flux in tumor-associated macrophages accelerate tumor development by promoting M2 polarization

    PubMed Central

    2014-01-01

    Background Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues, but relatively little is known about the key molecular in these cells that contribute to malignant phenotypes. Autophagic activity is a critical factor in tumor development that contributes to enhancing cellular fitness and survival in the hostile tumor microenvironment. However, the molecular basis and relations between autophagy and TAMs polarization remain unclear. Methods Cathepsin S (Cat S) expression was analyzed in human colon carcinoma and normal colon tissues. In vivo effects were evaluated using PancO2 subcutaneous tumor model and SL4 hepatic metastasis model. Immunofluorescence staining, flow cytometry and real-time PCR were done to examine TAMs polarization. Western blotting assay, transmission electron microscopy, mCherry-GFP-LC3 transfection and DQ-BSA degradation assays were carried out to determine its role in regulating autophagy. Results In the present study, we showed that the enhanced expression of Cat S correlated with the severity of histologic grade as well as clinical stage, metastasis, and recurrence, which are known indicators of a relatively poor prognosis of human colon carcinoma. Cat S knockout led to decreased tumor growth and metastasis. Moreover, Cat S knockout inhibited M2 macrophage polarization during tumor development. We further demonstrated that Cat S was required for not only autophagic flux but also the fusion processes of autophagosomes and lysosomes in TAMs. Importantly, we found that Cat S contributed to tumor development by regulating the M2 phenotype of TAMs through the activation of autophagy. Conclusions These results indicated that Cat S-mediated autophagic flux is an important mechanism for inducing M2-type polarization of TAMs, which leads to tumor development. These data provide strong evidence for a

  17. Numerical simulation of the influence of the elastic modulus of a tumor on laser-induced ultrasonics in soft tissue.

    PubMed

    An, Rong Rong; Luo, Xiao Sen; Shen, Zhong Hua

    2012-11-10

    The influence of the elastic modulus of a tumor (EMT) on the laser-generated thermoelastic force source and ultrasound waves are investigated by using the finite element method. Taking into account the effects of thermal diffusion, optical penetration, and finite duration of laser pulse, the transient temperature distribution is obtained. Applying this temperature field to structure analyses as thermal loading, the thermoelastic stress field and laser-induced ultrasound wave in soft tissues are obtained. The results show that there is a linear correlation between the maximum compressive stress and the elastic modulus of tissues. It is also shown that the features and frequency regions of the laser-induced ultrasound waveform have a close relationship with the EMT, which has been further verified by a corresponding experiment. PMID:23142902

  18. Impact of Stroma on the Growth, Microcirculation, and Metabolism of Experimental Prostate Tumors

    PubMed Central

    Zechmann, Christian M; Woenne, Eva C; Brix, Gunnar; Radzwill, Nicole; Ilg, Martin; Bachert, Peter; Peschke, Peter; Kirsch, Stefan; Kauczor, Hans-Ulrich; Delorme, Stefan; Semmler, Wolfhard; Kiessling, Fabian

    2007-01-01

    Abstract In prostate cancers (PCa), the formation of malignant stroma may substantially influence tumor phenotype and aggressiveness. Thus, the impact of the orthotopic and subcutaneous implantations of hormone-sensitive (H), hormone-insensitive (HI), and anaplastic (AT1) Dunning PCa in rats on growth, microcirculation, and metabolism was investigated. For this purpose, dynamic contrast-enhanced magnetic resonance imaging and 1H magnetic resonance spectroscopy ([1H]MRS) were applied in combination with histology. Consistent observations revealed that orthotopic H tumors grew significantly slower compared to subcutaneous ones, whereas the growth of HI and AT1 tumors was comparable at both locations. Histologic analysis indicated that glandular differentiation and a close interaction of tumor cells and smooth muscle cells (SMC) were associated with slow tumor growth. Furthermore, there was a significantly lower SMC density in subcutaneous H tumors than in orthotopic H tumors. Perfusion was observed to be significantly lower in orthotopic H tumors than in subcutaneous H tumors. Regional blood volume and permeability-surface area product showed no significant differences between tumor models and their implantation sites. Differences in growth between subcutaneous and orthotopic H tumors can be attributed to tumor-stroma interaction and perfusion. Here, SMC, may stabilize glandular structures and contribute to the maintenance of differentiated phenotype. PMID:17325744

  19. Capsaicin Inhibits Multiple Bladder Cancer Cell Phenotypes by Inhibiting Tumor-Associated NADH Oxidase (tNOX) and Sirtuin1 (SIRT1).

    PubMed

    Lin, Ming-Hung; Lee, Yi-Hui; Cheng, Hsiao-Ling; Chen, Huei-Yu; Jhuang, Fong-Han; Chueh, Pin Ju

    2016-01-01

    Bladder cancer is one of the most frequent cancers among males, and its poor survival rate reflects problems with aggressiveness and chemo-resistance. Recent interest has focused on the use of chemopreventatives (nontoxic natural agents that may suppress cancer progression) to induce targeted apoptosis for cancer therapy. Capsaicin, which has anti-cancer properties, is one such agent. It is known to preferentially inhibit a tumor-associated NADH oxidase (tNOX) that is preferentially expressed in cancer/transformed cells. Here, we set out to elucidate the correlation between tNOX expression and the inhibitory effects of capsaicin in human bladder cancer cells. We showed that capsaicin downregulates tNOX expression and decreases bladder cancer cell growth by enhancing apoptosis. Moreover, capsaicin was found to reduce the expression levels of several proteins involved in cell cycle progression, in association with increases in the cell doubling time and enhanced cell cycle arrest. Capsaicin was also shown to inhibit the activation of ERK, thereby reducing the phosphorylation of paxillin and FAK, which leads to decreased cell migration. Finally, our results indicate that RNA interference-mediated tNOX depletion enhances spontaneous apoptosis, prolongs cell cycle progression, and reduces cell migration and the epithelial-mesenchymal transition. We also observed a downregulation of sirtuin 1 (SIRT1) in these tNOX-knockdown cells, a deacetylase that is important in multiple cellular functions. Taken together, our results indicate that capsaicin inhibits the growth of bladder cancer cells by inhibiting tNOX and SIRT1 and thereby reducing proliferation, attenuating migration, and prolonging cell cycle progression. PMID:27367652

  20. Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.

    PubMed

    Liau, Jau-Yu; Tsai, Jia-Huei; Yang, Ching-Yao; Lee, Jen-Chieh; Liang, Cher-Wei; Hsu, Hung-Han; Jeng, Yung-Ming

    2015-09-01

    Alternative lengthening of telomeres (ALT) is a mechanism using homologous recombination to maintain telomere length and sustain limitless replicability of cancer cells. Recently, ALT has been found to be associated with inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. In this study, 119 tumors (88 angiosarcomas, 11 epithelioid hemangioendotheliomas, and 20 Kaposi sarcomas) were analyzed to determine the ALT status, its relationship to loss of ATRX/DAXX expression, and the clinicopathological features. In addition, the mutation status in the telomerase reverse transcriptase gene (TERT) promoter was also studied. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific fluorescence in situ hybridization assay showed 28% (17/61) of the primary angiosarcomas were ALT positive. Remarkably, ALT was highly associated with loss of ATRX expression: all but 2 ALT-positive angiosarcomas were ATRX deficient. Notably, hepatic angiosarcomas were frequently ATRX deficient (8/13) and/or ALT positive (8/12). None of the secondary angiosarcomas were ATRX/DAXX deficient or ALT positive. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. Forty-seven angiosarcomas were tested for TERT promoter mutation. Despite the fact that angiosarcoma occurs most commonly in sun-damaged skin, mutation was detected in only 1 radiation-associated angiosarcoma (2%). We conclude that ALT is an important telomere maintenance mechanism in primary angiosarcomas. This feature is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas. PMID:26190196

  1. A Comprehensive Analysis of Influence ERCC Polymorphisms Confer on the Development of Brain Tumors.

    PubMed

    Geng, Peiliang; Ou, Juanjuan; Li, Jianjun; Liao, Yunmei; Wang, Ning; Xie, Ganfeng; Sa, Rina; Liu, Chen; Xiang, Lisha; Liang, Houjie

    2016-05-01

    Within DNA repair genes, there lie a number of single nucleotide polymorphisms that may impair protein function and attenuate DNA repair capability, resulting in genomic instability and individual predisposition to malignancies. The purpose of this study was to assess the previously reported inconsistent association of polymorphisms in ERCC1 (rs11615, rs3212986), ERCC2 (rs13181, rs1799793, rs238406), and ERCC5 (rs17655) with the development of brain tumors. In the present work, we carried out a comprehensive meta-analysis of results from all published data (5 data sets for rs11615, 7 for rs3212986, 11 for rs13181, 5 for rs1799793, 3 for rs238406, and 4 for rs17655) to evaluate risk of brain tumors contributed by the polymorphisms being investigated. Either the analytic method described by Mantel and Haenszel or that proposed by DerSimonian and Laird was properly used to summarize the risk estimates (OR and 95 % CI). Data analyses were done with Stata version 12.0. Meta-analyses were performed for all polymorphisms, and only rs3212986 in the ERCC1 gene showed a significant association with glioma incidence. In the homozygote comparison, we found 1.26-fold elevated risk of glioma in relation to presence of the AA genotype (OR = 1.26, 95 % CI = 1.05-1.52, P OR = 0.013, P heterogeneity = 0.849, I (2) = 0.0 %). We also noted that individuals with the rs3212986-AA as compared to those with rs3212986-CC/CA had a 28 % higher risk to develop glioma (OR = 1.28, 95 % CI = 1.06-1.53, P OR = 0.008, P heterogeneity = 0.808, I (2) = 0.0 %). No major effects were observed for Caucasians or Asians in subgroup analysis by ethnicity. ERCC1 rs3212986 is a common single nucleotide polymorphism and may contribute toward individual susceptibility for glioma. Further research in this filed is required to verify the association obtained based on a relatively small number. PMID:26264164

  2. Differential expression of mitotic regulators and tumor microenvironment influences the regional growth pattern of solid sarcoma along the cranio-caudal axis.

    PubMed

    Chattopadhyay, Sukalpa; Chaklader, Malay; Chatterjee, Ritam; Law, Aditya; Law, Sujata

    2016-01-01

    Soft tissue sarcomas are relatively rare, unusual, anatomically diverse group of malignancies. According to the recent literature and medical bulletins, tumor growth and aggressiveness immensely relies on its anatomical locations. However, it is unclear whether the cranio-caudal anatomical axis of the mammalian body can influence sarcoma development and the underlying molecular mechanisms are not yet deciphered. Here, we investigated the growth pattern of solid sarcoma implanted into the murine cranial and caudal anatomical locations and tried to explore the location specific expression pattern of crucial mammalian mitotic regulators such as Aurora kinase A, Histone H3 and c-Myc in the cranio-caudally originated solid tumors. In addition, the influence of local tumor microenvironment on regional sarcoma growth was also taken into consideration. We found that solid sarcoma developed differentially when implanted into two different anatomical locations and most notably, enhanced tumor growth was observed in case of cranially implanted sarcoma than the caudal sarcoma. Interestingly, Aurora kinase A and c-Myc expression and histone H3 phosphorylation level were comparatively higher in the cranial tumor than the caudal. In addition, variation of tumor stroma in a location specific manner also facilitated tumor growth. Cranial sarcoma microenvironment was well vascularized than the caudal one and consequently, a significantly higher microvessel density count was observed which was parallel with low hypoxic response with sign of local tumor inflammation in this region. Taken together, our findings suggest that differential gradient of mitotic regulators together with varied angiogenic response and local tumor microenvironment largely controls solid sarcoma growth along the cranio-caudal anatomical axis. PMID:26658517

  3. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior.

    PubMed

    Roudsari, Laila C; Jeffs, Sydney E; Witt, Amber S; Gill, Bartley J; West, Jennifer L

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm(2), circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  4. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    PubMed Central

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity < 0.25) developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration. Our findings suggest vascular cells contribute to tumor progression and establish this culture system as a platform for studying tumor vascularization. PMID:27596933

  5. In vitro influence of hypoxia on bioluminescence imaging in brain tumor cells

    NASA Astrophysics Data System (ADS)

    Moriyama, Eduardo H.; Jarvi, Mark; Niedre, Mark; Mocanu, Joseph D.; Moriyama, Yumi; Li, Buhong; Lilge, Lothar; Wilson, Brian C.

    2007-02-01

    Bioluminescence Imaging (BLI) has been employed as an imaging modality to identify and characterize fundamental processes related to cancer development and response at cellular and molecular levels. This technique is based on the reaction of luciferin with oxygen in the presence of luciferase and ATP. A major concern in this technique is that tumors are generally hypoxic, either constitutively and/or as a result of treatment, therefore the oxygen available for the bioluminescence reaction could possibly be reduced to limiting levels, and thus leading to underestimation of the actual number of luciferase-labeled cells during in vivo procedures. In this report, we present the initial in vitro results of the oxygen dependence of the bioluminescence signal in rat gliosarcoma 9L cells tagged with the luciferase gene (9L luc cells). Bioluminescence photon emission from cells exposed to different oxygen tensions was detected by a sensitive CCD camera upon exposure to luciferin. The results showed that bioluminescence signal decreased at administered pO II levels below about 5%, falling by approximately 50% at 0.2% pO II. Additional experiments showed that changes in BLI was due to the cell inability to maintain normal levels of ATP during the hypoxic period reducing the ATP concentration to limiting levels for BLI.

  6. Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes

    PubMed Central

    Morley, Samantha; You, Sungyong; Pollan, Sara; Choi, Jiyoung; Zhou, Bo; Hager, Martin H.; Steadman, Kenneth; Spinelli, Cristiana; Rajendran, Kavitha; Gertych, Arkadiusz; Kim, Jayoung; Adam, Rosalyn M.; Yang, Wei; Krishnan, Ramaswamy; Knudsen, Beatrice S.; Di Vizio, Dolores; Freeman, Michael R.

    2015-01-01

    Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors. PMID:26179371

  7. Disentangling the relationship between tumor genetic programs and immune responsiveness.

    PubMed

    Bedognetti, Davide; Hendrickx, Wouter; Ceccarelli, Michele; Miller, Lance D; Seliger, Barbara

    2016-04-01

    Correlative studies in humans have demonstrated that an active immune microenvironment characterized by the presence of a T-helper 1 immune response typifies a tumor phenotype associated with better outcome and increased responsiveness to immune manipulation. This phenotype also signifies the counter activation of immune-regulatory mechanisms. Variables modulating the development of an effective anti-tumor immune response are increasingly scrutinized as potential therapeutic targets. Genetic alterations of cancer cells that functionally influence intratumoral immune response include mutational load, specific mutations of genes involved in oncogenic pathways and copy number aberrations involving chemokine and cytokine genes. Inhibiting oncogenic pathways that prevent the development of the immune-favorable cancer phenotype may complement modern immunotherapeutic approaches. PMID:26967649

  8. Influence of Cell Detachment on the Respiration Rate of Tumor and Endothelial Cells

    PubMed Central

    Danhier, Pierre; Copetti, Tamara; De Preter, Géraldine; Leveque, Philippe; Feron, Olivier; Jordan, Bénédicte F.; Sonveaux, Pierre; Gallez, Bernard

    2013-01-01

    Cell detachment is a procedure routinely performed in cell culture and a necessary step in many biochemical assays including the determination of oxygen consumption rates (OCR) in vitro. In vivo, cell detachment has been shown to exert profound metabolic influences notably in cancer but also in other pathologies, such as retinal detachment for example. In the present study, we developed and validated a new technique combining electron paramagnetic resonance (EPR) oximetry and the use of cytodex 1 and collagen-coated cytodex 3 dextran microbeads, which allowed the unprecedented comparison of the OCR of adherent and detached cells with high sensitivity. Hence, we demonstrated that both B16F10 melanoma cells and human umbilical vein endothelial cells (HUVEC) experience strong OCR decrease upon trypsin or collagenase treatments. The reduction of cell oxygen consumption was more pronounced with a trypsin compared to a collagenase treatment. Cells remaining in suspension also encounter a marked intracellular ATP depletion and an increase in the lactate production/glucose uptake ratio. These findings highlight the important influence exerted by cell adhesion/detachment on cell respiration, which can be probed with the unprecedented experimental assay that was developed and validated in this study. PMID:23382841

  9. Mechanical Signals As a Non-Invasive Means to Influence Mesenchymal Stem Cell Fate, Promoting Bone and Suppressing the Fat Phenotype

    PubMed Central

    Luu, Yen K.; Pessin, Jeffrey E.; Judex, Stefan; Rubin, Janet; Rubin, Clinton T.

    2010-01-01

    Pluripotent mesenchymal stem cells (MSCs) are considered ideal therapeutic targets in regenerative medicine, as they hold the capacity to differentiate into higher order connective tissues. The potential to harness MSCs for disease treatment and acceleration of repair will ultimately depend on an improved understanding of how physical and/or chemical signals regulate their activity, and the ability of exogenous stimuli to enhance MSC proliferation and define MSC fate. Recent appreciation that bone marrow osteoprogenitors are inversely proportional to adipocyte precursors suggests that their shared progenitor, the MSC, will commit to one lineage at the cost of the other. This interrelationship may contribute to the phenotype of sedentary subjects who have more fat and less bone, while conversely, to the outcome of exercise being less fat and more bone. Mechanical biasing of MSC lineage selection suggests that physical signals may influence the quantity of both fat and bone through developmental, as well as metabolic or adaptive pathways. Considered with the recent finding that low magnitude mechanical signals (LMMS) suppress the development of subcutaneous and visceral fat without elevating energy expenditure, this indicates that MSCs are ideally positioned as mechanosensitive elements central to musculoskeletal adaptation, but that the signals needn’t be large to be influential. The biasing of MSC differentiation by mechanical signals represents a unique means by which adiposity can be inhibited while simultaneously promoting a better skeleton, and may provide the basis for a safe, non-invasive, non-pharmacologic strategy to prevent both obesity and osteoporosis, yet uniquely – without targeting the resident fat or bone cell. PMID:22241295

  10. CTLs regulate tumor growth via cytostatic effects rather than cytotoxicity: a few T cells can influence the growth of many times more tumor cells

    PubMed Central

    Kakimi, Kazuhiro; Matsushita, Hirokazu; Hosoi, Akihiro; Miyai, Manami; Ohara, Osamu

    2014-01-01

    Cytotoxic T lymphocytes (CTLs) play a central role in antitumor immunity. We utilized B16 melanoma cells expressing the fluorescent ubiquitination-based cell cycle indicator B16-fucci implanted in host mice and adoptively transferred with pmel-1-TCR transgenic T cells to demonstrate that tumor growth reduction is largely dependent on interferon γ-mediated cell cycle arrest rather than the cytotoxic killing of tumor cells by CTLs. PMID:25949889

  11. The influence of toxic working environment on the urothelial bladder tumors characteristics, the experience of “Sf. Ioan” Clinical Emergency Hospital on selected series

    PubMed Central

    Drăguţescu, M; Geavlete, B; Multescu, R; Mihai, B; Moldoveanu, C; Geavlete, P

    2012-01-01

    Introduction: A correlation between urothelial bladder tumor incidence and exposure to various occupational toxic factors was established for more than a century. The aim of our study was to establish the relationship between these two features. Materials and methods: We analyzed one hundred consecutive bladder tumor patients treated in “Sf. Ioan” Clinical Emergency Hospital, Department of Urology. These cases were studied concerning their occupation and pathological findings. Results:We identified 58 patients having potential urothelial bladder tumors inducing occupations: dye industry, motor vehicle drivers and miners. Among these patients, the incidence of muscle invasive tumors was of 33%, of the high-grade tumors was of 69%, of the multiple tumors was of 60% and of the associated CIS lesions was of 38%. All these rates were significantly lower in the non-occupational hazard group: 12%, 26%, 29% and 14% respectively. Conclusions: Exposure to occupational toxic factors seems to influence the evolution of urothelial bladder tumor into more aggressive patterns. Further studies in this regard are necessary. PMID:23049632

  12. Cell line donor genotype and its influence on experimental phenotype: Toll-like receptor SNPs and potential variability in innate immunity.

    PubMed

    Tokarz, Sara A; DeValk, Jessica; Luo, Wenxiang; Pattnaik, Bikash R; Schrodi, Steven J; Pillers, De-Ann M

    2016-07-01

    Cell lines are used to model a disease and provide valuable information regarding phenotype, mechanism, and response to novel therapies. Derived from individuals of diverse genetic backgrounds, the cell's genetic complement predicts the phenotype, and although some lines have been sequenced, little emphasis has been placed on genotyping. Toll-like receptors (TLRs) are essential in initiating the inflammatory cascade in response to infection. TLR single nucleotide polymorphism (SNP) alleles may predict an altered innate immune response: a SNP can affect TLR-dependent pathways and may alter experimental results. Thus, genotype variation may have far-reaching implications when using cell lines to model phenotypes. We recommend that cell lines be genotyped and cataloged in a fashion similar to that used for bacteria, with cumulative information being archived in an accessible central database to facilitate the understanding of SNP cell phenotypes reported in the literature. PMID:27324283

  13. KSHV Induction of Angiogenic and Lymphangiogenic Phenotypes

    PubMed Central

    DiMaio, Terri A.; Lagunoff, Michael

    2012-01-01

    Kaposi’s sarcoma (KS) is a highly vascularized tumor supporting large amounts of neo-angiogenesis. The major cell type in KS tumors is the spindle cell, a cell that expresses markers of lymphatic endothelium. KSHV, the etiologic agent of KS, is found in the spindle cells of all KS tumors. Considering the extreme extent of angiogenesis in KS tumors at all stages it has been proposed that KSHV directly induces angiogenesis in a paracrine fashion. In accordance with this theory, KSHV infection of endothelial cells in culture induces a number of host pathways involved in activation of angiogenesis and a number of KSHV genes themselves can induce pathways involved in angiogenesis. Spindle cells are phenotypically endothelial in nature, and therefore, activation through the induction of angiogenic and/or lymphangiogenic phenotypes by the virus may also be directly involved in spindle cell growth and tumor induction. Accordingly, KSHV infection of endothelial cells induces cell autonomous angiogenic phenotypes to activate host cells. KSHV infection can also reprogram blood endothelial cells to lymphatic endothelium. However, KSHV induces some blood endothelial specific genes upon infection of lymphatic endothelial cells creating a phenotypic intermediate between blood and lymphatic endothelium. Induction of pathways involved in angiogenesis and lymphangiogenesis are likely to be critical for tumor cell growth and spread. Thus, induction of both cell autonomous and non-autonomous changes in angiogenic and lymphangiogenic pathways by KSHV likely plays a key role in the formation of KS tumors. PMID:22479258

  14. Tumor angiogenesis--characteristics of tumor endothelial cells.

    PubMed

    Hida, Kyoko; Maishi, Nako; Torii, Chisaho; Hida, Yasuhiro

    2016-04-01

    Tumor blood vessels provide nutrition and oxygen to the tumor, resulting in tumor progression. They also act as gatekeepers, inducing tumor metastasis. Thus, targeting tumor blood vessels is an important strategy in cancer therapy. Tumor endothelial cells (TECs), which line the inner layer of blood vessels of the tumor stromal tissue, are the main targets of anti-angiogenic therapy. Because new tumor blood vessels generally sprout from pre-existing vasculature, they have been considered to be the same as normal blood vessels. However, tumor blood vessels demonstrate a markedly abnormal phenotype that includes several important morphological changes. The degree of angiogenesis is determined by the balance between the angiogenic stimulators and inhibitors released by the tumor and host cells. Recent studies have revealed that TECs also exhibit altered characteristics which depend on the tumor microenvironment. Here, we review recent studies on TEC abnormalities and heterogeneity with respect to tumor progression and consider their therapeutic implications. PMID:26879652

  15. The influence of the local effect model parameters on the prediction of the tumor control probability for prostate cancer

    NASA Astrophysics Data System (ADS)

    Chanrion, M.-A.; Sauerwein, W.; Jelen, U.; Wittig, A.; Engenhart-Cabillic, R.; Beuve, M.

    2014-06-01

    In carbon ion beams, biological effects vary along the ion track; hence, to quantify them, specific radiobiological models are needed. One of them, the local effect model (LEM), in particular version I (LEM I), is implemented in treatment planning systems (TPS) clinically used in European particle therapy centers. From the physical properties of the specific ion radiation, the LEM calculates the survival probabilities of the cell or tissue type under study, provided that some determinant input parameters are initially defined. Mathematical models can be used to predict, for instance, the tumor control probability (TCP), and then evaluate treatment outcomes. This work studies the influence of the LEM I input parameters on the TCP predictions in the specific case of prostate cancer. Several published input parameters and their combinations were tested. Their influence on the dose distributions calculated for a water phantom and for a patient geometry was evaluated using the TPS TRiP98. Changing input parameters induced clinically significant modifications of the mean dose (up to a factor of 3.5), spatial dose distribution, and TCP predictions (up to factor of 2.6 for D50). TCP predictions were found to be more sensitive to the parameter threshold dose (Dt) than to the biological parameters α and β. Additionally, an analytical expression was derived for correlating α, β and Dt, and this has emphasized the importance of \\frac{D_t}{\\alpha /\\beta }. The improvement of radiobiological models for particle TPS will only be achieved when more patient outcome data with well-defined patient groups, fractionation schemes and well-defined end-points are available.

  16. Influence of tumor microenvironment on prognosis in colorectal cancer: Tissue architecture-dependent signature of endosialin (TEM-1) and associated proteins

    PubMed Central

    O'Shannessy, Daniel J.; Somers, Elizabeth B.; Chandrasekaran, Lakshmi K.; Nicolaides, Nicholas C.; Bordeaux, Jennifer; Gustavson, Mark D.

    2014-01-01

    Tumor survival is influenced by interactions between tumor cells and the stromal microenvironment. One example is Endosialin (Tumor Endothelial Marker-1 (TEM-1) or CD248), which is expressed primarily by cells of mesenchymal origin and some tumor cells. The expression, as a function of architectural masking, of TEM-1 and its pathway-associated proteins was quantified and examined for association with five-year disease-specific survival on a colorectal cancer (CRC) cohort divided into training (n=330) and validation (n=164) sets. Although stromal expression of TEM-1 had prognostic value, a more significant prognostic signature was obtained through linear combination of five compartment-specific expression scores (TEM-1 Stroma, TEM-1 Tumor Vessel, HIF2α Stromal Vessel, Collagen IV Tumor, and Fibronectin Stroma). This resulted in a single continuous risk score (TAPPS: TEM-1 Associated Pathway Prognostic Signature) which was significantly associated with decreased survival on both the training set [HR=1.76 (95%CI: 1.44-2.15); p<0.001] and validation set [HR=1.38 (95%CI: 1.02-1.88); p=0.04]. Importantly, since prognosis is a critical clinical question in Stage II patients, the TAPPS score also significantly predicted survival in the Stage II patient (n=126) cohort [HR=1.75 (95%CI: 1.22-2.52); p=0.002] suggesting the potential of using the TAPPS score to assess overall risk in CRC patients, and specifically in Stage II patients. PMID:24980818

  17. Influence of lipid components on gene delivery by polycation liposomes: Transfection efficiency, intracellular kinetics and in vivo tumor inhibition.

    PubMed

    Chen, Jinliang; Sun, Xiaoyi; Yu, Zhenwei; Gao, Jianqing; Liang, Wenquan

    2012-01-17

    Transfection efficiency of non-viral gene vectors is influenced by many factors, including chemical makeup, cellular uptake pathway and intracellular delivery. To investigate the effect of lipid saturation on transfection efficiency of polycation liposomes (PCLs), a soybean phospholipids (SPL), egg phospholipids (EPL) and hydrogenated soybean phosphatidylcholine (HSPC) series was used to prepare PCLs. Testing these PCLs in a luciferase assay indicated that with increasing saturation (SPLtumor inhibition efficiency compared with control and naked pCMV-IL-12 treatments in vivo. PMID:22119962

  18. APC mutations in colorectal tumors with mismatch repair deficiency.

    PubMed Central

    Huang, J; Papadopoulos, N; McKinley, A J; Farrington, S M; Curtis, L J; Wyllie, A H; Zheng, S; Willson, J K; Markowitz, S D; Morin, P; Kinzler, K W; Vogelstein, B; Dunlop, M G

    1996-01-01

    We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair. Images Fig. 2 PMID:8799152

  19. Partial hypoxia as a cause of radioresistance in a human tumor xenograft: its influence illustrated by the sensitizing effect of misonidazole and hyperbaric oxygen

    SciTech Connect

    Reynaud-Bougnoux, A.; Lespinasse, F.; Malaise, E.P.; Guichard, M.

    1986-08-01

    While previous studies with three human tumor xenografts suggest that contact-resistance plays a major role in the response of these tumors to radiation, it remains possible that partial hypoxia may provide an alternate explanation. The present study was carried out to check this possibility by investigating the influence of misonidazole (MISO) and hyperbaric oxygen (HBO) on both the initial and distal components of the survival curves of HRT18 tumor cells. The effect of a challenge dose of radiation on the initial radioresistance of this tumor was also studied. To assess the effects of MISO and HBO, tumor cell survival was determined by excision assay in two groups of tumor-bearing mice, one given MISO (1 mg/g body weight, i.p.) 45 min before irradiation and the other exposed to HBO (3.5 bars). MISO treatment caused greater sensitization than HBO. The enhancement ratios at the 5.10(-1) level were 1.7 (MISO) and 1.7 (HBO); at the 10(-1) level, they were 1.6 (MISO) and 1.4 (HBO); while at 10(-2), they were 1.6 (MISO) and 1.4 (HBO). These two sensitizing effects favor the hypothesis that solid tumors contain a compartment of partially hypoxic cells. To study the effect of a challenge radiation dose on initial radioresistance, tumors were given a challenge dose of 8 Gy, followed 24-48 hr later by doses ranging from 2-12 Gy. The challenge dose did not modify the shape of the survival curve.

  20. SU-E-I-96: A Study About the Influence of ROI Variation On Tumor Segmentation in PET

    SciTech Connect

    Li, L; Tan, S; Lu, W; D'Souza, W

    2014-06-01

    Purpose: To study the influence of different regions of interest (ROI) on tumor segmentation in PET. Methods: The experiments were conducted on a cylindrical phantom. Six spheres with different volumes (0.5ml, 1ml, 6ml, 12ml, 16ml and 20 ml) were placed inside a cylindrical container to mimic tumors of different sizes. The spheres were filled with 11C solution as sources and the cylindrical container was filled with 18F-FDG solution as the background. The phantom was continuously scanned in a Biograph-40 True Point/True View PET/CT scanner, and 42 images were reconstructed with source-to-background ratio (SBR) ranging from 16:1 to 1.8:1. We took a large and a small ROI for each sphere, both of which contain the whole sphere and does not contain any other spheres. Six other ROIs of different sizes were then taken between the large and the small ROI. For each ROI, all images were segmented by eitht thresholding methods and eight advanced methods, respectively. The segmentation results were evaluated by dice similarity index (DSI), classification error (CE) and volume error (VE). The robustness of different methods to ROI variation was quantified using the interrun variation and a generalized Cohen's kappa. Results: With the change of ROI, the segmentation results of all tested methods changed more or less. Compared with all advanced methods, thresholding methods were less affected by the ROI change. In addition, most of the thresholding methods got more accurate segmentation results for all sphere sizes. Conclusion: The results showed that the segmentation performance of all tested methods was affected by the change of ROI. Thresholding methods were more robust to this change and they can segment the PET image more accurately. This work was supported in part by National Natural Science Foundation of China (NNSFC), under Grant Nos. 60971112 and 61375018, and Fundamental Research Funds for the Central Universities, under Grant No. 2012QN086. Wei Lu was supported in

  1. Gadolinium-loaded chitosan nanoparticles for neutron-capture therapy: Influence of micrometric properties of the nanoparticles on tumor-killing effect.

    PubMed

    Ichikawa, Hideki; Uneme, Takeshi; Andoh, Tooru; Arita, Yuya; Fujimoto, Takuya; Suzuki, Minoru; Sakurai, Yoshinori; Shinto, Hiroyuki; Fukasawa, Tomonori; Fujii, Fumihiko; Fukumori, Yoshinobu

    2014-06-01

    As a nanoparticulate device for controlled delivery of Gd in NCT, the authors have developed gadolinium-loaded chitosan nanoparticles (Gd-nanoCPs). In the present study, influence of micrometric properties such as particle size, particle-surface charge and Gd content of Gd-nanoCPs on tumor-killing effect by Gd-NCT was investigated with Gd-nanoCPs. Two types of Gd-nanoCPs with different mean particle size, zeta potential and Gd-content (Gd-nanoCP-400; 391nm, 28mV, 9wt% and Gd-nanoCP-200; 214nm, 19mV, 24wt%) could be prepared by using chitosans with different molecular weights. Gd-nanoCPs incorporating 1.2mg of natural Gd were injected intratumorally once or twice to mice subcutaneously-bearing B16F10 melanoma. Eight hours after the last administration, thermal neutron was irradiated to tumor region of the mice. Remarkable tumor-growth was observed in both hot and cold control groups. In contrast, Gd-NCT groups showed significant tumor-growth suppression effect, though their efficacy was found to depend on the micrometric properties of Gd-nanoCPs. In particular, the Gd-nanoCP-200 exhibited stronger tumor-killing effect than the Gd-nanoCP-400 at the same Gd dose and it was still similar to Gd-nanoCP-400 in tumor-growth suppressing effect even at the half of Gd dose of Gd-nanoCP-400. This significance in tumor-killing effect would be ascribed from a higher Gd retention in the tumor tissue and an improved distribution of Gd with intratumorally administered Gd-nanoCP-200. Indeed, the Gd concentration in tumor tissue at the time corresponding to the onset of thermal neutron irradiation was determined to be significantly higher in Gd-nanoCP-200, compared with Gd-nanoCP-400. These results demonstrated that appropriate modification of Gd-nanoCPs in micrometric properties would be an effective way to improve the retention of Gd in the tumor tissue after intratumoral injection, leading to the enhanced tumor-killing effect in Gd-NCT. PMID:24462286

  2. HGFL supports mammary tumorigenesis by enhancing tumor cell intrinsic survival and influencing macrophage and T-cell responses

    PubMed Central

    Benight, Nancy M.; Wagh, Purnima K.; Zinser, Glendon M.; Peace, Belinda E.; Stuart, William D.; Vasiliauskas, Juozas; Pathrose, Peterson; Starnes, Sandra L.; Waltz, Susan E.

    2015-01-01

    The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the necessity of the endogenous Ron ligand, hepatocyte growth factor-like protein (HGFL) in mammary tumorigenesis. Herein, mammary tumor growth and metastasis were examined in mice overexpressing Ron in the mammary epithelium with or without HGFL. HGFL ablation decreased oncogenic Ron activation and delayed mammary tumor initiation. HGFL was important for tumor cell proliferation and survival. HGFL loss resulted in increased numbers of macrophages and T-cells within the tumor. T-cell proliferation and cytotoxicity dramatically increased in HGFL deficient mice. Biochemical analysis of HGFL proficient tumors showed increased local HGFL production, with HGFL loss decreasing β-catenin expression and NF-κB activation. Re-expression of HGFL in HGFL deficient tumor cells stimulated cell migration and invasion with coordinate activation of NF-κB and reduced apoptosis. Together, these results demonstrate critical in vivo functions for HGFL in promoting breast tumorigenesis and suggest that targeting HGFL may inhibit tumor growth and reactivate anti-tumor immune responses. PMID:25938541

  3. URINARY MUTAGENESIS AS AN EXPOSURE BIOMARKER OF COOKED-MEAT-ASSOCIATED MUTAGENS: INFLUENCE OF COOKING TEMPERATURE, PHENOTYPE, AND GENOTYPE IN A CONTROLLED METABOLIC FEEDING STUDY

    EPA Science Inventory

    ABSTRACT
    We evaluated urinary mutagenicity and selected phenotypes and genotypes in 60 subjects in a metabolic feeding study in which meat cooked at low temperature (100oC) was consumed for 1 week followed by meat cooked at high temperature (250oC) the second week. Meat coo...

  4. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    ERIC Educational Resources Information Center

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  5. Transcriptional profiling of macrophage and tumor cell interactions in vitro.

    PubMed

    Roudnicky, Filip; Hollmén, Maija

    2016-06-01

    Macrophages are important mediators of tumor progression and their function is broadly influenced by different microenvironmental stimuli. To understand the molecular basis of the tumor-supporting role of macrophages in aggressive breast cancer we co-cultured human peripheral monocytes with two breast cancer cell lines representing distinct aggressive cellular phenotype and transcriptionally profiled the changes occurring in both cells during in vitro activated crosstalk. Here we provide a detailed description of the experimental design, sample identity and analysis of the Illumina RNA-Seq data, which have been deposited into Gene Expression Omnibus (GEO): GSE75130. PMID:27081631

  6. Influence of Tumor Thrombus Location on the Outcome of External-beam Radiation Therapy in Advanced Hepatocellular Carcinoma With Macrovascular Invasion

    SciTech Connect

    Hou Jiazhou; Zeng Zhaochong; Zhang Jianying; Fan Jia; Zhou Jian; Zeng Mengsu

    2012-10-01

    Purpose: The present study evaluates the influence of portal vein (PV) vs. inferior vena cava (IVC) tumor thrombosis sites on the effectiveness of external-beam radiation therapy (EBRT) in advanced hepatocellular carcinoma (HCC) with macrovascular invasion. Methods and Materials: We retrospectively reviewed 181 HCC patients with PV and/or IVC tumor thrombi who were referred for EBRT at our institution between 2000 and 2009. EBRT was designed to focus on the tumor thrombi with or without primary intrahepatic tumors to deliver a median total conventional dose of 50 Gy (range, 30-60 Gy). Predictors of survival were identified using univariate and multivariate analyses. Results: The median survival was 10.2, 7.4, 17.4, and 8.5 months for patients with PV branch, PV trunk, IVC, and PV plus IVC tumor thrombosis, respectively. Unfavorable pretreatment predictors were associated by multivariate analysis with lower albumin and higher {alpha}-fetoprotein levels, poorer Child-Pugh liver function classification, multiple intrahepatic foci, lymph node metastases, thrombus location, less chance to receive post-EBRT transarterial chemoembolization (TACE) and the two-dimensional EBRT technique. In comparison to patients with PV tumor thrombosis, patients with IVC thrombi had a higher occurrence of solitary intrahepatic lesions (p = 0.027), well-controlled intrahepatic tumors (p < 0.001), and a better response to EBRT (p < 0.001), and they were more likely to receive post-EBRT TACE (p = 0.033). Conclusions: In HCC, patients with IVC thrombus treated with EBRT had a better response rate and longer survival than those with PV thrombus.

  7. Nucleoprotein structure influences the response of the mouse mammary tumor virus promoter to activation of the cyclic AMP signalling pathway.

    PubMed Central

    Pennie, W D; Hager, G L; Smith, C L

    1995-01-01

    Recent studies have provided evidence of crosstalk between steroid receptors and cyclic AMP (cAMP) signalling pathways in the regulation of gene expression. A synergism between intracellular phosphorylation inducers and either glucocorticoids or progestins has been shown to occur during activation of the mouse mammary tumor virus (MMTV) promoter. We have investigated the effect of 8-Br-cAMP and okadaic acid, modulators of cellular kinases and phosphatases, on the hormone-induced activation of the MMTV promoter in two forms: a transiently transfected template with a disorganized, accessible nucleoprotein structure and a stably replicating template with an ordered, inaccessible nucleoprotein structure. Both okadaic acid and 8-Br-cAMP synergize significantly with either glucocorticoids or progestins in activating the transiently transfected MMTV template. In contrast, 8-Br-cAMP, but not okadaic acid, is antagonistic to hormone-induced activation of the stably replicating MMTV template. Nuclear run-on experiments demonstrate that this inhibition is a transcriptional effect on both hormone-induced transcription and basal transcription. Surprisingly, 8-Br-cAMP does not inhibit glucocorticoid-induced changes in restriction enzyme access and nuclear factor 1 binding. However, association of a complex with the TATA box region is inhibited in the presence of 8-Br-cAMP. Thus, cAMP treatment interferes with the initiation process but does not inhibit interaction of the receptor with the template. Since the replicated, ordered MMTV templates and the transfected, disorganized templates show opposite responses to 8-Br-cAMP treatment, we conclude that chromatin structure can influence the response of a promoter to activation of the cAMP signalling pathway. PMID:7891707

  8. Anti-tumor effect and influence of Gekko gecko Linnaeus on the immune system of sarcoma 180-bearing mice.

    PubMed

    You, Qi; Han, Shiyu; Zhang, Yuanlong; Zheng, Jianhua

    2009-01-01

    Gekko gecko Linnaeus (GgL) is an extract used in traditional Chinese medicine. In the present study, we examined the anti-tumor activity of GgL and its effect on the immune system of mice. Sarcoma 180-bearing mice were used as the animal model, and cisplatin was applied as the positive control drug. The mice were randomly divided into six groups, and each group was treated with a different drug or drug concentration. The effects of GgL were evaluated based on its anti-tumor activity and prolongation of the lifespan, the lymphocyte transformation rate and pathological changes observed in the tumors. The results suggest that GgL has anti-tumor activities and up-regulates the immune system in a dose-dependent manner. This study provides original data related to the anti-tumor and immune up-regulating function of GgL. PMID:21475868

  9. Metabolic Phenotypes in Pancreatic Cancer

    PubMed Central

    Yu, Min; Zhou, Quanbo; Zhou, Yu; Fu, Zhiqiang; Tan, Langping; Ye, Xiao; Zeng, Bing; Gao, Wenchao; Zhou, Jiajia; Liu, Yimin; Li, Zhihua; Lin, Ye; Lin, Qing; Chen, Rufu

    2015-01-01

    Introduction The aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer. Methods We performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine-dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism. Results Longer overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose-dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (P<0.0001), lymphatic invasion (P<0.0001), and activated autophagic status in stroma (P = 0.0002). Mixed type and Warburg type had a significant association with shorter overall survival (P = 0.018). Non-canonical type and mixed type of glutamine-dependent metabolism comprised the highest percentage of tumors with vascular invasion (p = 0.0073), highest percentage of activated autophagy in tumors (P = 0.0034). Moreover, these two types of glutamine-dependent metabolism were significantly associated with shorter overall survival (P<0.001). Further analysis suggested that most of tumors were dependent on both glucose- and glutamine-dependent metabolism. After dividing the tumors according to the number of metabolism, we found that the increasing numbers of metabolism subtypes inversely associated with survival outcome. Conclusion

  10. Human tumor clonogenic assay for carcinoma of the lung. II. Factors that influence colony formation in soft agar.

    PubMed

    Kanzawa, F; Matsushima, Y; Hamburger, A W; Ishihara, J; Sasaki, Y; Shimizu, E; Eguchi, K; Shinkai, T; Saijo, N; Miyazawa, N

    1987-01-01

    The human tumor clonogenic assay (HTCA) has potential value for studies of both the chemosensitivity and biology of human tumors. However, many technical problems including low plating efficiencies and the preparation of sufficient numbers of viable cells remain. In this study, an improved method for disaggregation of solid tumors increased the yield of single cells. Consequently, more than 10 anticancer drugs could be tested in 94 of 168 specimens (56%). Removal of peripheral blood lymphocytes from cell suspensions derived from effusions also improved colony formation. Adequate growth for sensitivity testing (greater than 30 colonies/plate) was obtained in 122 cases (73%), inadequate growth for drug evaluation (5-29 colonies/plate) in 29 cases (17%), and no colony formation (less than 5 colonies/plate) in 17 cases (10%) of the 168 viable samples. The cloning efficiencies of cells derived from primary tumors (median 0.015%) were higher than those of cells derived from metastatic tumors (0.012%), and they varied with the location of the metastatic site. Cloning efficiencies varied markedly from specimen to specimen, and were unaffected by tumor histology, grade of differentiation, patient age, stage of disease, or prior chemotherapy. The HTCA is promising as a potential tool for studying the biology of tumors. PMID:3601316

  11. Influence of the PROP Bitter Taste Phenotype and Eating Attitudes on Energy Intake and Weight Status in Pre-adolescents: A 6-year Follow-up Study

    PubMed Central

    Oftedal, Katherine Nolen; Tepper, Beverly J.

    2013-01-01

    The PROP bitter-taste phenotype is a marker for food preferences and eating behavior, and may associate with differences in body weight in children. Previous work has shown that PROP status in combination with eating attitudes are better predictors of weight status in preadolescents, than either factor alone. However, no studies have examined the role of PROP phenotypes in body weight change in children over time. The primary objective of this study was to investigate current weight status and change in weight status in children from preschool (baseline) to preadolescence as a function of eating attitudes and PROP phenotype. Other measures included self-reported food intakes and physical activity by activity monitor. Seventy-three lean (BMI %-ile = 57.7 ± 3.2%) children with mean age=10.3 ± 0.5 yrs, participated in the follow up. There were no group differences in energy intake, current BMI-percentile or change in BMI percentile from baseline by PROP phenotype in either boys or girls. However, there was a trend for non-taster girls to show a downward shift in BMI-percentile at follow up. Hierarchical regression analysis revealed that baseline BMI percentile and physical activity energy expenditure were the strongest predictors of current weight (28.5% variance), followed by child restraint, the taster x gender interaction, and the maternal BMI x maternal emotional eating interaction, accounting for 7.1%, 6.0% and 4.8% of variance in the model, respectively. These findings suggest that PROP status and eating attitudes are modest predictors of weight status in preadolescent children. PMID:23680431

  12. Daddy issues: paternal effects on phenotype.

    PubMed

    Rando, Oliver J

    2012-11-01

    The once popular and then heretical idea that ancestral environment can affect the phenotype of future generations is coming back into vogue due to advances in the field of epigenetic inheritance. How paternal environmental conditions influence the phenotype of progeny is now a tractable question, and researchers are exploring potential mechanisms underlying such effects. PMID:23141533

  13. Mechanism of carcinogenesis in familial tumors.

    PubMed

    Tamura, Kazuo; Utsunomiya, Joji; Iwama, Takeo; Furuyama, Jun-ichi; Takagawa, Tetsuya; Takeda, Naohisa; Fukuda, Yoshihiro; Matsumoto, Takayuki; Nishigami, Takashi; Kusuhara, Kiyoshi; Sagayama, Ken; Nakagawa, Kazuhiko; Yamamura, Takehira

    2004-08-01

    It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive. PMID:15375699

  14. The influence of sex on life shortening and tumor induction in CBA/Cne mice exposed to x rays or fission neutrons

    SciTech Connect

    Di Majo, V.; Coppola, M.; Rebessi, S.; Saran, A.

    1996-07-01

    An experimental study of male and female CBA/Cne mice was set up at Casaccia primarily to investigate the influence of sex on long-term survival and tumor induction after exposure to high- and low-LET radiation. Mice were whole-body-irradiated at 3 months of age with fission-neutron doses of 0.1, 0.2, 0.4, 0.8, 1.2 and 1.8 Gy at the RSV-TAPIRO reactor (mean neutron energy 0.4 MeV, in terms of kerma, y{sub D} = 51.5 KeV/{mu}m), or with 250 KVp X-ray doses of 1, 3, 5 and 7 Gy. Control and irradiated animals were then followed for their entire life span. As a general finding, male CBA/Cne mice appear more susceptible to tumori-genesis than females. In particular, the incidences of induced acute myeloid leukemia and malignant lymphomas are significant only in male mice. Benign and malignant solid tumors of many types are observed in mice of both sexes, the most frequent being in the lung, liver and ovary. However, evidence for a radiation response is limited to the case of Harderian gland neoplasms. In addition, a comparison of the observed frequency of all irradiated compared to unirradiated animals bearing solid tumors shows that the total tumor occurrence is not altered markedly by radiation exposure. A decrease in survival time is observed for both sexes and radiation types and correlates well with increasing dose. Moreover, both sex and radiation quality appear to influence the life shortening. A similar dose dependence of survival time is found when tumor-free animals alone are considered, suggesting a non-specific component of life-shortening. 18 refs., 3 figs., 5 tabs.

  15. Numerical and experimental investigation of the influence of tumor size on laser-induced ultrasonics in soft tissue

    NASA Astrophysics Data System (ADS)

    An, Rongrong; Luo, Xiaosen; Shen, Zhonghua

    2014-04-01

    The generation and propagation of laser-induced ultrasonic waves in soft tissue systems are investigated using the finite element method. Taking into account the effects of thermal diffusion, optical penetration, tumor elastic modulus and finite laser pulse duration, the transient temperature distribution is obtained. Using this temperature field as thermal loading in structural analysis, the thermoelastic stress field and laser-induced ultrasound waves in soft tissues are obtained. The results show that the intensity of the positive peak in the ultrasound wave increases and the arrival of the longitudinal wave takes place sooner as the tumor size becomes larger. It is also found that the duration of the laser ultrasound signal becomes shorter as the size of the tumor decreases. Meanwhile, the percentage of the received ultrasonic signal in the high-frequency region increases as the size of the tumor decreases, as has been proved by the experimental results.

  16. Three-dimensional in vitro co-culture model of breast tumor using magnetic levitation.

    PubMed

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R; Dave, Bhuvanesh; Godin, Biana

    2014-01-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors. PMID:25270048

  17. Three-Dimensional In Vitro Co-Culture Model of Breast Tumor using Magnetic Levitation

    PubMed Central

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R.; Dave, Bhuvanesh; Godin, Biana

    2014-01-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors. PMID:25270048

  18. Megavoltage Computed Tomography Image Guidance With Helical Tomotherapy in Patients With Vertebral Tumors: Analysis of Factors Influencing Interobserver Variability

    SciTech Connect

    Levegruen, Sabine; Poettgen, Christoph; Abu Jawad, Jehad; Berkovic, Katharina; Hepp, Rodrigo; Stuschke, Martin

    2013-02-01

    Purpose: To evaluate megavoltage computed tomography (MVCT)-based image guidance with helical tomotherapy in patients with vertebral tumors by analyzing factors influencing interobserver variability, considered as quality criterion of image guidance. Methods and Materials: Five radiation oncologists retrospectively registered 103 MVCTs in 10 patients to planning kilovoltage CTs by rigid transformations in 4 df. Interobserver variabilities were quantified using the standard deviations (SDs) of the distributions of the correction vector components about the observers' fraction mean. To assess intraobserver variabilities, registrations were repeated after {>=}4 weeks. Residual deviations after setup correction due to uncorrectable rotational errors and elastic deformations were determined at 3 craniocaudal target positions. To differentiate observer-related variations in minimizing these residual deviations across the 3-dimensional MVCT from image resolution effects, 2-dimensional registrations were performed in 30 single transverse and sagittal MVCT slices. Axial and longitudinal MVCT image resolutions were quantified. For comparison, image resolution of kilovoltage cone-beam CTs (CBCTs) and interobserver variability in registrations of 43 CBCTs were determined. Results: Axial MVCT image resolution is 3.9 lp/cm. Longitudinal MVCT resolution amounts to 6.3 mm, assessed as full-width at half-maximum of thin objects in MVCTs with finest pitch. Longitudinal CBCT resolution is better (full-width at half-maximum, 2.5 mm for CBCTs with 1-mm slices). In MVCT registrations, interobserver variability in the craniocaudal direction (SD 1.23 mm) is significantly larger than in the lateral and ventrodorsal directions (SD 0.84 and 0.91 mm, respectively) and significantly larger compared with CBCT alignments (SD 1.04 mm). Intraobserver variabilities are significantly smaller than corresponding interobserver variabilities (variance ratio [VR] 1.8-3.1). Compared with 3-dimensional

  19. The -308 bp TNF gene polymorphism influences tumor necrosis factor expression in leprosy patients in Bahia State, Brazil.

    PubMed

    Oliveira, Joyce Moura; Rêgo, Jamile Leão; de Lima Santana, Nadja; Braz, Marcos; Jamieson, Sarra E; Vieira, Thaillamar Silva; Magalhães, Thaís Lamêgo; Machado, Paulo Roberto Lima; Blackwell, Jenefer M; Castellucci, Léa C

    2016-04-01

    Leprosy or Hansen's disease is a debilitating chronic granulomatous disease caused by Mycobacterium leprae, with high incidence and prevalence in Brazil. The -308 bp G/A single nucleotide polymorphism (SNP rs1800629) in the tumor necrosis factor (TNF) gene promoter is a proposed risk factor for leprosy. In Brazil, Northern India, Egypt and Nepal, the common G allele was associated with leprosy. In Eastern India, Thailand and Malawi the minor A allele was the risk factor. Allele A was previously associated with high TNF. We genotyped rs1800629 in 326 leprosy cases from Bahia State, Brazil, including 72 paucibacillary (PB) and 47 multibacillary (MB) without reactions, and 69 reversal reaction (RR) and 78 erythema nodosum leprosum (ENL) with reactions. Logistic regression was used to compare patient groups with 331 healthy controls. Relative TNF mRNA was determined in peripheral blood leukocytes by QRTPCR, and serum TNF levels measured by ELISA. We found that TNF mRNA expression was higher (P=0.03) in leprosy patients compared to endemic controls, but did not differ significantly between clinical subgroups. Carriage of the minor A allele was associated (P=0.003) with low TNF mRNA across leprosy patients. Nevertheless, we found no evidence for either allele at this SNP as a risk factor for leprosy per se (OR=1.12, 95% CI 0.79-1.60, P=0.52), PB (OR=0.99, 95% CI 0.54-1.81, P=0.97), MB (OR=0.86, 95% CI 0.40-1.83, P=0.70), RR (OR=1.37, 95% CI 0.79-2.38, P=0.27) or ENL (OR=0.76, 95% CI 0.40-1.45, P=0.42) when compared to endemic controls. Further studies are required to determine whether the influence of the minor A allele on TNF mRNA levels determines response to treatment, particularly in the context of ENL reaction treatment with anti-TNF therapies and RR reactions where treatment with prednisolone is known to reduce TNF levels. Our findings contribute to understanding TNF as an important determinant of leprosy immunopathology in Brazil. PMID:26829382

  20. An Emerging Allee Effect Is Critical for Tumor Initiation and Persistence

    PubMed Central

    Böttger, Katrin; Hatzikirou, Haralambos; Voss-Böhme, Anja; Cavalcanti-Adam, Elisabetta Ada; Herrero, Miguel A.; Deutsch, Andreas

    2015-01-01

    Tumor cells develop different strategies to cope with changing microenvironmental conditions. A prominent example is the adaptive phenotypic switching between cell migration and proliferation. While it has been shown that the migration-proliferation plasticity influences tumor spread, it remains unclear how this particular phenotypic plasticity affects overall tumor growth, in particular initiation and persistence. To address this problem, we formulate and study a mathematical model of spatio-temporal tumor dynamics which incorporates the microenvironmental influence through a local cell density dependence. Our analysis reveals that two dynamic regimes can be distinguished. If cell motility is allowed to increase with local cell density, any tumor cell population will persist in time, irrespective of its initial size. On the contrary, if cell motility is assumed to decrease with respect to local cell density, any tumor population below a certain size threshold will eventually extinguish, a fact usually termed as Allee effect in ecology. These results suggest that strategies aimed at modulating migration are worth to be explored as alternatives to those mainly focused at keeping tumor proliferation under control. PMID:26335202

  1. Estrogens metabolism associated with polymorphisms: influence of COMT G482a genotype on age at onset of canine mammary tumors.

    PubMed

    Dias Pereira, P; Lopes, C C; Matos, A J F; Pinto, D; Gärtner, F; Lopes, C; Medeiros, R

    2008-03-01

    Catechol-O-methyltransferase (COMT) is an important enzyme participating in inactivation of carcinogenic oestrogen metabolites. In humans there is a single nucleotide polymorphism in COMT gene (COMT val158met) that has been associated with an increased risk for developing breast cancer. In dogs, there is a single nucleotide polymorphism in COMT gene (G482A), but its relation with mammary carcinogenesis has never been investigated. The aim of this study was to focus on the evaluation of such polymorphism as a risk factor for the development of mammary tumors in bitches and on the analysis of its relationship with some clinicopathologic features (dog's age and weight, number and histologic type of the lesions, lymph node metastasis) of canine mammary neoplasms. A case-control study was conducted analyzing 90 bitches with mammary tumors and 84 bitches without evidence of neoplastic disease. The COMT G482A polymorphism was analyzed by PCR-RFLP. We found a protective effect of the polymorphism in age of onset of mammary tumors, although we could not establish a significant association between COMT genotype and other clinicopathologic parameters nor with mammary tumor risk overall. Animals carrying the variant allele have a threefold likelihood of developing mammary tumors after 9 years of age in comparison with noncarriers. The Kaplan-Meier method revealed significant differences in the waiting time for onset of malignant disease for A allele carrier (12.46 years) and noncarrier (11.13 years) animals. This investigation constitutes the first case-control study designed to assess the relationship between polymorphic genes and mammary tumor risk in dogs. Our results point to the combined effect of COMT genotype with other genetic and/or environmental risk factors as important key factors for mammary tumor etiopathogenesis. PMID:18424824

  2. A novel laboratory technique demonstrating the influences of RHD zygosity and the RhCcEe phenotype on erythrocyte D antigen expression

    PubMed Central

    McGann, Patrick T.; Despotovic, Jenny M.; Howard, Thad A.; Ware, Russell E.

    2015-01-01

    D antigen is the most immunogenic and clinically relevant antigen within the complex Rh blood group system. Variability of D antigen expression was first described decades ago but has rarely been investigated quantitatively, particularly in the context of RHD zygosity along with RhCcEe serological phenotype. With IRB approval, 107 deidentified blood samples were analyzed. Rh phenotypes were determined serologically by saline technique using monoclonal antibodies against D, C, c, E, and e antigens. RHD zygosity was determined using both PCR-restriction fragment length polymorphisms and quantitative real-time PCR techniques. A novel and robust method was developed for quantitation of erythrocyte D antigen sites using calibrated microspheres and flow cytometry, allowing correlation of D antigen density with RHD zygosity and expression of Rh CcEe antigens. Subjects homozygous for RHD expressed nearly twice the number of D antigen sites compared with RHD hemizygotes (33,560 ± 8,222 for DD versus 17,720 ± 4,471 for Dd, P < 0.0001). Expression of c or E antigens was associated with significantly increased erythrocyte D antigen expression, whereas presence of C or e antigens reduced expression. These data and this novel quantitation method will be important for future studies investigating the clinical relevance of D antigen variability. PMID:22121029

  3. Influence of chronic prolactin suppression during puberty on the development of dimethylbenz(a)anthracene-induced mammary tumors (41163). [Rats

    SciTech Connect

    Cohen, L.A.

    1981-06-01

    In order to assess the effect of early prolactin suppression on the subsequent development of dimethylbenz(a)anthracene (DMBA)-induced mammary cancers, the dopamine agonist, CB-154, was chronically administered to female Sprague-Dawley rats from Day 35 to Day 50 of age. DMBA was then administered and tumor development assessed over a 25-week period. It was found that animals treated with CB-154 exhibited decreased tumor incidence, a longer latent period, and fewer tumors/animal, when compared to vehicle controls. These results are consistent with the hypothesis that the sensitivity of the mammary gland to polycyclic aromatic hydrocarbon (PAH) carcinogenesis is determined by the level of differentiation of the gland at the time of carcinogen administration. Accordingly, perturbations in prolactin secretion patterns, early in life, may accelerate or retard the differentiation of the mammary gland thereby rendering it less susceptible to the carcinogenic effects of PAH.

  4. A Truncated form of CD200 (CD200S) Expressed on Glioma Cells Prolonged Survival in a Rat Glioma Model by Induction of a Dendritic Cell-Like Phenotype in Tumor-Associated Macrophages12

    PubMed Central

    Kobayashi, Kana; Yano, Hajime; Umakoshi, Akihiro; Matsumoto, Shirabe; Mise, Ayano; Funahashi, Yu; Ueno, Yoshitomo; Kamei, Yoshiaki; Takada, Yasutsugu; Kumon, Yoshiaki; Ohnishi, Takanori; Tanaka, Junya

    2016-01-01

    CD200 induces immunosuppression in myeloid cells expressing its receptor CD200R, which may have consequences for tumor immunity. We found that human carcinoma tissues express not only full-length CD200 (CD200L) but also its truncated form, CD200S. Although CD200S is reported to antagonize the immunosuppressive actions of CD200L, the role of CD200S in tumor immunity has never been investigated. We established rat C6 glioma cell lines that expressed either CD200L or CD200S; the original C6 cell line did not express CD200 molecules. The cell lines showed no significant differences in growth. Upon transplantation into the neonatal Wistar rat forebrain parenchyma, rats transplanted with C6-CD200S cells survived for a significantly longer period than those transplanted with the original C6 and C6-CD200L cells. The C6-CD200S tumors were smaller than the C6-CD200L or C6-original tumors, and many apoptotic cells were found in the tumor cell aggregates. Tumor-associated macrophages (TAMs) in C6-CD200S tumors displayed dendritic cell (DC)-like morphology with multiple processes and CD86 expression. Furthermore, CD3+, CD4+ or CD8+ cells were more frequently found in C6-CD200S tumors, and the expression of DC markers, granzyme, and perforin was increased in C6-CD200S tumors. Isolated TAMs from original C6 tumors were co-cultured with C6-CD200S cells and showed increased expression of DC markers. These results suggest that CD200S activates TAMs to become DC-like antigen presenting cells, leading to the activation of CD8+ cytotoxic T lymphocytes, which induce apoptotic elimination of tumor cells. The findings on CD200S action may provide a novel therapeutic modality for the treatment of carcinomas. PMID:27108386

  5. Differential influence of organ site on three subpopulations of a single mouse mammary tumor at two distinct steps in metastasis.

    PubMed

    Aslakson, C J; Rak, J W; Miller, B E; Miller, F R

    1991-02-01

    Tumor subpopulations 66c14, 168FARN, and 4T07 are drug-resistant variants selected from sister subpopulations derived from a single mouse mammary tumor. These subpopulations are heterogeneous in their capacities to form experimental metastatic growth in the lungs and liver. Initial survival kinetics of arrested cells, determined by the clearance of 125IUdR-labelled cells, and subsequent growth rates, determined by sequential recovery of clonogenic tumor cells from occult metastases, both correlated with organ-colonizing potential as determined by necropsy. The growth rates of these 3 subpopulations were determined in vitro in monolayer and in situ in the subcutis, in the liver following intrasplenic injection, and in the lung following intravenous injection. Clonogenic potential of all 3 lines was similar in vitro (54-59%). Growth rates in vitro (population doubling times 16.5-21 hr) and in the subcutis (tumor volume doubling times 5.2-7.4 days) were similar for the 3 subpopulations, but differed significantly in the liver and lungs. For line 4T07, the most metastatic line to both lung and liver, population doubling times in vitro and in the lung and liver were similar, ranging from 17 to 26 hr. For lines 66c14 and 168FARN, the growth rates in lungs and livers were much slower than in vitro. Line 66c14, which is relatively more metastatic to the lungs, grew much faster in the lung (39 hours) than in the liver (91 hr), but line 168FARN, which is relatively more metastatic to the liver, grew at a faster rate in the liver (37 hr) than in the lung (63 hr). Thus, 3 tumor subpopulations (seeds) derived from a single tumor were differentially affected by host organ factors (soil) at 2 distinct stages in the metastatic process. PMID:1993557

  6. Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA0 Cleavage Site

    PubMed Central

    Diederich, Sandra; Berhane, Yohannes; Embury-Hyatt, Carissa; Hisanaga, Tamiko; Handel, Katherine; Cottam-Birt, Colleen; Ranadheera, Charlene; Kobasa, Darwyn

    2015-01-01

    ABSTRACT Although a polybasic HA0 cleavage site is considered the dominant virulence determinant for highly pathogenic avian influenza (HPAI) H5 and H7 viruses, naturally occurring virus isolates possessing a polybasic HA0 cleavage site have been identified that are low pathogenic in chickens. In this study, we generated a reassortant H5N3 virus that possessed the hemagglutinin (HA) gene from H5N1 HPAI A/swan/Germany/R65/2006 and the remaining gene segments from low pathogenic A/chicken/British Columbia/CN0006/2004 (H7N3). Despite possessing the HA0 cleavage site GERRRKKR/GLF, this rH5N3 virus exhibited a low pathogenic phenotype in chickens. Although rH5N3-inoculated birds replicated and shed virus and seroconverted, transmission to naive contacts did not occur. To determine whether this virus could evolve into a HPAI form, it underwent six serial passages in chickens. A progressive increase in virulence was observed with the virus from passage number six being highly transmissible. Whole-genome sequencing demonstrated the fixation of 12 nonsynonymous mutations involving all eight gene segments during passaging. One of these involved the catalytic site of the neuraminidase (NA; R293K) and is associated with decreased neuraminidase activity and resistance to oseltamivir. Although introducing the R293K mutation into the original low-pathogenicity rH5N3 increased its virulence, transmission to naive contact birds was inefficient, suggesting that one or more of the remaining changes that had accumulated in the passage number six virus also play an important role in transmissibility. Our findings show that the functional linkage and balance between HA and NA proteins contributes to expression of the HPAI phenotype. IMPORTANCE To date, the contribution that hemagglutinin-neuraminidase balance can have on the expression of a highly pathogenic avian influenza virus phenotype has not been thoroughly examined. Reassortment, which can result in new hemagglutinin

  7. Anatomic Tumor Location Influences the Success of Contemporary Limb-Sparing Surgery and Radiation Among Adults With Soft Tissue Sarcomas of the Extremities

    SciTech Connect

    Korah, Mariam P.; Deyrup, Andrea T.; Monson, David K.; Oskouei, Shervin V.; Weiss, Sharon W.; Landry, Jerome; Godette, Karen D.

    2012-02-01

    Purpose: To examine the influence of anatomic location in the upper extremity (UE) vs. lower extremity (LE) on the presentation and outcomes of adult soft tissue sarcomas (STS). Methods and Materials: From 2001 to 2008, 118 patients underwent limb-sparing surgery (LSS) and external beam radiotherapy (RT) with curative intent for nonrecurrent extremity STS. RT was delivered preoperatively in 96 and postoperatively in 22 patients. Lesions arose in the UE in 28 and in the LE in 90 patients. Patients with UE lesions had smaller tumors (4.5 vs. 9.0 cm, p < 0.01), were more likely to undergo a prior excision (43 vs. 22%, p = 0.03), to have close or positive margins after resection (71 vs. 49%, p = 0.04), and to undergo postoperative RT (32 vs. 14%, p = 0.04). Results: Five-year actuarial local recurrence-free and distant metastasis-free survival rates for the entire group were 85 and 74%, with no difference observed between the UE and LE cohorts. Five-year actuarial probability of wound reoperation rates were 4 vs. 29% (p < 0.01) in the UE and LE respectively. Thigh lesions accounted for 84% of the required wound reoperations. The distribution of tumors within the anterior, medial, and posterior thigh compartments was 51%, 26%, and 23%. Subset analysis by compartment showed no difference in the probability of wound reoperation between the anterior and medial/posterior compartments (29 vs. 30%, p = 0.68). Neurolysis was performed during resection in (15%, 5%, and 67%, p < 0.01) of tumors in the anterior, medial, and posterior compartments. Conclusions: Tumors in the UE and LE differ significantly with respect to size and management details. The anatomy of the UE poses technical impediments to an R0 resection. Thigh tumors are associated with higher wound reoperation rates. Tumor resection in the posterior thigh compartment is more likely to result in nerve injury. A better understanding of the inherent differences between tumors in various extremity sites will assist in

  8. The Cellular Localization of Human Cytomegalovirus Glycoprotein Expression Greatly Influences the Frequency and Functional Phenotype of Specific CD4+ T Cell Responses

    PubMed Central

    Zuo, Jianmin; Ryan, Gordon B.; Begum, Jusnara; Moss, Paul A. H.

    2015-01-01

    CMV infection is a significant cause of morbidity and mortality in immunocompromised individuals, and the development of a vaccine is of high priority. Glycoprotein B (gB) is a leading vaccine candidate but the glycoprotein H (gH) pentameric complex is now recognized as the major target for neutralizing Abs. However, little is known about the T cell immune response against gH and glycoprotein L (gL) and this is likely to be an important attribute for vaccine immunogenicity. In this study, we examine and contrast the magnitude and phenotype of the T cell immune response against gB, gH, and gL within healthy donors. gB-specific CD4+ T cells were found in 95% of donors, and 29 epitopes were defined with gB-specific response sizes ranging from 0.02 to 2.88% of the CD4+ T cell pool. In contrast, only 20% of donors exhibited a T cell response against gH or gL. Additionally, gB-specific CD4+ T cells exhibited a more cytotoxic phenotype, with high levels of granzyme B expression. Glycoproteins were effectively presented following delivery to APCs but only gB-derived epitopes were presented following endogenous synthesis. gB expression was observed exclusively within vesicular structures colocalizing with HLA-DM whereas gH was distributed evenly throughout the cytoplasm. Grafting of the C-terminal domain from gB onto gH could not transfer this pattern of presentation. These results reveal that gB is a uniquely immunogenic CMV glycoprotein and this is likely to reflect its unique pattern of endogenous Ag presentation. Consideration may be required toward mechanisms that boost cellular immunity to gH and gL within future subunit vaccines. PMID:26363059

  9. VEGFR-1 targeted DNAzyme via transcatheter arterial delivery influences tumor vasculature assessed through dynamic contrast-enhanced magnetic resonance imaging.

    PubMed

    Zhang, Liqing; Zhao, Wei; Liang, Chen; Yi, Xiaoping; Pei, Yigang; Lin, Yiting; He, Jiang; Li, Wenzheng

    2016-09-01

    DNAzymes are synthetic single-stranded DNA oligonucleotides that bind and cleave target mRNA in a sequence-specific manner. Although the therapeutic potential has been demonstrated in both preclinical and clinical settings, the efficient delivery and in vivo assessment of the DNAzyme efficacy remain the vital unsolved issue. In the present study, we examined the feasibility of using transcatheter arterial chemoembolization (TACE) strategy to deliver a DNAzyme targeting VEGFR-1 and monitoring its effect on tumor angiogenesis in vivo via dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). In a rabbit liver cancer model (VX2), we showed that the DNAzyme was efficiently delivered into the tumor by TACE. DCE-MRI revealed that the VEGFR-1-targeted DNAzyme affected the tumor vasculature through inhibiting VEGFR-1 expression in vivo, which was reflected by a reduction of Ktrans and Kep, the parameters of tumor microvascular permeability. Our findings offer an efficient strategy of delivery and assessment of the VEGFR-1 DNAzyme, and further demonstrate the feasibility of DNAzyme for cancer therapy. PMID:27431919

  10. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation

    NASA Astrophysics Data System (ADS)

    Burke, Ryan M.; Madden, Kelley S.; Perry, Seth W.; Zettel, Martha L.; Brown, Edward B.

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  11. A novel tumor suppressor function of Kindlin-3 in solid cancer

    PubMed Central

    Menashi, Suzanne; Tost, Jorg; Podgorniak, Marie-Pierre; Sadoux, Aurelie; Daunay, Antoine; Teixeira, Luis; Soulier, Jean; Idbaih, Ahmed; Setterblad, Niclas; Fauvel, Françoise; Calvo, Fabien; Janin, Anne; Lebbé, Celeste; Mourah, Samia

    2014-01-01

    Kindlin-3 (FERMT-3) is known to be central in hemostasis and thrombosis control and its deficiency disrupts platelet aggregation and causes Leukocyte Adhesion Deficiency disease. Here we report that Kindlin-3 has a tumor suppressive role in solid cancer. Our present genetic and functional data show that Kindlin-3 is downregulated in several solid tumors by a mechanism involving gene hypermethylation and deletions. In vivo experiments demonstrated that Kindlin-3 knockdown in 2 tumor cell models (breast cancer and melanoma) markedly increases metastasis formation, in accord with the in vitro increase of tumor cell malignant properties. The metastatic phenotype was supported by a mechanism involving alteration in β3-integrin activation including decreased phosphorylation, interaction with talin and the internalization of its active form leading to less cell attachment and more migration/invasion. These data uncover a novel and unexpected tumor suppressor role of Kindin-3 which can influence integrins targeted therapies development. PMID:25344860

  12. Phenotypic heterogeneity of Streptococcus mutans in dentin.

    PubMed

    Rupf, S; Hannig, M; Breitung, K; Schellenberger, W; Eschrich, K; Remmerbach, T; Kneist, S

    2008-12-01

    Information concerning phenotypic heterogeneity of Streptococcus mutans in carious dentin is sparse. Matrix-assisted laser-desorption/ionization-time-of-flight mass-spectrometry (MALDI-TOF-MS) facilitates the phenotypic differentiation of bacteria to the subspecies level. To verify a supposed influence of restorative treatment on the phenotypic heterogeneity of S. mutans, we isolated and compared a total of 222 S. mutans strains from dentin samples of 21 human deciduous molars during caries excavation (T(1)) and 8 wks (T(2)) after removal of the temporary restoration. Phenotypic heterogeneity was determined by MALDI-TOF-MS and hierarchical clustering. Thirty-six distinct S. mutans phenotypes could be identified. Although indistinguishable phenotypes were found in the same teeth at T(1) and T(2), as well as in different teeth of individual participants, the phenotypic heterogeneity increased significantly, from 1.4 phenotypes per S. mutans-positive dentin sample at T(1) to 2.2 phenotypes at T(2). We attribute this to an adaptation of S. mutans to the modified environment under the restoration following caries excavation. PMID:19029088

  13. Cytokinins in Vinca rosea L. Crown Gall Tumor Tissue as Influenced by Compounds Containing Reduced Nitrogen 1

    PubMed Central

    Peterson, Jay B.; Miller, Carlos O.

    1976-01-01

    Several compounds containing reduced nitrogen markedly increased the yields of cell-division compounds extractable from an A6 Vinca rosea L. crown gall tumor tissue. Casein hydrolysate, several amino acids, and ammonium salts were effective. Both trans-zeatin and ribosyl-trans-zeatin were substantially increased in total amount per culture and in concentration. These two compounds have been identified by several criteria including mass spectra. The reduced nitrogen treatments also caused the appearance of a cytokinin not previously detected in this tissue; it has not yet been identified. The tumor tissue rapidly absorbed [8-14C]adenine from a liquid medium. Within 1 hour, the tissue converted some of the adenine to zeatin and ribosylzeatin, and greater degrees of conversion occurred in 2-, 4-, and 8-hour periods. The tissue grown on a medium containing ammonium chloride accumulated considerably greater quantities of the two cytokinins made from the labeled adenine during each incubation period. PMID:16659489

  14. Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment.

    PubMed

    Hu, Ke Yao; Wang, De Gui; Liu, Peng Fei; Cao, Yan Wei; Wang, Yong Hua; Yang, Xue Cheng; Hu, Cheng Xia; Sun, Li Jiang; Niu, Hai Tao

    2016-08-01

    Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) and monocarboxylate transporter 1 (MCT1) play important roles in tumor endothelial cells (ECs) and several biological processes. The present study was conducted to study the effects of PFKFB3 and MCT1 on cell proliferation and apoptosis in the tumor microenvironment by co-culture of HUVECs and T24, a bladder cancer (BC) cell line, using a microfluidic device. Immunofluorescence assay showed that HUVEC activity was significantly enhanced under co-culture with T24 cells, according to the stronger fluorescence intensity of CD31 and CD105 than that in the signal‑cultured cells. Quercetin treatment inhibited MCT1 expression but did not affect PFKFB3 expression. Knockdown of MCT1 or/and PFKFB3 increased the apoptosis rate of the HUVECs under single-culture and co-culture situations by staining with calcein and propidium iodide. Meanwhile, cell proliferation and lactic concentration were significantly decreased after the blocking of MCT1 or/and PFKFB3, as compared with that in the control group. No obvious differences in the effects on apoptosis, proliferation and lactic concentration were found between cells treated with quercetin and siMCT1. Thus, we concluded that the targeting of MCT1 and PFKFB3 regulated cell proliferation and apoptosis in BC cells by altering the tumor microenvironment, and quercetin exhibited a potential antitumor effect by targeting MCT1. PMID:27373212

  15. Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

    PubMed Central

    Sookoian, Silvia; Pirola, Carlos J.

    2016-01-01

    A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10−6, n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents –2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a –28% increase in serum ALT. PMID:27278285

  16. Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2016-01-01

    A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10(-6), n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents -2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a -28% increase in serum ALT. PMID:27278285

  17. Joint fitting reveals hidden interactions in tumor growth.

    PubMed

    Barberis, L; Pasquale, M A; Condat, C A

    2015-01-21

    Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Crucial to the system evolution are the interactions between these populations. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses alone, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination. PMID:25451531

  18. Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines

    PubMed Central

    Adalsteinsson, Viktor; Tahirova, Narmin; Tallapragada, Naren; Yao, Xiaosai; Campion, Liam; Angelini, Alessandro; Douce, Thomas B.; Huang, Cindy; Bowman, Brittany; Williamson, Christina; Kwon, Douglas S.; Wittrup, K. Dane; Love, J. Christopher

    2014-01-01

    Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via either or both of the CXCR1 and CXCR2 receptors, exerting profound impacts on tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors. PMID:23995780

  19. Social and biological factors influencing the outcomes of children with Wilms tumors in Kenya and other Sub-Saharan countries.

    PubMed

    Kumon, Kazuko; Kaneko, Yasuhiko

    2014-01-01

    Wilms tumor (WT) is a common pediatric solid tumor, and the 5-year event-free survival rate of patients with this tumor has reached 85-90% in developed countries, whereas those in developing countries were reported to be less than 50%. To overcome these disparities, physicians and investigators in developed and developing countries are currently performing research with the aim of the better management of children with WT in Kenya and other Sub-Saharan countries. Axt and colleagues published a study that increased understanding of clinicopathology of WT in Kenya on the basis of a comprehensive web-based WT registry. The study revealed that patients enrolled in the National Health Insurance Fund (NHIF) showed better completion rate of therapy and better event-free survival than those not enrolled, indicating insufficient health coverage for those not enrolled in the NHIF. Approximately 20-30% of Kenyan population is estimated to be covered by some forms of health insurance, mostly by the NHIF. This could be improved through various approaches. The report described that 2-year event-free survival rate was 52.7% for all patients, although loss to follow up was 50%; the findings indicate large problems both in the study results and also in the completion of treatment. It is crucial to determine at which point patients stopped their treatment and why. The development of standardized treatment protocol for WT is an urgent agenda. We hope that researchers in developed countries and health providers in Kenya can work together in future to conquer disparities in the outcomes of children with WT. PMID:26835323

  20. Different prognostic value of circulating and disseminated tumor cells in primary breast cancer: Influence of bisphosphonate intake?

    PubMed Central

    Kasimir-Bauer, Sabine; Reiter, Katharina; Aktas, Bahriye; Bittner, Ann-Kathrin; Weber, Stephan; Keller, Thomas; Kimmig, Rainer; Hoffmann, Oliver

    2016-01-01

    Disseminated tumor cells (DTCs) in the bone marrow (BM) and circulating tumor cells (CTCs) in blood of breast cancer patients (pts) are known to correlate with worse outcome. Here we demonstrate a different prognostic value of DTCs and CTCs and explain these findings by early clodronate intake. CTCs (n = 376 pts) were determined using the AdnaTest BreastCancer (Qiagen Hannover GmbH, Germany) and DTCs (n = 525 pts) were analyzed by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Clodronate intake was recommended in case of DTC-positivity. CTCs were detected in 22% and DTCs in 40% of the pts, respectively. DTCs were significantly associated with nodal status (p = 0.03), grading (p = 0.01), lymphangiosis (p = 0.03), PR status (p = 0.02) and clodronate intake (p < 0.0001), no significant associations were demonstrated for CTCs. CTCs significantly correlated with reduced PFS (p = 0.0227) and negative prognostic relevance was predominantly related to G2 tumors (p = 0.044), the lobular (p = 0.024) and the triple-negative subtype (p = 0.005), HR-negative pts (p = 0.001), postmenopausal women (p = 0.013) and patients who had received radiation therapy (p = 0.018). No prognostic significance was found for DTCs. Therefore early clodronate intake can improve prognosis of breast cancer patients and CTCs might be a high risk indicator for the onset of metastasis not limited to bone metastasis. PMID:27212060

  1. Sinus Tumors

    MedlinePlus

    ... Tumors Nasal Deformities Choanal Atresia Epiphora (Excessive Tearing) Disclosure Statement Printer Friendly Sinus Tumors Abtin Tabaee, MD Introduction Tumors of the nose and paranasal sinuses are rare, accounting for fewer than 1% of all tumors. These ...

  2. Bone tumor

    MedlinePlus

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  3. Methylator phenotype in colorectal cancer: A prognostic factor or not?

    PubMed

    Gallois, C; Laurent-Puig, P; Taieb, J

    2016-03-01

    Colorectal cancer (CRC) is due to different types of genetic alterations that are translated into different phenotypes. Among them, CpG island methylator phenotype (CIMP+) is the most recently involved in carcinogenesis of some CRC. The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes. CIMP+ are reported to be more frequently found in the elderly and in women. The tumors are more frequently located in the proximal part of the colon, BRAF mutated and are associated with microsatellite instability (MSI) phenotype. All sporadic MSI CRC belong to the methylator phenotype, however some non MSI CRC may also harbor a methylator phenotype. The prognostic value of CIMP is not well known. Most studies show a worse prognosis in CIMP+ CRC, and adjuvant treatments seem to be more efficient. We review here the current knowledge on prognostic and predictive values in CIMP+ CRC. PMID:26702883

  4. Influence of short-term protein malnutrition of mice on the phenotype and costimulatory signals of lymphocytes from spleen and Peyer's patches.

    PubMed

    Manhart, N; Vierlinger, K; Bergmeister, H; Boltz-Nitulescu, G; Spittler, A; Roth, E

    2000-03-01

    The objective of this study was to investigate the impact of short-term protein malnutrition (PM) on immunoglobulin A (IgA) production and on the number and phenotype of lymphocytes in Peyer's patches (PP) and in the spleen. Balb/c mice were fed for 4, 7, or 10 d with a protein-deficient diet (0.1% protein). We determined B lymphocytes (CD40(+)), T lymphocytes (CD3(+)), T-helper (CD4(+)), and T-suppressor (CD8(+)) cells and the expression of costimulatory signals B7.1 (CD80) and B7.2 (CD86) on B cells and their counter receptors CD28 and CTLA-4 on T cells by fluorescence-activated cell-sorting analysis. Luminal IgA concentration in the small intestine was determined by an enzyme-linked immunosorbent assay. Four days of PM caused a significant reduction in the number of mononuclear cells in the spleen (5.6 x 10(7) +/- 1 x 10(7) versus 2. 4 x 10(7) +/- 0.5 x 10(7), P < 0.001) and the PP (13 x 10(6) +/- 3 x 10(6) versus 8.6 x 10(6) +/- 2 x 10(6), P < 0.01). There was a relative increase of T cells in the spleen and a relative increase of B cells in the PP. Luminal IgA content of small intestine was significantly reduced after 4 d of PM (242 +/- 55 microg versus 173 +/- 39 microg, P < 0.05) and remained at about this level until day 10 of PM. Four days after PM, the costimulatory signals B7.1 and B7. 2 on B cells were upregulated in the PP but markedly downregulated in the spleen, which was inversely related to the expression of the counter receptor CD28 on T-helper cells. We conclude that short-term PM increases the activation of B cells in the PP but reduces the relative number and activation state of splenic B cells. Only 4 d of PM caused a systemic and intestinal immunodepression, as indicated by a markedly decreased content of mononuclear cells in the PP and the spleen. PMID:10705075

  5. The Influence of Insecticide Resistance, Age, Sex, and Blood Feeding Frequency on Thermal Tolerance of Wild and Laboratory Phenotypes of Anopheles funestus (Diptera: Culicidae).

    PubMed

    Lyons, C L; Oliver, S V; Hunt, R H; Coetzee, M

    2016-03-01

    Resistance to insecticides is a global phenomenon and is increasing at an unprecedented rate. How resistant and susceptible strains of malaria vectors might differ in terms of life history and basic biology is often overlooked, despite the potential importance of such information in light of changing climates. Here, we investigated the upper thermal limits (ULT50) of wild and laboratory strains of Anopheles funestus Giles mosquitoes, including resistance status, sex, age, and blood feeding status as potential factors influencing ULT50. No significant differences in ULT50 were observed between strains displaying different resistance patterns, nor was there a significant difference between wild and laboratory strains. In some instances, strains showed a senescence response, displaying decreased ULT50 with an increase in age, and differences between males and females (females displaying higher ULT50 than males). Blood feeding did not seem to influence ULT50 in any way. For An. funestus, it seems evident that there is no cost to resistance despite what is displayed in other anopheline species. This could have significant impacts for vector control, with resistant populations of An. funestus performing just as well, if not better, than susceptible strains, especially under changing environmental conditions such as those expected to occur with climate change. PMID:26718714

  6. SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice

    PubMed Central

    Hamilton, Melisa J.; Halvorsen, Elizabeth C.; LePard, Nancy E.; Bosiljcic, Momir; Ho, Victor W.; Lam, Vivian; Banáth, Judit

    2016-01-01

    SH2-containing-inositol-5′-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP−/− BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP−/− BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP−/− mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP−/− mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer. PMID:26683227

  7. [Ovarian germ cell tumors in girls].

    PubMed

    Nechushkina, I V; Karseladze, A I

    2015-01-01

    Morphological structure of tumor influences on the clinical course of the disease in children with germ cell tumors. Patients with ovarian dysgerminoma at the time of diagnosis are significantly older than patients with immature teratoma and yolk sac tumor. Immature teratoma and mixed germ cell tumors are significantly larger compared to other germ cell tumors. Yolk sac tumor and embryonal carcinoma are the most common cause of emergency surgical interventions and are accompanied by rupture of tumor capsule. PMID:26087605

  8. Factors Influencing Neurocognitive Outcomes in Young Patients With Benign and Low-Grade Brain Tumors Treated With Stereotactic Conformal Radiotherapy

    SciTech Connect

    Jalali, Rakesh; Mallick, Indranil; Dutta, Debnarayan

    2010-07-15

    Purpose: To present the effect of radiotherapy doses to different volumes of normal structures on neurocognitive outcomes in young patients with benign and low-grade brain tumors treated prospectively with stereotactic conformal radiotherapy (SCRT). Methods and Materials: Twenty-eight patients (median age, 13 years) with residual/progressive brain tumors (10 craniopharyngioma, 8 cerebellar astrocytoma, 6 optic pathway glioma and 4 cerebral low-grade glioma) were treated with SCRT to a dose of 54 Gy in 30 fractions over 6 weeks. Prospective neuropsychological assessments were done at baseline before RT and at subsequent follow-up examinations. The change in intelligence quotient (IQ) scores was correlated with various factors, including dose-volume to normal structures. Results: Although the overall mean full-scale IQ (FSIQ) at baseline before RT remained unchanged at 2-year follow-up after SCRT, one third of patients did show a >10% decline in FSIQ as compared with baseline. Logistic regression analysis demonstrated that patients aged <15 years had a significantly higher chance of developing a >10% drop in FSIQ than older patients (53% vs. 10%, p = 0.03). Dosimetric comparison in patients showing a >10% decline vs. patients showing a <10% decline in IQ revealed that patients receiving >43.2 Gy to >13% of volume of the left temporal lobe were the ones to show a significant drop in FSIQ (p = 0.048). Radiotherapy doses to other normal structures, including supratentorial brain, right temporal lobe, and frontal lobes, did not reveal any significant correlation. Conclusion: Our prospectively collected dosimetric data show younger age and radiotherapy doses to left temporal lobe to be predictors of neurocognitive decline, and may well be used as possible dose constraints for high-precision radiotherapy planning.

  9. Baseline Tumor Growth and Immune Control in Laboraotry Mice are Significantly Influenced by Sub-Thermoneutral Housing Temperature

    EPA Science Inventory

    We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20-26 •c; however, these subthermoneutral temperature...

  10. Cancer-Associated Fibroblasts in a Human HEp-2 Established Laryngeal Xenografted Tumor Are Not Derived from Cancer Cells through Epithelial-Mesenchymal Transition, Phenotypically Activated but Karyotypically Normal

    PubMed Central

    Wang, Mei; Wu, Chun-Ping; Pan, Jun-Yan; Zheng, Wen-Wei; Cao, Xiao-Juan; Fan, Guo-Kang

    2015-01-01

    Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression and even initiation. However, the origins of CAFs in various cancer types remain controversial, and one of the important hypothesized origins is through epithelial-mesenchymal transition (EMT) from cancer cells. In this study, we investigated whether the HEp-2 laryngeal cancer cells are able to generate CAFs via EMT during tumor formation, which is now still unknown. The laryngeal xenografted tumor model was established by inoculating the HEp-2 laryngeal cancer cell line in nude mice. Primary cultured CAFs from the tumor nodules and matched normal fibroblasts (NFs) from the adjacent connective tissues were subcultured, purified, and verified by immunofluorescence. Migration, invasion, and proliferation potentials were compared between the CAFs and NFs. A co-culture of CAFs with HEp-2 cells and a co-injection of CAFs with HEp-2 cells in nude mice were performed to examine the cancer-promoting potential of CAFs to further verify their identity. Karyotypic analyses of the CAFs, NFs, and HEp-2 cells were conducted. A co-culture of NFs with HEp-2 cells was also performed to examine the expression of activated markers of CAFs. A pathological examination confirmed that the laryngeal xenografted tumor model was successfully established, containing abundant CAFs. Immunocytochemical staining verified the purities and identities of the CAFs and NFs. Although the CAFs manifested higher migration, invasion, proliferation, and cancer-promoting capacities compared with the NFs, an analysis of chromosomes revealed that both the CAFs and NFs showed typical normal mouse karyotypes. In addition, the NFs co-cultured with HEp-2 cells did not show induced expressions of activated markers of CAFs. Our findings reveal that the CAFs in the HEp-2 established laryngeal xenografted tumor are not of laryngeal cancer origin but of mouse origin, indicating that the HEp-2 laryngeal cancer cells cannot generate their

  11. Downstream regulatory elements increase acute and latent herpes simplex virus type 2 latency-associated transcript expression but do not influence recurrence phenotype or establishment of latency.

    PubMed Central

    Yoshikawa, T; Stanberry, L R; Bourne, N; Krause, P R

    1996-01-01

    The role of putative promoter or activator sequences downstream of the herpes simplex virus type 2 latency-associated transcript (LAT) promoter and upstream of the LAT intron was investigated in vivo by constructing and evaluating mutant viruses with deletions in this region. The deletion of LAT promoter sequences upstream of the primary LAT transcript reduced levels of LAT expression during productive infections, compared with the LAT expression level of wild-type virus, and abolished LAT expression during latency. The deletion of the putative downstream regulatory elements reduced but did not eliminate LAT expression during productive and latent infections. The deletion of both regions almost completely eliminated acute LAT transcription, although additional acute LAT-region transcription directed by sequences upstream of either region was detected by reverse transcriptase PCR. The deletion of the downstream elements did not influence the ability of the virus to reactivate from latently infected guinea pigs relative to the ability of the wild-type virus to reactivate; thus, decreased LAT expression did not affect the frequency of recurrence. The deletion of both regions did not affect the ability of the virus to establish latency. We conclude that downstream regulatory elements are necessary for maximal acute LAT expression but do not constitute an independent promoter during latency and do not play an obvious role in the establishment of our reactivation from latency. PMID:8627672

  12. Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment

    PubMed Central

    Kim, Jaehong; Bae, Jong-Sup

    2016-01-01

    Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors. PMID:26966341

  13. Novel phenotypes of prediabetes?

    PubMed

    Häring, Hans-Ulrich

    2016-09-01

    This article describes phenotypes observed in a prediabetic population (i.e. a population with increased risk for type 2 diabetes) from data collected at the University hospital of Tübingen. We discuss the impact of genetic variation on insulin secretion, in particular the effect on compensatory hypersecretion, and the incretin-resistant phenotype of carriers of the gene variant TCF7L2 is described. Imaging studies used to characterise subphenotypes of fat distribution, metabolically healthy obesity and metabolically unhealthy obesity are described. Also discussed are ectopic fat stores in liver and pancreas that determine the phenotype of metabolically healthy and unhealthy fatty liver and the recently recognised phenotype of fatty pancreas. The metabolic impact of perivascular adipose tissue and pancreatic fat is discussed. The role of hepatokines, particularly that of fetuin-A, in the crosstalk between these organs is described. Finally, the role of brain insulin resistance in the development of the different prediabetes phenotypes is discussed. PMID:27344314

  14. The influence of NIR femtosecond laser radiation on the viability of 3D stem cell clusters and tumor spheroids

    NASA Astrophysics Data System (ADS)

    Uchugonova, Aisada; Riemann, Iris; Stracke, Frank; Gorjup, Erwin; LeHarzic, Ronan; König, Karsten

    2007-02-01

    Adult human and rat pancreas stem cells as well as tumor spheroids were irradiated with femtosecond laser pulses in the near infrared (NIR) spectral range at high transient GW/cm2 and TW/cm2 intensities. The cellular response to the laser exposure was probed by the detection of modifications of NAD(P)H autofluorescence, the formation of reactive oxygen species (ROS) and DNA strand breaks (TUNEL-assay), and viability (live/dead test). The results confirm that long-term scanning of stem cells can be performed at appropriate laser exposure parameters without a measurable impact on the cellular metabolism and vitality. In addition, it was proven that a targeted inactivation of a particular single stem cells or a single tumour cell inside a 3D cell cluster using single point illumination at TW/cm2 laser intensities can be performed without affecting neighbouring cells. Therefore multiphoton microscopes can be considered as biosafe tools for long-term analysis of stem cells as well as highly precise optical knocking out of single cells within cell clusters and tissues.

  15. Network motifs that stabilize the hybrid epithelial/mesenchymal phenotype

    NASA Astrophysics Data System (ADS)

    Jolly, Mohit Kumar; Jia, Dongya; Tripathi, Satyendra; Hanash, Samir; Mani, Sendurai; Ben-Jacob, Eshel; Levine, Herbert

    Epithelial to Mesenchymal Transition (EMT) and its reverse - MET - are hallmarks of cancer metastasis. While transitioning between E and M phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) phenotype that enables collective cell migration as a cluster of Circulating Tumor Cells (CTCs). These clusters can form 50-times more tumors than individually migrating CTCs, underlining their importance in metastasis. However, this hybrid E/M phenotype has been hypothesized to be only a transient one that is attained en route EMT. Here, via mathematically modeling, we identify certain `phenotypic stability factors' that couple with the core three-way decision-making circuit (miR-200/ZEB) and can maintain or stabilize the hybrid E/M phenotype. Further, we show experimentally that this phenotype can be maintained stably at a single-cell level, and knockdown of these factors impairs collective cell migration. We also show that these factors enable the association of hybrid E/M with high stemness or tumor-initiating potential. Finally, based on these factors, we deduce specific network motifs that can maintain the E/M phenotype. Our framework can be used to elucidate the effect of other players in regulating cellular plasticity during metastasis. This work was supported by NSF PHY-1427654 (Center for Theoretical Biological Physics) and the CPRIT Scholar in Cancer Research of the State of Texas at Rice University.

  16. Selection of Mesenchymal-Like Metastatic Cells in Primary Tumors – An in silico Investigation

    PubMed Central

    Narang, Vipin; Wong, Shek Yoon; Leong, Shiang Rong; Harish, Bindu; Abastado, Jean-Pierre; Gouaillard, Alexandre

    2012-01-01

    In order to metastasize, cancer cells must undergo phenotypic transition from an anchorage-dependent form to a motile form via a process referred to as epithelial to mesenchymal transition. It is currently unclear whether metastatic cells emerge late during tumor progression by successive accumulation of mutations, or whether they derive from distinct cell populations already present during the early stages of tumorigenesis. Similarly, the selective pressures that drive metastasis are poorly understood. Selection of cancer cells with increased proliferative capacity and enhanced survival characteristics may explain how some transformations promote a metastatic phenotype. However, it is difficult to explain how cancer cells that disseminate can emerge due to such selective pressure, since these cells usually remain dormant for prolonged periods of time. In the current study, we have used in silico modeling and simulation to investigate the hypothesis that mesenchymal-like cancer cells evolve during the early stages of primary tumor development, and that these cells exhibit survival and proliferative advantages within the tumor microenvironment. In an agent-based tumor microenvironment model, cancer cell agents with distinct sets of attributes governing nutrient consumption, proliferation, apoptosis, random motility, and cell adhesion were allowed to compete for space and nutrients. These simulation data indicated that mesenchymal-like cancer cells displaying high motility and low adhesion proliferate more rapidly and display a survival advantage over epithelial-like cancer cells. Furthermore, the presence of mesenchymal-like cells within the primary tumor influences the macroscopic properties, emergent morphology, and growth rate of tumors. PMID:22566967

  17. Phenotypic switching in bacteria

    NASA Astrophysics Data System (ADS)

    Merrin, Jack

    Living matter is a non-equilibrium system in which many components work in parallel to perpetuate themselves through a fluctuating environment. Physiological states or functionalities revealed by a particular environment are called phenotypes. Transitions between phenotypes may occur either spontaneously or via interaction with the environment. Even in the same environment, genetically identical bacteria can exhibit different phenotypes of a continuous or discrete nature. In this thesis, we pursued three lines of investigation into discrete phenotypic heterogeneity in bacterial populations: the quantitative characterization of the so-called bacterial persistence, a theoretical model of phenotypic switching based on those measurements, and the design of artificial genetic networks which implement this model. Persistence is the phenotype of a subpopulation of bacteria with a reduced sensitivity to antibiotics. We developed a microfluidic apparatus, which allowed us to monitor the growth rates of individual cells while applying repeated cycles of antibiotic treatments. We were able to identify distinct phenotypes (normal and persistent) and characterize the stochastic transitions between them. We also found that phenotypic heterogeneity was present prior to any environmental cue such as antibiotic exposure. Motivated by the experiments with persisters, we formulated a theoretical model describing the dynamic behavior of several discrete phenotypes in a periodically varying environment. This theoretical framework allowed us to quantitatively predict the fitness of dynamic populations and to compare survival strategies according to environmental time-symmetries. These calculations suggested that persistence is a strategy used by bacterial populations to adapt to fluctuating environments. Knowledge of the phenotypic transition rates for persistence may provide statistical information about the typical environments of bacteria. We also describe a design of artificial

  18. Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors.

    PubMed

    Weitzenfeld, Polina; Kossover, Olga; Körner, Cindy; Meshel, Tsipi; Wiemann, Stefan; Seliktar, Dror; Legler, Daniel F; Ben-Baruch, Adit

    2016-06-01

    Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype. PMID:26936935

  19. Spinal tumor

    MedlinePlus

    Tumor - spinal cord ... spinal tumors occur in the nerves of the spinal cord itself. Most often these are ependymomas and other ... gene mutations. Spinal tumors can occur: Inside the spinal cord (intramedullary) In the membranes (meninges) covering the spinal ...

  20. Cell Fusion Connects Oncogenesis with Tumor Evolution

    PubMed Central

    Zhou, Xiaofeng; Merchak, Kevin; Lee, Woojin; Grande, Joseph P.; Cascalho, Marilia; Platt, Jeffrey L.

    2016-01-01

    Cell fusion likely drives tumor evolution by undermining chromosomal and DNA stability and/or by generating phenotypic diversity; however, whether a cell fusion event can initiate malignancy and direct tumor evolution is unknown. We report that a fusion event involving normal, nontransformed, cytogenetically stable epithelial cells can initiate chromosomal instability, DNA damage, cell transformation, and malignancy. Clonal analysis of fused cells reveals that the karyotypic and phenotypic potential of tumors formed by cell fusion is established immediately or within a few cell divisions after the fusion event, without further ongoing genetic and phenotypic plasticity, and that subsequent evolution of such tumors reflects selection from the initial diverse population rather than ongoing plasticity of the progeny. Thus, one cell fusion event can both initiate malignancy and fuel evolution of the tumor that ensues. PMID:26066710

  1. Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters.

    PubMed

    Carr, Brian I; Pancoska, Petr; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Ludovico Rapaccini, Gian; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-06-01

    Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied network phenotyping strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Our aim was to validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory-based approach that compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Without reference to the actual tumor sizes, patients were classified by NPS into two subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-platelets relationship. These trends were combined with patient age, gender, and self-reported alcoholism into NPS personal patient profiles. We

  2. Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters

    PubMed Central

    Carr, Brian I.; Giannini, Edoardo G.; Farinati, Fabio; Ciccarese, Francesca; Rapaccini, Gian Ludovico; Marco, Maria Di; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-01-01

    Background Previous work has shown that 2 general processes contribute to hepatocellular cancer (HCC) prognosis. They are: a. liver damage, monitored by indices such as blood bilirubin, prothrombin time and AST; as well as b. tumor biology, monitored by indices such as tumor size, tumor number, presence of PVT and blood AFP levels. These 2 processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied Network Phenotyping Strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Aims To validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Methods Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory based approach, which compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Results Without reference to the actual tumor sizes, patients were classified by NPS into 2 subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-Platelets relationship. These trends were combined with patient age, gender and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual

  3. Tumor-associated macrophages: effectors of angiogenesis and tumor progression.

    PubMed

    Coffelt, Seth B; Hughes, Russell; Lewis, Claire E

    2009-08-01

    Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy. PMID:19269310

  4. DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

    PubMed Central

    Sarko, Dikran; Dennler, Patrick; Zimmermann, Kurt; Mier, Walter; Schibli, Roger

    2013-01-01

    Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N′-N′′-N′′′-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decalysine or (DOTA)5-decalysine to the antibody heavy chain (via Gln295/297) gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with 177Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA)-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA)3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA)5-decalysine)]2. The rapid elimination from the blood of chCE7agl-[(DOTA)-decalysine]2 (1.0±0.1% ID/g at 24 h) is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h). This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA)3 versus 11.7±1.4% ID/g (DOTA)5, p<0.005 at 24 h) and lower radioactivity levels in the liver (21.4±3.4 (DOTA)3 versus 5.8±0.7 (DOTA)5, p<0.005 at 24 h). We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA)5-decalysine) to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable

  5. Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities

    SciTech Connect

    Tommaso, Anne di; Hagen, Jussara; Tompkins, Van; Muniz, Viviane; Dudakovic, Amel; Kitzis, Alain; Ladeveze, Veronique; Quelle, Dawn E.

    2009-04-15

    The Alternative Reading Frame (ARF) protein suppresses tumorigenesis through p53-dependent and p53-independent pathways. Most of ARF's anti-proliferative activity is conferred by sequences in its first exon. Previous work showed specific amino acid changes occurred in that region during primate evolution, so we programmed those changes into human p14ARF to assay their functional impact. Two human p14ARF residues (Ala{sup 14} and Thr{sup 31}) were found to destabilize the protein while two others (Val{sup 24} and Ala{sup 41}) promoted more efficient p53 stabilization and activation. Despite those effects, all modified p14ARF forms displayed robust p53-dependent anti-proliferative activity demonstrating there are no significant biological differences in p53-mediated growth suppression associated with simian versus human p14ARF residues. In contrast, p53-independent p14ARF function was considerably altered by several residue changes. Val{sup 24} was required for p53-independent growth suppression whereas multiple residues (Val{sup 24}, Thr{sup 31}, Ala{sup 41} and His{sup 60}) enabled p14ARF to block or reverse the inherent chromosomal instability of p53-null MEFs. Together, these data pinpoint specific residues outside of established p14ARF functional domains that influence its expression and signaling activities. Most intriguingly, this work reveals a novel and direct role for p14ARF in the p53-independent maintenance of genomic stability.

  6. The Behavioural Phenotype of Angelman Syndrome

    ERIC Educational Resources Information Center

    Horsler, K.; Oliver, C.

    2006-01-01

    Background: The purpose of this review is to examine the notion of a behavioural phenotype for Angelman syndrome and identify methodological and conceptual influences on the accepted presentation. Methods: Studies examining the behavioural characteristics associated with Angelman syndrome are reviewed and methodology is described. Results:…

  7. Influence of Software Tool and Methodological Aspects of Total Metabolic Tumor Volume Calculation on Baseline [18F]FDG PET to Predict Survival in Hodgkin Lymphoma

    PubMed Central

    Kanoun, Salim; Tal, Ilan; Berriolo-Riedinger, Alina; Rossi, Cédric; Riedinger, Jean-Marc; Vrigneaud, Jean-Marc; Legrand, Louis; Humbert, Olivier; Casasnovas, Olivier; Brunotte, François; Cochet, Alexandre

    2015-01-01

    Aim To investigate the respective influence of software tool and total metabolic tumor volume (TMTV0) calculation method on prognostic stratification of baseline 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET) in newly diagnosed Hodgkin lymphoma (HL). Methods 59 patients with newly diagnosed HL were retrospectively included. [18F]FDG-PET was performed before any treatment. Four sets of TMTV0 were calculated with Beth Israel (BI) software: based on an absolute threshold selecting voxel with standardized uptake value (SUV) >2.5 (TMTV02.5), applying a per-lesion threshold of 41% of the SUVmax (TMTV041) and using a per-patient adapted threshold based on SUVmax of the liver (>125% and >140% of SUVmax of the liver background; TMTV0125 and TMTV0140). TMTV041 was also determined with commercial software for comparison of software tools. ROC curves were used to determine the optimal threshold for each TMTV0 to predict treatment failure. Results Median follow-up was 39 months. There was an excellent correlation between TMTV041 determined with BI and with the commercial software (r = 0.96, p<0.0001). The median TMTV0 value for TMTV041, TMTV02.5, TMTV0125 and TMTV0140 were respectively 160 (used as reference), 210 ([28;154] p = 0.005), 183 ([-4;114] p = 0.06) and 143ml ([-58;64] p = 0.9). The respective optimal TMTV0 threshold and area under curve (AUC) for prediction of progression free survival (PFS) were respectively: 313ml and 0.70, 432ml and 0.68, 450ml and 0.68, 330ml and 0.68. There was no significant difference between ROC curves. High TMTV0 value was predictive of poor PFS in all methodologies: 4-years PFS was 83% vs 42% (p = 0.006) for TMTV02.5, 83% vs 41% (p = 0.003) for TMTV041, 85% vs 40% (p<0.001) for TMTV0125 and 83% vs 42% (p = 0.004) for TMTV0140. Conclusion In newly diagnosed HL, baseline metabolic tumor volume values were significantly influenced by the choice of the method used for determination of volume. However, no significant

  8. Radiation-associated thyroid tumors: extent of operation and pathology technique influence the apparent incidence of carcinoma

    SciTech Connect

    Wilson, S.D.; Komorowski, R.; Cerletty, J.; Majewski, J.T.; Hooper, M.

    1983-10-01

    A prospective study and follow-up program of 2,118 patients with prior low-dose head and neck irradiation, entered into a thyroid screening project, allowed us to examine how the extent of operation and pathology technique influenced the incidence of thyroid carcinoma. Patients with palpable nodular thyroid disease were referred to their physicians with a recommendation for surgery: 107 patients had thyroid surgery in community hospitals (CHs) where enucleation of the nodule or lobectomy was the usual operation, and 29 patients had surgery at Milwaukee County Medical Complex (MCMC) where near-total thyroidectomy was routine. Lymph nodes were sampled in 69% of MCMC operations but in only 16% of CH operations. The pathologist's usual method at MCMC was to submit the total surgical specimen and to do serial sections. Less than total specimen examination and random sections typically were done in community hospitals. The mean age and sex ratio of the patients and size of thyroid lesions in the two groups were not different. Cancer was found in 59% (17/29) of patients who underwent operation at MCMC, while only 21% (22/107) of patients who underwent operation in CHs were found to have carcinoma (P less than 0.001). Surprisingly, there was nearly uniform agreement (99%) in the diagnoses made by MCMC and CH pathologists, and the incidence of microscopic foci of carcinoma was similar in both groups. We conclude that the incidence of thyroid carcinoma found in patients with prior head and neck irradiation who have had operation for thyroid nodules is related to the extent of thyroidectomy, routine lymph node sampling, the amount of resected thyroid tissue processed for histologic examination, and the absolute number of sections examined by the pathologist.

  9. Epigenetic reversion of breast carcinoma phenotype is accompaniedby DNA sequestration

    SciTech Connect

    Sandal, Tone; Valyi-Nagy, Klara; Spencer, Virginia A.; Folberg,Robert; Bissell, Mina J.; Maniotis, Andrew J.

    2006-07-19

    The importance of microenvironment and context in regulation of tissue-specific genes is finally well established. DNA exposure to, or sequestration from, nucleases can be used to detect differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we utilized an established 3-D assay where normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like vs tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion where the malignant cells are resistant to digestion relative to non-malignant cells. Reversion of the T4-2 breast cancer cells by either cAMP analogs, or a phospatidylinositol 3-kinase (P13K) inhibitor not only reverted the phenotype, but also the chromatin sensitivity to AluI. By using different cAMP-analogs, we show that the cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent-protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin also reverted the malignant phenotype, polarized the acini, and changed chromatin sequestration. These experiments show not only that modifying the tumor microenvironment can alter the organization of tumor cells but also that architecture of the tissues and the global chromatin organization are coupled and yet highly plastic.

  10. The expression of inducible cAMP early repressor (ICER) is altered in prostate cancer cells and reverses the transformed phenotype of the LNCaP prostate tumor cell line.

    PubMed

    Yehia, G; Razavi, R; Memin, E; Schlotter, F; Molina, C A

    2001-08-15

    Inducible cAMP early repressor (ICER) has been shown to be an important mediator of cAMP antiproliferative activity. In this report, it was found that cAMP retards LNCaP cell growth; in contrast, cAMP inhibits the growth of PC-3 and DU-145 cells. ICER protein levels were markedly reduced in prostate cancer epithelial cells and undetectable and uninducible by cAMP in LNCaP and DU 145 cells. Forced expression of ICER in LNCaP cells caused inhibition of cell growth and thymidine incorporation and halted cells at the G(1) phase of the cell cycle. These ICER-bearing LNCaP cells were rendered unable to grow in soft agar and unable to form tumors in nude mice. These results suggest that deregulation of ICER expression may be related to carcinogenesis of the prostate gland. PMID:11507053

  11. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

    PubMed Central

    Jolly, Mohit Kumar; Boareto, Marcelo; Huang, Bin; Jia, Dongya; Lu, Mingyang; Ben-Jacob, Eshel; Onuchic, José N.; Levine, Herbert

    2015-01-01

    Transitions between epithelial and mesenchymal phenotypes – the epithelial to ­mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) – are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M – and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell–cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary “bad actors” of metastasis. PMID:26258068

  12. Myths in the Diagnosis and Management of Orbital Tumors

    PubMed Central

    Gündüz, Kaan; Yanık, Özge

    2015-01-01

    Orbital tumors constitute a group of diverse lesions with a low incidence in the population. Tumors affecting the eye and ocular adnexa may also secondarily invade the orbit. Lack of accumulation of a sufficient number of cases with a specific diagnosis at various orbital centers, the paucity of prospective randomized studies, animal model studies, tissue bank, and genetic studies led to the development of various myths regarding the diagnosis and treatment of orbital lesions in the past. These myths continue to influence the diagnosis and treatment of orbital lesions by orbital specialists. This manuscript discusses some of the more common myths through case summaries and a review of the literature. Detailed genotypic analysis and genetic classification will provide further insight into the pathogenesis of many orbital diseases in the future. This will enable targeted treatments even for diseases with the same histopathologic diagnosis. Phenotypic variability within the same disease will be addressed using targeted treatments. PMID:26692710

  13. Myths in the Diagnosis and Management of Orbital Tumors.

    PubMed

    Gündüz, Kaan; Yanık, Özge

    2015-01-01

    Orbital tumors constitute a group of diverse lesions with a low incidence in the population. Tumors affecting the eye and ocular adnexa may also secondarily invade the orbit. Lack of accumulation of a sufficient number of cases with a specific diagnosis at various orbital centers, the paucity of prospective randomized studies, animal model studies, tissue bank, and genetic studies led to the development of various myths regarding the diagnosis and treatment of orbital lesions in the past. These myths continue to influence the diagnosis and treatment of orbital lesions by orbital specialists. This manuscript discusses some of the more common myths through case summaries and a review of the literature. Detailed genotypic analysis and genetic classification will provide further insight into the pathogenesis of many orbital diseases in the future. This will enable targeted treatments even for diseases with the same histopathologic diagnosis. Phenotypic variability within the same disease will be addressed using targeted treatments. PMID:26692710

  14. The influence of tumor oxygenation on 18F-FDG (Fluorine-18 Deoxyglucose) uptake: A mouse study using positron emission tomography (PET)

    PubMed Central

    Chan, Linda W; Hapdey, Sebastien; English, Sean; Seidel, Jurgen; Carson, Joann; Sowers, Anastasia L; Krishna, Murali C; Green, Michael V; Mitchell, James B; Bacharach, Stephen L

    2006-01-01

    Background This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of 18F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET). Results Tumor-bearing mice (squamous cell carcinoma) maintained at 37°C were studied while breathing either normal air or carbogen (95% O2, 5% CO2), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential 18F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of 18F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest 18F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, 18F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation. Conclusion Tumor 18F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance 18F-FDG functional imaging. PMID:16722588

  15. The Influence of Metastatic Lymph Node Ratio on the Treatment Outcomes in the Adjuvant Chemoradiotherapy in Stomach Tumors (ARTIST) Trial: A Phase III Trial

    PubMed Central

    Kim, Youjin; Kim, Kyoung-Mee; Choi, Min Gew; Lee, Jun Ho; Sohn, Tae Sung; Bae, Jae Moon; Kim, Sung; Lee, Su Jin; Kim, Seung Tae; Lee, Jeeyun; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki

    2016-01-01

    Purpose In the Adjuvant Chemoradiotherapy in Stomach Tumors (ARTIST) trial, we investigated whether chemoradiotherapy after D2 gastrectomy reduces the rate of recurrence. Recently, the ratio of metastatic lymph nodes to examined lymph nodes (N ratio) has been proposed as an independent prognostic factor in gastric cancer (GC). The aim of this study was to investigate the relationship between the metastatic N ratio and prognosis of GC after curative D2 surgery. Materials and Methods We retrospectively reviewed the data of 458 ARTIST patients who underwent D2 gastrectomy followed by adjuvant chemotherapy (XP, n=228) or chemoradiotherapy (XPRT, n=230). The disease-free survival (DFS) rates of patients were used to evaluate the influence of N ratio on the treatment outcome. To achieve this, 4 different N ratio categories (0%, 1%~9%, 10%~25%, and >25%) were compared on the basis of their influence on the treatment outcome. Results On multivariate analysis, the N ratio remained an independent prognostic factor for DFS. The hazard ratios (HRs) for the N ratio categories of 0%, 1%~9%, 10%~25%, and >25% were 1, 1.061, 1.202, and 3.571, respectively. In patients having N ratio >25%, the 5-year DFS rates were 55% and 28% for the XPRT and XP arms, respectively (HR, 0.527; 95% confidence interval, 0.307~0.904; P=0.020). Conclusions In patients with curatively resected GC, the N ratio was independently associated with DFS. Although this finding warrants further investigation in future prospective studies, the benefit of chemoradiotherapy for D2 resected GC appears to be more beneficial in cancers having N ratios >25%. PMID:27433396

  16. Metabolic phenotype of bladder cancer.

    PubMed

    Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo; Iacovelli, Roberto; Mazzucchelli, Roberta; Piva, Francesco; Scarpelli, Marina; Berardi, Rossana; Tortora, Giampaolo; Lopez-Beltran, Antonio; Cheng, Liang; Montironi, Rodolfo

    2016-04-01

    Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting targets for therapy. Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes (SRC-3, glucose transporter type 1 [GLUT1], GLUT3, lactic dehydrogenase A [LDHA], LDHB, hexokinase 1 [HK1], HK2, pyruvate kinase type M [PKM], and hypoxia-inducible factor 1-alpha [HIF-1α]), resulting in an overproduction of pyruvate, alanine and lactate. Concurrently, bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD]) and the fatty-acid synthesis (fatty acid synthase [FASN]), along with a decrease of AMP-activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. Moreover, AGL loss determines augmented levels of the serine-to-glycine enzyme

  17. Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences

    PubMed Central

    Loeb, Lawrence A.

    2016-01-01

    The mutator phenotype hypothesis was postulated more than 40 years ago. It was based on the multiple enzymatic steps required to precisely replicate the 6 billion bases in the human genome each time a normal cell divides. A reduction in this accuracy during tumor progression could be responsible for the striking heterogeneity of malignant cells within a tumor and for the rapidity by which cancers become resistant to therapy. PMID:27197248

  18. Tumor necrosis factor-induced reversal of adipocytic phenotype of 3T3-L1 cells is preceded by a loss of nuclear CCAAT/enhancer binding protein (C/EBP).

    PubMed Central

    Ron, D; Brasier, A R; McGehee, R E; Habener, J F

    1992-01-01

    Tumor necrosis factor (TNF)-treated 3T3-L1 adipocytes were used as a model for studying the effects of systemic inflammation on adipose tissue. Lipopolysaccharide-treated monocyte-conditioned medium or recombinant human TNF alpha induced morphological dedifferentiation of the adipocytes and led to loss of adipocyte specific gene expression. Gel shift, Southwestern and Western immunoblot analysis demonstrated that dedifferentiation was preceded by a decrease in the DNA binding activity and protein level of the transcription factor CCAAT/enhancer binding protein (C/EBP). Liver activating protein, a related protein that binds identical DNA sequences, increased during cytokine treatment. Both proteins activate specific enhancer elements located in the promoter region of many genes whose transcription is altered during systemic inflammation. Pulse-chase labeling followed by immunoprecipitation demonstrated that C/EBP is a rapidly turning over protein in adipocytes and that cytokine treatment led to a specific, time dependent decrease in its rate of synthesis. Because C/EBP binding sites have been shown to play an important role in regulating the expression of genes involved in adipocyte metabolism, we propose that the TNF-induced changes in the complement of transcription factors binding those sites may be important in the pathogenesis of inflammation-induced atrophy of adipose tissue. Images PMID:1729273

  19. Brain tumors.

    PubMed Central

    Black, K. L.; Mazziotta, J. C.; Becker, D. P.

    1991-01-01

    Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors, which are sparse in normal brain, is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors, the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors. Images PMID:1848735

  20. Hypoxic Tumor Environments Exhibit Disrupted Collagen I Fibers and Low Macromolecular Transport

    PubMed Central

    Kakkad, Samata M.; Penet, Marie-France; Akhbardeh, Alireza; Pathak, Arvind P.; Solaiyappan, Meiyappan; Raman, Venu; Leibfritz, Dieter; Glunde, Kristine; Bhujwalla, Zaver M.

    2013-01-01

    Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role of the extracellular matrix (ECM) in mediating this transport are unexplored. The dense mesh of fibers present in the ECM can especially influence the movement of macromolecules. Collagen 1 (Col1) fibers form a key component of the ECM in breast cancers. Here we characterized the influence of hypoxia on macromolecular transport in tumors, and the role of Col1 fibers in mediating this transport using an MDA-MB-231 breast cancer xenograft model engineered to express red fluorescent protein under hypoxia. Magnetic resonance imaging of macromolecular transport was combined with second harmonic generation microscopy of Col1 fibers. Hypoxic tumor regions displayed significantly decreased Col1 fiber density and volume, as well as significantly lower macromolecular draining and pooling rates, than normoxic regions. Regions adjacent to severely hypoxic areas revealed higher deposition of Col1 fibers and increased macromolecular transport. These data suggest that Col1 fibers may facilitate macromolecular transport in tumors, and their reduction in hypoxic regions may reduce this transport. Decreased macromolecular transport in hypoxic regions may also contribute to poor drug delivery and tumor recurrence in hypoxic regions. High Col1 fiber density observed around hypoxic regions may facilitate the escape of aggressive cancer cells from hypoxic regions. PMID:24349142

  1. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    PubMed

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  2. A Think Tank of TINK/TANKs: Tumor-Infiltrating/Tumor-Associated Natural Killer Cells in Tumor Progression and Angiogenesis

    PubMed Central

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M.

    2014-01-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This “polarization” has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as “TINKs”) and tumor-associated NK (altered peripheral NK cells, which here we call “TANKs”) are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  3. Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells.

    PubMed

    Nardella, Marta; Guglielmi, Loredana; Musa, Carla; Iannetti, Ilaria; Maresca, Giovanna; Amendola, Donatella; Porru, Manuela; Carico, Elisabetta; Sessa, Giuseppe; Camerlingo, Rosalba; Dominici, Carlo; Megiorni, Francesca; Milan, Marika; Bearzi, Claudia; Rizzi, Roberto; Pirozzi, Giuseppe; Leonetti, Carlo; Bucci, Barbara; Mercanti, Delio; Felsani, Armando; D'Agnano, Igea

    2015-10-20

    Tumor-initiating cells constitute a population within a tumor mass that shares properties with normal stem cells and is considered responsible for therapy failure in many cancers. We have previously demonstrated that knockdown of the nuclear envelope component Lamin A/C in human neuroblastoma cells inhibits retinoic acid-mediated differentiation and results in a more aggressive phenotype. In addition, Lamin A/C is often lost in advanced tumors and changes in the nuclear envelope composition occur during tumor progression. Based on our previous data and considering that Lamin A/C is expressed in differentiated tissues, we hypothesize that the lack of Lamin A/C could predispose cells toward a stem-like phenotype, thus influencing the development of tumor-initiating cells in neuroblastoma. This paper demonstrates that knockdown of Lamin A/C triggers the development of a tumor-initiating cell population with self-renewing features in human neuroblastoma cells. We also demonstrates that the development of TICs is due to an increased expression of MYCN gene and that in neuroblastoma exists an inverse relationship between LMNA and MYCN expression. PMID:26439802

  4. Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells

    PubMed Central

    Nardella, Marta; Guglielmi, Loredana; Musa, Carla; Iannetti, Ilaria; Maresca, Giovanna; Amendola, Donatella; Porru, Manuela; Carico, Elisabetta; Sessa, Giuseppe; Camerlingo, Rosalba; Dominici, Carlo; Megiorni, Francesca; Milan, Marika; Bearzi, Claudia; Rizzi, Roberto; Pirozzi, Giuseppe; Leonetti, Carlo; Bucci, Barbara; Mercanti, Delio; Felsani, Armando; D'Agnano, Igea

    2015-01-01

    Tumor-initiating cells constitute a population within a tumor mass that shares properties with normal stem cells and is considered responsible for therapy failure in many cancers. We have previously demonstrated that knockdown of the nuclear envelope component Lamin A/C in human neuroblastoma cells inhibits retinoic acid-mediated differentiation and results in a more aggressive phenotype. In addition, Lamin A/C is often lost in advanced tumors and changes in the nuclear envelope composition occur during tumor progression. Based on our previous data and considering that Lamin A/C is expressed in differentiated tissues, we hypothesize that the lack of Lamin A/C could predispose cells toward a stem-like phenotype, thus influencing the development of tumor-initiating cells in neuroblastoma. This paper demonstrates that knockdown of Lamin A/C triggers the development of a tumor-initiating cell population with self-renewing features in human neuroblastoma cells. We also demonstrates that the development of TICs is due to an increased expression of MYCN gene and that in neuroblastoma exists an inverse relationship between LMNA and MYCN expression. PMID:26439802

  5. Radiofrequency treatment alters cancer cell phenotype

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-07-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

  6. Radiofrequency treatment alters cancer cell phenotype

    PubMed Central

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-01-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment. PMID:26165830

  7. Up-regulation of the ATPase Inhibitory Factor 1 (IF1) of the Mitochondrial H+-ATP Synthase in Human Tumors Mediates the Metabolic Shift of Cancer Cells to a Warburg Phenotype*

    PubMed Central

    Sánchez-Cenizo, Laura; Formentini, Laura; Aldea, Marcos; Ortega, Álvaro D.; García-Huerta, Paula; Sánchez-Aragó, María; Cuezva, José M.

    2010-01-01

    The H+-ATP synthase is a reversible engine of mitochondria that synthesizes or hydrolyzes ATP upon changes in cell physiology. ATP synthase dysfunction is involved in the onset and progression of diverse human pathologies. During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1). The expression of IF1 in human tissues and its participation in the development of human pathology are unknown. Here, we have developed monoclonal antibodies against human IF1 and determined its expression in paired normal and tumor biopsies of human carcinomas. We show that the relative mitochondrial content of IF1 increases significantly in carcinomas, suggesting the participation of IF1 in oncogenesis. The expression of IF1 varies significantly in cancer cell lines. To investigate the functional activity of IF1 in cancer, we have manipulated its cellular content. Overexpression of IF1 or of its pH-insensitive H49K mutant in cells that express low levels of IF1 triggers the up-regulation of aerobic glycolysis and the inhibition of oxidative phosphorylation with concurrent mitochondrial hyperpolarization. Treatment of the cells with the H+-ATP synthase inhibitor oligomycin mimicked the effects of IF1 overexpression. Conversely, small interfering RNA-mediated silencing of IF1 in cells that express high levels of IF1 promotes the down-regulation of aerobic glycolysis and the increase in oxidative phosphorylation. Overall, these findings support that the mitochondrial content of IF1 controls the activity of oxidative phosphorylation mediating the shift of cancer cells to an enhanced aerobic glycolysis, thus supporting an oncogenic role for the de-regulated expression of IF1 in cancer. PMID:20538613

  8. Multiple Sporadic Colorectal Cancers Display a Unique Methylation Phenotype

    PubMed Central

    Gonzalo, Victoria; Lozano, Juan Jose; Alonso-Espinaco, Virginia; Moreira, Leticia; Muñoz, Jenifer; Pellisé, Maria; Castellví-Bel, Sergi; Bessa, Xavier; Andreu, Montserrat; Xicola, Rosa M.; Llor, Xavier; Ruiz-Ponte, Clara; Carracedo, Angel; Jover, Rodrigo; Castells, Antoni; Balaguer, Francesc

    2014-01-01

    Epigenetics are thought to play a major role in the carcinogenesis of multiple sporadic colorectal cancers (CRC). Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the epigenetic signature of multiple CRC using a genome-scale DNA methylation profiling. We analyzed 12 patients with synchronous CRC and 29 age-, sex-, and tumor location-paired patients with solitary tumors from the EPICOLON II cohort. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significant results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP); KRAS and BRAF mutations and mismatch repair deficiency status. Functional annotation clustering was performed. We identified 102 CpG sites that showed significant DNA hypermethylation in multiple tumors with respect to the solitary counterparts (difference in β value ≥0.1). Methylight assays validated the results for 4 selected genes (p = 0.0002). Eight out of 12(66.6%) multiple tumors were classified as CIMP-high, as compared to 5 out of 29(17.2%) solitary tumors (p = 0.004). Interestingly, 76 out of the 102 (74.5%) hypermethylated CpG sites found in multiple tumors were also seen in CIMP-high tumors. Functional analysis of hypermethylated genes found in multiple tumors showed enrichment of genes involved in different tumorigenic functions. In conclusion, multiple CRC are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity. PMID:24643221

  9. Multiple sporadic colorectal cancers display a unique methylation phenotype.

    PubMed

    Gonzalo, Victoria; Lozano, Juan Jose; Alonso-Espinaco, Virginia; Moreira, Leticia; Muñoz, Jenifer; Pellisé, Maria; Castellví-Bel, Sergi; Bessa, Xavier; Andreu, Montserrat; Xicola, Rosa M; Llor, Xavier; Ruiz-Ponte, Clara; Carracedo, Angel; Jover, Rodrigo; Castells, Antoni; Balaguer, Francesc

    2014-01-01

    Epigenetics are thought to play a major role in the carcinogenesis of multiple sporadic colorectal cancers (CRC). Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the epigenetic signature of multiple CRC using a genome-scale DNA methylation profiling. We analyzed 12 patients with synchronous CRC and 29 age-, sex-, and tumor location-paired patients with solitary tumors from the EPICOLON II cohort. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significant results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP); KRAS and BRAF mutations and mismatch repair deficiency status. Functional annotation clustering was performed. We identified 102 CpG sites that showed significant DNA hypermethylation in multiple tumors with respect to the solitary counterparts (difference in β value ≥0.1). Methylight assays validated the results for 4 selected genes (p = 0.0002). Eight out of 12(66.6%) multiple tumors were classified as CIMP-high, as compared to 5 out of 29(17.2%) solitary tumors (p = 0.004). Interestingly, 76 out of the 102 (74.5%) hypermethylated CpG sites found in multiple tumors were also seen in CIMP-high tumors. Functional analysis of hypermethylated genes found in multiple tumors showed enrichment of genes involved in different tumorigenic functions. In conclusion, multiple CRC are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity. PMID:24643221

  10. Ultrastructural and phenotypic characterization of CABA I, a new human ovarian cancer cell line.

    PubMed

    Dolo, V; Ginestra, A; Violini, S; Miotti, S; Festuccia, C; Miceli, D; Migliavacca, M; Rinaudo, C; Romano, F M; Brisdelli, F; Canevari, S; Pavan, A; Vittorelli, M L

    1997-01-01

    We have established an ovarian cancer cell line (CABA I) from ascitic fluid obtained from a patient with papillary adenocarcinoma of the ovary prior to drug treatment. The epithelial origin of the cell line was confirmed by morphology and by immunofluorescence analysis using anticytokeratin antibodies. Ultrastructural analysis revealed a very irregular membrane surface and a clear cytoplasm rich in electron-lucent vesicles. CABA I cells grow rapidly in culture (doubling time 18 h) in an anchorage-independent manner. Exogenously added beta-estradiol and epidermal growth factor (EGF) treatments did not influence cell growth rate. FACS analysis to determine the phenotypic profile of tumor-associated antigen, membrane receptor, and adhesion molecule expression indicated that the cell line was positive for different members of the c-erbB family, for alpha 6 and beta 1 integrin receptors, and intensively positive for HLA class I antigens and the folate receptor. Molecular characterization revealed no mutations for c-myc and c-k-ras genes, but did detect an exon 5 mutation in the p53 gene. CABA I cells grew poorly as heterotransplants in nude mice, and tumors showed long latency periods. Because early (15-20) and late (55-60) passage cells maintain the same growth and phenotypic characteristics, the CABA I cell line might provide a good in vitro model system to investigate the cellular and molecular events involved in ovarian carcinogenesis. PMID:9220498

  11. Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype.

    PubMed

    Carr, Brian I; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Ludovico Rapaccini, Gian; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-04-01

    Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness. PMID:24787296

  12. Genetic resources for phenotyping

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotyping of structured populations, along with molecular genotyping, will be essential for marker development in peanut. This research is essential for making the peanut genome sequence and genomic tools useful to breeders because it makes the connection between genes, gene markers, genetic maps...

  13. Down Syndrome: Cognitive Phenotype

    ERIC Educational Resources Information Center

    Silverman, Wayne

    2007-01-01

    Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies…

  14. Hyaluronan Polymer Length, Grafting Density, and Surface Poly(ethylene glycol) Coating Influence in Vivo Circulation and Tumor Targeting of Hyaluronan-Grafted Liposomes

    PubMed Central

    2015-01-01

    Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5–8, 50–60, and 175–350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175–350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5–8, 50–60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery. PMID:24806526

  15. Hyaluronan polymer length, grafting density, and surface poly(ethylene glycol) coating influence in vivo circulation and tumor targeting of hyaluronan-grafted liposomes.

    PubMed

    Qhattal, Hussaini Syed Sha; Hye, Tanvirul; Alali, Amer; Liu, Xinli

    2014-06-24

    Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5-8, 50-60, and 175-350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175-350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5-8, 50-60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery. PMID:24806526

  16. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas.

    PubMed

    Mezawa, Yoshihiro; Orimo, Akira

    2016-09-01

    Carcinoma-associated fibroblasts (CAFs) constitute a substantial proportion of the non-neoplastic mesenchymal cell compartment in various human tumors. These fibroblasts are phenotypically converted from their progenitors via interactions with nearby cancer cells during the course of tumor progression. The resulting CAFs, in turn, support the growth and progression of carcinoma cells. These fibroblasts have a major influence on the hallmarks of carcinoma and promote tumor malignancy through the secretion of tumor-promoting growth factors, cytokines and exosomes, as well as through the remodeling of the extracellular matrix. Coevolution of CAFs and carcinoma cells during tumorigenesis is therefore essential for progression into fully malignant tumors. Recent studies have revealed the molecular mechanisms underlying CAF functions, especially in tumor invasion, metastasis and drug resistance and have highlighted the significant heterogeneity among these cells. In this review, we summarize the impacts of recently identified roles of tumor-promoting CAFs and discuss the therapeutic implications of targeting the heterotypic interactions of these fibroblasts with carcinoma cells. Graphical Abstract ᅟ. PMID:27506216

  17. Chromosome X modulates incidence of testicular germ cell tumors in Ter mice.

    PubMed

    Hammond, Shirley; Zhu, Rui; Youngren, Kirsten K; Lam, Josephine; Anderson, Philip; Matin, Angabin

    2007-12-01

    Germ cell tumor development in humans has been proposed to be part of testicular dysgenesis syndrome (TDS), which manifests as undescended testes, sterility, hypospadias, and, in extreme cases, as germ cell tumors. Males of the Ter mouse strain show interesting parallels to TDS because they either lack germ cells and are sterile or develop testicular germ cell tumors. We found that these defects in Ter mice are due to mutational inactivation of the Dead-end (Dnd1) gene. Here we report that chromosome X modulates germ cell tumor development in Ter mice. We tested whether the X or the Y chromosome influences tumor incidence. We used chromosome substitution strains to generate two new mouse strains: 129-Ter/Ter that carry either a C57BL/6J (B6)-derived chromosome (Chr) X or Y. We found that Ter/Ter males with B6-Chr X, but not B6-Chr Y, showed a significant shift in propensity from testicular tumor development to sterile testes phenotype. Thus, our studies provide unambiguous evidence that genetic factors from Chr X modulate the incidence of germ cell tumors in mice with inactivated Dnd1. PMID:18049836

  18. Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update

    PubMed Central

    Gurzu, Simona; Turdean, Sabin; Kovecsi, Attila; Contac, Anca Otilia; Jung, Ioan

    2015-01-01

    Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail. PMID:25984514

  19. Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update.

    PubMed

    Gurzu, Simona; Turdean, Sabin; Kovecsi, Attila; Contac, Anca Otilia; Jung, Ioan

    2015-05-16

    Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail. PMID:25984514

  20. Root phenotyping: from component trait in the lab to breeding.

    PubMed

    Kuijken, René C P; van Eeuwijk, Fred A; Marcelis, Leo F M; Bouwmeester, Harro J

    2015-09-01

    In the last decade cheaper and faster sequencing methods have resulted in an enormous increase in genomic data. High throughput genotyping, genotyping by sequencing and genomic breeding are becoming a standard in plant breeding. As a result, the collection of phenotypic data is increasingly becoming a limiting factor in plant breeding. Genetic studies on root traits are being hampered by the complexity of these traits and the inaccessibility of the rhizosphere. With an increasing interest in phenotyping, breeders and scientists try to overcome these limitations, resulting in impressive developments in automated phenotyping platforms. Recently, many such platforms have been thoroughly described, yet their efficiency to increase genetic gain often remains undiscussed. This efficiency depends on the heritability of the phenotyped traits as well as the correlation of these traits with agronomically relevant breeding targets. This review provides an overview of the latest developments in root phenotyping and describes the environmental and genetic factors influencing root phenotype and heritability. It also intends to give direction to future phenotyping and breeding strategies for optimizing root system functioning. A quantitative framework to determine the efficiency of phenotyping platforms for genetic gain is described. By increasing heritability, managing effects caused by interactions between genotype and environment and by quantifying the genetic relation between traits phenotyped in platforms and ultimate breeding targets, phenotyping platforms can be utilized to their maximum potential. PMID:26071534

  1. Macrophages in Tumor Microenvironments and the Progression of Tumors

    PubMed Central

    Hao, Ning-Bo; Lü, Mu-Han; Fan, Ya-Han; Cao, Ya-Ling; Zhang, Zhi-Ren; Yang, Shi-Ming

    2012-01-01

    Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF-α, iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF-β, and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy. PMID:22778768

  2. Tumor Types

    MedlinePlus

    ... acoustic neuroma is also known as a schwannoma, vestibular schwannoma, or neurilemmoma. Characteristics Arises from cells that ... multiple CNS tumors, including neurofibromas, multiple meningiomas, bilateral vestibular schwannomas, optic nerve gliomas, and spinal cord tumors. ...

  3. Modification of the tumor microenvironment to enhance immunity.

    PubMed

    Liao, Yu-Pei; Schaue, Dorthe; McBride, William H

    2007-01-01

    The growth and spread of cancer depends as much on the host response to tumor as on the biological characteristics of the tumor itself. This interaction is at its most intimate and dynamic within the tumor microenvironment. It is here that the battle is fought that leads to mutual evolution of tumor and host cell phenotypes. Contributing to this evolutionary process are physiological changes distinctive for the tumor microenvironment, such as hypoxia, low nutrient levels, low extracellular pH, and high interstitial fluid pressure. These largely result from the chaotic intratumoral vasculature but are impacted by the nature of the tumor and the inflammatory and wound healing responses that are generated. Numerous infiltrating immune cells, including macrophages, lymphocytes, natural killer cells and dendritic cells infiltrate the tumor, contributing to high levels of growth factors, hormones, and cytokines. We suggest that the integrated interplay between host and tumor factors results in distinct phenotypes that determine the response to therapy as well as tumor behavior. Targeting the tumor microenvironment to awaken or reawaken immune cells, or to redirect it from a pro-tumor to an anti-tumor state, will require understanding of this phenotype. Current conventional therapies target tumors not tumor cells and clearly affect the host infiltrate and the physiological characteristics of the tumor microenvironment. This may an advantage that has yet to be effectively exploited due to lack of knowledge of existing phenotypes resulting from the tumor-host interactions. The same lack of knowledge impacts outcomes of clinical immunotherapy (IT) trials that have so far not broken through the ceiling of 10% success rate that seems to exist even in melanoma. It seems obvious that more could be achieved by combining therapies that tackle malignancies from multiple angles, with the tumor microenvironment conditioned to support a powerful effector arm generated by IT. The

  4. Behavioural phenotypes predict disease susceptibility and infectiousness.

    PubMed

    Araujo, Alessandra; Kirschman, Lucas; Warne, Robin W

    2016-08-01

    Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. PMID:27555652

  5. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype

    PubMed Central

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  6. Meningocele in a Congolese Female with Beckwith-Wiedemann Phenotype

    PubMed Central

    Mbuyi-Musanzayi, Sébastien; Lubala Kasole, Toni; Lumaka, Aimé; Kayembe Kitenge, Tony; Kabamba Ngombe, Leon; Kalenga Muenze, Prosper; Lukusa Tshilobo, Prosper; Tshilombo Katombe, François; Banza Lubaba Nkulu, Célestin; Devriendt, Koenraad

    2014-01-01

    Beckwith-Wiedemann syndrome (BWS) is a rare congenital syndrome characterized by an overgrowth, macroglossia, exomphalos, and predisposition to embryonal tumors. Central nervous abnormalities associated with BWS are rare. We describe a one-day-old Congolese female who presented meningocele associated with BWS phenotype. PMID:25610673

  7. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype.

    PubMed

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  8. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  9. Urogenital tumors

    SciTech Connect

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  10. The influence of physical activity on the profile of immune response cells and cytokine synthesis in mice with experimental breast tumors induced by 7,12-dimethylbenzanthracene.

    PubMed

    Abdalla, Douglas R; Murta, Eddie F C; Michelin, Márcia A

    2013-05-01

    This study aims to investigate cytokine synthesis by lymphocytes in the presence of mammary tumors and the interaction with physical activity. For this study, we used 56 female Balb/c, 8-week-old, virgin mice with a body mass between 20 and 30 g. The mice were divided into four groups: a no tumor/nontrained control group; a no tumor/trained group subjected to physical training of swimming in water (30 ± 4°C) for 45 min, five times per week for 8 weeks; a tumor/nontrained (sedentary) group in which the animals received 7,12-dimethylbenzanthracene [(DMBA) 1 mg/ml weekly for 6 weeks)]; and a tumor/trained group in which animals were subjected to the aforementioned DMBA tumor induction and swim training protocols. After the experimental period, immune cells were collected from spleen cell specimens, placed in culture, and stimulated with lipopolysaccharide. The presence of cluster of differentiation (CD)3, CD4, and CD8 markers and the expression of interferon-γ, interleukin (IL)-2, IL-4, IL-10, IL-12, transforming growth factor β, and tumor necrosis factor α cytokines were assessed by flow cytometry and enzyme-linked immunosorbent assay. Physical activity increased the quantities of lymphocytes producing interferon γ, IL-2, IL-12, and tumor necrosis factor α and decreased the quantities of lymphocytes and macrophages expressing IL-4, IL-10, and transforming growth factor β. In contrast, tumor induction, in the absence of swim training, reduced Th1 cytokine levels while increasing the presence of Th2 cytokines and Treg cells. Physical activity promoted reductions in the incidence of tumor development and promoted immune system polarization toward an antitumor Th1 response pattern profile. PMID:22976388

  11. Modeling Tumor Invasion: Effects of Native Vascularity and Tumor Metabolism

    NASA Astrophysics Data System (ADS)

    Gawlinski, Edward

    2001-03-01

    A hybrid cellular automaton model is described and used to simulate early tumor growth and examine the roles of host tissue vascular density and tumor metabolism in the ability of a small number of monoclonal transformed cells to develop into an invasive tumor. The model incorporates normal cells, tumor cells, necrotic or empty space, and a random network of native microvessels as components of a cellular automaton state vector. Diffusion of glucose and lactic acid (the latter resulting from the tumor's excessive reliance on anaerobic metabolism) to and from the microvessels, and their utilization or production by cells, is modeled through the solution of differential equations. In this way, the cells and microvessels affect the extracellular concentrations of glucose and acid which, in turn, affect the rules governing the evolution of the automaton's state vector. Simulations of the model demonstrate that: (i) high tumor acid production is favorable for tumor growth and invasion, however for every acid production rate, there exists a range of optimal microvessel densities (leading to a local pH favorable to tumor but not to normal cells) for which growth and invasion is most effective, (ii) at vascular densities below this range, both tumor and normal cells die due to excessively low pH, (iii) for vascular densities above the optimal range the microvessel network is highly efficient at removing acid and therefore the tumor cells lose their advantage over normal cells gained by high local acid concentration. While significant spatial gradients of glucose formed, no regions of detrimentally poor glucose perfusion (for either cell type) were observed, regardless of microvessel density. Depending on metabolic phenotype, a variety of tumor morphologies similar to those clinically observed were realized in the simulations. Lastly, a sharp transition (analogous to that of the adenoma-carcinoma sequence) between states of initial tumor confinement and efficient

  12. Nuclear medicine imaging of gastro-entero-pancreatic neuroendocrine tumors. The key role of cellular differentiation and tumor grade: from theory to clinical practice

    PubMed Central

    Rust, Edmond; Hubele, Fabrice; Marzano, Ettore; Goichot, Bernard; Pessaux, Patrick; Kurtz, Jean-Emmanuel

    2012-01-01

    Abstract Nuclear medicine imaging is a powerful diagnostic tool for the management of patients with gastro-entero-pancreatic neuroendocrine tumors, mainly developed considering some cellular characteristics that are specific to the neuroendocrine phenotype. Hence, overexpression of specific trans membrane receptors as well as the cellular ability to take up, accumulate, and decarboxylate amine precursors have been considered for diagnostic radiotracer development. Moreover, the glycolytic metabolism, which is not a specific energetic pathway of neuroendocrine tumors, has been proposed for radionuclide imaging of neuroendocrine tumors. The results of scintigraphic examinations reflect the pathologic features and tumor metabolic properties, allowing the in vivo characterization of the disease. In this article, the influence of both cellular differentiation and tumor grade in the scintigraphic pattern is reviewed according to the literature data. The relationship between nuclear imaging results and prognosis is also discussed. Despite the existence of a relationship between the results of scintigraphic imaging and cellular differentiation, tumor grade and patient outcome, the mechanism explaining the variability of the results needs further investigation. PMID:22743056

  13. Hepatic gluconeogenesis influences (13)C enrichment in lactate in human brain tumors during metabolism of [1,2-(13)C]acetate.

    PubMed

    Pichumani, Kumar; Mashimo, Tomoyuki; Vemireddy, Vamsidhara; Kovacs, Zoltan; Ratnakar, James; Mickey, Bruce; Malloy, Craig R; DeBerardinis, Ralph J; Bachoo, Robert M; Maher, Elizabeth A

    2016-07-01

    (13)C-enriched compounds are readily metabolized in human malignancies. Fragments of the tumor, acquired by biopsy or surgical resection, may be acid-extracted and (13)C NMR spectroscopy of metabolites such as glutamate, glutamine, 2-hydroxyglutarate, lactate and others provide a rich source of information about tumor metabolism in situ. Recently we observed (13)C-(13)C spin-spin coupling in (13)C NMR spectra of lactate in brain tumors removed from patients who were infused with [1,2-(13)C]acetate prior to the surgery. We found, in four patients, that infusion of (13)C-enriched acetate was associated with synthesis of (13)C-enriched glucose, detectable in plasma. (13)C labeled glucose derived from [1,2-(13)C]acetate metabolism in the liver and the brain pyruvate recycling in the tumor together lead to the production of the (13)C labeled lactate pool in the brain tumor. Their combined contribution to acetate metabolism in the brain tumors was less than 4.0%, significantly lower than the direct oxidation of acetate in the citric acid cycle in tumors. PMID:27020407

  14. Cellular Potts Modeling of Tumor Growth, Tumor Invasion, and Tumor Evolution

    PubMed Central

    Szabó, András; Merks, Roeland M. H.

    2013-01-01

    Despite a growing wealth of available molecular data, the growth of tumors, invasion of tumors into healthy tissue, and response of tumors to therapies are still poorly understood. Although genetic mutations are in general the first step in the development of a cancer, for the mutated cell to persist in a tissue, it must compete against the other, healthy or diseased cells, for example by becoming more motile, adhesive, or multiplying faster. Thus, the cellular phenotype determines the success of a cancer cell in competition with its neighbors, irrespective of the genetic mutations or physiological alterations that gave rise to the altered phenotype. What phenotypes can make a cell “successful” in an environment of healthy and cancerous cells, and how? A widely used tool for getting more insight into that question is cell-based modeling. Cell-based models constitute a class of computational, agent-based models that mimic biophysical and molecular interactions between cells. One of the most widely used cell-based modeling formalisms is the cellular Potts model (CPM), a lattice-based, multi particle cell-based modeling approach. The CPM has become a popular and accessible method for modeling mechanisms of multicellular processes including cell sorting, gastrulation, or angiogenesis. The CPM accounts for biophysical cellular properties, including cell proliferation, cell motility, and cell adhesion, which play a key role in cancer. Multiscale models are constructed by extending the agents with intracellular processes including metabolism, growth, and signaling. Here we review the use of the CPM for modeling tumor growth, tumor invasion, and tumor progression. We argue that the accessibility and flexibility of the CPM, and its accurate, yet coarse-grained and computationally efficient representation of cell and tissue biophysics, make the CPM the method of choice for modeling cellular processes in tumor development. PMID:23596570

  15. The significance of macrophage phenotype in cancer and biomaterials

    SciTech Connect

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.

  16. The significance of macrophage phenotype in cancer and biomaterials

    DOE PAGESBeta

    Bygd, Hannah C.; Forsmark, Kiva D.; Bratlie, Kaitlin M.

    2014-11-25

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successfulmore » implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials.« less

  17. The significance of macrophage phenotype in cancer and biomaterials.

    PubMed

    Bygd, Hannah C; Forsmark, Kiva D; Bratlie, Kaitlin M

    2014-12-01

    Macrophages have long been known to exhibit heterogeneous and plastic phenotypes. They show functional diversity with roles in homeostasis, tissue repair, immunity and disease. There exists a spectrum of macrophage phenotypes with varied effector functions, molecular determinants, cytokine and chemokine profiles, as well as receptor expression. In tumor microenvironments, the subset of macrophages known as tumor-associated macrophages generates byproducts that enhance tumor growth and angiogenesis, making them attractive targets for anti-cancer therapeutics. With respect to wound healing and the foreign body response, there is a necessity for balance between pro-inflammatory, wound healing, and regulatory macrophages in order to achieve successful implantation of a scaffold for tissue engineering. In this review, we discuss the multitude of ways macrophages are known to be important in cancer therapies and implanted biomaterials. PMID:26932379

  18. Apoptosis in irradiated murine tumors.

    PubMed

    Stephens, L C; Ang, K K; Schultheiss, T E; Milas, L; Meyn, R E

    1991-09-01

    Early radiation responses of transplantable murine ovarian (OCaI) and hepatocellular (HCaI) carcinomas were examined at 6, 24, 48, 96, and 144 h after single photon doses of 25, 35, or 45 Gy. Previous studies using tumor growth delay and tumor radiocurability assays had shown OCaI tumors to be relatively radiosensitive and HCaI tumors to be radioresistant. At 6 h, approximately 20% of nuclei in OCaI tumors showed aberrations characteristic of cell death by apoptosis. This contrasted to an incidence of 3% in HCaI tumors. Mitotic activity was eliminated in OCaI tumors but was only transiently suppressed in HCaI tumors. At 24-96 h, OCaI tumors continued to display apoptosis and progressive necrosis, whereas HCaI tumors responded by exhibiting marked pleomorphism. Factors other than mitotic activity may influence tumor radiosensitivity, and one of these may be susceptibility to induction of apoptosis (programmed cell death), because this was a prominent early radiation response by the radiosensitive OCaI tumors. PMID:1886987

  19. Intramolecular phenotypic capacitance in a modular RNA molecule

    PubMed Central

    Hayden, Eric J.; Bendixsen, Devin P.; Wagner, Andreas

    2015-01-01

    Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA’s ancient role in life suggests that phenotypic capacitance may have influenced evolution since life’s origins. PMID:26401020

  20. Intramolecular phenotypic capacitance in a modular RNA molecule.

    PubMed

    Hayden, Eric J; Bendixsen, Devin P; Wagner, Andreas

    2015-10-01

    Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA's ancient role in life suggests that phenotypic capacitance may have influenced evolution since life's origins. PMID:26401020

  1. Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes

    PubMed Central

    Han, Kyung Eun; Choi, Seung-il; Chung, Woo Suk; Jung, Se Hwan; Katsanis, Nicholas; Kim, Tae-im

    2012-01-01

    Purpose To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta-induced) gene that causes granular corneal dystrophy type 2 (GCD2). Methods We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors. Results We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another. Conclusions GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary. PMID:22815629

  2. Phenotype accessibility and noise in random threshold gene regulatory networks.

    PubMed

    Pinho, Ricardo; Garcia, Victor; Feldman, Marcus W

    2014-01-01

    Evolution requires phenotypic variation in a population of organisms for selection to function. Gene regulatory processes involved in organismal development affect the phenotypic diversity of organisms. Since only a fraction of all possible phenotypes are predicted to be accessed by the end of development, organisms may evolve strategies to use environmental cues and noise-like fluctuations to produce additional phenotypic diversity, and hence to enhance the speed of adaptation. We used a generic model of organismal development --gene regulatory networks-- to investigate how different levels of noise on gene expression states (i.e. phenotypes) may affect access to new, unique phenotypes, thereby affecting phenotypic diversity. We studied additional strategies that organisms might adopt to attain larger phenotypic diversity: either by augmenting their genome or the number of gene expression states. This was done for different types of gene regulatory networks that allow for distinct levels of regulatory influence on gene expression or are more likely to give rise to stable phenotypes. We found that if gene expression is binary, increasing noise levels generally decreases phenotype accessibility for all network types studied. If more gene expression states are considered, noise can moderately enhance the speed of discovery if three or four gene expression states are allowed, and if there are enough distinct regulatory networks in the population. These results were independent of the network types analyzed, and were robust to different implementations of noise. Hence, for noise to increase the number of accessible phenotypes in gene regulatory networks, very specific conditions need to be satisfied. If the number of distinct regulatory networks involved in organismal development is large enough, and the acquisition of more genes or fine tuning of their expression states proves costly to the organism, noise can be useful in allowing access to more unique phenotypes

  3. Phenotype Accessibility and Noise in Random Threshold Gene Regulatory Networks

    PubMed Central

    Feldman, Marcus W.

    2015-01-01

    Evolution requires phenotypic variation in a population of organisms for selection to function. Gene regulatory processes involved in organismal development affect the phenotypic diversity of organisms. Since only a fraction of all possible phenotypes are predicted to be accessed by the end of development, organisms may evolve strategies to use environmental cues and noise-like fluctuations to produce additional phenotypic diversity, and hence to enhance the speed of adaptation. We used a generic model of organismal development --gene regulatory networks-- to investigate how different levels of noise on gene expression states (i.e. phenotypes) may affect access to new, unique phenotypes, thereby affecting phenotypic diversity. We studied additional strategies that organisms might adopt to attain larger phenotypic diversity: either by augmenting their genome or the number of gene expression states. This was done for different types of gene regulatory networks that allow for distinct levels of regulatory influence on gene expression or are more likely to give rise to stable phenotypes. We found that if gene expression is binary, increasing noise levels generally decreases phenotype accessibility for all network types studied. If more gene expression states are considered, noise can moderately enhance the speed of discovery if three or four gene expression states are allowed, and if there are enough distinct regulatory networks in the population. These results were independent of the network types analyzed, and were robust to different implementations of noise. Hence, for noise to increase the number of accessible phenotypes in gene regulatory networks, very specific conditions need to be satisfied. If the number of distinct regulatory networks involved in organismal development is large enough, and the acquisition of more genes or fine tuning of their expression states proves costly to the organism, noise can be useful in allowing access to more unique phenotypes

  4. Bioimaging for quantitative phenotype analysis.

    PubMed

    Chen, Weiyang; Xia, Xian; Huang, Yi; Chen, Xingwei; Han, Jing-Dong J

    2016-06-01

    With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses. PMID:26850283

  5. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth

    PubMed Central

    Huang, Jianfeng; Li, Lena; Lian, Jihong; Schauer, Silvia; Vesely, Paul W.; Kratky, Dagmar; Hoefler, Gerald; Lehner, Richard

    2016-01-01

    Summary The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh–/– tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh–/– mice. Mechanistically, reduced tumor growth in Ces3/Tgh–/– mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth. PMID:27050512

  6. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth.

    PubMed

    Huang, Jianfeng; Li, Lena; Lian, Jihong; Schauer, Silvia; Vesely, Paul W; Kratky, Dagmar; Hoefler, Gerald; Lehner, Richard

    2016-04-12

    The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh(-/-) tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh(-/-) mice. Mechanistically, reduced tumor growth in Ces3/Tgh(-/-) mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth. PMID:27050512

  7. TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation

    PubMed Central

    Atretkhany, Kamar-Sulu N.; Nosenko, Maxim A.; Gogoleva, Violetta S.; Zvartsev, Ruslan V.; Qin, Zhihai; Nedospasov, Sergei A.; Drutskaya, Marina S.

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo. PMID:27148266

  8. TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation.

    PubMed

    Atretkhany, Kamar-Sulu N; Nosenko, Maxim A; Gogoleva, Violetta S; Zvartsev, Ruslan V; Qin, Zhihai; Nedospasov, Sergei A; Drutskaya, Marina S

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo. PMID:27148266

  9. Deciphering Genomic Underpinnings of Quantitative MRI-based Radiomic Phenotypes of Invasive Breast Carcinoma.

    PubMed

    Zhu, Yitan; Li, Hui; Guo, Wentian; Drukker, Karen; Lan, Li; Giger, Maryellen L; Ji, Yuan

    2015-01-01

    Magnetic Resonance Imaging (MRI) has been routinely used for the diagnosis and treatment of breast cancer. However, the relationship between the MRI tumor phenotypes and the underlying genetic mechanisms remains under-explored. We integrated multi-omics molecular data from The Cancer Genome Atlas (TCGA) with MRI data from The Cancer Imaging Archive (TCIA) for 91 breast invasive carcinomas. Quantitative MRI phenotypes of tumors (such as tumor size, shape, margin, and blood flow kinetics) were associated with their corresponding molecular profiles (including DNA mutation, miRNA expression, protein expression, pathway gene expression and copy number variation). We found that transcriptional activities of various genetic pathways were positively associated with tumor size, blurred tumor margin, and irregular tumor shape and that miRNA expressions were associated with the tumor size and enhancement texture, but not with other types of radiomic phenotypes. We provide all the association findings as a resource for the research community (available at http://compgenome.org/Radiogenomics/). These findings pave potential paths for the discovery of genetic mechanisms regulating specific tumor phenotypes and for improving MRI techniques as potential non-invasive approaches to probe the cancer molecular status. PMID:26639025

  10. Deciphering Genomic Underpinnings of Quantitative MRI-based Radiomic Phenotypes of Invasive Breast Carcinoma

    PubMed Central

    Zhu, Yitan; Li, Hui; Guo, Wentian; Drukker, Karen; Lan, Li; Giger, Maryellen L.; Ji, Yuan

    2015-01-01

    Magnetic Resonance Imaging (MRI) has been routinely used for the diagnosis and treatment of breast cancer. However, the relationship between the MRI tumor phenotypes and the underlying genetic mechanisms remains under-explored. We integrated multi-omics molecular data from The Cancer Genome Atlas (TCGA) with MRI data from The Cancer Imaging Archive (TCIA) for 91 breast invasive carcinomas. Quantitative MRI phenotypes of tumors (such as tumor size, shape, margin, and blood flow kinetics) were associated with their corresponding molecular profiles (including DNA mutation, miRNA expression, protein expression, pathway gene expression and copy number variation). We found that transcriptional activities of various genetic pathways were positively associated with tumor size, blurred tumor margin, and irregular tumor shape and that miRNA expressions were associated with the tumor size and enhancement texture, but not with other types of radiomic phenotypes. We provide all the association findings as a resource for the research community (available at http://compgenome.org/Radiogenomics/). These findings pave potential paths for the discovery of genetic mechanisms regulating specific tumor phenotypes and for improving MRI techniques as potential non-invasive approaches to probe the cancer molecular status. PMID:26639025

  11. Fibroids: Genotype and Phenotype.

    PubMed

    Ordulu, Zehra

    2016-03-01

    Fibroids represent a major public health care problem as the most prevalent pelvic tumors in women of reproductive age and as the leading cause of gynecologic surgeries in the United States. The recent advances in the genomic technologies including genome-wide association studies and high-throughput sequencing provide insight into their pathogenesis and molecular classification. Understanding the molecular basis of fibroids may facilitate development of effective targeted treatment options of this very common disease. PMID:26710305

  12. Combined influence of teichoic acids from Staphylococcus aureus and heterometallik Cu/Cd ethylenediamine complex on peritoneal macrophages and tumor cells.

    PubMed

    Nikulina, V V; Garmanchuk, L V; Senchylo, N V; Nikolaenko, T V; Dzhus, O I; Ostapchenko, L I; Khranovska, N M

    2014-01-01

    We investigated the effects of teichoic acid (TA) from Staphylococcus aureus Wood 46 on tumor growth and metastasis of the experimental Lewis lung carcinoma (LLC) in mice. Intranasal administration of TA alone aggravated both tumor growth and metastasis, whereas combined administration of TA with a synthetic bimetallic (copper : cadmium) ethylene diamine complex PO244 resulted in pronounced antitumor and antimetastatic effects. The group of animals subjected to the combined treatment with TA and PO244 manifested the highest degree of lymphocyte infiltration into the tumor tissue, compared to the control group and those exposed to TA or PO244 alone. Moreover, the combined treatment negatively affected the adhesive properties of peritoneal macrophages in the LLC bearing mice. Co-cultivation of the isolated macrophages with primary LLC cultures revealed signific