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Sample records for accelerates tumor progression

  1. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling

    PubMed Central

    Hakim, Fahed; Wang, Yang; Zhang, Shelley XL; Zheng, Jiamao; Yolcu, Esma S.; Carreras, Alba; Khlayfa, Abdelnaby; Shirwan, Haval; Almendros, Isaac; Gozal, David

    2014-01-01

    Fragmented sleep (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that SF promotes tumor growth and progression through pro-inflammatory TLR4 signaling. In the design, we compared mice that were exposed to SF one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis three weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that SF enhanced tumor size and weight compared to control mice. Increased invasiveness was apparent in SF tumors, which penetrated the tumor capsule into surrounding tissues including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in SF tumors where they were distributed in a relatively closer proximity to the tumor capsule, compared to control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by SF persisted. In contrast, these more aggressive features produced by SF were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways. PMID:24448240

  2. Accelerated tumor progression in mice lacking the ATP receptor P2X7.

    PubMed

    Adinolfi, Elena; Capece, Marina; Franceschini, Alessia; Falzoni, Simonetta; Giuliani, Anna L; Rotondo, Alessandra; Sarti, Alba C; Bonora, Massimo; Syberg, Susanne; Corigliano, Domenica; Pinton, Paolo; Jorgensen, Niklas R; Abelli, Luigi; Emionite, Laura; Raffaghello, Lizzia; Pistoia, Vito; Di Virgilio, Francesco

    2015-02-15

    The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. PMID:25542861

  3. Nonlinear ghost waves accelerate the progression of high-grade brain tumors

    NASA Astrophysics Data System (ADS)

    Pardo, Rosa; Martínez-González, Alicia; Pérez-García, Víctor M.

    2016-10-01

    We study a reduced continuous model describing the evolution of high grade gliomas in response to hypoxic events through the interplay of different cellular phenotypes. We show that hypoxic events, even when sporadic and/or limited in space, may have a crucial role on the acceleration of high grade gliomas growth. Our modeling approach is based on two cellular phenotypes. One of them is more migratory and a second one is more proliferative. Transitions between both phenotypes are driven by the local oxygen values, assumed in this simple model to be uniform. Surprisingly, even very localized in time hypoxia events leading to transient migratory populations have the potential to accelerate the tumor's invasion speed up to speeds close to those of the migratory phenotype. The high invasion speed persists for times much longer than the lifetime of the hypoxic event. Moreover, the phenomenon is observed both when the migratory cells form a persistent wave of cells located on the invasion front and when they form a evanescent "ghost" wave disappearing after a short time by decay to the more proliferative phenotype. Our findings are obtained through numerical simulations of the model equations both in 1D and higher dimensional scenarios. We also provide a deeper mathematical analysis of some aspects of the problem such as the conditions for the existence of persistent waves of cells with a more migratory phenotype.

  4. Progress on plasma accelerators

    SciTech Connect

    Chen, P.

    1986-05-01

    Several plasma accelerator concepts are reviewed, with emphasis on the Plasma Beat Wave Accelerator (PBWA) and the Plasma Wake Field Accelerator (PWFA). Various accelerator physics issues regarding these schemes are discussed, and numerical examples on laboratory scale experiments are given. The efficiency of plasma accelerators is then revealed with suggestions on improvements. Sources that cause emittance growth are discussed briefly.

  5. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. PMID:24477002

  6. Progress in advanced accelerator concepts

    SciTech Connect

    Sessler, A.M.

    1994-08-01

    A review is given of recent progress in this field, drawing heavily upon material presented at the Workshop on Advanced Accelerator Concepts, The Abbey, June 12--18, 1994. Attention is addressed to (1) plasma based concepts, (2) photo-cathodes, (3) radio frequency sources and Two-Beam Accelerators, (4) near and far-field schemes (including collective accelerators), (5) beam handling and conditioning, and (6) exotic collider concepts (such as photon colliders and muon colliders).

  7. Muon Collider Progress: Accelerators

    SciTech Connect

    Zisman, Michael S.

    2011-09-10

    A muon collider would be a powerful tool for exploring the energy-frontier with leptons, and would complement the studies now under way at the LHC. Such a device would offer several important benefits. Muons, like electrons, are point particles so the full center-of-mass energy is available for particle production. Moreover, on account of their higher mass, muons give rise to very little synchrotron radiation and produce very little beamstrahlung. The first feature permits the use of a circular collider that can make efficient use of the expensive rf system and whose footprint is compatible with an existing laboratory site. The second feature leads to a relatively narrow energy spread at the collision point. Designing an accelerator complex for a muon collider is a challenging task. Firstly, the muons are produced as a tertiary beam, so a high-power proton beam and a target that can withstand it are needed to provide the required luminosity of ~1 × 10{sup 34} cm{sup –2}s{sup –1}. Secondly, the beam is initially produced with a large 6D phase space, which necessitates a scheme for reducing the muon beam emittance (“cooling”). Finally, the muon has a short lifetime so all beam manipulations must be done very rapidly. The Muon Accelerator Program, led by Fermilab and including a number of U.S. national laboratories and universities, has undertaken design and R&D activities aimed toward the eventual construction of a muon collider. Design features of such a facility and the supporting R&D program are described.

  8. Progress on laser plasma accelerators

    SciTech Connect

    Chen, P.

    1986-04-01

    Several laser plasma accelerator schemes are reviewed, with emphasis on the Plasma Beat Wave Accelerator (PBWA). Theory indicates that a very high acceleration gradient, of order 1 GeV/m, can exist in the plasma wave driven by the beating lasers. Experimental results obtained on the PBWA experiment at UCLA confirms this. Parameters related to the PBWA as an accelerator system are derived, among them issues concerning the efficiency and the laser power and energy requirements are discussed.

  9. Progress of Laser-Driven Plasma Accelerators

    NASA Astrophysics Data System (ADS)

    Nakajima, Kazuhisa

    2007-07-01

    There is a great interest worldwide in plasma accelerators driven by ultra-intense lasers which make it possible to generate ultra-high gradient acceleration and high quality particle beams in a much more compact size compared with conventional accelerators. A frontier research on laser and plasma accelerators is focused on high energy electron acceleration and ultra-short X-ray and Tera Hertz radiations as their applications. These achievements will provide not only a wide range of sciences with benefits of a table-top accelerator but also a basic science with a tool of ultrahigh energy accelerators probing an unknown extremely microscopic world. Harnessing the recent advance of ultra-intense ultra-short pulse lasers, the worldwide research has made a tremendous breakthrough in demonstrating high-energy high-quality particle beams in a compact scale, so called "dream beams on a table top", which represents monoenergetic electron beams from laser wakefield accelerators and GeV acceleration by capillary plasma-channel laser wakefield accelerators. This lecture reviews recent progress of results on laser-driven plasma based accelerator experiments to quest for particle acceleration physics in intense laser-plasma interactions and to present new outlook for the GeV-range high-energy laser plasma accelerators.

  10. Progress of Laser-Driven Plasma Accelerators

    SciTech Connect

    Nakajima, Kazuhisa

    2007-07-11

    There is a great interest worldwide in plasma accelerators driven by ultra-intense lasers which make it possible to generate ultra-high gradient acceleration and high quality particle beams in a much more compact size compared with conventional accelerators. A frontier research on laser and plasma accelerators is focused on high energy electron acceleration and ultra-short X-ray and Tera Hertz radiations as their applications. These achievements will provide not only a wide range of sciences with benefits of a table-top accelerator but also a basic science with a tool of ultrahigh energy accelerators probing an unknown extremely microscopic world.Harnessing the recent advance of ultra-intense ultra-short pulse lasers, the worldwide research has made a tremendous breakthrough in demonstrating high-energy high-quality particle beams in a compact scale, so called ''dream beams on a table top'', which represents monoenergetic electron beams from laser wakefield accelerators and GeV acceleration by capillary plasma-channel laser wakefield accelerators. This lecture reviews recent progress of results on laser-driven plasma based accelerator experiments to quest for particle acceleration physics in intense laser-plasma interactions and to present new outlook for the GeV-range high-energy laser plasma accelerators.

  11. Macrophage Diversity Enhances Tumor Progression and Metastasis

    PubMed Central

    Qian, Binzhi; Pollard, Jeffrey W.

    2016-01-01

    There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation they create an inflammatory environment that is mutagenic and which promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration, invasion, and suppress anti-tumor immunity. At metastatic sites macrophages prepare the target tissue for arrival of tumor cells and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets. PMID:20371344

  12. Translational progress on tumor biomarkers

    PubMed Central

    Guo, Hongwei; Zhou, Xiaolin; Lu, Yi; Xie, Liye; Chen, Qian; Keller, Evan T; Liu, Qian; Zhou, Qinghua; Zhang, Jian

    2015-01-01

    There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine. PMID:26557902

  13. Chaotic dynamics in accelerator physics. Progress report

    SciTech Connect

    Cary, J.R.

    1992-11-30

    Substantial progress was in several areas of accelerator dynamics. For developing understanding of longitudinal adiabatic dynamics, and for creating efficiency enhancements of recirculating free-electron lasers, was substantially completed. A computer code for analyzing the critical KAM tori that bound the dynamic aperture in circular machines was developed. Studies of modes that arise due to the interaction of coating beams with a narrow-spectrum impedance have begun. During this research educational and research ties with the accelerator community at large have been strengthened.

  14. Chemokines in tumor development and progression

    SciTech Connect

    Mukaida, Naofumi; Baba, Tomohisa

    2012-01-15

    Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

  15. Are biomechanical changes necessary for tumor progression?

    NASA Astrophysics Data System (ADS)

    Kas, Josef A.; Fritsch, Anatol; Kiessling, Tobias; Nnetu, David K.; Pawlizak, Steve; Wetzel, Franziska; Zink, Mareike

    2011-03-01

    With an increasing knowledge in tumor biology an overwhelming complexity becomes obvious which roots in the diversity of tumors and their heterogeneous molecular composition. Nevertheless in all solid tumors malignant neoplasia, i.e. uncontrolled growth, invasion of adjacent tissues, and metastasis, occurs. Physics sheds some new light on cancer by approaching this problem from a functional, materials perspective. Recent results indicate that all three pathomechanisms require changes in the active and passive cellular biomechanics. Malignant transformation causes cell softening for small deformations which correlates with an increased rate of proliferation and faster cell migration. The tumor cell's ability to strain harden permits tumor growth against a rigid tissue environment. A highly mechanosensitive, enhanced cell contractility is a prerequisite that tumor cells can cross its tumor boundaries and that this cells can migrate through the extracellular matrix. Insights into the biomechanical changes during tumor progression may lead to selective treatments by altering cell mechanics. Such drugs would not cure by killing cancer cells, but slow down tumor progression with only mild side effects and thus may be an option for older and frail patients.

  16. Chemokines in tumor progression and metastasis.

    PubMed

    Sarvaiya, Purvaba J; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S

    2013-12-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer, non-hodgkin's lymphoma, etc. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  17. Chemokines in tumor progression and metastasis

    PubMed Central

    Sarvaiya, Purvaba J.; Guo, Donna; Ulasov, Ilya; Gabikian, Patrik; Lesniak, Maciej S.

    2013-01-01

    Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer and non-hodgkin's lymphoma among many others. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis. PMID:24259307

  18. Microenvironmental regulation of tumor progression and metastasis

    PubMed Central

    Quail, DF; Joyce, JA

    2014-01-01

    Cancers develop in complex tissue environments, which they depend upon for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable, and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that reeducation of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here, we will discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, and recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects. PMID:24202395

  19. MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION

    PubMed Central

    Rutkowski, Melanie R.; Stephen, Tom L.; Svoronos, Nikolaos; Allegrezza, Michael J.; Tesone, Amelia J.; Perales-Puchalt, Alfredo; Brencicova, Eva; Escovar-Fadul, Ximena; Nguyen, Jenny M.; Cadungog, Mark G.; Zhang, Rugang; Salatino, Mariana; Tchou, Julia; Rabinovich, Gabriel A.; Conejo-Garcia, Jose R.

    2014-01-01

    The dominant TLR5R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal locations by increasing systemic IL-6, which drives mobilization of myeloid derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening anti-tumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently up-regulated in TLR5-unresponsive tumor-bearing mice, but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, anti-tumor immunity and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism. PMID:25533336

  20. Are biomechanical changes necessary for tumor progression?

    NASA Astrophysics Data System (ADS)

    Kas, Josef A.

    2014-03-01

    Already the Roman Celsus recognized rigid tissue as characteristic for solid tumors. Conversely, changes towards a weaker cytoskeleton have been described as a feature of cancer cells since the early days of tumor biology. It remains unclear if a carcinoma's rigid signature stems from more inflexible cells or is caused by the stroma. Despite that the importance of cell biomechanics for tumor progression becomes more and more evident the chicken-and-egg problem to what extent cancer cells already change their mechanical properties within the solid tumor in order to transgress its boundary or mechanical changes are induced by the microenvironment when the cell has left the tumor has been discussed highly controversial. Comprehensive clinical biomechanical measurements only exist from tumor tissue without the possibility to identify individual cells or from individual cancer cells from pleural effusions. Since the biomechanical properties of cells in carcinomas remain unknown measurements on individual cells that directly stem out of primary tumor samples are required, which we have conducted. We found in cervix and mammary carcinomas a distinctive increase of softer cells as well as contractile cells. A soft and contractile cell is like a strong elastic rope. The cell can generate a strong tensile tension to pull its self along and is soft against compression to avoid jamming.

  1. SuperB Progress Report for Accelerator

    SciTech Connect

    Biagini, M.E.; Boni, R.; Boscolo, M.; Buonomo, B.; Demma, T.; Drago, A.; Esposito, M.; Guiducci, S.; Mazzitelli, G.; Pellegrino, L.; Preger, M.A.; Raimondi, P.; Ricci, R.; Rotundo, U.; Sanelli, C.; Serio, M.; Stella, A.; Tomassini, S.; Zobov, M.; Bertsche, K.; Brachman, A.; /SLAC /Novosibirsk, IYF /INFN, Pisa /Pisa U. /Orsay, LAL /Annecy, LAPP /LPSC, Grenoble /IRFU, SPP, Saclay /DESY /Cockroft Inst. Accel. Sci. Tech. /U. Liverpool /CERN

    2012-02-14

    This report details the progress made in by the SuperB Project in the area of the Collider since the publication of the SuperB Conceptual Design Report in 2007 and the Proceedings of SuperB Workshop VI in Valencia in 2008. With this document we propose a new electron positron colliding beam accelerator to be built in Italy to study flavor physics in the B-meson system at an energy of 10 GeV in the center-of-mass. This facility is called a high luminosity B-factory with a project name 'SuperB'. This project builds on a long history of successful e+e- colliders built around the world, as illustrated in Figure 1.1. The key advances in the design of this accelerator come from recent successes at the DAFNE collider at INFN in Frascati, Italy, at PEP-II at SLAC in California, USA, and at KEKB at KEK in Tsukuba Japan, and from new concepts in beam manipulation at the interaction region (IP) called 'crab waist'. This new collider comprises of two colliding beam rings, one at 4.2 GeV and one at 6.7 GeV, a common interaction region, a new injection system at full beam energies, and one of the two beams longitudinally polarized at the IP. Most of the new accelerator techniques needed for this collider have been achieved at other recently completed accelerators including the new PETRA-3 light source at DESY in Hamburg (Germany) and the upgraded DAFNE collider at the INFN laboratory at Frascati (Italy), or during design studies of CLIC or the International Linear Collider (ILC). The project is to be designed and constructed by a worldwide collaboration of accelerator and engineering staff along with ties to industry. To save significant construction costs, many components from the PEP-II collider at SLAC will be recycled and used in this new accelerator. The interaction region will be designed in collaboration with the particle physics detector to guarantee successful mutual use. The accelerator collaboration will consist of several groups at present universities and national

  2. Mitochondrial Redox Signaling and Tumor Progression

    PubMed Central

    Chen, Yuxin; Zhang, Haiqing; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

    2016-01-01

    Cancer cell can reprogram their energy production by switching mitochondrial oxidative phosphorylation to glycolysis. However, mitochondria play multiple roles in cancer cells, including redox regulation, reactive oxygen species (ROS) generation, and apoptotic signaling. Moreover, these mitochondrial roles are integrated via multiple interconnected metabolic and redox sensitive pathways. Interestingly, mitochondrial redox proteins biphasically regulate tumor progression depending on cellular ROS levels. Low level of ROS functions as signaling messengers promoting cancer cell proliferation and cancer invasion. However, anti-cancer drug-initiated stress signaling could induce excessive ROS, which is detrimental to cancer cells. Mitochondrial redox proteins could scavenger basal ROS and function as “tumor suppressors” or prevent excessive ROS to act as “tumor promoter”. Paradoxically, excessive ROS often also induce DNA mutations and/or promotes tumor metastasis at various stages of cancer progression. Targeting redox-sensitive pathways and transcriptional factors in the appropriate context offers great promise for cancer prevention and therapy. However, the therapeutics should be cancer-type and stage-dependent. PMID:27023612

  3. Alcohol Use Accelerates HIV Disease Progression

    PubMed Central

    Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, John Bryan; Campa, Adriana

    2010-01-01

    Abstract The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV+ adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4+ cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23–6.85, p = 0.015) more likely to present a decline of CD4 to ≤200 cells/μl, independent of baseline CD4+ cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to ≤200 cells/mm3 (HR = 7.76: 95% CI: 1.2–49.2, p = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4+ cell decline (HR = 3.57: 95% CI: 1.24–10.31, p = 0.018). Frequent alcohol intake was associated with higher viral load over time (β = 0.259, p = 0.038). This significance was maintained in those receiving ART (β = 0.384, p = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4+ cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART. PMID:20455765

  4. DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression

    PubMed Central

    Sato, Fuyuki; Bhawal, Ujjal K.; Yoshimura, Tomohiro; Muragaki, Yasuteru

    2016-01-01

    Clock genes, major regulators of circadian rhythm, are involved in tumor progression. We have shown that clock genes basic helix-loop-helix (BHLH) transcription factors, differentiated embryonic chondrocyte gene 1 (DEC1/BHLHE40/Sharp2/Stra13) and DEC2 (BHLHE41/Sharp1) play important roles in circadian rhythm, cell proliferation, apoptosis, hypoxia response, various stresses, and epithelial-to-mesenchymal transition (EMT) of tumor cells. Various stresses, such as exposure to transforming growth factor-beta (TGF-β), hypoxia, cytokines, serum-free, and anti-tumor drugs affect DEC1 and DEC2 expression. An increased or decreased expression of DEC1 and DEC2 regulated tumor progression. However, DEC1 and DEC2 have opposite effects in tumor progression, where the reason behind remains unclear. We found that DEC2 has circadian expression in implanted mouse sarcoma cells, suggesting that DEC2 regulates tumor progression under circadian rhythm. In addition to that, we showed that DEC1 and DEC2 regulate target genes via positive or negative feedback system in tumor progression. We propose that DEC1 and DEC2 act as an accelerator or a brake in tumor progression. In this review, we summarize current progress of knowledge in the function of DEC1 and DEC2 genes in tumor progression. PMID:26819638

  5. UCLA accelerator research & development. Progress report

    SciTech Connect

    1997-09-01

    This report discusses work on advanced accelerators and beam dynamics at ANL, BNL, SLAC, UCLA and Pulse Sciences Incorporated. Discussed in this report are the following concepts: Wakefield acceleration studies; plasma lens research; high gradient rf cavities and beam dynamics studies at the Brookhaven accelerator test facility; rf pulse compression development; and buncher systems for high gradient accelerator and relativistic klystron applications.

  6. Accelerator Technology Division progress report, FY 1992

    SciTech Connect

    Schriber, S.O.; Hardekopf, R.A.; Heighway, E.A.

    1993-07-01

    This report briefly discusses the following topics: The Ground Test Accelerator Program; Defense Free-Electron Lasers; AXY Programs; A Next Generation High-Power Neutron-Scattering Facility; JAERI OMEGA Project and Intense Neutron Sources for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Supercollider; The High-Power Microwave (HPM) Program; Neutral Particle Beam (NPB) Power Systems Highlights; Industrial Partnering; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Accelerator Theory and Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  7. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.

    PubMed

    Rutkowski, Melanie R; Stephen, Tom L; Svoronos, Nikolaos; Allegrezza, Michael J; Tesone, Amelia J; Perales-Puchalt, Alfredo; Brencicova, Eva; Escovar-Fadul, Ximena; Nguyen, Jenny M; Cadungog, Mark G; Zhang, Rugang; Salatino, Mariana; Tchou, Julia; Rabinovich, Gabriel A; Conejo-Garcia, Jose R

    2015-01-12

    The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism. PMID:25533336

  8. Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.

    PubMed

    Wu, Yuan-Yuan; V Nguyen, Andrew; Wu, Xiao-Xuan; Loh, Mingyu; Vu, Michelle; Zou, Yiyu; Liu, Qiang; Guo, Peng; Wang, Yanhua; Montgomery, Leslie L; Orlofsky, Amos; Rand, Jacob H; Lin, Elaine Y

    2014-12-01

    Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism. PMID:25451155

  9. Accelerator Technology Division progress report, FY 1993

    SciTech Connect

    Schriber, S.O.; Hardekopf, R.A.; Heighway, E.A.

    1993-12-31

    This report discusses the following topics: A Next-Generation Spallation-Neutron Source; Accelerator Performance Demonstration Facility; APEX Free-Electron Laser Project; The Ground Test Accelerator (GTA) Program; Intense Neutron Source for Materials Testing; Linac Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Radio-Frequency Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operation.

  10. Extracellular Vesicles in Brain Tumor Progression.

    PubMed

    D'Asti, Esterina; Chennakrishnaiah, Shilpa; Lee, Tae Hoon; Rak, Janusz

    2016-04-01

    also impact the emission rates, types, cargo, and biogenesis of EVs, as reflected by preliminary analyses pointing to differences in profiles of EV-regulating genes (vesiculome) between molecular subtypes of glioblastoma, and in other brain tumors. Molecular regulators of vesiculation can also act as oncogenes. These intimate connections suggest the context-specific roles of different EV subsets in the progression of specific brain tumors. Advanced efforts are underway to capture these events through the use of EVs circulating in biofluids as biomarker reservoirs and to guide diagnostic and therapeutic decisions. PMID:26993504

  11. Progress Towards Doubling the Beam Power at Fermilab's Accelerator Complex

    SciTech Connect

    Kourbanis, ioanis

    2014-06-01

    After a 14 month shutdown accelerator modifications and upgrades are in place to allow us doubling of the Main Injector beam power. We will discuss the past MI high power operation and the current progress towards doubling the power.

  12. Progress Towards Doubling the Beam Power at Fermilab's Accelerator Complex

    SciTech Connect

    Kourbanis, Ioanis

    2014-07-01

    After a 16 month shutdown to reconfigure the Fermilab Accelerators for high power operations, the Fermilab Accelerator Complex is again providing beams for numerous Physics Experiments. By using the Recycler to slip stack protons while the Main Injector is ramping, the beam power at 120 GeV can reach 700 KW, a factor of 2 increase. The progress towards doubling the Fermilab's Accelerator complex beam power will be presented.

  13. Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.

    PubMed

    Rao, Velidi H; Vogel, Kristen; Yanagida, Jodi K; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K; Hansen, Laura A

    2015-10-01

    Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness. PMID:24798404

  14. Theoretical problems in accelerator physics. Progress report

    SciTech Connect

    Not Available

    1994-08-01

    This is the second progress report submitted under the author`s current grant and covers progress made since the submission of the first progress report in August 1993. During this period the author has continued to spend approximately one half of his time at SLAC and most of the projects reported here were carried out in collaboration with individuals and groups at SLAC. Except where otherwise noted, reference numbers in the text refer to the attached list of current contract publications. Copies of the publications, numbered in agreement with the publication list, are included with this report.

  15. 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

  16. Prediction of brain tumor progression using a machine learning technique

    NASA Astrophysics Data System (ADS)

    Shen, Yuzhong; Banerjee, Debrup; Li, Jiang; Chandler, Adam; Shen, Yufei; McKenzie, Frederic D.; Wang, Jihong

    2010-03-01

    A machine learning technique is presented for assessing brain tumor progression by exploring six patients' complete MRI records scanned during their visits in the past two years. There are ten MRI series, including diffusion tensor image (DTI), for each visit. After registering all series to the corresponding DTI scan at the first visit, annotated normal and tumor regions were overlaid. Intensity value of each pixel inside the annotated regions were then extracted across all of the ten MRI series to compose a 10 dimensional vector. Each feature vector falls into one of three categories:normal, tumor, and normal but progressed to tumor at a later time. In this preliminary study, we focused on the trend of brain tumor progression during three consecutive visits, i.e., visit A, B, and C. A machine learning algorithm was trained using the data containing information from visit A to visit B, and the trained model was used to predict tumor progression from visit A to visit C. Preliminary results showed that prediction for brain tumor progression is feasible. An average of 80.9% pixel-wise accuracy was achieved for tumor progression prediction at visit C.

  17. Immunological Consequences of Epithelial-Mesenchymal Transition in Tumor Progression.

    PubMed

    Chockley, Peter J; Keshamouni, Venkateshwar G

    2016-08-01

    Microenvironments that tumor cells encounter are different during the stages of cancer progression-primary tumor, metastasis, and at the metastatic site. This suggests potential differences in immune surveillance of primary tumor and metastasis. Epithelial-mesenchymal transition (EMT) is a key reversible process in which cancer cells transition into highly motile and invasive cells for dissemination. Only a tiny proportion successfully metastasize, supporting the notion of metastasis-specific immune surveillance. EMT involves extensive molecular reprogramming of cells conferring many clinically relevant features to cancer cells and affects tumor cell interactions within the tumor microenvironment. We review the impact of tumor immune infiltrates on tumor cell EMT and the consequences of EMT in shaping the immune microenvironment of tumors. The usefulness of EMT as a model to investigate metastasis-specific immune surveillance mechanisms are also explored. Finally, we discuss potential implications of EMT for tumor immunogenicity, as well as current immunotherapies and future strategies. PMID:27431984

  18. 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

  19. Rare Tumors in Children: Progress Through Collaboration

    PubMed Central

    Furman, Wayne L.; Schultz, Kris A.; Ferrari, Andrea; Helman, Lee; Krailo, Mark D.

    2015-01-01

    Rare pediatric tumors account for approximately 10% of all childhood cancers, which in themselves are a rare entity. The diverse histologies and clinical behaviors of rare pediatric tumors pose challenges to the investigation of their biologic and clinical features. National and international cooperative groups such as the Rare Tumor Committee of the Children's Oncology Group, Rare Tumors in Pediatric Age Project, and European Cooperative Study Group for Pediatric Rare Tumors have developed several initiatives to advance knowledge about rare pediatric cancers. However, these programs have been only partially effective, necessitating the development of alternative mechanisms to study these challenging diseases. In this article, we review the current national and international collaborative strategies to study rare pediatric cancers and alternative methods under exploration to enhance those efforts, such as independent registries and disease-specific, National Cancer Institute–sponsored clinics. PMID:26304909

  20. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    PubMed

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease. PMID:14517400

  1. Cancer Progression and Tumor Growth Kinetics

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan; Kalpathy-Cramer, Jayashree; Wilkerson, Julia; Sprinkhuizen, Sara; Song, Yi-Qiao; Bates, Susan; Rosen, Bruce; Fojo, Tito

    2013-03-01

    We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed. Work supported by the National Science Foundation and the National Institutes of Health

  2. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis. PMID:27075625

  3. Regulation of prostate cancer progression by the tumor microenvironment.

    PubMed

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  4. Disruption of gut homeostasis by opioids accelerates HIV disease progression

    PubMed Central

    Meng, Jingjing; Sindberg, Gregory M.; Roy, Sabita

    2015-01-01

    Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. PMID:26167159

  5. [Metastasis and progression mechanisms of soft tissue tumors].

    PubMed

    Steinestel, K; Wardelmann, E

    2015-11-01

    Invasion and metastatic dissemination of tumor cells defines prognosis not only in patients with epithelial, but also mesenchymal neoplasms. Early and clinically inapparent micrometastases occur in many patients, and the risk for metastasis correlates with the tumor subtype and histologic tumor grade. In recent years and analogous to the situation in epithelial tumors, mechanisms of tumor cell dissemination in soft tissue tumors have been increasingly understood, and it has been shown that reorganization of the actin cytoskeleton plays a key role in these processes. This review summarizes current knowledge on the mechanisms of progression and metastasis of soft tissue tumors and points out possible targets for novel anti-invasive and anti-metastatic therapies. PMID:26324521

  6. LOXL2 in epithelial cell plasticity and tumor progression.

    PubMed

    Cano, Amparo; Santamaría, Patricia G; Moreno-Bueno, Gema

    2012-09-01

    Several members of the lysyl oxidase family have recently emerged as important regulators of tumor progression. Among them, LOXL2 has been shown to be involved in tumor progression and metastasis of several tumor types, including breast carcinomas. Secreted LOXL2 participates in the remodeling of the extracellular matrix of the tumor microenvironment, in a similar fashion to prototypical lysyl oxidase. In addition, new intracellular functions of LOXL2 have been described, such as its involvement in the regulation of the epithelial-to-mesenchymal transition, epithelial cell polarity and differentiation mediated by transcriptional repression mechanisms. Importantly, intracellular (perinuclear) expression of LOXL2 is associated with poor prognosis and distant metastasis of specific tumor types, such as larynx squamous cell carcinoma and basal breast carcinomas. These recent findings open new avenues for the therapeutic utility of LOXL2. PMID:23030485

  7. Proprotein Convertases in Tumor Progression and Malignancy

    PubMed Central

    Khatib, Abdel-Majid; Siegfried, Géraldine; Chrétien, Michel; Metrakos, Peter; Seidah, Nabil G.

    2002-01-01

    The mammalian subtilisin/kexin-like proprotein convertase (PC) family has been implicated in the activation of a wide spectrum of proteins. These proteins are usually synthesized as inactive precursors before their conversion to fully mature bioactive forms. A large majority of these active proteins such as matrix metalloproteases, growth factors, and adhesion molecules are crucial in the processes of cellular transformation, acquisition of the tumorigenic phenotype, and metastases formation. Inhibition of PCs significantly affects the malignant phenotype of various tumor cells. In addition to direct tumor cell proliferation and migration blockade, PC inhibitors can also be used to target tumor angiogenesis. In this Review article we discuss a number of recent findings on the clinical relevance of PCs in cancer patients, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells. Thus, PC inhibitors may constitute new promising agents for the treatment of multiple tumors and/or in adjuvant therapy to prevent recurrence. PMID:12057895

  8. Progress in Modeling Electron Cloud Effects in HIF Accelerators

    NASA Astrophysics Data System (ADS)

    Cohen, R. H.; Friedman, A.; Molvik, A. W.; Azevedo, A.; Vay, J.-L.; Furman, M. A.; Stoltz, P. H.

    2003-10-01

    Stray electrons can arise in positive-charge accelerators for heavy ion fusion (or other applications) from ionization of gas (ambient or released from walls), or via secondary emission. Their accumulation is affected by the beam potential and duration, and the accelerating and confining fields. We present electron orbit simulations which show the resultant e-cloud distribution; ion simulations with prescribed e-clouds which show the effect on ion beam quality; a gyro-averaged model for including electron dynamics in ion simulations, and its implementation status; and progress in merging the capabilities of WARP (3-D PIC code for HIF) (D.P. Grote, A. Friedman, I. Haber, Proc. 1996 Comp. Accel. Physics Conf., AIP Proc. 391), 51 (1996), with those of POSINST (e-clouds in high-energy accelerators) (M.A. Furman, LBNL-41482/CBP Note 247/LHC Project Report 180, May 20, 1998).

  9. Activation of mesenchymal stem cells by macrophages promotes tumor progression through immune suppressive effects

    PubMed Central

    Jia, Xiao-hua; Feng, Guo-wei; Wang, Zhong-liang; Du, Yang; Shen, Chen; Hui, Hui; Peng, Dong; Li, Zong-jin; Kong, De-ling; Tian, Jie

    2016-01-01

    Cancer development and progression is linked to tumor-associated macrophages (TAMs). Distinct TAMs subsets perform either protective or pathogenic effects in cancer. A protective role in carcinogenesis has been described for M1 macrophages, which activate antitumor mechanisms. By comparison, TAMs isolated from solid and metastatic tumors have a suppressive M2-like phenotype, which could support multiple aspects of tumor progression. Currently, it has not been clearly understood how macrophages in tumor-associated stroma could be hijacked to support tumor growth. Mesenchymal stem cells (MSCs) actively interact with components of the innate immune system and display both anti-inflammatory and pro-inflammatory effects. Here, we tested whether MSCs could favor the tumor to escape from immunologic surveillance in the presence of M1 macrophages. We found that MSCs educated by M1 condition medium (cMSCs) possessed a greatly enhanced ability in promoting tumor growth in vivo. Examination of cytokines/chemokines showed that the cMSCs acquired a regulatory profile, which expressed high levels of iNOS and MCP1. Consistent with an elevated MCP1 expression in cMSCs, the tumor-promoting effect of the cMSCs depended on MCP1 mediated macrophage recruitment to tumor sites. Furthermore, IL-6 secreted by the cMSCs could polarize infiltrated TAMs into M2-like macrophages. Therefore, when macrophages changed into M1 pro-inflammation type in tumor microenvironment, the MSCs would act as poor sensors and switchers to accelerate tumor growth. PMID:26988913

  10. Evolutionary Game Theory Analysis of Tumor Progression

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Liao, David; Sturm, James; Austin, Robert

    2014-03-01

    Evolutionary game theory applied to two interacting cell populations can yield quantitative prediction of the future densities of the two cell populations based on the initial interaction terms. We will discuss how in a complex ecology that evolutionary game theory successfully predicts the future densities of strains of stromal and cancer cells (multiple myeloma), and discuss the possible clinical use of such analysis for predicting cancer progression. Supported by the National Science Foundation and the National Cancer Institute.

  11. Accelerator Technology Program. Progress report, January-June 1980

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1980-03-01

    The activities of Los Alamos Scientific Laboratory's (LASL) Accelerator Technology (AT) Division during the first six months of calendar 1980 are discussed. This report is organized around major projects of the Division, reflecting a wide variety of applications and sponsors. The first section summarizes progress on the Proton Storage Ring to be located between LAMPF and the LASL Pulsed Neutron Research facility, followed by a section on the gyrocon, a new type of high-power, high-efficiency radio-frequency (rf) amplifier. The third section discusses the racetrack microtron being developed jointly by AT Division and the National Bureau of Standards; the fourth section concerns the free-electron studies. The fifth section covers the radio-frequency quadrupole linear accelerator, a new concept for the acceleration of low-velocity particles; this section is followed by a section discussing heavy ion fusion accelerator development. The next section reports activities in the Fusion Materials Irradiation Test program, a collaborative effort with the Hanford Engineering Development Laboratory. The final section deals first with development of H/sup -/ ion sources and injectors, then with accelerator instrumentation and beam dynamics.

  12. Progress in photodynamic therapy on tumors

    NASA Astrophysics Data System (ADS)

    Tian, Y. Y.; Wang, L. L.; Wang, W.

    2008-10-01

    Photodynamic therapy (PDT) is a promising treatment on neoplastic pathologic tissues, which involves the administration of a photosensitizing agent followed by the exposure of the tissue to visible nonthermal light. Light energy is captured and transferred to other molecules resulting in the formation of short-lived energetic species, which interact with biological systems and then produce tissue damage. Photosensitizer can be taken up selectively by tumor cells because of the upregulation of low-density lipoprotein receptor-mediated endocytosis and the acidic tumor environments. In recent years, the application of PDT in the treatment of malignant lesions has increased dramatically. The first health agency approval for PDT was granted for Photofrin in Canada in 1993, and, now, it is licensed in many countries for the treatment of cancers. Although Photofrin is the most commonly used photosensitizer, it has significant side effects. Therefore, major effort has been invested in the development of new sensitizers and, to this end, many photosensitizers have been described and some are now in clinical trials.

  13. KSHV-Mediated Angiogenesis in Tumor Progression

    PubMed Central

    Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

    2016-01-01

    Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. PMID:27447661

  14. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    PubMed

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. PMID:27117662

  15. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-09-14

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  16. Targeting YAP-dependent MDSC infiltration impairs tumor progression

    PubMed Central

    Wang, Guocan; Lu, Xin; Dey, Prasenjit; Deng, Pingna; Wu, Chia Chin; Jiang, Shan; Fang, Zhuangna; Zhao, Kun; Konaparthi, Ramakrishna; Hua, Sujun; Zhang, Jianhua; Li-Ning-Tapia, Elsa M.; Kapoor, Avnish; Wu, Chang-Jiun; Patel, Neelay Bhaskar; Guo, Zhenglin; Ramamoorthy, Vandhana; Tieu, Trang N.; Heffernan, Tim; Zhao, Di; Shang, Xiaoying; Khadka, Sunada; Hou, Pingping; Hu, Baoli; Jin, Eun-Jung; Yao, Wantong; Pan, Xiaolu; Ding, Zhihu; Shi, Yanxia; Li, Liren; Chang, Qing; Troncoso, Patricia; Logothetis, Christopher J.; McArthur, Mark J.; Chin, Lynda; Wang, Y. Alan; DePinho, Ronald A.

    2015-01-01

    The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer. Significance We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival. PMID:26701088

  17. Second harmonic generation reveals matrix alterations during breast tumor progression

    NASA Astrophysics Data System (ADS)

    Burke, Kathleen; Tang, Ping; Brown, Edward

    2013-03-01

    Alteration of the extracellular matrix in tumor stroma influences efficiency of cell locomotion away from the primary tumor into surrounding tissues and vasculature, thereby affecting metastatic potential. We study matrix changes in breast cancer through the use of second harmonic generation (SHG) of collagen in order to improve the current understanding of breast tumor stromal development. Specifically, we utilize a quantitative analysis of the ratio of forward to backward propagating SHG signal (F/B ratio) to monitor collagen throughout ductal and lobular carcinoma development. After detection of a significant decrease in the F/B ratio of invasive but not in situ ductal carcinoma compared with healthy tissue, the collagen F/B ratio is investigated to determine the evolution of fibrillar collagen changes throughout tumor progression. Results are compared with the progression of lobular carcinoma, whose F/B signature also underwent significant evolution during progression, albeit in a different manner, which offers insight into varying methods of tissue penetration and collagen manipulation between the carcinomas. This research provides insights into trends of stromal reorganization throughout breast tumor development.

  18. [Multiple involvements of LRP-1 receptor in tumor progression].

    PubMed

    Langlois, B; Emonard, H; Martiny, L; Dedieu, S

    2009-01-01

    Extensive proteolytic remodeling processes constitute a critical step during tumor progression. The endocytic receptor low-density lipoprotein receptor-related protein-1 (LRP-1), by its function in the clearance of multiple extracellular proteases involved in metastatic spreading, has long been considered as a putative tumor suppressor. Moreover, the receptor is likely to control the peritumoral microenvironment by internalization of growth factors and matricial proteins and could therefore participate to the control of signaling events involved in survival and proliferation of cancer cells. Nevertheless, recent data lead to reconsider the initially attributed antitumor properties of LRP-1. A more complex model seems to emerge in which LRP-1 could constitute a sensor of pericellular environment and regulate the membrane proteome dynamics. By its control of focal adhesions composition and turn-over, regulation of the cytoskeleton organization and integrin endocytic recycling, LRP-1 appears as a crucial actor of the epithelial-mesenchymal transition, thereby reinforcing the aggressive phenotype of malignant cells. LRP-1 partitioning into rafts and association with tissue-type and tumor grade specific intracellular scaffold proteins appear crucial to determine its function in tumor progression. Those emerging aspects present numerous promising perspectives in oncology and allow envisaging the development of innovative strategies of control of tumor progression through the targeting of LRP-1. PMID:19233571

  19. CDC42 inhibition suppresses progression of incipient intestinal tumors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations in the APC or Beta-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer x...

  20. Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer

    PubMed Central

    Miwa, Hazuki E; Koba, Wade R; Fine, Eugene J; Giricz, Orsi; Kenny, Paraic A; Stanley, Pamela

    2013-01-01

    Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the mouse mammary tumor virus (MMTV) promoter. However, the penetrance of the tumor phenotype became variable in mixed FVB/N and C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3−/−/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3−/−/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors and lung metastasis. Nevertheless, activation of extracellular signal-regulated kinase (ERK)1/2 or protein kinase B (AKT) was reduced in ∼20-week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of focal adhesion kinase (FAK), protein tyrosine kinase Src, and p38 mitogen-activated protein kinase were similar to that of controls. All the eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least 10 galectin and 7 N-glycan N-acetylglucosaminyl (GlcNAc)-transferase (MGAT) genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identification of key galectins that promote mammary tumor progression in mice is not straightforward because all the eight galectin genes are expressed; and high levels of MGAT3, galectin-4, -8, -10, -13 and -14 transcripts correlate with better relapse-free survival in human breast cancer. PMID:24037315

  1. Male patients presenting with rapidly progressive puberty associated with malignant tumors

    PubMed Central

    Kim, Soo Jung; Ko, A Ra; Jung, Mo Kyung; Kim, Ki Eun; Chae, Hyun Wook; Kim, Duk Hee; Kim, Ho-Seong

    2016-01-01

    In males, precocious puberty (PP) is defined as the development of secondary sexual characteristics before age 9 years. PP is usually idiopathic; though, organic abnormalities including tumors are more frequently found in male patients with PP. However, advanced puberty in male also can be an important clinical manifestation in tumors. We report 2 cases of rapidly progressive puberty in males, each associated with a germ-cell tumor. First, an 11-year-old boy presented with mild fever and weight loss for 1 month. Physical examination revealed a pubertal stage of G3P3 with 10-mL testes. Investigations revealed advanced bone age (16 years) with elevated basal luteinizing hormone and testosterone levels. An anterior mediastinal tumor was identified by chest radiography and computed tomography, and elevated α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG) levels were noted. Histopathologic analysis confirmed a yolk-sac tumor. Second, a 12-year-old boy presented with diplopia, polydipsia, and polyuria for 4 months. Physical examination revealed a pubertal stage of G3P3 with 8-mL testes. Bone age was advanced (16 years) and laboratory tests indicated panhypopituitarism with elevated testosterone level. A mixed germ-cell tumor was diagnosed with elevated AFP and β-hCG levels. Of course, these patients also have other symptoms of suspecting tumors, however, rapidly progressive puberty can be the more earlier screening sign of tumors. Therefore, in male patients with accelerated or advanced puberty, malignancy should be considered, with evaluation of tumor markers. In addition, advanced puberty in male should be recognized more widely as a unique sign of neoplasm. PMID:27104181

  2. Progress toward a prototype recirculating ion induction accelerator

    SciTech Connect

    Friedman, A.; Barnard, J.J.; Cable, M.D.

    1996-06-01

    The U.S. Inertial Fusion Energy (IFE) Program is developing the physics and technology of ion induction accelerators, with the goal of electric power production by means of heavy ion beam-driven inertial fusion (commonly called heavy ion fusion, or HIF). Such accelerators are the principal candidates for inertial fusion power production applications, because they are expected to enjoy high efficiency, inherently high pulse repetition frequency (power plants are expected to inject and burn several fusion targets per second), and high reliability. In addition (and in contrast with laser beams, which are focused with optical lenses) heavy-ion beams will be focused onto the target by magnetic fields, which cannot be damaged by target explosions. Laser beams are used in present-day and planned near-term facilities (such as LLNUs Nova and the National Ignition Facility, which is being designed) because they can focus beams onto very small, intensely illuminated spots for scaled experiments and because the laser technology is already available. An induction accelerator works by passing the beam through a series of accelerating modules, each of which applies an electromotive force to the beam as it goes by; effectively, the beam acts as the secondary winding of a series of efficient one-turn transformers. The authors present plans for and progress toward the development of a small (4.5-m-diam) prototype recirculator, which will accelerate singly charged potassium ions through 15 laps, increasing the ion energy from 80 to 320 keV and the beam current from 2 to 8 mA. Beam confinement and bending are effected with permanent-magnet quadrupoles and electric dipoles, respectively. The design is based on scaling laws and on extensive particle and fluid simulations of the behavior of the space charge-dominated beam.

  3. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity

    PubMed Central

    Zhang, Lisa J.; Xiong, Yin; Nilubol, Naris; He, Mei; Bommareddi, Swaroop; Zhu, Xuguang; Jia, Li; Xiao, Zhen; Park, Jeong-Won; Xu, Xia; Patel, Dhaval; Willingham, Mark C.; Cheng, Sheue-yann; Kebebew, Electron

    2015-01-01

    Cancer gender disparity has been observed for a variety of human malignancies. Thyroid cancer is one such cancer with a higher incidence in women, but more aggressive disease in men. There is scant evidence on the role of sex hormones on cancer initiation/progression. Using a transgenic mouse model of follicular thyroid cancer (FTC), we found castration led to lower rates of cancer in females and less advanced cancer in males. Mechanistically, less advanced cancer in castrated males was due to increased expression of tumor suppressor (Glipr1, Sfrp1) and immune-regulatory genes and higher tumor infiltration with M1 macrophages and CD8 cells. Functional study showed that GLIPR1 reduced cell growth and increased chemokine secretion (Ccl5) that activates immune cells. Our data demonstrate that testosterone regulates thyroid cancer progression by reducing tumor suppressor gene expression and tumor immunity. PMID:25576159

  4. Accelerator technology program. Progress report, January-December 1979

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1980-11-01

    The activities of Los Alamos Scientific Laboratory's (LASL) Accelerator Technology (AT) Division during the calendar year 1979 are highlighted, with references to more detailed reports. This report is organized around the major projects of the Division, reflecting a wide variety of applications and sponsors. The first section covers the Fusion Materials Irradiation Test program, a collaborative effort with the Hanford Engineering Development Laboratory; the second section summarizes progress on the Proton Storage Ring to be built between LAMPF and the LASL Pulsed Neutron Research facility. A new project that achieved considerable momentum during the year is described next - the free-electron laser studies; the following section discusses the status of the Pion Generator for Medical Irradiation program. Next, two more new programs, the racetrack microtron being developed jointly by AT-Division and the National Bureau of Standards and the radio-frequency (rf) accelerator development for heavy ion fusion, are outlined. Development activities on a new type of high-power, high-efficiency rf amplifier called the gyrocon are then reported, and the final sections cover development of H/sup -/ ion sources and injectors, and linear accelerator instrumentation and beam dynamics.

  5. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Accelerates the Progression of Renal Fibrosis in Lupus Nephritis by Activating SMAD and p38 MAPK in TGF-β1 Signaling Pathway.

    PubMed

    Liu, Zhiqin; Xue, Leixi; Liu, Zhichun; Huang, Jun; Wen, Jian; Hu, Ji; Bo, Lin; Yang, Ru

    2016-01-01

    This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used for in vivo experiments and human proximal tubular cells (HK2 cells) were used for in vitro experiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, and α-SMA proteins. In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway. PMID:27365897

  6. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Accelerates the Progression of Renal Fibrosis in Lupus Nephritis by Activating SMAD and p38 MAPK in TGF-β1 Signaling Pathway

    PubMed Central

    Liu, Zhiqin; Xue, Leixi; Liu, Zhichun; Huang, Jun; Wen, Jian; Hu, Ji; Bo, Lin; Yang, Ru

    2016-01-01

    This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used for in vivo experiments and human proximal tubular cells (HK2 cells) were used for in vitro experiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, and α-SMA proteins. In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway. PMID:27365897

  7. Hyaluronidase Hyal1 Increases Tumor Cell Proliferation and Motility through Accelerated Vesicle Trafficking*

    PubMed Central

    McAtee, Caitlin O.; Berkebile, Abigail R.; Elowsky, Christian G.; Fangman, Teresa; Barycki, Joseph J.; Wahl, James K.; Khalimonchuk, Oleh; Naslavsky, Naava; Caplan, Steve; Simpson, Melanie A.

    2015-01-01

    Hyaluronan (HA) turnover accelerates metastatic progression of prostate cancer in part by increasing rates of tumor cell proliferation and motility. To determine the mechanism, we overexpressed hyaluronidase 1 (Hyal1) as a fluorescent fusion protein and examined its impact on endocytosis and vesicular trafficking. Overexpression of Hyal1 led to increased rates of internalization of HA and the endocytic recycling marker transferrin. Live imaging of Hyal1, sucrose gradient centrifugation, and specific colocalization of Rab GTPases defined the subcellular distribution of Hyal1 as early and late endosomes, lysosomes, and recycling vesicles. Manipulation of vesicular trafficking by chemical inhibitors or with constitutively active and dominant negative Rab expression constructs caused atypical localization of Hyal1. Using the catalytically inactive point mutant Hyal1-E131Q, we found that enzymatic activity of Hyal1 was necessary for normal localization within the cell as Hyal1-E131Q was mainly detected within the endoplasmic reticulum. Expression of a HA-binding point mutant, Hyal1-Y202F, revealed that secretion of Hyal1 and concurrent reuptake from the extracellular space are critical for rapid HA internalization and cell proliferation. Overall, excess Hyal1 secretion accelerates endocytic vesicle trafficking in a substrate-dependent manner, promoting aggressive tumor cell behavior. PMID:25855794

  8. Impact of the physical microenvironment on tumor progression and metastasis.

    PubMed

    Spill, Fabian; Reynolds, Daniel S; Kamm, Roger D; Zaman, Muhammad H

    2016-08-01

    The tumor microenvironment is increasingly understood to contribute to cancer development and progression by affecting the complex interplay of genetic and epigenetic changes within the cells themselves. Moreover, recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior such as proliferation, cancer stem cell properties, and metastatic potential. Whereas initial assays have focused on basic ECM physical properties, such as stiffness, novel in vitro systems are becoming increasingly sophisticated in differentiating between distinct physical cues-ECM pore size, fiber alignment, and molecular composition-and elucidating the different roles these properties play in driving tumor progression and metastasis. Combined with advances in our understanding of the mechanisms responsible for how cells sense these properties, a new appreciation for the role of mechanics in cancer is emerging. PMID:26938687

  9. [Research progress on anti-tumor effect of Huaier].

    PubMed

    Yang, Ai-lin; Hu, Zhong-dong; Tu, Peng-fei

    2015-12-01

    Huaier (Trametes robiniophila) has been widely used as an adjuvant drug for cancer treatment in China. The anti-cancer effect of Huaier extract has been confirmed in liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, and so on. The main mechanisms by which Huaier exerts an anti-neoplastic effect include inhibition of the growth and proliferation of cancer cells, induction of apoptosis of cancer cells, suppression of angiogenesis, inhibition of the invasion and migration of cancer cells, regulation of oncogenes and tumor suppressor genes expression, improving immunity, and reversal of drug resistance in cancer cells. In order to provide references for further study and clinical application on anti-tumor effect of Huaier, the latest research progress on anti-tumor effect of Huaier in recent years is summarized in this paper. PMID:27245026

  10. [Research progress of tumor infiltrating lymphocytes in breast cancer].

    PubMed

    Huang, Jiahui; Chen, Xiaosong; Shen, Kunwei

    2015-09-01

    Breast cancer is a heterogeneous disease. The formation and progression of tumor and the sensitivity to treatment differs from patient to patient. In addition to the widely used molecular subtype, novel markers are needed to better personalize the treatment of breast cancer. Tumor infiltrating lymphocyte (TIL) have been consistently documented in breast cancer lesions especially in triple negative and human epidermal growth factor receptor-2 positive breast cancer. Several clinical trials have revealed that TIL are associated with prognosis and can predict therapeutic efficacy of special therapy. TIL could be divided to different subtypes including CD8 + TIL, CD4 + TIL, cytotoxic T lymphocyte-associated antigen-4 + TIL, programmed death-1 + TIL. They play different roles in the process of anti-tumor immunity and can predict different prognosis. Screening out special TIL subtype which is well associated with prognosis and therapeutic efficacy and developing targeting immunotherapy can help to improve outcomes of breast cancer patients. PMID:26654152

  11. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

    PubMed Central

    Sierra, Jose Rafael; Corso, Simona; Caione, Luisa; Cepero, Virna; Conrotto, Paolo; Cignetti, Alessandro; Piacibello, Wanda; Kumanogoh, Atsushi; Kikutani, Hitoshi; Comoglio, Paolo Maria; Tamagnone, Luca; Giordano, Silvia

    2008-01-01

    Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target. PMID:18559453

  12. Th17 Cells in Protection from Tumor or Promotion of Tumor Progression

    PubMed Central

    Young, M. Rita I.

    2016-01-01

    The roles of inflammation and inflammatory cells such as Th17 cells in the development and progression of cancer have been extensively studied. However, the results have been varied, with conflicting conclusions. Most studies have focused on changes in inflammatory phenotypes once cancers have developed and disease is progressing. Far fewer studies have looked at the immune phenotypic changes that occur during progression of premalignant lesions to cancer. The impact of inflammation and, in particular, Th17 cells on tumor biology is summarized in this review, with a focus on the differences in the outcomes of studies. Possible explanations for the contradictory conclusions are also suggested. PMID:27453801

  13. Cancer-associated mesenchymal stem cells aggravate tumor progression

    PubMed Central

    Kudo-Saito, Chie

    2015-01-01

    Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs. PMID:25883937

  14. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  15. 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

  16. 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

  17. CDC42 inhibition suppresses progression of incipient intestinal tumors

    PubMed Central

    Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao; Hoffman, Andrew; Sun, Jiaxin; Das, Soumyashree; Vedula, Pavan; Li, Guangxun; Fu, Jiang; Walker, Francesca; Yang, Chung S.; Yi, Zheng; Hsu, Wei; Yu, Da-Hai; Shen, Lanlan; Rodriguez, Alexis J.; Taketo, Makoto M.; Bonder, Edward M.; Verzi, Michael P.; Gao, Nan

    2014-01-01

    Mutations in the APC or β-catenin genes are well established initiators of colorectal cancer (CRC), yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacological approaches in mouse CRC and human CRC xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations. Similarly, human CRC with relatively higher levels of CDC42 activity were particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem-cell-enriched Rho family exchange factor Arhgef4. Our results suggest that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective CRC intervention. PMID:25113996

  18. SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas.

    PubMed

    Matsuo, Koichi; Satoh, Seiji; Okabe, Hiroshi; Nomura, Akinari; Maeda, Toshiki; Yamaoka, Yoshio; Ikai, Iwao

    2003-03-01

    Accumulation of loss of heterozygosity (LOH) on chromosome 16 is frequently observed in human hepatocellular carcinomas (HCCs). To identify tumor-suppressor genes (TSGs) involved in hepatocarcinogenesis, we performed deletion mapping of chromosome 16 in 59 HCCs. Three commonly deleted regions, located in 16q12.1, 16q22.1, and 16q24.2, were observed. Because there has been no study on LOH at locus 16q12.1 in HCCs, we focused on this region. By searching the Human Genome Database at the National Center for Biotechnology Information web site, we identified 14 known genes in 16q12.1 as TSG candidates. Among these, the expression of SIAH1 was markedly downregulated in HCCs, and inactivation of SIAH1 expression was associated with LOH at 16q12.1. A mutation analysis of SIAH1 revealed no somatic mutations, but one single nucleotide polymorphism was found among the 35 HCCs investigated. Subsequently, we evaluated the relation between SIAH1 expression, confirmed by semiquantitative RT-PCR, and clinicopathological parameters in HCCs. SIAH1 was significantly downregulated in advanced HCCs, including poorly differentiated tumors, larger tumors, and tumors in advanced stages. These findings suggest that inactivation of SIAH1 plays an important role in HCC progression. PMID:12557228

  19. [Inactivation of failsafe programs by Twist oncoproteins and tumor progression].

    PubMed

    Puisieux, A

    2008-01-01

    Multicellular organisms have developed innate defense mechanisms to prevent the expansion of abnormal cells with significant proliferative potential. The two major safeguard mechanisms are premature senescence, which is characterized by definitive cell cycle arrest, and apoptosis, the most common form of programmed cell death. In normal and premalignant cells, the control of these processes is coupled to the regulation of cell proliferation, mainly through the p16 (Ink4A) -Rb and ARF-p53 intracellular signaling pathways. Hence, in benign tumors, aberrant mitogenic activity is counterbalanced by the induction of these oncosuppressive pathways, leading to either apoptosis or senescence which both limit tumor outgrowth. Progression towards malignant and potentially metastatic tumors requires the inhibition of these failsafe programs. Based on our work on Twist oncoproteins, we propose a presentation of recent data on cellular mechanisms by which cancer cells override the surveillance machinery and escape senescence and apoptosis, and we will describe the biological impact of this process on tumor metastasis. PMID:19061727

  20. Expression of DNA damage response genes indicate progressive breast tumors.

    PubMed

    Gochhait, Sailesh; Dar, Surabhi; Pal, Ranjana; Gupta, Pawan; Bamezai, Rameshwar N K

    2009-01-18

    To assess how the abnormal expression of DNA damage response (DDR) genes correlate with oncogenesis, we analyzed mRNA levels of ATM-CHK2-P53 axis in 65 sporadic breast tumors by real-time PCR followed by evaluation of P53 protein and its activation status in representative samples. Univariate analysis showed a significantly higher transcript level for ATM (P=0.002), MDM2 (P=0.015) and p21 (P=0.013) in stage 1 tumors when compared against those of later stages. Although p53 transcript levels showed the characteristic increase in stage 1, a fourfold increase of p53 in N3 tumors than other nodal stages (P=0.0007) significantly increased its expression in stage 3B. The accumulated p53 at stage 3B, confirmed also at the protein level (P=0.012), was rendered nonfunctional by reduced P53 activation (p-P53Ser15; P=0.00007) or increased rate of mutation, substantiated further by the corresponding failure of upregulation of downstream genes, MDM2 and p21. We conclude that the alteration of DDR expression facilitates tumor progression and its possible therapeutic implications need to be studied in future. PMID:18805634

  1. The GroEL protein of Porphyromonas gingivalis accelerates tumor growth by enhancing endothelial progenitor cell function and neovascularization.

    PubMed

    Lin, F-Y; Huang, C-Y; Lu, H-Y; Shih, C-M; Tsao, N-W; Shyue, S-K; Lin, C-Y; Chang, Y-J; Tsai, C-S; Lin, Y-W; Lin, S-J

    2015-06-01

    Porphyromonas gingivalis is a bacterial species that causes destruction of periodontal tissues. Additionally, previous evidence indicates that GroEL from P. gingivalis may possess biological activities involved in systemic inflammation, especially inflammation involved in the progression of periodontal diseases. The literature has established a relationship between periodontal disease and cancer. However, it is unclear whether P. gingivalis GroEL enhances tumor growth. Here, we investigated the effects of P. gingivalis GroEL on neovasculogenesis in C26 carcinoma cell-carrying BALB/c mice and chick eggs in vivo as well as its effect on human endothelial progenitor cells (EPC) in vitro. We found that GroEL treatment accelerated tumor growth (tumor volume and weight) and increased the mortality rate in C26 cell-carrying BALB/c mice. GroEL promoted neovasculogenesis in chicken embryonic allantois and increased the circulating EPC level in BALB/c mice. Furthermore, GroEL effectively stimulated EPC migration and tube formation and increased E-selectin expression, which is mediated by eNOS production and p38 mitogen-activated protein kinase activation. Additionally, GroEL may enhance resistance against paclitaxel-induced cell cytotoxicity and senescence in EPC. In conclusion, P. gingivalis GroEL may act as a potent virulence factor, contributing to the neovasculogenesis of tumor cells and resulting in accelerated tumor growth. PMID:25220060

  2. Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice.

    PubMed

    Assi, Mohamad; Derbré, Frédéric; Lefeuvre-Orfila, Luz; Rébillard, Amélie

    2016-02-01

    More than 50% of patients with advanced stages of colon cancer suffer from progressive loss of skeletal muscle, called cachexia, resulting in reduced quality of life and shortened survival. It is becoming evident that reactive oxygen species (ROS) regulate pathways controlling skeletal muscle atrophy. Herein we tested the hypothesis that antioxidant supplementation could prevent skeletal muscle atrophy in a model of cachectic Colon 26 (C26) tumor-bearing mice. Seven-week-old BALB/c mice were subcutaneously inoculated with colon 26 (C26) cancer cells or PBS. Then C26-mice were daily gavaged during 22 days either with PBS (vehicle) or an antioxidant cocktail whose composition is close to that of commercial dietary antioxidant supplements (rich in catechins, quercetin and vitamin C). We found that antioxidants enhanced weight loss and caused premature death of mice. Antioxidants supplementation failed to prevent (i) the increase in plasma TNF-α levels and systemic oxidative damage, (ii) skeletal muscle atrophy and (iii) activation of the ubiquitin-proteasome system (MuRF-1, MAFbx and polyubiquitinated proteins). Accordingly, immunohistological staining for Ki-67 and the expression of cell cycle inhibitors demonstrated that tumor of supplemented mice developed faster with a concomitant decrease in oxidative damage. Previous studies have shown that the use of catechins and quercetin separately can improve the musculoskeletal function in cachectic animals. However, our results indicate that the combination of these antioxidants reduced survival and enhanced cachexia in C26-mice. PMID:26708754

  3. Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  4. Tumor-derived exosomes in cancer progression and treatment failure

    PubMed Central

    Shen, Bo; Feng, Jifeng

    2015-01-01

    Exosomes have diameter within the range of 30-100nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  5. Tumor-derived exosomes in cancer progression and treatment failure.

    PubMed

    Yu, Shaorong; Cao, Haixia; Shen, Bo; Feng, Jifeng

    2015-11-10

    Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy. PMID:26452221

  6. The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

    PubMed Central

    McGarvey, Terry; Wang, Huiyi; Lal, Priti; Puthiyaveettil, Raghunath; Tomaszewski, John; Sepulveda, Jorge; Labelle, Ed; Weiss, Jayne S.; Nickerson, Michael L.; Kruth, Howard S.; Brandt, Wolfgang; Wessjohann, Ludger A.; Malkowicz, S. Bruce

    2011-01-01

    Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression. PMID:21740188

  7. Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction

    PubMed Central

    McDonald, Paul C.; Chafe, Shawn C.; Dedhar, Shoukat

    2016-01-01

    Hypoxia is an important contributor to the heterogeneity of the microenvironment of solid tumors and is a significant environmental stressor that drives adaptations which are essential for the survival and metastatic capabilities of tumor cells. Critical adaptive mechanisms include altered metabolism, pH regulation, epithelial-mesenchymal transition, angiogenesis, migration/invasion, diminished response to immune cells and resistance to chemotherapy and radiation therapy. In particular, pH regulation by hypoxic tumor cells, through the modulation of cell surface molecules such as extracellular carbonic anhydrases (CAIX and CAXII) and monocarboxylate transporters (MCT-1 and MCT-4) functions to increase cancer cell survival and enhance cell invasion while also contributing to immune evasion. Indeed, CAIX is a vital regulator of hypoxia mediated tumor progression, and targeted inhibition of its function results in reduced tumor growth, metastasis, and cancer stem cell function. However, the integrated contributions of the repertoire of hypoxia-induced effectors of pH regulation for tumor survival and invasion remain to be fully explored and exploited as therapeutic avenues. For example, the clinical use of anti-angiogenic agents has identified a conundrum whereby this treatment increases hypoxia and cancer stem cell components of tumors, and accelerates metastasis. Furthermore, hypoxia results in the infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) and Tumor Associated Macrophages (TAMs), and also stimulates the expression of PD-L1 on tumor cells, which collectively suppress T-cell mediated tumor cell killing. Therefore, combinatorial targeting of angiogenesis, the immune system and pH regulation in the context of hypoxia may lead to more effective strategies for curbing tumor progression and therapeutic resistance, thereby increasing therapeutic efficacy and leading to more effective strategies for the treatment of patients with

  8. In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression

    PubMed Central

    Kamiyama, Miki; Naguro, Isao; Ichijo, Hidenori

    2015-01-01

    It has been widely accepted that tumor cells and normal stromal cells in the host environment coordinately modulate tumor progression. Mitogen-activated protein kinase pathways are the representative stress-responsive cascades that exert proper cellular responses to divergent environmental stimuli. Genetically engineered mouse models and chemically induced tumorigenesis models have revealed that components of the MAPK pathway not only regulate the behavior of tumor cells themselves but also that of surrounding normal stromal cells in the host environment during cancer pathogenesis. The individual functions of MAPK pathway components in tumor initiation and progression vary depending on the stimuli and the stromal cell types involved in tumor progression, in addition to the molecular isoforms of the components and the origins of the tumor. Recent studies have indicated that MAPK pathway components synergize with environmental factors (e.g. tobacco smoke and diet) to affect tumor initiation and progression. Moreover, some components play distinct roles in the course of tumor progression, such as before and after the establishment of tumors. Hence, a comprehensive understanding of the multifaceted functions of MAPK pathway components in tumor initiation and progression is essential for the improvement of cancer therapy. In this review, we focus on the reports that utilized knockout, conditional knockout, and transgenic mice of MAPK pathway components to investigate the effects of MAPK pathway components on tumor initiation and progression in the host environment. PMID:25880821

  9. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression.

    PubMed

    Menheniott, Trevelyan R; O'Connor, Louise; Chionh, Yok Teng; Däbritz, Jan; Scurr, Michelle; Rollo, Benjamin N; Ng, Garrett Z; Jacobs, Shelley; Catubig, Angelique; Kurklu, Bayzar; Mercer, Stephen; Minamoto, Toshinari; Ong, David E; Ferrero, Richard L; Fox, James G; Wang, Timothy C; Sutton, Philip; Judd, Louise M; Giraud, Andrew S

    2016-04-01

    Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. PMID:26974160

  10. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

    PubMed Central

    Menheniott, Trevelyan R.; O’Connor, Louise; Chionh, Yok Teng; Scurr, Michelle; Rollo, Benjamin N.; Ng, Garrett Z.; Jacobs, Shelley; Catubig, Angelique; Kurklu, Bayzar; Mercer, Stephen; Minamoto, Toshinari; Ong, David E.; Ferrero, Richard L.; Fox, James G.; Wang, Timothy C.; Judd, Louise M.; Giraud, Andrew S.

    2016-01-01

    Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori–infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. PMID:26974160

  11. Accelerator technology program. Progress report, January-June 1981

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-05-01

    This report covers the activities of Los Alamos National Laboratory's Accelerator Technology Division during the first 6 months of calendar 1981. We discuss the Division's major projects, which reflect a variety of applications and sponsors. The varied technologies concerned with the Proton Storage ring are concerned with the Proton Storage Ring are continuing and are discussed in detail. For the racetrack microtron (RTM) project, the major effort has been the design and construction of the demonstration RTM. Our development of the radio-frequency quadrupole (RFQ) linear accelerator continues to stimulate interest for many possible applications. Frequent contacts from other laboratories have revealed a wide acceptance of the RFQ principle in solving low-velocity acceleration problems. In recent work on heavy ion fusion we have developed ideas for funneling beams from RFQ linacs; the funneling process is explained. To test as many aspects as possible of a fully integrated low-energy portion of a Pion generator for Medical Irradiation (PIGMI) Accelerator, a prototype accelerator was designed to take advantage of several pieces of existing accelerator hardware. The important principles to be tested in this prototype accelerator are detailed. Our prototype gyrocon has been extensively tested and modified; we discuss results from our investigations. Our work with the Fusion Materials Irradiation Test Facility is reviewed in this report.

  12. Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series

    PubMed Central

    Dunn-Pirio, Anastasie M.; Billakota, Santoshi; Peters, Katherine B.

    2016-01-01

    Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature. PMID:27462237

  13. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

    PubMed Central

    Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M; Rowbotham, Samuel P; Mohseni, Morvarid; Wagner, Darcy E; Beede, Alexander M; Montoro, Daniel T; Sinkevicius, Kerstin W; Walton, Zandra E; Barrios, Juliana; Weiss, Daniel J; Camargo, Fernando D; Wong, Kwok-Kin; Kim, Carla F

    2014-01-01

    Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. PMID:24497554

  14. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells

    NASA Astrophysics Data System (ADS)

    Dhodapkar, Madhav V.; Krasovsky, Joseph; Olson, Kara

    2002-10-01

    Most untreated cancer patients develop progressive tumors. We tested the capacity of T lymphocytes from patients with clinically progressive, multiple myeloma to develop killer function against fresh autologous tumor. In this malignancy, it is feasible to reproducibly evaluate freshly isolated tumor cells and T cells from the marrow tumor environment. When we did this with seven consecutive patients, with all clinical stages of disease, we did not detect reactivity to autologous cancer cells. However, both cytolytic and IFN--producing responses to autologous myeloma were generated in six of seven patients after stimulation ex vivo with dendritic cells that had processed autologous tumor cells. The antitumor effectors recognized fresh autologous tumor but not nontumor cells in the bone marrow, myeloma cell lines, dendritic cells loaded with tumor-derived Ig, or allogeneic tumor. Importantly, these CD8+ effectors developed with similar efficiency by using T cells from both the blood and the bone marrow tumor environment. Therefore, even in the setting of clinical tumor progression, the tumor bed of myeloma patients contains T cells that can be activated readily by dendritic cells to kill primary autologous tumor.

  15. Loss of Mig6 accelerates initiation and progression of mutant epidermal growth factor receptor-driven lung adenocarcinoma

    PubMed Central

    Maity, Tapan K.; Venugopalan, Abhilash; Linnoila, Ilona; Cultraro, Constance M.; Giannakou, Andreas; Nemati, Roxanne; Zhang, Xu; Webster, Joshua D.; Ritt, Daniel; Ghosal, Sarani; Hoschuetzky, Heinz; Simpson, R. Mark; Biswas, Romi; Politi, Katerina; Morrison, Deborah K.; Varmus, Harold E.; Guha, Udayan

    2015-01-01

    Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here we demonstrate that Mig6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for Mig6 to delay mutant EGFR-driven tumor initiation and progression in mouse models. PMID:25735773

  16. Luteolin suppresses development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats.

    PubMed

    Cook, Matthew T; Mafuvadze, Benford; Besch-Williford, Cynthia; Ellersieck, Mark R; Goyette, Sandy; Hyder, Salman M

    2016-02-01

    Postmenopausal women undergoing hormone-replacement therapy containing both progestins and estrogens are at an increased risk of developing breast cancer compared with women taking estrogen alone. We recently demonstrated that medroxyprogesterone acetate, a progestin commonly used for hormone-replacement therapy, accelerates development of mammary carcinogenesis in 7,12-dimethylbenz(a)anthracene‑treated Sprague-Dawley rats. Synthetic antiprogestins used to block the deleterious effects of progestins, are themselves associated with toxic side-effects. In order to circumvent this, we used the aforementioned model to identify less toxic natural compounds that may prevent the development of progestin-accelerated tumors. Luteolin, a naturally-occurring flavonoid commonly found in fruits and vegetables, has previously been shown to possess anticancer properties. In our studies, both low (1 mg/kg) and high (25 mg/kg) doses of luteolin significantly suppressed progestin-dependent increases in tumor incidence, while increasing tumor latency and reducing the occurrence of large (>300 mm3) mammary tumors. However, an intermediate dose of luteolin (10 mg/kg), while suppressing the development of large tumors, did not affect either tumor incidence or latency. Immunohistochemical analysis of tumor tissues revealed that all concentrations of luteolin (1, 10, and 25 mg/kg) significantly reduced levels of VEGF within tumors. The suppressive effects of luteolin on tumor incidence and volume, together with its ability to reduce VEGF and blood vessels, persisted even after treatment was terminated. This suggests that luteolin possesses anti‑angiogenic properties which could mechanistically explain its capacity to control tumor progression. Thus luteolin may be a valuable, non-toxic, naturally-occurring anticancer compound which may potentially be used to combat progestin-accelerated mammary tumors. PMID:26719029

  17. TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression

    PubMed Central

    Rutkowski, Melanie R; Conejo-Garcia, Jose R

    2015-01-01

    We have reported that TLR5-mediated recognition of commensal microbiota modulates systemic tumor-promoting inflammation and malignant progression of tumors at distal locations. Approximately 7–10% of the general population harbors a deleterious single nucleotide polymorphism in TLR5, implicating a novel role for genetic variation during the initiation and progression of cancer. PMID:26405577

  18. Recent progress on photonic band gap accelerator cavities

    SciTech Connect

    Smith, D.R.; Li, D.; Vier, D.C.

    1997-02-01

    We report on the current status of our program to apply Photonic Band Gap (PBG) concepts to produce novel high-energy, high-intensity accelerator cavities. The PBG design on which we have concentrated our initial efforts consists of a square array of metal cylinders, terminated by conducting or superconducting sheets, and surrounded by microwave absorber on the periphery of the structure. A removed cylinder from the center of the array constitutes a site defect where a localized electromagnetic mode can occur. In previous work, we have proposed that this structure could be utilized as an accelerator cavity, with advantageous properties over conventional cavity designs. In the present work, we present further studies, including MAFIA-based numerical calculations and experimental measurements, demonstrating the feasibility of using the proposed structure in a real accelerator application.

  19. YKL-40/CHI3L1 drives inflammation on the road of tumor progression.

    PubMed

    Libreros, Stephania; Iragavarapu-Charyulu, Vijaya

    2015-12-01

    Inflammation plays a vital role at different stages of tumor progression. The development of tumors is affected by inflammatory mediators produced by the tumor and the host. YKL-40/chitinase-3-like-1 protein is often up-regulated in inflammation-associated diseases. With the use of chronic inflammatory disease systems, we describe the role of YKL-40/chitinase-3-like-1 protein in enhancing the inflammatory response and its implications in tumorigenesis. We also discuss how pre-existing inflammation enhances tumor growth and metastasis. In this mini-review, we highlight the effect of YKL-40/chitinase-3-like-1 protein-associated inflammation in promoting tumor progression. PMID:26310833

  20. Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression

    PubMed Central

    Biswas, Swati; Guix, Marta; Rinehart, Cammie; Dugger, Teresa C.; Chytil, Anna; Moses, Harold L.; Freeman, Michael L.; Arteaga, Carlos L.

    2007-01-01

    We investigated whether TGF-β induced by anticancer therapies accelerates tumor progression. Using the MMTV/PyVmT transgenic model of metastatic breast cancer, we show that administration of ionizing radiation or doxorubicin caused increased circulating levels of TGF-β1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan–TGF-β antibody. Circulating polyomavirus middle T antigen–expressing tumor cells did not grow ex vivo in the presence of the TGF-β antibody, suggesting autocrine TGF-β is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-β receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-β on the cancer cells. These data implicate TGF-β induced by anticancer therapy as a prometastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-β inhibitors. PMID:17415413

  1. 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

  2. Accelerator technology program. Progress report, July-December 1981

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-08-01

    We report on the major projects of the Los Alamos National Laboratory's Accelerator Technology Division during the last 6 months of calendar year 1981. We have continued work on the radio-frequency quadrupole linear accelerator; we are doing studies of octupole focusing. We have completed the design study on an unusual electron-linear radiographic machine that could obtain x rays of turbine engines operating under simulated flight-maneuver conditions on a centrifuge. In September we completed the 5-y PIon Generator for Medical Irradiation (PIGMI) program to develop the concept and technology for an accelerator-based facility to treat cancer in a hospital environment. The design and construction package for the site, building, and utilities for the Fusion Materials Irradiation Test (FMIT) facility has been completed, and we have begun to concentrate on tests of the rf power equipment and on the design, procurement, and installation of the 2-MeV proto-type accelerator. The Proton Storage Ring project has continued to mature. The main effort on the racetrack microtron (RTM) has been on the design and construction of various components for the demonstration RTM. On the gyrocon radio-frequency generator project, the gyrocon was rebuilt with a new electron gun and new water-cooled gun-focus coil; these new components have performed well. We have initiated a project to produce a klystron analysis code that will be useful in reducing the electrical-energy demand for accelerators. A free-electron laser amplifier experiment to test the performance of a tapered wiggler at high optical power has been successfully completed.

  3. Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression

    PubMed Central

    Mammoto, Tadanori; Jiang, Amanda; Jiang, Elisabeth; Panigrahy, Dipak; Kieran, Mark W.; Mammoto, Akiko

    2014-01-01

    Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression. PMID:23928381

  4. RECENT PROGRESS TOWARD A MUON RECIRCULATING LINEAR ACCELERATOR

    SciTech Connect

    Slawomir Bogacz, Vasiliy Morozov, Yves Roblin, Kevin Beard

    2012-07-01

    Both Neutrino Factories (NF) and Muon Colliders (MC) require very rapid acceleration due to the short lifetime of muons. After a capture and bunching section, a linac raises the energy to about 900 MeV, and is followed by one or more Recirculating Linear Accelerators (RLA), possibly followed by a Rapid Cycling Synchnotron (RCS) or Fixed-Field Alternating Gradient (FFAG) ring. A RLA reuses the expensive RF linac section for a number of passes at the price of having to deal with different energies within the same linac. Various techniques including pulsed focusing quadruopoles, beta frequency beating, and multipass arcs have been investigated via simulations to improve the performance and reduce the cost of such RLAs.

  5. Accelerator technology program. Progress report, July-December 1980

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-01-01

    The activities of Los Alamos National Laboratory's Accelerator Technology Division are discussed. This report covers the last six months of calendar 1980 and is organized around the Division's major projects. These projects reflect a wide variety of applications and sponsors. The major technological innovations promoted by the Pion Generator for Medical Irradiation (PIGMI) program have been developed; accelerator technologies relevant to the design of a medically practical PIGMI have been identified. A new group in AT Division deals with microwave and magnet studies; we describe the status of some of their projects. We discuss the prototype gyrocon, which has been completed, and the development of the radio-frequency quadrupole linear accelerator, which continues to stimulate interest for many possible applications. One section of this report briefly describes the results of a design study for an electron beam ion source that is ideally suited as an injector for a heavy ion linac; another section reports on a turbine engine test facility that will expose operating turbine engines to simulated maneuver forces. In other sections we discuss various activities: the Fusion Materials Irradiation Test program, the free-electron laser program, the racetrack microtron project, the Proton Storage ring, and H/sup -/ ion sources and injectors.

  6. Beyond Subprime Learning: Accelerating Progress in Early Education. Policy Brief

    ERIC Educational Resources Information Center

    Bornfreund, Laura; McCann, Clare; Williams, Conor; Guernsey, Lisa

    2014-01-01

    Earlier this year, in "Subprime Learning: Early Education in America since the Great Recession," the current state of early education in the U.S. was surveyed by examining progress over the last five years . It was found that while the public, political, and research consensus is stronger than ever, the field remains in dire need of…

  7. Fibroblast activation protein α in tumor microenvironment: Recent progression and implications (Review)

    PubMed Central

    ZI, FUMING; HE, JINGSONG; HE, DONGHUA; LI, YI; YANG, LI; CAI, ZHEN

    2015-01-01

    Accumulated evidence has demonstrated that the microenvironment of a given tumor is important in determining its drug resistance, tumorigenesis, progression and metastasis. These microenvironments, like tumor cells, are vital targets for cancer therapy. The cross-talk between tumor cells and cancer-associated fibroblasts (CAFs, alternatively termed activated fibroblasts) is crucial in regulating the drug resistance, tumorigenesis, neoplastic progression, angiogenesis, invasion and metastasis of a tumor. Fibroblast activation protein α (FAPα) is a transmembrane serine protease and is highly expressed on CAFs present in >90% of human epithelial neoplasms. FAPα activity, alongside that of gelatinase and type I collagenase, has become increasingly important in cancer therapy due to its effectiveness in modulating tumor behavior. In this review, recent progression in the knowledge of the role of FAPα in tumor microenvironments is discussed. PMID:25593080

  8. Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy

    SciTech Connect

    Massimino, Maura . E-mail: maura.massimino@istitutotumori.mi.it; Gandola, Lorenza; Spreafico, Filippo; Luksch, Roberto; Collini, Paola; Giangaspero, Felice; Simonetti, Fabio; Casanova, Michela; Cefalo, Graziella; Pignoli, Emanuele; Ferrari, Andrea; Terenziani, Monica; Podda, Marta; Meazza, Cristina; Polastri, Daniela; Poggi, Geraldina; Ravagnani, Fernando; Fossati-Bellani, Franca

    2006-03-15

    Purpose: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare and have a grim prognosis, frequently taking an aggressive course with local relapse and metastatic spread. We report the results of a mono-institutional therapeutic trial. Methods and Materials: We enrolled 15 consecutive patients to preradiation chemotherapy (CT) consisting of high-dose methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose carboplatin, craniospinal irradiation (CSI) with hyperfractionated accelerated radiotherapy (HART) plus focal boost, maintenance with vincristine/lomustine or consolidation with high-dose thiotepa followed by autologous stem-cell rescue. Results: Median age was 9 years; 7 were male, 8 female. Site of disease was pineal in 3, elsewhere in 12. Six patients were had no evidence of disease after surgery (NED). Of those with evidence of disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED patients, 2 had complete response (CR) and 2 partial response (PR) after CT, 4 stable disease, and 1 progressive disease. Of the 7 ED patients before radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR + PR after CT and 71% after HART. Because of rapid progression in 2 of the first 5 patients, high-dose thiotepa was systematically adopted after HART in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1 locally with dissemination, 1 with dissemination) a mean of 6 months after starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of 13 months. Three-year progression-free survival, event-free survival, and overall survival were 54%, 34%, and 61%, respectively. Conclusion: Hyperfractionated accelerated RT was the main tool in obtaining responses in S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs. 3/5 relapses), though the outcome remained unsatisfactory despite the adoption of this intensive treatment.

  9. Final Progress Report - Heavy Ion Accelerator Theory and Simulation

    SciTech Connect

    Haber, Irving

    2009-10-31

    The use of a beam of heavy ions to heat a target for the study of warm dense matter physics, high energy density physics, and ultimately to ignite an inertial fusion pellet, requires the achievement of beam intensities somewhat greater than have traditionally been obtained using conventional accelerator technology. The research program described here has substantially contributed to understanding the basic nonlinear intense-beam physics that is central to the attainment of the requisite intensities. Since it is very difficult to reverse intensity dilution, avoiding excessive dilution over the entire beam lifetime is necessary for achieving the required beam intensities on target. The central emphasis in this research has therefore been on understanding the nonlinear mechanisms that are responsible for intensity dilution and which generally occur when intense space-charge-dominated beams are not in detailed equilibrium with the external forces used to confine them. This is an important area of study because such lack of detailed equilibrium can be an unavoidable consequence of the beam manipulations such as acceleration, bunching, and focusing necessary to attain sufficient intensity on target. The primary tool employed in this effort has been the use of simulation, particularly the WARP code, in concert with experiment, to identify the nonlinear dynamical characteristics that are important in practical high intensity accelerators. This research has gradually made a transition from the study of idealized systems and comparisons with theory, to study the fundamental scaling of intensity dilution in intense beams, and more recently to explicit identification of the mechanisms relevant to actual experiments. This work consists of two categories; work in direct support beam physics directly applicable to NDCX and a larger effort to further the general understanding of space-charge-dominated beam physics.

  10. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  11. A novel thermal treatment modality for controlling breast tumor growth and progression.

    PubMed

    Xie, Yifan; Liu, Ping; Xu, Lisa X

    2012-01-01

    The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future. PMID:23367225

  12. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression.

    PubMed

    Sharma, Ankur; Yeow, Wen-Shuz; Ertel, Adam; Coleman, Ilsa; Clegg, Nigel; Thangavel, Chellappagounder; Morrissey, Colm; Zhang, Xiaotun; Comstock, Clay E S; Witkiewicz, Agnieszka K; Gomella, Leonard; Knudsen, Erik S; Nelson, Peter S; Knudsen, Karen E

    2010-12-01

    Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. PMID:21099110

  13. The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

    PubMed Central

    Rabender, Christopher S.; Alam, Asim; Sundaresan, Gobalakrishnan; Cardnell, Robert J.; Yakovlev, Vasily A.; Mukhopadhyay, Nitai D.; Graves, Paul; Zweit, Jamal; Mikkelsen, Ross B.

    2015-01-01

    Here evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast to normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on HPLC analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid and head and neck tumors compared to normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by clonogenic assay, Ki67 staining and 18F-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and as a consequence nitric oxide synthase activity generates more peroxynitrite and superoxide anion than nitric oxide resulting in important tumor growth promoting and anti-apoptotic signaling properties. Implications The synthetic BH4, Kuvan®, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. PMID:25724429

  14. Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors.

    PubMed

    Walsh, Meghaan P; Duncan, Brynn; Larabee, Shannon; Krauss, Aviva; Davis, Jessica P E; Cui, Yongzhi; Kim, Su Young; Guimond, Martin; Bachovchin, William; Fry, Terry J

    2013-01-01

    Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine. PMID:23554941

  15. Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

    PubMed Central

    Larabee, Shannon; Krauss, Aviva; Davis, Jessica P. E.; Cui, Yongzhi; Kim, Su Young; Guimond, Martin; Bachovchin, William; Fry, Terry J.

    2013-01-01

    Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine. PMID:23554941

  16. IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment.

    PubMed

    Benevides, Luciana; da Fonseca, Denise Morais; Donate, Paula Barbim; Tiezzi, Daniel Guimarães; De Carvalho, Daniel D; de Andrade, Jurandyr M; Martins, Gislaine A; Silva, João S

    2015-09-15

    The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors. PMID:26208902

  17. Accelerating Regulatory Progress in Multi-Institutional Research

    PubMed Central

    Paolino, Andrea R.; Lauf, Sherry Lee; Pieper, Lisa E.; Rowe, Jared; Vargas, Ileana M.; Goff, Melissa A.; Daley, Matthew F.; Tuzzio, Leah; Steiner, John F.

    2014-01-01

    Purpose: Multi-institutional collaborations are necessary in order to create large and robust data sets that are needed to answer important comparative effectiveness research (CER) questions. Before scientific work can begin, a complex maze of administrative and regulatory requirements must be efficiently navigated to avoid project delays. Innovation: Staff from research, regulatory, and administrative teams involved in three HMO Research Network (HMORN) multi-institutional collaborations developed and employed novel approaches: to secure and maintain Institutional Review Board (IRB) approvals; to enable data sharing, and to expedite subawards for two data-only minimal risk studies. These novel approaches accelerated required processes and approvals while maintaining regulatory, human subjects, and institutional protections. Credibility: Outcomes from the processes described here are compared with processes outlined in the research and regulatory literature and with processes that have been used in previous multisite research collaborations. Conclusion and Discussion: Research, regulatory, and administrative staff are essential contributors to the success of multi-institutional collaborations. Their flexibility, creativity, and effective communication skills can lead to the development of efficient approaches to achieving the necessary oversight for these complex projects. Elements of these specific strategies can be adapted and used by other research networks. Other efforts in these areas should be evaluated and shared. The processes that help develop a “learning research system” play an important and complementary role in sustaining multi-institutional research collaborations. PMID:25848593

  18. The New Deal: A Potential Role for Secreted Vesicles in Innate Immunity and Tumor Progression

    PubMed Central

    Benito-Martin, Alberto; Di Giannatale, Angela; Ceder, Sophia; Peinado, Héctor

    2015-01-01

    Tumors must evade the immune system to survive and metastasize, although the mechanisms that lead to tumor immunoediting and their evasion of immune surveillance are far from clear. The first line of defense against metastatic invasion is the innate immune system that provides immediate defense through humoral immunity and cell-mediated components, mast cells, neutrophils, macrophages, and other myeloid-derived cells that protect the organism against foreign invaders. Therefore, tumors must employ different strategies to evade such immune responses or to modulate their environment, and they must do so prior metastasizing. Exosomes and other secreted vesicles can be used for cell–cell communication during tumor progression by promoting the horizontal transfer of information. In this review, we will analyze the role of such extracellular vesicles during tumor progression, summarizing the role of secreted vesicles in the crosstalk between the tumor and the innate immune system. PMID:25759690

  19. 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

  20. Accessing key steps of human tumor progression in vivo by using an avian embryo model

    NASA Astrophysics Data System (ADS)

    Hagedorn, Martin; Javerzat, Sophie; Gilges, Delphine; Meyre, Aurélie; de Lafarge, Benjamin; Eichmann, Anne; Bikfalvi, Andreas

    2005-02-01

    Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening. angiogenesis | animal model alternatives | glioblastoma

  1. Kidney cancer progression linked to shifts in tumor metabolism

    Cancer.gov

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  2. Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression.

    PubMed

    Boulay, Pierre-Luc; Mitchell, Louise; Turpin, Jason; Huot-Marchand, Julie-Émilie; Lavoie, Cynthia; Sanguin-Gendreau, Virginie; Jones, Laura; Mitra, Shreya; Livingstone, Julie M; Campbell, Shirley; Hallett, Michael; Mills, Gordon B; Park, Morag; Chodosh, Lewis; Strathdee, Douglas; Norman, Jim C; Muller, William J

    2016-05-01

    Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple-negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the pathobiologic role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model coexpressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and -deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context of ErbB2-positive breast cancer and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression. Cancer Res; 76(9); 2662-74. ©2016 AACR. PMID:26933086

  3. Progress on the diagnosis and evaluation of brain tumors

    PubMed Central

    Gao, Huile

    2013-01-01

    Abstract Brain tumors are one of the most challenging disorders encountered, and early and accurate diagnosis is essential for the management and treatment of these tumors. In this article, diagnostic modalities including single-photon emission computed tomography, positron emission tomography, magnetic resonance imaging, and optical imaging are reviewed. We mainly focus on the newly emerging, specific imaging probes, and their potential use in animal models and clinical settings. PMID:24334439

  4. (Study of plant cells and tumors): Progress report

    SciTech Connect

    Not Available

    1989-01-01

    Studies of the cell and molecular biology of animal cell tumors has long been recognized as a fertile and productive area for obtaining new and fundamental insights into mechanisms regulating the growth and differentiation of animal cells. As a novel approach to studying similar phenomena in plant cells, we have isolated a number of tumors in the small cruciferous plant Arabidopsis thaliana and have begun to characterize these at the cellular and molecular levels. Studies at the cellular level should lead to new insights into the relationships between hormones, cell growth and cell differentiation, while studies at the molecular level may reveal and allow us to isolate genes involved either in the hormone response, or in other important aspects of the cells' growth regulatory network. Tumors were induced on the plant by irradiation of seed or seedlings with Co-60 gamma rays. When placed in culture, these tumors were able to grow on hormone-free medium, in contrast to normal plant tissues which requires both an auxin and a cytokinin for growth. In the first phase of this project, we have concentrated on characterizing the growth, general phenotype, and hormonal sensitivity of the tumors. These studies will lead into a molecular analysis of the changes expressed in each tumor which may be responsible for the altered phenotype. 7 refs., 1 tab.

  5. Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression*

    PubMed Central

    Mills, Lisa D.; Zhang, Lizhi; Marler, Ronald; Svingen, Phyllis; Fernandez-Barrena, Maite G.; Dave, Maneesh; Bamlet, William; McWilliams, Robert R.; Petersen, Gloria M.; Faubion, William; Fernandez-Zapico, Martin E.

    2014-01-01

    The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways. PMID:24737325

  6. AIP1 expression in tumor niche suppresses tumor progression and metastasis

    PubMed Central

    Ji, Weidong; Li, Yonghao; He, Yun; Yin, Mingzhu; Zhou, Huanjiao Jenny; Boggon, Titus J.; Zhang, Haifeng; Min, Wang

    2015-01-01

    Studies from tumor cells suggest that tumor suppressor AIP1 inhibits epithelial-mesenchymal transition (EMT). However, the role of AIP1 in the tumor microenvironment has not been examined. We show that a global or vascular endothelial cell (EC)-specific deletion of the AIP1 gene in mice augments tumor growth and metastasis in melanoma and breast cancer models. AIP1-deficient vascular environment not only enhances tumor neovascularization and increases pre-metastatic niche formation, but also secrets tumor EMT-promoting factors. These effects from AIP1 loss are associated with increased VEGFR2 signaling in the vascular EC and could be abrogated by systemic administration of VEGFR2 kinase inhibitors. Mechanistically, AIP1 blocks VEGFR2-dependent signaling by directly binding to the phosphotyrosine residues within the activation loop of VEGFR2. Our data reveal that AIP1, by inhibiting VEGFR2-dependent signaling in tumor niche, suppresses tumor EMT switch, tumor angiogenesis and tumor pre-metastatic niche formation to limit tumor growth and metastasis. PMID:26139244

  7. Education for Dynamic Economies: Action Plan To Accelerate Progress towards Education for All (EFA).

    ERIC Educational Resources Information Center

    World Bank, Washington, DC.

    The World Bank's development committee met and reviewed the paper, "Education for Dynamic Economies." The paper assessed progress and identified key issues and challenges in meeting the goals of universal primary education. It concluded that these goals were unlikely to be attained without accelerated action at the country level and a scaling up…

  8. Long-term ex vivo and in vivo monitoring of tumor progression by using dual luciferases.

    PubMed

    Morita, Naoki; Haga, Sanae; Ohmiya, Yoshihiro; Ozaki, Michitaka

    2016-03-15

    We propose a new concept of tumor progression monitoring using dual luciferases in living animals to reduce stress for small animals and the cost of luciferin. The secreted Cypridina luciferase (CLuc) was used as an ex vivo indicator to continuously monitor tumor progression. On the other hand, the non-secreted firefly luciferase was used as an in vivo indicator to analyze the spatial distribution of the tumor at suitable time points indicated by CLuc. Thus, the new monitoring systems that use dual luciferases are available, allowing long-term bioluminescence imaging under minimal stress for the experimental animals. PMID:26717897

  9. Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression

    PubMed Central

    Lucas, Morghan C.; Timpson, Paul

    2016-01-01

    Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

  10. Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression.

    PubMed

    Vennin, Claire; Herrmann, David; Lucas, Morghan C; Timpson, Paul

    2016-01-01

    Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

  11. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    PubMed

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR. PMID:27216179

  12. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting.

    PubMed

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  13. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress

    PubMed Central

    Dong, Xiaowei; Mumper, Russell J

    2010-01-01

    Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. P-glycoprotein is an important and the best-known membrane transporter involved in MDR. Several strategies have been used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have shown the ability to target tumors based on their unique physical and biological properties. To date, nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR. This article focuses on nanotechnology-based formulations and current nanomedicine approaches to address MDR in tumors and discusses the proposed mechanisms of action. PMID:20528455

  14. DCA promotes progression of neuroblastoma tumors in nude mice

    PubMed Central

    Feuerecker, Benedikt; Seidl, Christof; Pirsig, Sabine; Bruchelt, Gernot; Senekowitsch-Schmidtke, Reingard

    2015-01-01

    Even in the presence of oxygen most cancer cells convert glucose to lactate via pyruvate instead of performing oxidative phosphorylation (aerobic glycolysis-Warburg effect). Thus, it has been considered to shift pyruvate - the metabolite of aerobic glycolysis - to acetylCoA by activation of pyruvate dehydrogenase (PDH). AcetylCoA will then be metabolized by oxidative phosphorylation. Therefore, the purpose of this study was to shift tumor cells from aerobic glycolysis to oxidative phosphorylation using dichloroacetate (DCA), an inhibitor of PDH-kinase. The effects of DCA were assayed in vitro in Neuro-2a (murine neuroblastoma), Kelly and SK-N-SH (human neuroblastoma) as well as SkBr3 (human breast carcinoma) cell lines. The effects of DCA on tumor development were investigated in vivo using NMRI nu/nu mice bearing subcutaneous Neuro-2a xenografts. For that purpose animals were treated continuously with DCA in the drinking water. Tumor volumes were monitored using caliper measurements and via [18F]-FDG-positron emission tomography. DCA treatment increased viability/proliferation in Neuro-2a and SkBr3 cells, but did not cause significant alterations of PDH activity. However, no significant effects of DCA could be observed in Kelly and SK-N-SH cells. Accordingly, in mice bearing Neuro-2a xenografts, DCA significantly increased tumor proliferation compared to mock-treated mice. Thus, we could demonstrate that DCA - an indicated inhibitor of tumor growth - efficiently promotes tumor growth in Neuro-2a cells in vitro and in vivo. PMID:25973318

  15. Experimental and theoretical investigation of high gradient acceleration. Progress report, June 1, 1991--February 1, 1992

    SciTech Connect

    Bekefi, G.; Chen, C.; Chen, S.; Danly, B.; Temkin, R.J.; Wurtele, J.S.

    1992-02-01

    This report contains a technical progress summary of the research conducted under the auspices of DOE Grant No. DE-FG0291ER-40648. ``Experimental and Theoretical Investigations of High Gradient Acceleration.`` This grant supports three research tasks: Task A consists of the design and fabrication of a 17GHz of photocathode gun, Task B supports the testing of high gradient acceleration using a 33GHz structure, and Task C comprises theoretical investigations, both in support of the experimental tasks and on critical physics issues for the development of high energy linear colliders. This report is organized as follows. The development of an rf gun design and research progress on the picosecond laser system is summarized in Sec. 2, the status of the studies of the LBL/Haimson high gradient structure, using a 50 MW free-electron laser is summarized in Sec. 3, and theoretical research progress is described in Sec. 4. Supporting material is contained in Appendices A-G.

  16. MMP3-Mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction

    PubMed Central

    Banik, Debarati; Netherby, Colleen S.; Bogner, Paul N.; Abrams, Scott I.

    2015-01-01

    Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung metastasis in an orthotopic mouse model of mammary carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in tumor progression, which unveils new therapeutic opportunities. PMID:26008967

  17. Growth hormone therapy and risk of recurrence/progression in intracranial tumors: a meta-analysis.

    PubMed

    Shen, Liang; Sun, Chun Ming; Li, Xue Tao; Liu, Chuan Jin; Zhou, You Xin

    2015-10-01

    Growth hormone deficiency is common in intracranial tumors, which is usually treated with surgery and radiotherapy. A number of previous studies have investigated the relationship between the growth hormone replacement therapy (GHRT) and risk of tumor recurrence/progression; however, the evidence remains controversial. We conducted a meta-analysis of published studies to estimate the potential relation between GHRT and intracranial tumors recurrence/progression. Three comprehensive databases, PUBMED, EMBASE, and Cochrane Library, were researched with no limitations, covering all published studies till the end of July, 2014. Reference lists from identified studies were also screened for additional database. The summary relative risks (RR) and 95% confidence intervals (CI) were calculated by fixed-effects models for estimation. Fifteen eligible studies, involving more than 2232 cases and 3606 controls, were included in our meta-analysis. The results indicated that intracranial tumors recurrence/progression was not associated with GHRT (RR 0.48, 95% CI 0.39-0.56), and for children, the pooled RR was 0.44 and 95% CI was 0.34-0.54. In subgroup analysis, risks of recurrence/progression were decreased for craniopharyngioma, medulloblastoma, astrocytoma, glioma, but not for pituitary adenomas, and non-functioning pituitary adenoma (NFPA), ependymoma. Results from our analysis indicate that GHRT decreases the risk of recurrence/progression in children with intracranial tumors, craniopharyngioma, medulloblastoma, astrocytoma, or glioma. However, GHRT for pituitary adenomas, NFPA, and ependymoma was not associated with the recurrence/progression of the tumors. GH replacement seems safe from the aspect of risk of tumor progression. PMID:26048536

  18. Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage.

    PubMed Central

    Shibata, M A; Liu, M L; Knudson, M C; Shibata, E; Yoshidome, K; Bandey, T; Korsmeyer, S J; Green, J E

    1999-01-01

    The dramatic increase in apoptosis observed during the development of preneoplastic mammary lesions is associated with a significant elevation in Bax expression in C3(1)/SV40 large T antigen (TAg) transgenic mice. The significance of Bax expression during tumor progression in vivo was studied by generating double-transgenic mice carrying the C3(1)/TAg transgene and mutant alleles for bax. C3(1)/TAg transgenic mice carrying mutant bax alleles exhibited accelerated rates of tumor growth, increased tumor numbers, larger tumor mass and decreased survival rates compared with mice carrying wild-type bax. Accelerated tumorigenesis associated with the bax+/- genotype did not require the loss of function of the second bax allele. Thus, haploid insufficiency of bax is enough to accelerate tumor progression, suggesting that the protective effect of Bax is dose-dependent. While levels of apoptosis in the preneoplastic lesions, but not carcinomas, were reduced in bax+/- or bax-/- mice compared with bax+/+ mice, rates of cellular proliferation in mammary lesions were similar among all bax genotypes. These data demonstrate that bax is a critical suppressor of mammary tumor progression at the stage of preneoplastic mammary lesion development through the upregulation of apoptosis, but that this protective effect is lost during the transition from preneoplasia to invasive carcinoma. PMID:10329616

  19. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment

    PubMed Central

    Hatipoglu, Gökçe; Hock, Stefan W; Weiss, Ruth; Fan, Zheng; Sehm, Tina; Ghoochani, Ali; Buchfelder, Michael; Savaskan, Nicolai E; Eyüpoglu, Ilker Y

    2015-01-01

    Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on

  20. Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression

    PubMed Central

    Felix, Klaus; Gaida, Matthias M.

    2016-01-01

    A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma. PMID:26929737

  1. Multiwalled Carbon Nanotubes Inhibit Tumor Progression in a Mouse Model.

    PubMed

    García-Hevia, Lorena; Villegas, Juan C; Fernández, Fidel; Casafont, Íñigo; González, Jesús; Valiente, Rafael; Fanarraga, Mónica L

    2016-05-01

    Understanding the molecular mechanisms underlying the biosynthetic interactions between particular nanomaterials with specific cells or proteins opens new alternatives in nanomedicine and nanotoxicology. Multiwalled carbon nanotubes (MWCNTs) have long been explored as drug delivery systems and nanomedicines against cancer. There are high expectations for their use in therapy and diagnosis. These filaments can translocate inside cultured cells and intermingle with the protein nanofilaments of the cytoskeleton, interfering with the biomechanics of cell division mimicking the effect of traditional microtubule-binding anti-cancer drugs such as paclitaxel. Here, it is shown how MWCNTs can trigger significant anti-tumoral effects in vivo, in solid malignant melanomas produced by allograft transplantation. Interestingly, the MWCNT anti-tumoral effects are maintained even in solid melanomas generated from paclitaxel-resistant cells. These findings provide great expectation in the development of groundbreaking adjuvant synthetic microtubule-stabilizing chemotherapies to overcome drug resistance in cancer. PMID:26866927

  2. Alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV.

    PubMed

    Qin, Yannan; Zhong, Yaogang; Ma, Tianran; Wu, Fei; Wu, Haoxiang; Yu, Hanjie; Huang, Chen; Li, Zheng

    2016-04-01

    The incidence of hepatocellular carcinoma (HCC) is closely correlated with hepatitis B virus (HBV)-induced liver cirrhosis. Structural changes in the glycans of serum and tissue proteins are reliable indicators of liver damage. However, little is known about the alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV infection. This study compared the differential expression of liver glycopatterns in 7 sets of normal pericarcinomatous tissues (PCTs), cirrhotic, and tumor tissues from patients with liver cirrhosis and HCC induced by HBV using lectin microarrays. Fluorescence-based lectin histochemistry and lectin blotting were further utilized to validate and assess the expression and distribution of certain glycans in 9 sets of corresponding liver tissue sections. Eight lectins (e.g., Jacalin and AAL) revealed significant difference in cirrhotic tissues versus PCTs. Eleven lectins (e.g., EEL and SJA) showed significant alteration during cirrhotic and tumor progression. The expression of Galα1-3(Fucα1-2)Gal (EEL) and fucosyltransferase 1 was mainly increasing in the cytoplasm of hepatocytes during PCTs-cirrhotic-tumor tissues progression, while the expression of T antigen (ACA and PNA) was decreased sharply in cytoplasm of tumor hepatocytes. Understanding the precision alteration of liver glycopatterns related to the development of hepatitis, cirrhosis, and tumor induced by HBV infection may help elucidate the molecular mechanisms underlying the progression of chronic liver diseases and develop new antineoplastic therapeutic strategies. PMID:26833199

  3. Composite implants coated with biodegradable polymers prevent stimulating tumor progression

    NASA Astrophysics Data System (ADS)

    Litviakov, N. V.; Tverdokhlebov, S. I.; Perelmuter, V. M.; Kulbakin, D. E.; Bolbasov, E. N.; Tsyganov, M. M.; Zheravin, A. A.; Svetlichnyi, V. A.; Cherdyntseva, N. V.

    2016-08-01

    In this experiment we studied oncologic safety of model implants created using the solution blow spinning method with the use of the PURASORB PL-38 polylactic acid polymer and organic mineral filler which was obtained via laser ablation of a solid target made of dibasic calcium phosphate dihydrate. For this purpose the implant was introduced into the area of Wistar rats' iliums, and on day 17 after the surgery the Walker sarcoma was transplanted into the area of the implant. We evaluated the implant's influence on the primary tumor growth, hematogenous and lymphogenous metastasis of the Walker sarcoma. In comparison with sham operated animals the implant group demonstrated significant inhibition of hematogenous metastasis on day 34 after the surgery. The metastasis inhibition index (MII) equaled 94% and the metastases growth inhibition index (MGII) equaled 83%. The metastasis frequency of the Walker sarcoma in para aortic lymph nodes in the implant group was not statistically different from the control frequency; there was also no influence of the implant on the primary tumor growth noted. In case of the Walker sarcoma transplantation into the calf and the palmar pad of the ipsilateral limb to the one with the implant in the ilium, we could not note any attraction of tumor cells to the implant area, i.e. stimulation of the Walker sarcoma relapse by the implant. Thus, the research concluded that the studied implant meets the requirements of oncologic safety.

  4. RPRD1B promotes tumor growth by accelerating the cell cycle in endometrial cancer.

    PubMed

    Wang, Yuan; Qiu, Haifeng; Hu, Weixu; Li, Shaoru; Yu, Jinjin

    2014-03-01

    RPRD1B, the regulation of nuclear pre-mRNA domain containing 1B gene, functions as a cell cycle manipulator and has been found overexpressed in a small panel of endometrial cancer types. In the present study, we investigated the roles of RPRD1B in endometrial cancer using various in vitro and in vivo experiments. According to our results, RPRD1B mRNA was significantly upregulated in endometrial cancer tissues (P=0.0012). RPRD1B overexpression was correlated with tumor stage (P=0.0004), histology type (P=0.0146) and depth of myometrial invasion (P=0.024). In vitro, RPRD1B promoted cellular proliferation (P=0.032 for MTT assay and P=0.018 for colony formation assay), and accelerated the cell cycle (P=0.007) by upregulating cyclin D1, CDK4 and CDK6, while knockdown of RPRD1B suppressed cellular proliferation (P=0.02 for MTT assay and P=0.031 for colony formation assay), and led to G1 phase arrest (P=0.025) through downregulating cyclin D1, CDK4 and CDK6. Consistently, in the nude mice model, RPRD1B overexpression significantly accelerated the tumor xenograft growth (P=0.0012), accompanied by elevated Ki-67 and cyclin D1. In addition, we demonstrated that downregulating RPRD1B could sensitize Ishikawa cells to Raloxifene (P=0.01). In summary, we demonstrated that RPRD1B was frequently overexpressed in human endometrial cancer. Both in vitro and in vivo, over-abundant RPRD1B could promote tumor growth and accelerate cellular cell cycle. In addition, knockdown of RPRD1B also increased cell sensitivity to Raloxifene, making RPRD1B a potent therapeutic target for endometrial cancer, particularly in patients with resistance to the selective ER modulators. PMID:24452636

  5. An epitope-specific novel anti-EMMPRIN polyclonal antibody inhibits tumor progression

    PubMed Central

    Walter, Miriam; Simanovich, Elina; Brod, Vera; Lahat, Nitza; Bitterman, Haim; Rahat, Michal A.

    2016-01-01

    ABSTRACT Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) mediates tumor cell–macrophage interactions, and has been shown to induce both matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). However, the epitope responsible for MMP induction is controversial, and the epitope responsible for VEGF induction is yet unknown. We generated a novel anti-EMMPRIN antibody directed against a specific epitope that successfully inhibited the production of both MMP-9 and VEGF in tumor cell–macrophage in vitro co-culture systems, exhibiting a U-shaped dose response. Furthermore, this antibody efficiently inhibited in vivo tumor progression in both the RENCA renal cell carcinoma and CT26 colon carcinoma subcutaneous tumor models, and reduced tumor size and number of metastatic foci in the 4T1 orthotopic model. This was achieved by inhibiting angiogenesis as assessed by immunohistochemical staining for the endothelial marker CD31, by inhibiting tumor cell proliferation as assessed by the staining for Ki-67, and by enhancing tumor cell apoptosis as assessed in the TUNEL assay. Moreover, administration of the antibody recruited more macrophages into the tumor, and skewed the tumor microenvironment for macrophages from TGFβ-dominated anti-inflammatory microenvironment, to a less immunosuppressive one. The antibody improved the ability of stimulated macrophages to perform antibody-dependent cell cytotoxicity (ADCC) and kill tumor cells. Thus, our new antibody maps the epitope capable of inducing both MMPs and VEGF, and places EMMPRIN as a good target for cancer therapy. PMID:27057452

  6. [Progression of tumors: etiologic, morphologic and molecular-biological aspects].

    PubMed

    Turosov, V S

    1992-01-01

    Two aspects can be distinguished in multistage carcinogenesis: etiological one (every stage is induced by a specific for this stage agent) and morphobiological aspect (every stage is characterized by specific morphological, genetic and other properties). The schema of the multistage carcinogenesis is presented in which morphological stages (diffuse and focal hyperplasia, benign tumours, dysplasia, carcinoma in situ, various phases of malignant tumour progression) are placed against genetic alterations. L. Foulds concept of tumour progression is discussed with special emphasis on precancerous stages, possibilities of cancer development de novo, and independent progression of different tumour characters. The following types of carcinogenesis are listed on the basis of interrelationship between etiological and genetic factors: 1) carcinogenesis induced by genotoxic agents; a) one agent is acting at high dose and for a long time thus ensuring the activation of protooncogenes and all stages of tumour progression (initiation, promotion, various phases of malignant tumour); b) those acting during a very short time, however sufficient for developing the genetic program working automatically without further exposure to known carcinogens (irradiation in case of the atomic bomb explosion or effect of short-living alkylating agents): in this case there is no stage of promotion; 2) carcinogenesis by non-genotoxic carcinogens (their mode of action is still unclear, the only human example is carcinogenesis by hormones); 3) development of tumours in frane of the two (or three) stage carcinogenesis when every stage is provoked by its own etiological factor, no human examples are known as yet; 4) development of tumours due to the genetic mechanism making the organism highly susceptible to the minimal doses of carcinogens as is the case with skin cancer by ultraviolet light in patients with xeroderma pigmentosum, the genetic damage in itself has nothing to do with tumour formation; 5

  7. Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression

    PubMed Central

    Xie, Tao; Musteanu, Monica; Lopez-Casas, Pedro P.; Shields, David J.; Olson, Peter; Rejto, Paul A.; Hidalgo, Manuel

    2015-01-01

    Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy due to its propensity to invade and rapidly metastasize and remains very difficult to manage clinically. One major hindrance towards a better understanding of PDAC is the lack of molecular data sets and models representative of end stage disease. Moreover, it remains unclear how molecularly similar patient-derived xenograft (PDX) models are to the primary tumor from which they were derived. To identify potential molecular drivers in metastatic pancreatic cancer progression, we obtained matched primary tumor, metastases and normal (peripheral blood) samples under a rapid autopsy program and performed whole exome sequencing (WES) on tumor as well as normal samples. PDX models were also generated, sequenced and compared to tumors. Across the matched data sets generated for three patients, there were on average approximately 160 single-nucleotide mutations in each sample. The majority of mutations in each patient were shared among the primary and metastatic samples and, importantly, were largely retained in the xenograft models. Based on the mutation prevalence in the primary and metastatic sites, we proposed possible clonal evolution patterns marked by functional mutations affecting cancer genes such as KRAS, TP53 and SMAD4 that may play an important role in tumor initiation, progression and metastasis. These results add to our understanding of pancreatic tumor biology, and demonstrate that PDX models derived from advanced or end-stage likely closely approximate the genetics of the disease in the clinic and thus represent a biologically and clinically relevant pre-clinical platform that may enable the development of effective targeted therapies for PDAC. PMID:26555578

  8. Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy.

    PubMed

    Detappe, Alexandre; Kunjachan, Sijumon; Sancey, Lucie; Motto-Ros, Vincent; Biancur, Douglas; Drane, Pascal; Guieze, Romain; Makrigiorgos, G Mike; Tillement, Olivier; Langer, Robert; Berbeco, Ross

    2016-09-28

    Radiation therapy is a major treatment regimen for more than 50% of cancer patients. The collateral damage induced on healthy tissues during radiation and the minimal therapeutic effect on the organ-of-interest (target) is a major clinical concern. Ultra-small, renal clearable, silica based gadolinium chelated nanoparticles (SiGdNP) provide simultaneous MR contrast and radiation dose enhancement. The high atomic number of gadolinium provides a large photoelectric cross-section for increased photon interaction, even for high-energy clinical radiation beams. Imaging and therapy functionality of SiGdNP were tested in cynomolgus monkeys and pancreatic tumor-bearing mice models, respectively. A significant improvement in tumor cell damage (double strand DNA breaks), growth suppression, and overall survival under clinical radiation therapy conditions were observed in a human pancreatic xenograft model. For the first time, safe systemic administration and systematic renal clearance was demonstrated in both tested species. These findings strongly support the translational potential of SiGdNP for MR-guided radiation therapy in cancer treatment. PMID:27423325

  9. Fibroblasts—a key host cell type in tumor initiation, progression, and metastasis

    PubMed Central

    Strell, Carina; Rundqvist, Helene

    2012-01-01

    Tumor initiation, growth, invasion, and metastasis occur as a consequence of a complex interplay between the host environment and cancer cells. Fibroblasts are now recognized as a key host cell type involved in host–cancer signaling. This review discusses some recent studies that highlight the roles of fibroblasts in tumor initiation, early progression, invasion, and metastasis. Some clinical studies describing the prognostic significance of fibroblast-derived markers and signatures are also discussed. PMID:22509805

  10. Loss of p53 Attenuates the Contribution of IL-6 Deletion on Suppressed Tumor Progression and Extended Survival in Kras-Driven Murine Lung Cancer

    PubMed Central

    Chen, Zhao; Zhang, Jishuai; Wang, Yanxiao; Chen, Jicheng; Li, Xiubin; Ye, Hui; Tang, Chuanhao; Cheng, Xuan; Hou, Ning; Yang, Xiao; Wong, Kwok-Kin

    2013-01-01

    Interleukin-6 (IL-6) is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC) reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6-/- mice with KrasG12D mutant mice, which develop lung tumors after activation of mutant KrasG12D, to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. KrasG12D; IL-6-/- mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than KrasG12D mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated KrasG12D; p53flox/flox; IL-6-/- mice, which developed lung cancer with a trend for reduced metastases and longer survival than KrasG12D; p53flox/flox mice. Tumors from KrasG12D; IL-6-/- mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3 (pSTAT3) than KrasG12D mice; however, these changes were not present between tumors from KrasG12D; p53flox/flox; IL-6-/- and KrasG12D; p53flox/flox mice. Upregulation of pSTAT3 and phosphorylated AKT (pAKT) were observed in KrasG12D tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion. PMID:24260500

  11. STAT3 in Epithelial Cells Regulates Inflammation and Tumor Progression to Malignant State in Colon1

    PubMed Central

    Nguyen, Andrew V; Wu, Yuan-Yuan; Liu, Qiang; Wang, Donghai; Nguyen, Stephanie; Loh, Ricky; Pang, Joey; Friedman, Kenneth; Orlofsky, Amos; Augenlicht, Leonard; Pollard, Jeffrey W; Lin, Elaine Y

    2013-01-01

    Chronic inflammation is an important risk factor for the development of colorectal cancer; however, the mechanism of tumorigenesis especially tumor progression to malignancy in the inflamed colon is still unclear. Our study shows that epithelial signal transducer and activator of transcription 3 (STAT3), persistently activated in inflamed colon, is not required for inflammation-induced epithelial overproliferation and the development of early-stage tumors; however, it is essential for tumor progression to advanced malignancy. We found that one of the mechanisms that epithelial STAT3 regulates in tumor progression might be to modify leukocytic infiltration in the large intestine. Activation of epithelial STAT3 promotes the infiltration of the CD8+ lymphocyte population but inhibits the recruitment of regulatory T (Treg) lymphocytes. The loss of Stat3 in epithelial cells promoted the expression of cytokines/chemokines including CCL19, CCL28, and RANTES, which are known to be able to recruit Treg lymphocytes. Linked to these changes was the pathway mediated by sphingosine 1-phosphate receptor 1 and sphingosine 1-phosphate kinases, which is activated in colonic epithelial cells in inflamed colon with functional STAT3 but not in epithelial cells deleted of STAT3. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine. PMID:24027425

  12. Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models*

    PubMed Central

    Yun, Jason P.; Behan, James W.; Heisterkamp, Nora; Butturini, Anna; Klemm, Lars; Ji, Lingyun; Groffen, John; Müschen, Markus; Mittelman, Steven D.

    2010-01-01

    Obesity is associated with an increased incidence of many cancers, including leukemia, though it is unknown whether leukemia incidence is increased directly by obesity, or rather by associated genetic, lifestyle, health, or socio-economic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and IL-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to demonstrate that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity. PMID:20823291

  13. Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model

    PubMed Central

    Lascano, Valeria; Guadagnoli, Marco; Schot, Jan G.; Luijks, Dieuwertje M.; Guikema, Jeroen E. J.; Cameron, Katherine; Hahne, Michael; Pals, Steven; Slinger, Erik; Kipps, Thomas J.; van Oers, Marinus H. J.; Eldering, Eric; Medema, Jan Paul

    2013-01-01

    Although in vitro studies pointed to the tumor necrosis factor family member APRIL (a proliferation-inducing ligand) in mediating survival of chronic lymphocytic leukemia (CLL) cells, clear evidence for a role in leukemogenesis and progression in CLL is lacking. APRIL significantly prolonged in vitro survival of CD5+B220dull leukemic cells derived from the murine Eμ-TCL1-Tg (TCL1-Tg [transgenic]) model for CLL. APRIL-TCL1 double-Tg mice showed a significantly earlier onset of leukemia and disruption of splenic architecture, and survival was significantly reduced. Interestingly, clonal evolution of CD5+B220dull cells (judged by BCR clonality) did not seem to be accelerated by APRIL; both mouse strains were oligoclonal at 4 months. Although APRIL binds different receptors, APRIL-mediated leukemic cell survival depended on tumor necrosis factor receptor superfamily member 13B (TACI) ligation. These findings indicate that APRIL has an important role in CLL and that the APRIL-TACI interaction might be a selective novel therapeutic target for human CLL. PMID:24100449

  14. Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

    PubMed

    Morr, Simon; Qiu, Jingxin; Prasad, Dheerendra; Mechtler, Laszlo L; Fenstermaker, Robert A

    2016-07-01

    Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment. PMID:27181792

  15. Starved and Asphyxiated: How Can CD8+ T Cells within a Tumor Microenvironment Prevent Tumor Progression

    PubMed Central

    Zhang, Ying; Ertl, Hildegund C. J.

    2016-01-01

    Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy. PMID:26904023

  16. Plasticity underlies tumor progression: role of Nodal signaling.

    PubMed

    Bodenstine, Thomas M; Chandler, Grace S; Seftor, Richard E B; Seftor, Elisabeth A; Hendrix, Mary J C

    2016-03-01

    The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry, and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its reexpression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition. PMID:26951550

  17. Potential role of tumor microenvironment in the progression of oral cancer.

    PubMed

    Patil, Shankargouda; Rao, Roopa; Raj, Thirumal

    2015-03-01

    The stromal cells adjacent to the tumor including the fibroblasts, infammatory cells, lymphatic and vascular endothelial cells constitute the 'tumor microenvironment' (TM).(1) Recent in vivo and invitro studies have emphasized the role of stromal components on the growth, differentiation and invasiveness of the tumor cells. In addition, vascular, lymphatic or perineural invasion have proven to have independent prognostic value.(2) Despite the compelling evidence correlating the TM with the initiation and progression of cancer, our knowledge on the role of the genes mediating the various cellular interactions in the tumour stroma is limited.(2,3). PMID:26057928

  18. Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression

    PubMed Central

    Kooi, Irsan E.; Mol, Berber M.; Moll, Annette C.; van der Valk, Paul; de Jong, Marcus C.; de Graaf, Pim; van Mil, Saskia E.; Schouten-van Meeteren, Antoinette Y.N.; Meijers-Heijboer, Hanne; Kaspers, Gertjan L.; te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C.

    2015-01-01

    Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Research in context Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with

  19. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

    PubMed Central

    Yang, Li; Pang, Yanli; Moses, Harold L.

    2010-01-01

    Transforming growth factor β (TGF-β) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-β remain unclear. TGF-β exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-β enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-β regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-β regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-β antagonists and biomarkers for patient selection and efficacy of TGF-β antagonist treatment. PMID:20538542

  20. SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.

    PubMed

    Tanaka, Masamitsu; Shimamura, Shintaro; Kuriyama, Sei; Maeda, Daichi; Goto, Akiteru; Aiba, Namiko

    2016-01-15

    Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. PMID:26577701

  1. Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study

    NASA Astrophysics Data System (ADS)

    Priya, Mallika; Satish Rao, Bola Sadashiva; Chandra, Subhash; Datta, Anirbit; Nayak, Subramanya G.; Mahato, Krishna Kishore

    2015-10-01

    The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000 mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB® algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. The prediction accuracies of the analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 92.31, 87.5, and 95.2%, respectively. Also, receiver operator characteristics area under the curve analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 0.95, 0.85, and 0.93, respectively. The ability of photoacoustic measurements in the objective assessment of tumor progression has been clearly demonstrated, indicating its clinical potential.

  2. Monitoring breast tumor progression by photoacoustic measurements: a xenograft mice model study.

    PubMed

    Priya, Mallika; Satish Rao, Bola Sadashiva; Chandra, Subhash; Datta, Anirbit; Nayak, Subramanya G; Mahato, Krishna Kishore

    2015-10-01

    The current study reports the photoacoustic spectroscopy-based assessment of breast tumor progression in a nude mice xenograft model. The tumor was induced through subcutaneous injection of MCF-7 cells in female nude mice and was monitored for 20 days until the tumor volume reached 1000  mm3. The tumor tissues were extracted at three different time points (days 10, 15, and 20) after tumor inoculation and subjected to photoacoustic spectral recordings in time domain ex vivo at 281 nm pulsed laser excitations. The spectra were converted into the frequency domain using the fast Fourier transformed tools of MATLAB® algorithms and further utilized to extract seven statistical features (mean, median, area under the curve, variance and standard deviation, skewness and kurtosis) from each time point sample to assess the tumor growth with wavelet principal component analysis based logistic regression analysis performed on the data. The prediction accuracies of the analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 92.31, 87.5, and 95.2%, respectively. Also, receiver operator characteristics area under the curve analysis for day 10 versus day 15, day 15 versus day 20, and day 10 versus day 20 were found to be 0.95, 0.85, and 0.93, respectively. The ability of photoacoustic measurements in the objective assessment of tumor progression has been clearly demonstrated, indicating its clinical potential. PMID:26442962

  3. Role of the tumor microenvironment in regulating apoptosis and cancer progression.

    PubMed

    Yaacoub, Katherine; Pedeux, Remy; Tarte, Karin; Guillaudeux, Thierry

    2016-08-10

    Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented. PMID:27224890

  4. A PDE approach for quantifying and visualizing tumor progression and regression

    NASA Astrophysics Data System (ADS)

    Sintay, Benjamin J.; Bourland, J. Daniel

    2009-02-01

    Quantification of changes in tumor shape and size allows physicians the ability to determine the effectiveness of various treatment options, adapt treatment, predict outcome, and map potential problem sites. Conventional methods are often based on metrics such as volume, diameter, or maximum cross sectional area. This work seeks to improve the visualization and analysis of tumor changes by simultaneously analyzing changes in the entire tumor volume. This method utilizes an elliptic partial differential equation (PDE) to provide a roadmap of boundary displacement that does not suffer from the discontinuities associated with other measures such as Euclidean distance. Streamline pathways defined by Laplace's equation (a commonly used PDE) are used to track tumor progression and regression at the tumor boundary. Laplace's equation is particularly useful because it provides a smooth, continuous solution that can be evaluated with sub-pixel precision on variable grid sizes. Several metrics are demonstrated including maximum, average, and total regression and progression. This method provides many advantages over conventional means of quantifying change in tumor shape because it is observer independent, stable for highly unusual geometries, and provides an analysis of the entire three-dimensional tumor volume.

  5. K+ channels and cell cycle progression in tumor cells

    PubMed Central

    Ouadid-Ahidouch, Halima; Ahidouch, Ahmed

    2013-01-01

    K+ ions play a major role in many cellular processes. The deregulation of K+ signaling is associated with a variety of diseases such as hypertension, atherosclerosis, or diabetes. K+ ions are important for setting the membrane potential, the driving force for Ca2+ influx, and regulate volume of growing cells. Moreover, it is increasingly recognized that K+ channels control cell proliferation through a novel signaling mechanisms triggered and modulated independently of ion fluxes. In cancer, aberrant expression, regulation and/or sublocalization of K+ channels can alter the downstream signals that converge on the cell cycle machinery. Various K+ channels are involved in cell cycle progression and are needed only at particular stages of the cell cycle. Consistent with this idea, the expression of Eag1 and HERG channels fluctuate along the cell cycle. Despite of acquired knowledge, our understanding of K+ channels functioning in cancer cells requires further studies. These include identifying the molecular mechanisms controlling the cell cycle machinery. By understanding how K+ channels regulate cell cycle progression in cancer cells, we will gain insights into how cancer cells subvert the need for K+ signal and its downstream targets to proliferate. PMID:23970866

  6. Carbidopa abrogates L-dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression.

    PubMed

    Wafa, Latif A; Cheng, Helen; Plaa, Nathan; Ghaidi, Fariba; Fukumoto, Takahiro; Fazli, Ladan; Gleave, Martin E; Cox, Michael E; Rennie, Paul S

    2012-06-15

    The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression. PMID:21780103

  7. Potential markers of tongue tumor progression selected by cDNA microarray.

    PubMed

    Carinci, F; Lo Muzio, L; Piattelli, A; Rubini, C; Chiesa, F; Ionna, F; Palmieri, A; Maiorano, E; Pastore, A; Laino, G; Dolci, M; Pezzetti, F

    2005-01-01

    Squamous cell carcinoma (SCC), the most frequent malignant tumor of the oral cavity, generally exhibits a poor prognosis and metastases are the main cause of death. This tumor often arises from pre-malignant lesions. To date, it is difficult to predict if and which pre-malignant lesions may progress into oral SCC using traditional methods. For these reasons, several studies are trying to identify markers useful in the progression of pre-malignant lesions and tumors. To define the genetic expression profile of tongue tumor progression we compared 9 dysplasias (DS), 8 tumors without metastasis (TWM), 11 metastasizing SCCs (MT) of the tongue, and a baseline of 11 normal tissues by using cDNA microarray containing 19.2 K clones. We initially applied hierarchical agglomerative clustering based on information from all 6026 clones. Results were obtained by performing a two steps analysis: a Significance Analysis of Microarray (SAM) and a Gene Ontology search. One hundred and five clones have statistically significant different expression levels (FDR < 0.01) between DS and TWM, whereas 570 genes have statistically significant difference expression levels between TWM and MT (FDR < 0.01) as detected by SAM. By filtering with FatiGo only 33 genes were differentially expressed in TWN, respect to DS, whereas 155 genes were differentially expressed in MT respect to TWM. We detected some genes which encode for oncogenes, transcription factors and cell cycle regulators as potential markers of DS progression. Examples are BAG4, PAX3 and CCNI, respectively. Among potential markers of metastases are some genes related to cell mobility (TSPAN-2 and SNTA1), intercellular adhesion (integrin alpha 7) or extracellular matrix components (ADAMTS2 and cathepsin O). Additionally, under-expressed genes encoded apoptosis-related proteins (PDCD4 and CASP4). In conclusion, we identified several genes differentially expressed in tumor progression which can potentially help in better classifying

  8. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; Cuomo, Arturo; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression. PMID:26064880

  9. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    PubMed Central

    Wang, Wei-Lin W.; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  10. Vitamin D, intermediary metabolism and prostate cancer tumor progression.

    PubMed

    Wang, Wei-Lin W; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This "anti-Warburg effect" is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  11. Impact of Schedule Duration on Head and Neck Radiotherapy: Accelerated Tumor Repopulation Versus Compensatory Mucosal Proliferation

    SciTech Connect

    Fenwick, John D.; Pardo-Montero, Juan; Nahum, Alan E.; Malik, Zafar I.

    2012-02-01

    Purpose: To determine how modelled maximum tumor control rates, achievable without exceeding mucositis tolerance (tcp{sub max-early}) vary with schedule duration for head and neck squamous cell carcinoma (HNSCC). Methods and materials: Using maximum-likelihood techniques, we have fitted a range of tcp models to two HNSCC datasets (Withers' and British Institute of Radiology [BIR]), characterizing the dependence of tcp on duration and equivalent dose in 2 Gy fractions (EQD{sub 2}). Models likely to best describe future data have been selected using the Akaike information criterion (AIC) and its quasi-AIC extension to overdispersed data. Setting EQD{sub 2}s in the selected tcp models to levels just tolerable for mucositis, we have plotted tcp{sub max-early} against schedule duration. Results: While BIR dataset tcp fits describe dose levels isoeffective for tumor control as rising significantly with schedule protraction, indicative of accelerated tumor repopulation, repopulation terms in fits to Withers' dataset do not reach significance after accounting for overdispersion of the data. The tcp{sub max-early} curves calculated from tcp fits to the overall Withers' and BIR datasets rise by 8% and 0-4%, respectively, between 20 and 50 days duration; likewise, tcp{sub max-early} curves calculated for stage-specific cohorts also generally rise slowly with increasing duration. However none of the increases in tcp{sub max-early} calculated from the overall or stage-specific fits reach significance. Conclusions: Local control rates modeled for treatments which lie just within mucosal tolerance rise slowly but insignificantly with increasing schedule length. This finding suggests that whereas useful gains may be made by accelerating unnecessarily slow schedules until they approach early reaction tolerance, little is achieved by shortening schedules further while reducing doses to remain within mucosal tolerance, an approach that may slightly worsen outcomes.

  12. Plasma viral RNA load predicts disease progression in accelerated feline immunodeficiency virus infection.

    PubMed Central

    Diehl, L J; Mathiason-Dubard, C K; O'Neil, L L; Hoover, E A

    1996-01-01

    Viral RNA load has been shown to indicate disease stage and predict the rapidity of disease progression in human immunodeficiency virus type 1 (HIV-1)-infected individuals. We had previously demonstrated that feline immunodeficiency virus (FIV) RNA levels in plasma correlate with disease stage in infected cats. Here we expand upon those observations by demonstrating that plasma virus load is 1 to 2 logs higher in cats with rapidly progressive FIV disease than in long-term survivors. Differences in plasma FIV RNA levels are evident by 1 to 2 weeks after infection and are consistent throughout infection. We also evaluated humoral immune responses in FIV-infected cats for correlation with survival times. Total anti-FIV antibody titers did not differ between cats with rapidly progressive FIV disease and long-term survivors. These findings indicate that virus replication plays an important role in FIV disease progression, as it does in HIV-1 disease progression. The parallels in virus loads and disease progressions between HIV-1 and FIV support the idea that the accelerated disease model is well suited for the study of therapeutic agents directed at reducing lentiviral replication. PMID:8642679

  13. Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma.

    PubMed

    Behnes, Carl Ludwig; Bremmer, Felix; Hemmerlein, Bernhard; Strauss, Arne; Ströbel, Philipp; Radzun, Heinz-Joachim

    2014-02-01

    Tumor-associated macrophages (TAMs) play a key role in cancer development. Especially, the immunosuppressive M2 phenotype is associated with increased tumor growth, invasiveness and metastasis. The differentiation of macrophages to the alternative phenotype M2 is mediated, inter alia, by macrophage colony-stimulating factor (M-CSF). Papillary renal cell carcinoma (RCC) represents a rare tumor type which, based upon histological criteria, can be subdivided into two subtypes (I and II), of which type II is associated with poor prognosis. In both subtypes, typically, a dense infiltrate of macrophages is found. In the present study, the expression of CD68, CD163, M-CSF, Ki-67, and CD31 was examined in 30 type I and 30 type II papillary RCCs (n = 60). Both types of papillary RCCs contained an equally dense infiltrate of CD68-positive macrophages. Nearly all macrophages in papillary RCC type II expressed CD163, a characteristic for M2 macrophages. In type I papillary RCC, less than 30 % of macrophages expressed CD163. Furthermore, tumor cells in type II papillary RCC expressed significantly more M-CSF and showed increased (Ki-67 expression defined) proliferative activity in comparison with type I papillary RCC. In addition, the (CD31 defined) capillary density was higher in type II than in type I papillary RCC. A dense infiltrate of M2 phenotype TAM and high M-CSF expression in tumor cells are key features of type II papillary RCC. These findings might explain why the prognosis of papillary RCC type II is worse than that of type I. PMID:24327306

  14. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

    PubMed Central

    Hong, In-Sun

    2016-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

  15. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types.

    PubMed

    Hong, In-Sun

    2016-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a 'danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

  16. Low expression of ARHI is associated with shorter progression-free survival in pancreatic endocrine tumors.

    PubMed

    Dalai, Irene; Missiaglia, Edoardo; Barbi, Stefano; Butturini, Giovanni; Doglioni, Claudio; Falconi, Massimo; Scarpa, Aldo

    2007-03-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET) and poorly differentiated endocrine carcinomas (PDECs) (P < .001 and P < .001, respectively). Moreover, ARHI expression among WDEC samples was more heterogeneous than in WDET, with several tumors showing level of expression analogous to that observed in PDECs. A significant correlation between lower ARHI expression and shorter survival (P = .020) was identified, and a low ARHI expression was associated to a shorter time to progression (P < .001), even considering the proliferation index Ki67 in the multivariate analysis. ARHI is involved in PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse. PMID:17401457

  17. Deletion of tumor progression locus 2 attenuates alcohol induced hepatic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine threonine kinase that functions as a critical regulator of inflammator...

  18. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    PubMed Central

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  19. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.

    PubMed

    Chang, Chih-Hao; Qiu, Jing; O'Sullivan, David; Buck, Michael D; Noguchi, Takuro; Curtis, Jonathan D; Chen, Qiongyu; Gindin, Mariel; Gubin, Matthew M; van der Windt, Gerritje J W; Tonc, Elena; Schreiber, Robert D; Pearce, Edward J; Pearce, Erika L

    2015-09-10

    Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer. PMID:26321679

  20. Killing Is Not Enough: How Apoptosis Hijacks Tumor-Associated Macrophages to Promote Cancer Progression.

    PubMed

    Weigert, Andreas; Mora, Javier; Sekar, Divya; Syed, Shahzad; Brüne, Bernhard

    2016-01-01

    Macrophages are a group of heterogeneous cells of the innate immune system that are crucial to the initiation, progression, and resolution of inflammation. Moreover, they control tissue homeostasis in healthy tissue and command a broad sensory arsenal to detect disturbances in tissue integrity. Macrophages possess a remarkable functional plasticity to respond to irregularities and to initiate programs that allow overcoming them in order to return back to normal. Thus, macrophages kill malignant or transformed cells, rearrange extracellular matrix, take up and recycle cellular as well as molecular debris, initiate cellular growth cascades, and favor directed migration of cells. As an example, apoptotic death of bystander cells is sensed by macrophages, initiating functional responses that support all hallmarks of cancer. In this chapter, we describe how tumor cell apoptosis hijacks tumor-associated macrophages to promote tumor growth. We propose that tumor therapy should not only kill malignant cells but also target the interaction of the host with apoptotic cancer cells, as this might be efficient to limit the protumor action of apoptotic cells and boost the antitumor potential of macrophages. Leaving the apoptotic cell/macrophage interaction untouched might also limit the benefit of conventional tumor cell apoptosis-focused therapy since surviving tumor cells might receive overwhelming support by the wound healing response that apoptotic tumor cells will trigger in local macrophages, thereby enhancing tumor recurrence. PMID:27558823

  1. Real-time Imaging of Tumor Progression in a Fluorescent Orthotopic Mouse Model of Thyroid Cancer

    PubMed Central

    TRAN CAO, HOP S.; KAUSHAL, SHARMEELA; SNYDER, CYNTHIA S.; ONGKEKO, WEG M.; HOFFMAN, ROBERT M.; BOUVET, MICHAEL

    2015-01-01

    There is a need for a clinically relevant mouse model of thyroid cancer that enables real-time, non-invasive monitoring of tumor growth, progression, and drug response over time. Human thyroid cancer cell lines NPA (papillary) and KAK-1 (anaplastic) were stably transfected to express either red or green fluorescent protein. Cancer cells were injected into the thyroid glands of 8-week-old athymic mice. The animals were imaged with whole-body fluorescence imaging weekly and sacrificed when premorbid. At necropsy, the primary tumor was resected en bloc with the respiratory system for processing and analysis. Histology was performed on fixed tissue specimens for review of morphologic findings. Both anaplastic and papillary thyroid cancer cell lines led to robust development of orthotopic fluorescent tumors in nude mice. Injection of 5×105 cancer cells was sufficient for tumor development. Tumors were visualized for both cell lines via non-invasive imaging as early as 3 weeks post-implantation and were monitored over time. Time to premorbid condition varied between mice and was associated with a primary tumor growth pattern (early local compression of the esophagus vs. late metastatic disease) rather than tumor size. At necropsy, tumor fluorescence demonstrated metastases in the lungs, lymph nodes and vessels that were not visible under white light. Thus an orthotopic mouse model of thyroid cancer has been developed that replicates the major clinical features of thyroid cancer and enables real-time, non-invasive monitoring of tumor progression. This model should permit preclinical evaluation of novel thyroid cancer therapeutics. PMID:21115887

  2. 4th international conference on tumor progression and therapeutic resistance: meeting report

    PubMed Central

    Prabhu, Varun V; El-Deiry, Wafik S

    2015-01-01

    The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field. PMID:25782066

  3. Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

    PubMed Central

    Bourguignon, Lilly Y. W.

    2016-01-01

    Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20–25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients. PMID:27070574

  4. Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression.

    PubMed

    McConkey, David J; Lee, Sangkyou; Choi, Woonyoung; Tran, Mai; Majewski, Tadeusz; Lee, Sooyong; Siefker-Radtke, Arlene; Dinney, Colin; Czerniak, Bogdan

    2010-01-01

    Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid malignancies. Although "field effects" that affect the entire bladder mucosa appear to initiate disease, tumors develop along 2 distinct biological "tracks" that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors ("forerunner genes") that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the 2 major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as "epithelial-to-mesenchymal transition" (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells ("cancer stem cells") but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the 2 major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation. PMID:20610280

  5. Prep1 (pKnox1)-deficiency leads to spontaneous tumor development in mice and accelerates EmuMyc lymphomagenesis: a tumor suppressor role for Prep1.

    PubMed

    Longobardi, E; Iotti, G; Di Rosa, P; Mejetta, S; Bianchi, F; Fernandez-Diaz, L C; Micali, N; Nuciforo, P; Lenti, E; Ponzoni, M; Doglioni, C; Caniatti, M; Di Fiore, P P; Blasi, F

    2010-04-01

    The Prep1 homeodomain transcription factor is essential for embryonic development. 25% of hypomorphic Prep1(i/i) embryos, expressing the gene at 2% of the normal levels, survive pregnancy and live a normal-length life. Later in life, however, these mice develop spontaneous pre-tumoral lesions or solid tumors (lymphomas and carcinomas). In addition, transplantation of E14.5 fetal liver (FL) Prep1(i/i) cells into lethally irradiated mice induces lymphomas. In agreement with the above data, haploinsufficiency of a different Prep1-deficient (null) allele accelerates EmuMyc lymphoma growth. Therefore Prep1 has a tumor suppressor function in mice. Immunohistochemistry on tissue micrroarrays (TMA) generated from three distinct human cohorts comprising a total of some 1000 human tumors revealed that 70% of the tumors express no or extremely low levels of Prep1, unlike normal tissues. Our data in mice are thus potentially relevant to human cancer. PMID:20106730

  6. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    SciTech Connect

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  7. The dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment

    PubMed Central

    Moon, Eui Jung; Giaccia, Amato

    2015-01-01

    The Cap’N’Collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains,. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression. PMID:25458917

  8. The DACH/EYA/SIX gene network and its role in tumor initiation and progression.

    PubMed

    Liu, Yu; Han, Na; Zhou, Si; Zhou, Rong; Yuan, Xun; Xu, Hanxiao; Zhang, Cuntai; Yin, Tiejun; Wu, Kongming

    2016-03-01

    The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients. PMID:26096807

  9. Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance.

    PubMed

    Watson, Adrienne L; Rahrmann, Eric P; Moriarity, Branden S; Choi, Kwangmin; Conboy, Caitlin B; Greeley, Andrew D; Halfond, Amanda L; Anderson, Leah K; Wahl, Brian R; Keng, Vincent W; Rizzardi, Anthony E; Forster, Colleen L; Collins, Margaret H; Sarver, Aaron L; Wallace, Margaret R; Schmechel, Stephen C; Ratner, Nancy; Largaespada, David A

    2013-06-01

    Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors. PMID:23535903

  10. Combining Microbubbles and Ultrasound for Drug Delivery to Brain Tumors: Current Progress and Overview

    PubMed Central

    Liu, Hao-Li; Fan, Ching-Hsiang; Ting, Chien-Yu; Yeh, Chih-Kuang

    2014-01-01

    Malignant glioma is one of the most challenging central nervous system (CNS) diseases, which is typically associated with high rates of recurrence and mortality. Current surgical debulking combined with radiation or chemotherapy has failed to control tumor progression or improve glioma patient survival. Microbubbles (MBs) originally serve as contrast agents in diagnostic ultrasound but have recently attracted considerable attention for therapeutic application in enhancing blood-tissue permeability for drug delivery. MB-facilitated focused ultrasound (FUS) has already been confirmed to enhance CNS-blood permeability by temporally opening the blood-brain barrier (BBB), thus has potential to enhance delivery of various kinds of therapeutic agents into brain tumors. Here we review the current preclinical studies which demonstrate the reports by using FUS with MB-facilitated drug delivery technology in brain tumor treatment. In addition, we review newly developed multifunctional theranostic MBs for FUS-induced BBB opening for brain tumor therapy. PMID:24578726

  11. Experimental and theoretical investigation of high gradient acceleration. Progress report, February 1, 1992--January 31, 1993

    SciTech Connect

    Wurtele, J.S.; Bekefi, G.; Chen, C.; Chen, S.C.; Temkin, R.J.

    1993-01-01

    This report contains a technical progress summary of the research conducted under the auspices of DOE Grant No. DE-AC02-91-ER40648, ``Experimental and Theoretical Investigations of High Gradient Acceleration``. This grant supports three research tasks: Task A consists of the design, fabrication and testing of a 17GHz RF photocathode gun, which can produce 2ps electron pulses with up to 1nC of charge at 2MeV energy and at a 1OHz repetition rate. Task B supports the testing of high gradient acceleration at 33GHz structure, and Task C comprises theoretical investigations, both in support of the experimental tasks and on critical physics issues for the development of high energy linear colliders.

  12. Progress toward externally powered x-band dielectric-loaded accelerating structures.

    SciTech Connect

    Gai, W.; Power, J. G.; Liu, W.; Jing, C.; Gold, S. H.; Kinead, A. K.; Tantawi, S. G.; Dolgashev, V.; Kanareykin, A.; Konecny, R.; Wanming, L.

    2010-06-01

    We summarize recent progress in a program to develop externally powered dielectric-loaded accelerating (DLA) structures that can sustain high accelerating gradients. High-power RF tests of earlier structures showed strong multipactor loading. In addition, arcing at dielectric joints between the uniform DLA structure and matching sections at either end limited the achievable gradient. In this paper, we study the onset of multipactor in a DLA structure. We also study the effect of thin-film TiN coatings applied by atomic layer deposition and the effect of a reduction in the inner diameter of the structure. Test results of these structures show significant decreases in multipactor loading. We also test new structure designs that eliminate separate dielectric matching sections and, thus, the requirement for dielectric joints, including a DLA structure using a coaxial coupler and a clamped DLA structure. The clamped structure demonstrated a significantly improved gradient without breakdown.

  13. Accelerator research studies. Technical progress report, June 1, 1991--May 31, 1992

    SciTech Connect

    Not Available

    1992-02-01

    The Accelerator Research Studies program at the University of Maryland, sponsored by the Department of Energy under grant number DE-FG05-91ER40642, is currently in the first year of a three-year funding cycle. The program consists of the following three tasks: TASK A, Study of Transport and Longitudinal Compression of Intense, High-Brightness Beams, TASK B, Study of Collective Ion Acceleration by Intense Electron Beams and Pseudospark Produced High Brightness Electron Beams; TASK C, Study of a Gyroklystron High-power Microwave Source for Linear Colliders. In this report we document the progress that has been made during the past year for each of the three tasks.

  14. Accelerator research studies. Technical progress report, June 1, 1992--May 31, 1993

    SciTech Connect

    Not Available

    1993-03-01

    The Accelerator Research Studies program at the University of Maryland, sponsored by the Department of Energy under grant number DE-FG05-91ER40642, is currently in the second year of a three-year funding cycle. The program consists of the following three tasks: TASK A, ``Study of Transport and Longitudinal Compression of Intense, High-Brightness Beams,`` (P.I., M. Reiser); TASK B, ``Study of Collective Ion Acceleration by Intense Electron Beams and Pseudospark Produced High Brightness Electron Beams,`` (Co-P.I.`s, W.W. Destler, M. Reiser, M.J. Rhee, and C.D. Striffler); TASK C, ``Study of a Gyroklystron High-Power Microwave Source for Linear Colliders,`` (Co-P.I.`s, V.L. Granatstein, W. Lawson, M. Reiser, and C.D. Striffler). In this report we document the progress that has been made during the past year for each of the three tasks.

  15. Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression

    PubMed Central

    Hendrickson, Whitney K.; Flavin, Richard; Kasperzyk, Julie L.; Fiorentino, Michelangelo; Fang, Fang; Lis, Rosina; Fiore, Christopher; Penney, Kathryn L.; Ma, Jing; Kantoff, Philip W.; Stampfer, Meir J.; Loda, Massimo; Mucci, Lorelei A.; Giovannucci, Edward

    2011-01-01

    Purpose Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies. Patients and Methods We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI. Results Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression. Conclusion High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression. PMID:21537045

  16. Endothelial progenitor cells promote tumor growth and progression by enhancing new vessel formation

    PubMed Central

    Zhao, Xin; Liu, Huan-Qiu; Li, Ji; Liu, Xiao-Liang

    2016-01-01

    Tumor growth and progression require new blood vessel formation to deliver nutrients and oxygen for further cell proliferation and to create a neovascular network exit for tumor cell metastasis. Endothelial progenitor cells (EPCs) are a bone marrow (BM)-derived stem cell population that circulates in the peripheral circulation and homes to the tumor bed to participate in new blood vessel formation. In addition to structural support to nascent vessels, these cells can also regulate the angiogenic process by paracrine secretion of a number of proangiogenic growth factors and cytokines, thus playing a crucial role in tumor neovascularization and development. Inhibition of EPC-mediated new vessel formation may be a promising therapeutic strategy in tumor treatment. EPC-mediated neovascularization is a complex process that includes multiple steps and requires a series of cytokines and modulators, thus understanding the underlying mechanisms may provide anti-neovasculogenesis targets that may be blocked for the prevention of tumor development. The present review stresses the process and contribution of EPCs to the formation of new blood vessels in solid tumors, in an attempt to gain an improved understanding of the underlying cellular and molecular mechanisms involved, and to provide a potential effective therapeutic target for cancer treatment. PMID:27446353

  17. The Global Nutrition Report 2014: actions and accountability to accelerate the world's progress on nutrition.

    PubMed

    Haddad, Lawrence; Achadi, Endang; Bendech, Mohamed Ag; Ahuja, Arti; Bhatia, Komal; Bhutta, Zulfiqar; Blössner, Monika; Borghi, Elaine; Colecraft, Esi; de Onis, Mercedes; Eriksen, Kamilla; Fanzo, Jessica; Flores-Ayala, Rafael; Fracassi, Patrizia; Kimani-Murage, Elizabeth; Nago Koukoubou, Eunice; Krasevec, Julia; Newby, Holly; Nugent, Rachel; Oenema, Stineke; Martin-Prével, Yves; Randel, Judith; Requejo, Jennifer; Shyam, Tara; Udomkesmalee, Emorn; Reddy, K Srinath

    2015-04-01

    In 2013, the Nutrition for Growth Summit called for a Global Nutrition Report (GNR) to strengthen accountability in nutrition so that progress in reducing malnutrition could be accelerated. This article summarizes the results of the first GNR. By focusing on undernutrition and overweight, the GNR puts malnutrition in a new light. Nearly every country in the world is affected by malnutrition, and multiple malnutrition burdens are the "new normal." Unfortunately, the world is off track to meet the 2025 World Health Assembly (WHA) targets for nutrition. Many countries are, however, making good progress on WHA indicators, providing inspiration and guidance for others. Beyond the WHA goals, nutrition needs to be more strongly represented in the Sustainable Development Goal (SDG) framework. At present, it is only explicitly mentioned in 1 of 169 SDG targets despite the many contributions improved nutritional status will make to their attainment. To achieve improvements in nutrition status, it is vital to scale up nutrition programs. We identify bottlenecks in the scale-up of nutrition-specific and nutrition-sensitive approaches and highlight actions to accelerate coverage and reach. Holding stakeholders to account for delivery on nutrition actions requires a well-functioning accountability infrastructure, which is lacking in nutrition. New accountability mechanisms need piloting and evaluation, financial resource flows to nutrition need to be made explicit, nutrition spending targets should be established, and some key data gaps need to be filled. For example, many UN member states cannot report on their WHA progress and those that can often rely on data >5 y old. The world can accelerate malnutrition reduction substantially, but this will require stronger accountability mechanisms to hold all stakeholders to account. PMID:25740908

  18. UCLA accelerator research and development. Progress report, [November 1, 1991--July 31, 1992

    SciTech Connect

    Cline, D.B.

    1992-09-01

    This progress report covers work supported by the above DOE grant over the period November 1, 1991 to July 31, 1992. The work is a program of experimental and theoretical studies in advanced particle accelerator research and development for high energy physics applications. The program features research at particle beam facilities in the United States and includes research on novel high power sources, novel focussing systems (e.g. plasma lens), beam monitors, novel high brightness, high current gun systems, and novel flavor factories in particular the {phi} Factory.

  19. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients.

    PubMed

    Pannu, Vaishali; Rida, Padmashree C G; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J; Rudd, Katie; Gupta, Meenakshi V; Reid, Michelle D; Cantuaria, Guilherme; Walczak, Claire E; Aneja, Ritu

    2015-03-20

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  20. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

    PubMed Central

    Pannu, Vaishali; Rida, Padmashree C.G.; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire E.; Aneja, Ritu

    2015-01-01

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  1. Tumor-promoting functions of transforming growth factor-β in progression of cancer

    PubMed Central

    2012-01-01

    Transforming growth factor-β (TGF-β) elicits both tumor-suppressive and tumor-promoting functions during cancer progression. Here, we describe the tumor-promoting functions of TGF-β and how these functions play a role in cancer progression. Normal epithelial cells undergo epithelial-mesenchymal transition (EMT) through the action of TGF-β, while treatment with TGF-β and fibroblast growth factor (FGF)-2 results in transdifferentiation into activated fibroblastic cells that are highly migratory, thereby facilitating cancer invasion and metastasis. TGF-β also induces EMT in tumor cells, which can be regulated by oncogenic and anti-oncogenic signals. In addition to EMT promotion, invasion and metastasis of cancer are facilitated by TGF-β through other mechanisms, such as regulation of cell survival, angiogenesis, and vascular integrity, and interaction with the tumor microenvironment. TGF-β also plays a critical role in regulating the cancer-initiating properties of certain types of cells, including glioma-initiating cells. These findings thus may be useful for establishing treatment strategies for advanced cancer by inhibiting TGF-β signaling. PMID:22111550

  2. Pathological functions of the small GTPase Arf6 in cancer progression: Tumor angiogenesis and metastasis

    PubMed Central

    Hongu, Tsunaki; Yamauchi, Yohei; Funakoshi, Yuji; Katagiri, Naohiro; Ohbayashi, Norihiko; Kanaho, Yasunori

    2016-01-01

    ABSTRACT Although several lines of evidence have shown that the small GTPase ADP-ribosylation factor 6 (Arf6) plays pivotal roles in cancer progression of several types of cancers, little is known about the functions of Arf6 in tumor microenvironment. We demonstrated that Arf6 in vascular endothelial cells (VECs) plays a crucial role in tumor angiogenesis and growth using endothelial cell-specific Arf6 conditional knockout mice into which B16 melanoma and Lewis lung carcinoma cells were implanted. It was also found that Arf6 in VECs positively regulates hepatocyte growth factor (HGF)-induced β1 integrin recycling, which is a critical event for tumor angiogenesis by promoting cell migration. Importantly, pharmacological inhibition of HGF-induced Arf6 activation significantly suppresses tumor angiogenesis and growth in mice, suggesting that Arf6 signaling would be a potential target for anti-angiogenic therapy. In this manuscript, we summarize the multiple roles of Arf6 in cancer progression, particularly in cancer cell invasion/metastasis and our recent findings on tumor angiogenesis, and discuss a possible approach to develop innovative anti-cancer drugs. PMID:26909552

  3. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    SciTech Connect

    Lee, Percy; Weerasuriya, Dilani K.; Lavori, Philip W.; Quon, Andrew; Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu; Wakelee, Heather A.; Donington, Jessica S.; Graves, Edward E.; Loo, Billy W.

    2007-10-01

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  4. Prediction of brain tumor progression using multiple histogram matched MRI scans

    NASA Astrophysics Data System (ADS)

    Banerjee, Debrup; Tran, Loc; Li, Jiang; Shen, Yuzhong; McKenzie, Frederic; Wang, Jihong

    2011-03-01

    In a recent study [1], we investigated the feasibility of predicting brain tumor progression based on multiple MRI series and we tested our methods on seven patients' MRI images scanned at three consecutive visits A, B and C. Experimental results showed that it is feasible to predict tumor progression from visit A to visit C using a model trained by the information from visit A to visit B. However, the trained model failed when we tried to predict tumor progression from visit B to visit C, though it is clinically more important. Upon a closer look at the MRI scans revealed that histograms of MRI scans such as T1, T2, FLAIR etc taken at different times have slight shifts or different shapes. This is because those MRI scans are qualitative instead of quantitative so MRI scans taken at different times or by different scanners might have slightly different scales or have different homogeneities in the scanning region. In this paper, we proposed a method to overcome this difficulty. The overall goal of this study is to assess brain tumor progression by exploring seven patients' complete MRI records scanned during their visits in the past two years. There are ten MRI series in each visit, including FLAIR, T1-weighted, post-contrast T1-weighted, T2-weighted and five DTI derived MRI volumes: ADC, FA, Max, Min and Middle Eigen Values. After registering all series to the corresponding DTI scan at the first visit, we applied a histogram matching algorithm to non-DTI MRI scans to match their histograms to those of the corresponding MRI scans at the first visit. DTI derived series are quantitative and do not require the histogram matching procedure. A machine learning algorithm was then trained using the data containing information from visit A to visit B, and the trained model was used to predict tumor progression from visit B to visit C. An average of 72% pixel-wise accuracy was achieved for tumor progression prediction from visit B to visit C.

  5. Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression.

    PubMed

    Surh, Inok; Rundhaug, Joyce; Pavone, Amy; Mikulec, Carol; Abel, Erika; Fischer, Susan M

    2011-06-01

    Prostaglandin E(2) (PGE(2) ) has been shown to promote the development of murine skin tumors. EP1 is 1 of the 4 PGE(2) G-protein-coupled membrane receptors expressed by murine keratinocytes. EP1 mRNA levels were increased ∼2-fold after topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or exposure to ultraviolet (UV) light, as well as increased ∼3- to 12-fold in tumors induced by 7,12-dimethyl-benz[a]anthracene (DMBA) initiation/TPA promotion or by UV exposure. To determine the effect of EP1 levels on tumor development, we generated BK5.EP1 transgenic mice that overexpress EP1 in the basal layer of the epidermis. Skins of these mice were histologically indistinguishable from wild type (WT) mice and had similar levels of proliferation after TPA treatment. Using a DMBA/TPA carcinogenesis protocol, BK5.EP1 mice had a reduced tumor multiplicity compared to WT mice, likely due to the observed down-regulation of protein kinase C (PKC). However, the BK5.EP1 mice had an ∼8-fold higher papilloma to carcinoma conversion rate. When DMBA/anthralin was used, BK5.EP1 mice produced more tumors than WT mice, as well as a ninefold increase in carcinomas, indicating that the tumor response is dependent on the type of tumor promoter agent used. Additionally, although almost undetectable in WT mice, cyclooxygenase-2 (COX-2) was expressed in the untreated epidermis of BK5.EP1 mice. While TPA highly induced COX-2 in WT mice, COX-2 expression in the BK5.EP1 mice did not change after TPA treatment; PGE(2) levels were likewise affected. These data indicate that EP1 is more important in tumor progression than in tumor promotion and that it indirectly regulates COX-2 expression. PMID:21268127

  6. PROX1 is involved in progression of rectal neuroendocrine tumors, NETs.

    PubMed

    Jernman, Juha; Kallio, Pauliina; Hagström, Jaana; Välimäki, Matti J; Haapasalo, Hannu; Alitalo, Kari; Arola, Johanna; Haglund, Caj

    2015-09-01

    PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway. PMID:26063416

  7. The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

    PubMed Central

    Shilo, Asaf; Siegfried, Zahava; Karni, Rotem

    2015-01-01

    In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing. PMID:27308389

  8. Accelerating Progress in Eating Disorders Prevention: A Call for Policy Translation Research and Training.

    PubMed

    Austin, S Bryn

    2016-01-01

    The public health burden of eating disorders is well documented, and over the past several decades, researchers have made important advances in the prevention of eating disorders and related problems with body image. Despite these advances, however, several critical limitations to the approaches developed to date leave the field far from achieving the large-scale impact that is needed. This commentary provides a brief review of what achievements in prevention have been made and identifies the gaps that limit the potential for greater impact on population health. A plan is then offered with specific action steps to accelerate progress in high-impact prevention, most compellingly by promoting a shift in priorities to policy translation research and training for scholars through the adoption of a triggers-to-action framework. Finally, the commentary provides an example of the application of the triggers-to-action framework as practiced at the Strategic Training Initiative for the Prevention of Eating Disorders, a program based at the Harvard T. H. Chan School of Public Health and Boston Children's Hospital. Much has been achieved in the nearly 30 years of research carried out for the prevention of eating disorders and body image problems, but several critical limitations undermine the field's potential for meaningful impact. Through a shift in the field's priorities to policy translation research and training with an emphasis on macro-environmental influences, the pace of progress in prevention can be accelerated and the potential for large-scale impact substantially improved. PMID:25880718

  9. Two-Year Accelerated Corneal Cross-Linking Outcome in Patients with Progressive Keratoconus

    PubMed Central

    Jurowski, Piotr

    2015-01-01

    Purpose. To evaluate the long-term results of accelerated corneal cross-linking (CXL) in patients with progressive keratoconus. Methods. Sixteen patients underwent accelerated CXL at 6 mW/cm2 for 15 minutes in one eye. The follow-up visits were scheduled on 7 days, 14 days, and 3, 12, and 24 months after the treatment. Results. There were no significant differences (P > 0.05) between preoperative and 2-year postoperative mean values, respectively, in terms of uncorrected visual acuity, best spectacle-corrected visual acuity, maximum keratometry Kmax⁡, minimum keratometry Kmin⁡, corneal astigmatism, and corneal eccentricity index. We noted a significant flattening of the cornea in 18.7% of patients with a higher preoperative Kmax⁡ value (>50 D) and its steepening in patients with a lower Kmax⁡ value (<50 D) (6.25%). There was no significant difference in the central corneal thickness and the apical corneal thickness preoperatively and 2 years postoperatively. The mean demarcation line depth was 282 ± 11 μm. Persistent corneal haze was noted in 25% of patients. Conclusions. Accelerated CXL appears to be a relatively effective procedure for the treatment of keratoconus in 2-year follow-up. PMID:25629044

  10. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    NASA Astrophysics Data System (ADS)

    Löser, Reik; Pietzsch, Jens

    2015-06-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge towards their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

  11. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    PubMed Central

    Löser, Reik; Pietzsch, Jens

    2015-01-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes. PMID:26157794

  12. [Current Research of the Roles of IL-35 in Tumor Progression].

    PubMed

    Huang, Chongbiao; Tian, Ye; Cui, Yan; Xu, Jie; Xin, Liang; Yang, Xueling; Qi, Daliang

    2016-04-20

    Interleukin(IL)-35 is a new member of the interleukin-12 superfamily. Since its first report in 2007, IL-35 rapidly became a research highlight in the field of immunology. Like other IL-12 superfamily members, IL-35 was a heterodimer which was composed of an α chain P35 and a β chain Epstein-Barr virus induced gene 3 (EBI3). Recent research work revealed two distinct roles of IL-35. Firstly, IL-35 is highly expressed in some kinds of inflammatory diseases and autoimmune diseases and plays import roles in the pathogenesis. Secondly, IL-35 is positively expressed in some cancers and plays some roles in the process of tumor progression. Here we demonstrate the structure and the signalling of IL-35. We reviewed the the roles of IL-35 in promoting tumor progression. PMID:27118652

  13. Extract of Vernonia condensata, Inhibits Tumor Progression and Improves Survival of Tumor-allograft Bearing Mouse.

    PubMed

    Thomas, Elizabeth; Gopalakrishnan, Vidya; Somasagara, Ranganatha R; Choudhary, Bibha; Raghavan, Sathees C

    2016-01-01

    Medicinal plants are considered as one of the ideal sources for cancer therapy due to their bioactive contents and low toxicity to humans. Vernonia genus is one of the common medicinal plants, which has wide spread usage in food and medicine. However, there are limited studies to explore its anticancer properties. In the current study, we have used Vernonia condensata, to explore its anticancer activity using various approaches. Here, we show that extract prepared from Vernonia condensata (VCE) exhibits cytotoxic properties against various cancer cells in a dose- and time-dependent manner. Interestingly, when treated with VCE, there was no significant cytotoxicity in peripheral blood mononuclear cells (PBMCs). Flow cytometry analysis revealed that although VCE induced cell death, arrest was not observed. VCE treatment led to disruption of mitochondrial membrane potential in a concentration dependent manner resulting in activation of apoptosis culminating in cell death. Immunoblotting studies revealed that VCE activated intrinsic pathway of apoptosis. More importantly, VCE treatment resulted in tumor regression leading to significant enhancement in life span in treated mice, without showing any detectable side effects. Therefore, for the first time our study reveals the potential of extract from Vernonia condensata to be used as an anticancer agent. PMID:27009490

  14. Extract of Vernonia condensata, Inhibits Tumor Progression and Improves Survival of Tumor-allograft Bearing Mouse

    PubMed Central

    Thomas, Elizabeth; Gopalakrishnan, Vidya; Somasagara, Ranganatha R.; Choudhary, Bibha; Raghavan, Sathees C.

    2016-01-01

    Medicinal plants are considered as one of the ideal sources for cancer therapy due to their bioactive contents and low toxicity to humans. Vernonia genus is one of the common medicinal plants, which has wide spread usage in food and medicine. However, there are limited studies to explore its anticancer properties. In the current study, we have used Vernonia condensata, to explore its anticancer activity using various approaches. Here, we show that extract prepared from Vernonia condensata (VCE) exhibits cytotoxic properties against various cancer cells in a dose- and time-dependent manner. Interestingly, when treated with VCE, there was no significant cytotoxicity in peripheral blood mononuclear cells (PBMCs). Flow cytometry analysis revealed that although VCE induced cell death, arrest was not observed. VCE treatment led to disruption of mitochondrial membrane potential in a concentration dependent manner resulting in activation of apoptosis culminating in cell death. Immunoblotting studies revealed that VCE activated intrinsic pathway of apoptosis. More importantly, VCE treatment resulted in tumor regression leading to significant enhancement in life span in treated mice, without showing any detectable side effects. Therefore, for the first time our study reveals the potential of extract from Vernonia condensata to be used as an anticancer agent. PMID:27009490

  15. Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

    PubMed Central

    Reeves, Raymond; Edberg, Dale D.; Li, Ying

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  16. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells.

    PubMed

    Reeves, R; Edberg, D D; Li, Y

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  17. Sapodilla plum (Achras sapota) induces apoptosis in cancer cell lines and inhibits tumor progression in mice.

    PubMed

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  18. A stochastic model featuring acid-induced gaps during tumor progression

    NASA Astrophysics Data System (ADS)

    Athni Hiremath, Sandesh; Surulescu, Christina

    2016-03-01

    In this paper we propose a phenomenological model for the formation of an interstitial gap between the tumor and the stroma. The gap is mainly filled with acid produced by the progressing edge of the tumor front. Our setting extends existing models for acid-induced tumor invasion models to incorporate several features of local invasion like formation of gaps, spikes, buds, islands, and cavities. These behaviors are obtained mainly due to the random dynamics at the intracellular level, the go-or-grow-or-recede dynamics on the population scale, together with the nonlinear coupling between the microscopic (intracellular) and macroscopic (population) levels. The wellposedness of the model is proved using the semigroup technique and 1D and 2D numerical simulations are performed to illustrate model predictions and draw conclusions based on the observed behavior.

  19. Sapodilla Plum (Achras sapota) Induces Apoptosis in Cancer Cell Lines and Inhibits Tumor Progression in Mice

    PubMed Central

    Srivastava, Mrinal; Hegde, Mahesh; Chiruvella, Kishore K.; Koroth, Jinsha; Bhattacharya, Souvari; Choudhary, Bibha; Raghavan, Sathees C.

    2014-01-01

    Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID:25142835

  20. One-year outcomes of conventional and accelerated collagen crosslinking in progressive keratoconus

    PubMed Central

    Chow, Vanissa W. S.; Chan, Tommy C. Y.; Yu, Marco; Wong, Victoria W. Y.; Jhanji, Vishal

    2015-01-01

    We compared one-year outcomes of conventional (3 mW/cm2, 365-nm ultraviolet-A light, 30 minutes) and accelerated (18 mW/cm2, 365-nm ultraviolet-A light, 5 minutes) collagen crosslinking (CXL) in patients with progressive keratoconus. Main outcome measures were change in keratometry, uncorrected visual acuity (UCVA), and best-corrected visual acuity (BCVA). Nineteen patients in each group completed 1-year follow-up. Preoperatively, there were no inter-group differences for age, keratometry, corneal thickness, and spherical equivalent (p > 0.127). One year postoperatively, maximum and minimum keratometry were flattened by 1.6 diopters (p < 0.023) and 2 diopters (p < 0.047) respectively after conventional CXL, and, 0.47 diopters (p = 0.471) and 0.19 diopters (p = 0.120) respectively after accelerated CXL. Association analysis showed significant negative association between baseline maximum keratometry and change in maximum keratometry after accelerated CXL (p = 0.002) but not after conventional CXL (p = 0.110). Corneal thickness was reduced significantly in both groups (p = 0.017). An improvement in UCVA (p < 0.001) and BCVA (p < 0.022) was noted in both groups along with a reduction in spherical equivalent postoperatively (p < 0.026). There were no inter-group differences for any of the parameters postoperatively (p > 0.184). Although no statistically significant differences were observed between both treatment modalities, a more effective topographic flattening was observed with conventional CXL as compared to accelerated CXL in this study. PMID:26404661

  1. A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression.

    PubMed

    Singh, S P; Schwartz, M P; Tokuda, E Y; Luo, Y; Rogers, R E; Fujita, M; Ahn, N G; Anseth, K S

    2015-01-01

    Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase-degradable peptide crosslinker (KKCGGPQG↓IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion. PMID:26638791

  2. A synthetic modular approach for modeling the role of the 3D microenvironment in tumor progression

    PubMed Central

    Singh, S. P.; Schwartz, M. P.; Tokuda, E. Y.; Luo, Y.; Rogers, R. E.; Fujita, M.; Ahn, N. G.; Anseth, K. S.

    2015-01-01

    Here, we demonstrate the flexibility of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels for modeling tumor progression. The PEG hydrogels were formed using thiol-ene chemistry to incorporate a matrix metalloproteinase-degradable peptide crosslinker (KKCGGPQG↓IWGQGCKK) permissive to proteolytic remodeling and the adhesive CRGDS peptide ligand. Tumor cell function was investigated by culturing WM239A melanoma cells on PEG hydrogel surfaces or encapsulating cells within the hydrogels, and either as monocultures or indirect (non-contact) cocultures with primary human dermal fibroblasts (hDFs). WM239A cluster size and proliferation rate depended on the shear elastic modulus for cells cultured on PEG hydrogels, while growth was inhibited by coculture with hDFs regardless of hydrogel stiffness. Cluster size was also suppressed by hDFs for WM239A cells encapsulated in PEG hydrogels, which is consistent with cells seeded on top of hydrogels. Notably, encapsulated WM239A clusters and single cells adopted invasive phenotypes in the hDF coculture model, which included single cell and collective migration modes that resembled invasion from human melanoma patient-derived xenograft tumors encapsulated in equivalent PEG hydrogels. Our combined results demonstrate that peptide-functionalized PEG hydrogels provide a useful platform for investigating aspects of tumor progression in 2D and 3D microenvironments, including single cell migration, cluster growth and invasion. PMID:26638791

  3. Evaluation of the effects of hyaluronic acid-carboxymethyl cellulose barrier on ovarian tumor progression

    PubMed Central

    2014-01-01

    Background Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study’s objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management. Methods We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts. Results We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier. Conclusions For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks. PMID:24739440

  4. Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression

    PubMed Central

    Palmer, T. D.; Martínez, C. H.; Vasquez; Hebron, K.; Jones-Paris, C.; Arnold, S.A.; Chan, S.M.; Chalasani, V.; Gomez-Lemus, J.A.; Williams, A.K.; Chin, J.L.; Giannico, G.A.; Ketova, T.; Lewis, J.D.; Zijlstra, A.

    2013-01-01

    Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151free) correlates clinically with tumor progression and metastasis. Clustering CD151free through its integrin-binding domain promotes accumulation in areas of cell-cell contact leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151free clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histological detection of CD151free in prostate cancer correlates with poor patient outcome. When CD151free is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151free as an independent predictor of survival. Moreover, the detection of CD151free can stratify survival among patients with elevated PSA. Cumulatively these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151free with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. PMID:24220242

  5. Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages.

    PubMed

    Kumar, S; Torres, M P; Kaur, S; Rachagani, S; Joshi, S; Johansson, S L; Momi, N; Baine, M J; Gilling, C E; Smith, L M; Wyatt, T A; Jain, M; Joshi, S S; Batra, S K

    2015-04-16

    Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-ras(G12D)) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-ras(G12D); Pdx-1cre) and their control unfloxed (LSL-K-ras(G12D)) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m(3)) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation. PMID:24909166

  6. Magnetic Shielding Accelerates the Proliferation of Human Neuroblastoma Cell by Promoting G1-Phase Progression

    PubMed Central

    Liu, Ying; Bartlett, Perry F.; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  7. Magnetic shielding accelerates the proliferation of human neuroblastoma cell by promoting G1-phase progression.

    PubMed

    Mo, Wei-chuan; Zhang, Zi-jian; Liu, Ying; Bartlett, Perry F; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  8. Optimal technique of linear accelerator-based stereotactic radiosurgery for tumors adjacent to brainstem.

    PubMed

    Chang, Chiou-Shiung; Hwang, Jing-Min; Tai, Po-An; Chang, You-Kang; Wang, Yu-Nong; Shih, Rompin; Chuang, Keh-Shih

    2016-01-01

    Stereotactic radiosurgery (SRS) is a well-established technique that is replacing whole-brain irradiation in the treatment of intracranial lesions, which leads to better preservation of brain functions, and therefore a better quality of life for the patient. There are several available forms of linear accelerator (LINAC)-based SRS, and the goal of the present study is to identify which of these techniques is best (as evaluated by dosimetric outcomes statistically) when the target is located adjacent to brainstem. We collected the records of 17 patients with lesions close to the brainstem who had previously been treated with single-fraction radiosurgery. In all, 5 different lesion catalogs were collected, and the patients were divided into 2 distance groups-1 consisting of 7 patients with a target-to-brainstem distance of less than 0.5cm, and the other of 10 patients with a target-to-brainstem distance of ≥ 0.5 and < 1cm. Comparison was then made among the following 3 types of LINAC-based radiosurgery: dynamic conformal arcs (DCA), intensity-modulated radiosurgery (IMRS), and volumetric modulated arc radiotherapy (VMAT). All techniques included multiple noncoplanar beams or arcs with or without intensity-modulated delivery. The volume of gross tumor volume (GTV) ranged from 0.2cm(3) to 21.9cm(3). Regarding the dose homogeneity index (HIICRU) and conformity index (CIICRU) were without significant difference between techniques statistically. However, the average CIICRU = 1.09 ± 0.56 achieved by VMAT was the best of the 3 techniques. Moreover, notable improvement in gradient index (GI) was observed when VMAT was used (0.74 ± 0.13), and this result was significantly better than those achieved by the 2 other techniques (p < 0.05). For V4Gy of brainstem, both VMAT (2.5%) and IMRS (2.7%) were significantly lower than DCA (4.9%), both at the p < 0.05 level. Regarding V2Gy of normal brain, VMAT plans had attained 6.4 ± 5%; this was significantly better (p < 0.05) than

  9. Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors

    PubMed Central

    Villarejo, Ana; Molina-Ortiz, Patricia; Montenegro, Yenny; Moreno-Bueno, Gema; Morales, Saleta; Santos, Vanesa; Gridley, Tom; Pérez-Moreno, Mirna A.; Peinado, Héctor; Portillo, Francisco; Calés, Carmela; Cano, Amparo

    2015-01-01

    Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 −/− mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 −/− mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID:25784375

  10. Microfluidic culture models to study the hydrodynamics of tumor progression and therapeutic response.

    PubMed

    Buchanan, Cara; Rylander, Marissa Nichole

    2013-08-01

    The integration of tissue engineering strategies with microfluidic technologies has enabled the design of in vitro microfluidic culture models that better adapt to morphological changes in tissue structure and function over time. These biomimetic microfluidic scaffolds accurately mimic native 3D microenvironments, as well as permit precise and simultaneous control of chemical gradients, hydrodynamic stresses, and cellular niches within the system. The recent application of microfluidic in vitro culture models to cancer research offers enormous potential to aid in the development of improved therapeutic strategies by supporting the investigation of tumor angiogenesis and metastasis under physiologically relevant flow conditions. The intrinsic material properties and fluid mechanics of microfluidic culture models enable high-throughput anti-cancer drug screening, permit well-defined and controllable input parameters to monitor tumor cell response to various hydrodynamic conditions or treatment modalities, as well as provide a platform for elucidating fundamental mechanisms of tumor physiology. This review highlights recent developments and future applications of microfluidic culture models to study tumor progression and therapeutic targeting under conditions of hydrodynamic stress relevant to the complex tumor microenvironment. PMID:23616255

  11. Loss of Snail2 favors skin tumor progression by promoting the recruitment of myeloid progenitors.

    PubMed

    Villarejo, Ana; Molina-Ortiz, Patricia; Montenegro, Yenny; Moreno-Bueno, Gema; Morales, Saleta; Santos, Vanesa; Gridley, Tom; Pérez-Moreno, Mirna A; Peinado, Héctor; Portillo, Francisco; Calés, Carmela; Cano, Amparo

    2015-05-01

    Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression. PMID:25784375

  12. 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

  13. High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

    PubMed Central

    2009-01-01

    Background Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression. Methods Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer. Results The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies. Conclusion The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer. PMID:19878561

  14. The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway

    PubMed Central

    Salah, Zaidoun; Itzhaki, Ella; Aqeilan, Rami I

    2014-01-01

    The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway. PMID:25350971

  15. ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression

    PubMed Central

    Aljarah, Ali Kadhim; Ide, Hiroki; Li, Yi; Kashiwagi, Eiji; Netto, George J.; Zheng, Yichun; Miyamoto, Hiroshi

    2015-01-01

    Little is known about biological significance of ELK1, a transcriptional factor that activates downstream targets including c-fos proto-oncogene, in bladder cancer. Recent preclinical evidence also suggests the involvement of androgen receptor (AR) signaling in bladder cancer progression. In this study, we aim to investigate the functions of ELK1 in bladder cancer growth and their regulation by AR signals. Immunohistochemistry in bladder tumor specimens showed that the levels of phospho-ELK1 (p-ELK1) expression were significantly elevated in urothelial neoplasms, compared with non-neoplastic urothelium tissues, and were also correlated with AR positivity. Patients with p-ELK1-positive non-muscle-invasive and muscle-invasive tumors had significantly higher risks for tumor recurrence and progression, respectively. In AR-positive bladder cancer cell lines, dihydrotestosterone treatment increased ELK1 expression (mRNA, protein) and its nuclear translocation, ELK1 transcriptional activity, and c-fos expression, which was restored by an anti-androgen hydroxyflutamide. ELK1 silencing via short hairpin RNA (shRNA) resulted in decreases in cell viability/colony formation, and cell migration/invasion as well as an increase in apoptosis. Importantly, ELK1 appears to require activated AR to regulate bladder cancer cell proliferation, but not cell migration. Androgen also failed to significantly induce AR transactivation in ELK1-knockdown cells. In accordance with our in vitro findings, ELK1-shRNA expression considerably retarded tumor formation as well as its growth in xenograft-bearing male mice. Our results suggest that ELK1 plays an important role in bladder tumorigenesis and cancer progression, which is further induced by AR activation. Accordingly, ELK1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer. PMID:26342199

  16. 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.

  17. Enhanced neutrophil activity is associated with shorter time to tumor progression in glioblastoma patients

    PubMed Central

    Rahbar, Afsar; Cederarv, Madeleine; Wolmer-Solberg, Nina; Tammik, Charlotte; Stragliotto, Giuseppe; Peredo, Inti; Fornara, Olesja; Xu, Xinling; Dzabic, Mensur; Taher, Chato; Skarman, Petra; Söderberg-Nauclér, Cecilia

    2016-01-01

    ABSTRACT Glioblastoma multiforme (GBM) is a highly malignant tumor with a poor outcome that is often positive for human cytomegalovirus (HCMV). GBM patients often have excessive numbers of neutrophils and macrophages near and within the tumor. Here, we characterized the cytokine patterns in the blood of GBM patients with and without Valganciclovir treatment. Furthermore, we determined whether neutrophil activation is related to HCMV status and patient outcome. Blood samples for analyses of cytokines and growth factors were collected from 42 GBM patients at the time of diagnosis (n = 42) and at weeks 12 and 24 after surgery. Blood neutrophils of 28 GBM patients were examined for CD11b expression. The levels of pro- and anti-inflammatory cytokines and chemokines—including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, transforming growth factor (TGF)-β1, interferon-γ, interferon-α, tumor necrosis factor α, and monocyte chemoattractant protein (MCP)-1were analyzed with a bead-based flow cytometry assay. During the first six months after surgery, neutrophil activity was increased in 12 patients and was unchanged or decreased in 16. Patients with increased neutrophil activity had enhanced IL-12p70, high grade HCMV and a shorter time to tumor progression (TTP) than patients without or decreased neutrophil activity (median TTP; 5.4 vs. 12 months, 95% confidence interval; 1.6–10 vs. 0.1–0.6, hazard ratio = 3 vs. 0.4, p = 0.004). The levels of IL-12p70 were significantly decreased in Valganciclovir treated patients (n = 22, T 12W vs. T 24W, p = 0.03). In conclusion, our findings suggest that neutrophil activation is an early sign of tumor progression in GBM patients. PMID:27057448

  18. A 1 GeV Laser Wakefield Accelerator: Experimental Progress at the l'OASIS Facility of LBNL

    NASA Astrophysics Data System (ADS)

    Leemans, W. P.; Geddes, C. G. R.; Toth, C. S.; van Tilborg, J.; Nagler, B.; Michel, P.; Nakamura, K.; Esarey, E.; Schroeder, C. B.; Gonsalves, A.; Spence, D. J.; Hooker, S. M.; Filip, C.; Cowan, T.

    2004-11-01

    Experimental progress towards a 1 GeV laser-driven plasma-based accelerator will be discussed. The design of the 1 GeV accelerator module consists of two components: (1) an all-optical electron injector and (2) a plasma channel for laser guiding and electron acceleration to high energy via the laser wakefield acceleration (LWFA) mechanism. Experimental results on the injector development include the demonstration of laser guiding at relativistic intensities in preformed plasmas and production of quasi-monochromatic electron beams with energy around 100 MeV. Progress on guiding 100 TW laser pulses in capillary-discharge-based plasma channels will be discussed and integration of these channels with the all-optical injector will be reported.

  19. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

    PubMed Central

    Hatting, M; Spannbauer, M; Peng, J; Al Masaoudi, M; Sellge, G; Nevzorova, Y A; Gassler, N; Liedtke, C; Cubero, F J; Trautwein, C

    2015-01-01

    Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0–144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130f/f and gp130Δhepa animals. However, gp130Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC. PMID:25741592

  20. Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells.

    PubMed

    Dittmar, Thomas; Zänker, Kurt S

    2015-01-01

    The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that "accidental" tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. PMID:26703575

  1. Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells

    PubMed Central

    Dittmar, Thomas; Zänker, Kurt S.

    2015-01-01

    The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that “accidental” tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. PMID:26703575

  2. Progress in Wind-and-React Bi-2212 Accelerator Magnet Technology

    SciTech Connect

    Godeke, A.; Cheng, D.; Dietderich, D.R.; Hannaford, C.R.; Prestemon, S.O.; Sabbi, G.; Wang, X.; Hikichi, Y.; Nishioka, J.; Hasegawa, T.

    2009-08-16

    We report on our progress in the development of the technology for the application of Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub 8+x}(Bi-2212) in Wind-and-React accelerator magnets. A series of superconducting subscale coils has been manufactured at LBNL and reacted at the wire manufacturer SWCC. Selected coils are impregnated and tested in self-field, even though the coils exhibited leakage during the partial melt heat treatment. Other coils have been disassembled after reaction and submitted to critical current (Ic) tests on individual cable sections. We report on the results of the current carrying capacity of the coils. Voltage-current (VI) transitions were reproducibly measured up to a quench currents around 1400 A, which is 25% of the expected performance. The results indicate that the coils are limited by the inner windings. We further compare possibilities to use Bi-2212 and Nb{sub 3}Sn tilted solenoid, and YBa{sub 2}Cu{sub 3}O{sub 7-{delta}} (YBCO) racetrack inserts to increase the magnetic field in HD2, a 36 mm bore Nb{sub 3}Sn dipole magnet which recently achieved a bore magnetic field of 13.8 T. The application of Bi-2212 and/or YBCO in accelerator type magnets, if successful, will open the road to higher magnetic fields, far surpassing the limitations of Nb{sub 3}Sn magnet technology.

  3. Progress on laser plasma accelerator development using transverselyand longitudinally shaped plasmas

    SciTech Connect

    Leemans, Wim P.; Esarey, E.; Geddes, C.G.R.; Toth, Cs.; Schroeder, C.B.; Nakamura, K.; Gonsalves, A.J.; Panasenko, D.; Cormier-Michel, E.; Plateau, G.R.; Lin, C.; Bruhwiler, D.L.; Cary, J.R.

    2009-03-31

    A summary of progress at Lawrence Berkeley National Laboratory is given on: (1) experiments on down-ramp injection; (2) experiments on acceleration in capillary discharge plasma channels; and (3) simulations of a staged laser wakefield accelerator (LWFA). Control of trapping in a LWFA using plasma density down-ramps produced electron bunches with absolute longitudinal and transverse momentum spreads more than ten times lower than in previous experiments (0.17 and 0.02 MeV Ic FWHM, respectively) and with central momenta of 0.76 +- 0.02 MeV Ic, stable over a week of operation. Experiments were also carried out using a 40 TW laser interacting with a hydrogen-filled capillary discharge waveguide. For a 15 mm long, 200 mu m diameter capillary, quasi-monoenergetic bunches up to 300 MeV were observed. By detuning discharge delay from optimum guiding performance, self-trapping was found to be stabilized. For a 33 mm long, 300 mu m capillary, a parameter regime with high energy bunches, up to 1 Ge V, was found. In this regime, peak electron energy was correlated with the amount of trapped charge. Simulations show that bunches produced on a down-ramn and iniected into a channel-guided LWFA can produce stable beams with 0.2 MeV Ic-class momentum spread at high energies.

  4. Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

    PubMed Central

    Micalizzi, Douglas S.; Farabaugh, Susan M.

    2010-01-01

    From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer. PMID:20490631

  5. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

    PubMed

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M

    2016-05-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype. PMID:27089513

  6. Role and molecular mechanism of heterogeneous nuclear ribonucleoprotein K in tumor development and progression

    PubMed Central

    LU, JING; GAO, FENG-HOU

    2016-01-01

    Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a member of the hnRNP family, which exists in the nucleus and the cytoplasm simultaneously. It is a multifunctional protein that can participate in a variety of regulatory progressions of gene expression and signal transduction, such as chromatin remodeling, transcription, RNA alternative splicing and translation. hnRNP K not only directly binds to the kinases, but also recruits the associated factors regarding transcription, splicing and translation to control gene expression, and therefore, it serves as a docking platform for integrating transduction pathways to nucleic acid-directed processes. Numerous studies also show that abnormal expression of hnRNP K is closely associated with the tumor formation. This protein is overexpressed in numerous types of cancer and its aberrant cytoplasmic localization is also associated with a worse prognosis for patients. These results consistently indicate that hnRNP K has a key role in cancer progression. To understand the hnRNP K pathophysiological process in tumor disease, the previous research results regarding the association between hnRNP K and tumors were reviewed. PMID:27284403

  7. NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

    PubMed Central

    Moreira, Frederico; Kiehl, Tim-Rasmus; So, Kelvin; Ajeawung, Norbert F.; Honculada, Carmelita; Gould, Peter; Pieper, Russell O.; Kamnasaran, Deepak

    2011-01-01

    Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n = 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival. PMID:21703424

  8. Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

    PubMed Central

    Dennemärker, J; Lohmüller, T; Mayerle, J; Tacke, M; Lerch, MM; Coussens, LM; Peters, C; Reinheckel, T

    2011-01-01

    To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)–HPV16).We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14–HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14–HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease. PMID:20023699

  9. Role of stereotactic radiosurgery with a linear accelerator in treatment of intracranial arteriovenous malformations and tumors in children.

    PubMed

    Loeffler, J S; Rossitch, E; Siddon, R; Moore, M R; Rockoff, M A; Alexander, E

    1990-05-01

    Between 1986 and 1988, 16 children were treated for 10 arteriovenous malformations and 6 recurrent intracranial tumors with stereotactic radiation therapy using a modified Clinac 6/100 linear accelerator. The median age of our patients was 10.5 years. For the group with arteriovenous malformation, follow-up ranged from 6 months to 37 months (median was 20 months). No patient bled during the follow-up period. Five of eight patients with follow-up longer than 12 months have achieved complete obliteration of their arteriovenous malformation by angiogram. The four remaining patients who have not achieved a complete obliteration are awaiting their 2-year posttreatment angiogram. The other patient has been treated within the year and have not yet been studied. Five of the six recurrent tumor patients are alive with a median follow-up of 8 months. The remaining patient was controlled locally, but he died of recurrent disease outside the area treated with radiosurgery. The radiographic responses of these patients have included three complete responses, two substantial reductions in tumor volume (greater than 50%) and one stabilization. Despite previous radiotherapy, there have been no significant complications in these patients. We conclude that stereotactic radiation therapy using a standard linear accelerator is an effective and safe technique in the treatment of selected intracranial arteriovenous malformations and tumors in children. In addition, stereotactic radiosurgery may have unique applications in the treatment of localized primary and recurrent pediatric brain tumors. PMID:2184409

  10. The Bisecting GlcNAc on N-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression

    PubMed Central

    Song, Yinghui; Aglipay, Jason A.; Bernstein, Joshua D.; Goswami, Sumanta; Stanley, Pamela

    2010-01-01

    The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration and hepatoma formation. Here we show that Chinese hamster ovary (CHO) cells expressing Mgat3 and the Polyoma Middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in MMTV/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly, have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway, and reduced amounts of functionally-glycosylated α-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell-autonomous mechanism serving to retard tumor progression by reducing growth factor signaling. PMID:20395209

  11. Accelerating progress at contaminated sediment sites: moving from guidance to practice.

    PubMed

    Bridges, Todd S; Nadeau, Steven C; McCulloch, Megan C

    2012-04-01

    Contaminated sediments are a pervasive problem in the United States. Significant economic, ecological, and social issues are intertwined in addressing the nation's contaminated sediment problem. Managing contaminated sediments has become increasingly resource intensive, with some investigations costing tens of millions of dollars and the majority of remediation projects proceeding at a slow pace. At present, the approaches typically used to investigate, evaluate, and remediate contaminated sediment sites in the United States have largely fallen short of producing timely, risk-based, cost-effective, long-term solutions. With the purpose of identifying opportunities for accelerating progress at contaminated sediment sites, the US Army Corps of Engineers-Engineer Research and Development Center and the Sediment Management Work Group convened a workshop with experienced experts from government, industry, consulting, and academia. Workshop participants identified 5 actions that, if implemented, would accelerate the progress and increase the effectiveness of risk management at contaminated sediment sites. These actions included: 1) development of a detailed and explicit project vision and accompanying objectives, achievable short-term and long-term goals, and metrics of remedy success at the outset of a project, with refinement occurring as needed throughout the duration of the project; 2) strategic engagement of stakeholders in a more direct and meaningful process; 3) optimization of risk reduction, risk management processes, and remedy selection addressing 2 important elements: a) the deliberate use of early action remedies, where appropriate, to accelerate risk reduction; and b) the systematic and sequential development of a suite of actions applicable to the ultimate remedy, starting with monitored natural recovery and adding engineering actions as needed to satisfy the project's objectives; 4) an incentive process that encourages and rewards risk reduction; and 5

  12. Tumor progression locus 2 (TPL2) is a novel target for regulating obesity associated liver inflammation and steatosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tumor progression locus 2 (TPL2) is a MAP 3-kinase that is required for toll receptor and tumor necrosis factor-alpha (TNF-alpha) stimulation of the ERK/MAP kinase cascade. TPL-2 knockout (KO) mice exhibit a dramatic reduction in LPS induced TNF-alpha production due to defective ERK-1/2 activation....

  13. Simultaneous inference of cancer pathways and tumor progression from cross-sectional mutation data.

    PubMed

    Raphael, Benjamin J; Vandin, Fabio

    2015-06-01

    Recent cancer sequencing studies provide a wealth of somatic mutation data from a large number of patients. One of the most intriguing and challenging questions arising from this data is to determine whether the temporal order of somatic mutations in a cancer follows any common progression. Since we usually obtain only one sample from a patient, such inferences are commonly made from cross-sectional data from different patients. This analysis is complicated by the extensive variation in the somatic mutations across different patients, variation that is reduced by examining combinations of mutations in various pathways. Thus far, methods to reconstruct tumor progression at the pathway level have restricted attention to known, a priori defined pathways. In this work we show how to simultaneously infer pathways and the temporal order of their mutations from cross-sectional data, leveraging on the exclusivity property of driver mutations within a pathway. We define the pathway linear progression model, and derive a combinatorial formulation for the problem of finding the optimal model from mutation data. We show that with enough samples the optimal solution to this problem uniquely identifies the correct model with high probability even when errors are present in the mutation data. We then formulate the problem as an integer linear program (ILP), which allows the analysis of datasets from recent studies with large numbers of samples. We use our algorithm to analyze somatic mutation data from three cancer studies, including two studies from The Cancer Genome Atlas (TCGA) on large number of samples on colorectal cancer and glioblastoma. The models reconstructed with our method capture most of the current knowledge of the progression of somatic mutations in these cancer types, while also providing new insights on the tumor progression at the pathway level. PMID:25785493

  14. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  15. Beyond a tumor suppressor: Soluble E-cadherin promotes the progression of cancer.

    PubMed

    Hu, Qi-Ping; Kuang, Jing-Ya; Yang, Qing-Kai; Bian, Xiu-Wu; Yu, Shi-Cang

    2016-06-15

    E-cadherin (E-cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane-tethered form and a soluble form. Full-length E-cad is membrane tethered. As a type I transmembrane glycoprotein, E-cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E-cad (sE-cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full-length E-cad. The production of sE-cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE-cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE-cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE-cad in tumorigenesis and tumor progression and its significance in clinical therapeutics. PMID:26704932

  16. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

    PubMed Central

    Pàez-Ribes, Marta; Allen, Elizabeth; Hudock, James; Takeda, Takaaki; Okuyama, Hiroaki; Viñals, Francesc; Inoue, Masahiro; Bergers, Gabriele; Hanahan, Douglas; Casanovas, Oriol

    2009-01-01

    SUMMARY Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies. PMID:19249680

  17. Steering tumor progression through the transcriptional response to growth factors and stroma.

    PubMed

    Feldman, Morris E; Yarden, Yosef

    2014-08-01

    Tumor progression can be understood as a collaborative effort of mutations and growth factors, which propels cell proliferation and matrix invasion, and also enables evasion of drug-induced apoptosis. Concentrating on EGFR, we discuss downstream signaling and the initiation of transcriptional events in response to growth factors. Specifically, we portray a wave-like program, which initiates by rapid disappearance of two-dozen microRNAs, followed by an abrupt rise of immediate early genes (IEGs), relatively short transcripts encoding transcriptional regulators. Concurrent with the fall of IEGs, some 30-60 min after stimulation, a larger group, the delayed early genes, is up-regulated and its own fall overlaps the rise of the final wave of late response genes. This late wave persists and determines long-term phenotype acquisition, such as invasiveness. Key regulatory steps in the orderly response to growth factors provide a trove of potential oncogenes and tumor suppressors. PMID:24873881

  18. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications.

    PubMed

    Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

    2016-03-01

    Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer. PMID:26791754

  19. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression.

    PubMed

    Miyauchi, Jeremy T; Chen, Danling; Choi, Matthew; Nissen, Jillian C; Shroyer, Kenneth R; Djordevic, Snezana; Zachary, Ian C; Selwood, David; Tsirka, Stella E

    2016-03-01

    Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID:26755653

  20. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression

    PubMed Central

    Miyauchi, Jeremy T.; Chen, Danling; Choi, Matthew; Nissen, Jillian C.; Shroyer, Kenneth R.; Djordevic, Snezana; Zachary, Ian C.; Selwood, David; Tsirka, Stella E.

    2016-01-01

    Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID:26755653

  1. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress

    PubMed Central

    2014-01-01

    Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3–5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer. PMID:24886523

  2. Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer

    PubMed Central

    Huang, Chang-Shuo; Tang, Shye-Jye; Chung, Ling-Yen; Yu, Cheng-Ping; Ho, Jar-Yi; Cha, Tai-Lung; Hsieh, Chii-Cheng; Wang, Hsiao-Hsien

    2014-01-01

    Galectin-1, a β-galactoside–binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1–silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-κB (NF-κB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-κB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease. PMID:24511119

  3. Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- b1 haploinsufficiency.

    PubMed

    Pandey, Jyotsna; Umphress, Sarah M; Kang, Yang; Angdisen, Jerry; Naumova, Alena; Mercer, Kim L; Jacks, Tyler; Jakowlew, Sonia B

    2007-12-01

    Oncogenic K-ras is one of the most common genetic alterations in human lung adenocarcinomas. In addition, inactivation of clusters of tumor suppressor genes is required to bring about classical characteristics of cancer including angiogenesis as a prelude to invasion and metastasis. Transforming growth factor-beta (TGF-beta) 1 is a tumor suppressor gene that is implicated in lung cancer progression. Although in vitro studies have shown that TGF-beta1 and Ras pathways cooperate during tumorigenesis, the biology of interaction of TGF-beta1 and Ras has not been studied in in vivo tumorigenesis. We hypothesized that inactivation of TGF-beta1 in addition to oncogeneic activation of K-ras would lead to early initiation and faster progression to lung adenocarcinoma and invasion and metastasis. Heterozygous (HT) TGF-beta1 mice were mated with latent activatable (LA) mutated K-ras mice to generate TGF-beta1(+/+), K-ras LA (wild-type (WT)/LA) and TGF-beta1(+/-), K-ras LA (HT/LA) mice. Both HT/LA and WT/LA mice developed spontaneous lung tumors, but HT/LA mice progressed to adenocarcinomas significantly earlier compared with WT/LA mice. In addition, WT/LA adenocarcinomas had significantly higher angiogenic activity compared with HT/LA adenocarcinomas. Thus, while oncogenic K-ras mutation and insensitivity to the growth regulatory effects of TGF-beta1 is essential for initiation and progression of mouse lung tumors to adenocarcinoma, a full gene dosage of TGF-beta1 is required for tumor-induced angiogenesis and invasive potential. This study identifies a number of genes not previously associated with lung cancer that are involved in tumor induction and progression. In addition, we provide evidence that progression to invasive angiogenic lesions requires TGF-beta1 responsiveness in addition to Ras mutation. PMID:17690114

  4. Overview: Progression-Free Survival as an Endpoint in Clinical Trials with Solid Tumors

    PubMed Central

    Korn, Ronald L.; Crowley, John J.

    2013-01-01

    Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors, because of both practical and clinical considerations. Although in its simplest form PFS is the time from randomization to a pre-defined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint, and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. PMID:23669420

  5. Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor Progression

    PubMed Central

    Schedin, Pepper; Keely, Patricia J.

    2011-01-01

    Cells of the mammary gland are in intimate contact with other cells and with the extracellular matrix (ECM), both of which provide not only a biochemical context, but a mechanical context as well. Cell-mediated contraction allows cells to sense the stiffness of their microenvironment, and respond with appropriate mechanosignaling events that regulate gene expression and differentiation. ECM composition and organization are tightly regulated throughout development of the mammary gland, resulting in corresponding regulation of the mechanical environment and proper tissue architecture. Mechanical regulation is also at play during breast carcinoma progression, as changes in ECM deposition, composition, and organization accompany breast carcinoma. These changes result in stiffer matrices that activate mechanosignaling pathways and thereby induce cell proliferation, facilitate local tumor cell invasion, and promote progression. Thus, understanding the role of forces in the mammary gland is crucial to understanding both normal developmental and pathological processes. PMID:20980442

  6. Mesenchymal Stem Cells Develop Tumor Tropism but Do Not Accelerate Breast Cancer Tumorigenesis in a Somatic Mouse Breast Cancer Model

    PubMed Central

    Usha, Lydia; Rao, Geetha; Christopherson II, Kent; Xu, Xiulong

    2013-01-01

    The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves. PMID:24069135

  7. LOSS OF P130 ACCELERATES TUMOR DEVELOPMENT IN A MOUSE MODEL FOR HUMAN SMALL CELL LUNG CARCINOMA

    PubMed Central

    Schaffer, Bethany E.; Park, Kwon-Sik; Yiu, Gloria; Conklin, Jamie F.; Lin, Chenwei; Burkhart, Deborah L.; Karnezis, Anthony N.; Sweet-Cordero, Alejandro; Sage, Julien

    2010-01-01

    Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. While SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple knockout mouse model. The histopathological features of the triple mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130 mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130 mutant mice provide a novel pre-clinical mouse model to identify novel therapeutic targets against SCLC. PMID:20406986

  8. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.

    PubMed

    Stuart, Emma; Buchert, Michael; Putoczki, Tracy; Thiem, Stefan; Farid, Ryan; Elzer, Joachim; Huszar, Dennis; Waring, Paul M; Phesse, Toby J; Ernst, Matthias

    2014-02-01

    Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo. PMID:24398427

  9. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression

    PubMed Central

    Martinson, Holly A.; Jindal, Sonali; Durand-Rougely, Clarissa; Borges, Virginia F.; Schedin, Pepper

    2014-01-01

    Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its pre-pregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3+ regulatory T cells and IL-10+ macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are six-fold larger than nulliparous group tumors, have decreased CD4+ and CD8+ T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL-10 treatment. Relevance to women is implicated, as we find post-lactational human breast tissue has transient high IL-10+ and Foxp3+ immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer. PMID:25187059

  10. Cocaine Reduces Thymic Endocrine Function: Another Mechanism for Accelerated HIV Disease Progression

    PubMed Central

    Campa, Adriana; Smith, Sylvia; Huffman, Fatma; Newman, Fred; Baum, Marianna K.

    2011-01-01

    Abstract Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4+ cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4+ cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4+ and CD8+ cell counts and the CD4+/CD8+ ratio, and the covariate effects of substance use cross-sectionally in 80 HIV+ active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = −0.908,95% CI: −1.704, −0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4+ cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides

  11. Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells.

    PubMed

    Hoeppner, Luke H; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P; Wang, Enfeng; Yang, Ping; Roden, Anja C; Peikert, Tobias; Molina, Julian R; Mukhopadhyay, Debabrata

    2015-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  12. Dopamine D2 Receptor Agonists Inhibit Lung Cancer Progression by Reducing Angiogenesis and Tumor Infiltrating Myeloid Derived Suppressor Cells

    PubMed Central

    Hoeppner, Luke H.; Wang, Ying; Sharma, Anil; Javeed, Naureen; Van Keulen, Virginia P.; Wang, Enfeng; Yang, Ping; Roden, Anja C.; Peikert, Tobias; Molina, Julian R.; Mukhopadhyay, Debabrata

    2014-01-01

    We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history. PMID:25226814

  13. Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression

    PubMed Central

    Bergmann, Christoph; Strauss, Laura; Wieckowski, Eva; Czystowska, Malgorzata; Albers, Andreas; Wang, Yun; Zeidler, Reinhard; Lang, Stephan; Whiteside, Theresa L.

    2008-01-01

    Background: Tumor-derived membranous vesicles (MV) isolated from HNSCC patients' sera induce apoptosis of activated CD8+ T cells. We tested if MV molecular profile and activity correlate with disease progression. Methods: CD8+ Jurkat cells were incubated with MAGE 3/6+, FasL+, MHC class I+ MV isolated from sera of 60 HNSCC patients and 25 normal controls (NC) by exclusion chromatography and ultracentrifugation. Z-VAD-FITC binding to Jurkat was measured and correlated with clinical data. Results: MV from patients' but not from NC sera induced Jurkat cell apoptosis. 45% T cells+MV from N1–N3 patients were apoptotic vs. 18% T cells+MV from N0 patients (p<0.008). MV from patients with active disease (AD) expressed higher FasL levels than MV from patients with no evident disease (NED) or NC (p≤0.01). Conclusion: MAGE 3/6+, FasL+ and MHCI+ MV in sera of patients induced T-cell apoptosis which correlated with disease activity and the presence of LN metastases. PMID:19073006

  14. p28 in Treating Younger Patients With Recurrent or Progressive Central Nervous System Tumors

    ClinicalTrials.gov

    2015-10-19

    Teratoid Tumor, Atypical; Choroid Plexus Neoplasms; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Brainstem Tumors; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Medulloblastoma; Neuroectodermal Tumor, Primitive

  15. [Initiation, promotion, initiation experiments with radon and cigarette smoke: Lung tumors in rats]. Progress report

    SciTech Connect

    Moolgavkar, S.H.

    1994-10-01

    During the past several years, the authors have made considerable progress in modeling carcinogenesis in general, and in modeling radiation carcinogenesis, in particular. They present an overview of their progress in developing stochastic carcinogenesis models and applying them to experimental and epidemiologic data sets. Traditionally, cancer models have been used for the analysis of incidence (or prevalence) data in epidemiology and time to tumor data in experimental studies. The relevant quantities for the analysis of these data are the hazard function and the probability of tumor. The derivation of these quantities is briefly described here. More recently, the authors began to use these models for the analysis of data on intermediate lesions on the pathway to cancer. Such data are available in experimental carcinogenesis studies, in particular in initiation and promotion studies on the mouse skin and the rat liver. If however, quantitative information on intermediate lesions on the pathway to lung cancer were to be come available at some future date, the methods that they have developed for the analysis of initiation-promotion experiments could easily be applied to the analysis of these lesions. The mathematical derivations here are couched in terms of a particular two-mutation model of carcinogenesis. Extension to models postulating more than two mutations is not always straightforward.

  16. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression.

    PubMed

    Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R; Yamada, Hiroshi Y; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W; Steele, Vernon E; Rao, Chinthalapally V

    2015-06-20

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  17. Regulative Effect of Nampt on Tumor Progression and Cell Viability in Human Colorectal Cancer

    PubMed Central

    Lv, Xiaoqun; Zhang, Lingyun; Zhu, Yanyan; Said, Harun M.; Shi, Jimin; Xu, Guoxiong

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer disease. Here we examined Nampt expression in patients with CRC and the effect of Nampt on cell viability in CRC cells. Nampt protein was overexpressed in colorectal adenoma as well as colorectal carcinoma. The immunoreactive staining of Nampt was negative in the adjacent normal colorectal tissue, weak in colorectal adenoma, and strong in colorectal carcinoma, which may represent tumor progression. Further evaluation of clinical data showed that Nampt expression was not correlated with the clinicopathological characteristics of CRC. Additionally, our in vitro studies demonstrated that Nampt promotes CRC cell viability, whereas the Nampt inhibitor FK866 suppressed CRC cell viability, which was in concordance with the previous studies in other cancer cells. Treatment with Nampt-siRNA reduced the Nampt protein expression resulting in the inhibition of the cell viability of HCT116 and Caco2. Thus, the involvement of Nampt in cell growth indicates that Nampt may play an important role in colorectal tumorigenesis. As a consequence, our results suggest that Nampt may be considered as a progression marker of colorectal tumor and a potentially therapeutic target for the treatment of CRC. PMID:26284136

  18. MicroRNAs and Growth Factors: An Alliance Propelling Tumor Progression

    PubMed Central

    Kedmi, Merav; Sas-Chen, Aldema; Yarden, Yosef

    2015-01-01

    Tumor progression requires cancer cell proliferation, migration, invasion, and attraction of blood and lymph vessels. These processes are tightly regulated by growth factors and their intracellular signaling pathways, which culminate in transcriptional programs. Hence, oncogenic mutations often capture growth factor signaling, and drugs able to intercept the underlying biochemical routes might retard cancer spread. Along with messenger RNAs, microRNAs play regulatory roles in growth factor signaling and in tumor progression. Because growth factors regulate abundance of certain microRNAs and the latter modulate the abundance of proteins necessary for growth factor signaling, the two classes of molecules form a dense web of interactions, which are dominated by a few recurring modules. We review specific examples of the alliance formed by growth factors and microRNAs and refer primarily to the epidermal growth factor (EGF) pathway. Clinical applications of the crosstalk between microRNAs and growth factors are described, including relevance to cancer therapy and to emergence of resistance to specific drugs. PMID:26287249

  19. Four individually druggable MET hotspots mediate HGF-driven tumor progression

    PubMed Central

    Basilico, Cristina; Hultberg, Anna; Blanchetot, Christophe; de Jonge, Natalie; Festjens, Els; Hanssens, Valérie; Osepa, Sjudry-Ilona; De Boeck, Gitte; Mira, Alessia; Cazzanti, Manuela; Morello, Virginia; Dreier, Torsten; Saunders, Michael; de Haard, Hans; Michieli, Paolo

    2014-01-01

    Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2–3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2–3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2–3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer. PMID:24865428

  20. Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis.

    PubMed

    Shi, Hengliang; Du, Jin; Wang, Lei; Zheng, Bao; Gong, Hui; Wu, Yuxuan; Tang, Yuan; Gao, Yong; Yu, Rutong

    2014-10-01

    Ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) plays important roles in multiple physiological process because it can ubiquitinate various substrates such as ErbB3, BRUCE, MyD88, C/EBPβ, and Parkin, and so forth. In addition to the physiological function, it was also found to be involved in tumor progression. It has been shown that loss of Nrdp1 enhances breast cancer cell growth. Up to now, the role of Nrdp1 in glioma has not been elucidated. Here, we reported that Nrdp1 as well as cleaved caspase 3 was lower expressed in human glioma tissues comparing with the nontumorous. And then we found that the expression of Nrdp1 and cleaved caspase 3 was increased in the treatment of Temozolomide (TMZ), a drug for glioma chemotherapy. Further investigation indicated that transient transfection of Nrdp1 significantly promoted cell apoptosis by aggravating the degradation of BRUCE and activation of caspase 3. In addition, overexpression of Nrdp1 augmented TMZ induced apoptosis by evaluating the degradation of BRUCE and the activation of caspase 3, while silencing of Nrdp1 reduced the sensitivity to the TMZ by inhibiting the degradation of BRUCE and the activation of caspase 3 in human glioma cells. These observations show that Nrdp1 is a pro-apoptotic protein in human glioma and lower expression of Nrdp1 in human glioma may promote tumor progression by reducing apoptosis, suggesting that Nrdp1 may be an important regulator in the development of human glioma. PMID:25355637

  1. Tumor suppressor Lzap regulates cell cycle progression, doming and zebrafish epiboly

    PubMed Central

    Liu, Dan; Wang, Wen-Der; Melville, David B.; Cha, Yong I.; Yin, Zhirong; Issaeva, Natalia; Knapik, Ela W.; Yarbrough, Wendell G.

    2012-01-01

    Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID:21523853

  2. Research progress of oncogene and tumor suppressor gene in bladder cancer.

    PubMed

    Zhang, X; Han, C; He, J

    2015-12-01

    Bladder cancer is amongst the most common malignant tumor of the urinary tract system and has the worst outcomes. The factors related to the occurrence and progression of this urological cancer has received considerable research attention. The discovery of marker genes enhances the sensitivity and specificity of early diagnosis and treatment of bladder cancer. Furthermore, these genes can be used as targets for antitumor drugs. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis could improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Several studies on the biological characters and mechanism of the related proteins have provided a theoretical basis for the diagnosis and treatment of bladder cancer. In this review article, we summarized the status of the current studies in this field. PMID:25634585

  3. Fatty acid synthase overexpression in adult testicular germ cell tumors: potential role in the progression of non-seminomatous germ cell tumors.

    PubMed

    Miyai, Kosuke; Iwaya, Keiichi; Asano, Tomohiko; Tamai, Seiichi; Matsubara, Osamu; Tsuda, Hitoshi

    2014-02-01

    Overexpression of fatty acid synthase (FASN), which is a key enzyme responsible for the endogenous synthesis of fatty acids, and its association with multistep progression have been demonstrated in various human malignant tumors. We aimed to clarify the potential role of FASN overexpression in the development and progression of adult testicular germ cell tumors (TGCTs). From the primary sites of a cohort of 113 TGCT cases, we obtained 221 histological components: 53 intratubular germ cell neoplasias, unclassified (IGCNUs), 84 seminomas, 32 embryonal carcinomas, seven choriocarcinomas, 21 yolk sac tumors, and 24 teratomas. Samples were analyzed for overexpression of FASN by immunohistochemistry. Intensities of immunoreactivity and the fraction of positive cells were classified into each four categories (intensity, 0 to 3; fraction, 0-10 % = 1, 11-50 % = 2, 51-80 % = 3, and >80 % = 4). The overall score was determined by multiplication of both scores and overall scores greater than 6 were considered FASN overexpression. On a component basis, FASN overexpression was detected in 8 % of seminomas but not in IGCNUs (0 %) and was detected frequently in non-seminomatous germ cell tumors (NSGCTs) (88 % of embryonal carcinomas, all choriocarcinomas, 81 % of yolk sac tumors, and 54 % of teratomas). There were no cases of a mixed tumor (i.e., a tumor with multiple histological components) that overexpressed FASN in seminoma components but not in co-existing NSGCT components, suggesting sequential progression. Our immunohistochemical data suggest that FASN overexpression occurs as a late event during the progression from IGCNUs/seminomas to NSGCTs. PMID:24337182

  4. Long intergenic non-coding RNA 00152 promotes tumor cell cycle progression by binding to EZH2 and repressing p15 and p21 in gastric cancer

    PubMed Central

    Kong, Rong; Xu, Tong-peng; Xia, Rui; Zhang, Er-bao; Shu, Yong-qian

    2016-01-01

    Long noncoding RNAs (lncRNAs) play important regulatory roles in several human cancers. Integrated analysis revealed that expression of long intergenic non-coding RNA 152 (LINC00152) was significantly upregulated in gastric cancer (GC). Further analysis in a cohort of 97 GC patients revealed that LINC00152 expression was positively correlated with tumor invasion depth, lymph node metastasis, higher TNM stage, and poor survival. Gene set enrichment analysis revealed that cell proliferation and cell cycle progression were increased in patients with high LINC00152 expression. In both GC cell lines and xenograft systems, LINC00152 overexpression facilitated GC cell proliferation by accelerating the cell cycle, whereas LINC00152 knockdown had the opposite effect. Moreover, by binding to enhancer of zeste homolog 2 (EZH2), LINC00152 promotes GC tumor cell cycle progression by silencing the expression of p15 and p21. These findings suggest that LINC00152 may play contribute to the progression of GC and may be an effective therapeutic target. PMID:26799422

  5. Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression

    PubMed Central

    Weatherly, D. Brent; Angeletti, Ruth H.; Lee, Sunhee C.

    2014-01-01

    The tumor microenvironment including glial cells and their inflammatory products regulates brain tumor development and progression. We have previously established that human glioma cells are exquisitely sensitive to IL-1 stimulation leading us to undertake a comparative analysis of the secretome of unstimulated and cytokine (IL-1)-stimulated glioblastoma cells. We performed label-free quantitative proteomic analysis and detected 190 proteins which included cytokines, chemokines, growth factors, proteases, cell adhesion molecules, extracellular matrix (ECM) and related proteins. Measuring area under the curve (AUC) of peptides for quantitation, the IL-1-induced secretome contained 13 upregulated and 5 downregulated extracellular proteins (p<0.05) compared to controls. Of these, IL-8, CCL2, TNC, Gal-1 and PTX3 were validated as upregulated and SERPINE1, STC2, CTGF and COL4A2 were validated as downregulated factors by immunochemical methods. A major representation of the ECM and related proteins in the glioblastoma secretome and their modulation by IL-1 suggested that IL-1 induces its effect in part by altering TGFβ expression, activity and signaling. These findings enhance our understanding of IL-1-induced modulation of glioma microenvironment, with implications for increased tumor invasion, migration and angiogenesis. They further provide novel targets for the glioblastoma intervention. PMID:24503185

  6. Progress in the surgical treatment of malignant liver tumors in children.

    PubMed

    Otte, Jean-Bernard

    2010-06-01

    During the last decade, important progress has been made in the surgical treatment of malignant liver tumors in children. For hepatoblastoma, there is a general consensus for combining surgical resection with neoadjuvant (and adjuvant) chemotherapy. Long-term disease-free survival of around 85-90% can be achieved for resectable HB involving no more than three sections of the liver (PRETEXT I-III). For unresectable HB without extrahepatic invasion (PRETEXT IV with involvement of all four sections and some cases of PRETEXT III with invasion of, or close contact with major venous structures), similar results can be obtained with total hepatectomy and liver transplantation. For hepatocellular carcinoma, most often without underlying liver disease in children of the western world, results of resection with partial hepatectomy remain dismal, due to a high rate of recurrence. In contrast, remarkable survival rates have been obtained during the last decade with liver transplantation. There is no argument, either biological or based on evidence, that the selection of pediatric candidates for transplantation should be based on the same criteria as in adult patients (the Milan criteria). Optimization of results require to concentrate children with a malignant liver tumors in specialized, multidisciplinary pediatric centers with expertise in chemotherapy and in both major liver resections and transplantation. Enrolling these children in prospective trials should be encouraged, as well as prospective registration of transplanted patients in PLUTO (Pediatric Liver Unresectable Tumor Observatory-http://Pluto.cineca.org) in order to clarify issues unresolved by retrospective studies. PMID:20227190

  7. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

    SciTech Connect

    Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Yeonsil; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young-Hwa; Park, Young Woo; Koh, Sang Seok

    2014-11-07

    Highlights: • PMAb83, a human monoclonal antibody against PAUF, impaired tumor progression in vivo. • PMAb83 attenuated aggressiveness of tumor cells and suppressed angiogenesis. • PMAb83 in combination with gemcitabine conferred improved survival of mouse model. - Abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31{sup +} vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.

  8. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

    PubMed

    Gu, Jian-Wei; Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-05-15

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer

  9. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice

    PubMed Central

    Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-01-01

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n = 6) or a high-fat (60%, HF, n = 6) diet for 12 weeks. In the eighth week of the dietary program, 106 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3 ± 1.7 vs. 41.5 ± 1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062 ± 0.005 vs. 0.032 ± 0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62 ± 0.63 vs. 1.98 ± 0.27 g; p < 0.01) and IMD (173 ± 3.7 vs. 139 ± 4.3 IM#/mm2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3 ± 3.8 vs. 49.5 ± 4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69 ± 7.1 vs. 48 ± 3.5 pg/ml) and visceral fat VEGF levels (424.4 ± 39.5 vs. 208.5 ± 22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n = 6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77 ± 1.14 vs. 0.94 ± 0.16 pg/mg tissue; n = 6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor

  10. Survival of residual neutrophils and accelerated myelopoiesis limit the efficacy of antibody-mediated depletion of Ly-6G+ cells in tumor-bearing mice.

    PubMed

    Moses, Katrin; Klein, Johanna C; Männ, Linda; Klingberg, Anika; Gunzer, Matthias; Brandau, Sven

    2016-06-01

    Expansion of Ly-6G(+) myeloid cells has been reported in most murine cancer models. However, divergent findings exist regarding the role and effect of these cells on host immunity and tumor progression. Antibody-mediated depletion of Ly-6G(+) cells is a common technique to assess the in vivo relevance of these cells. Interpretation of results crucially depends on the efficacy and course of depletion. We established murine head and neck cancer models and analyzed the efficacy of antibody-mediated depletion by flow cytometry, conventional histology, and intravital imaging with a novel Ly-6G-transgenic mouse model. The first phase of depletion was characterized by effective elimination of Ly-6G(+) cells from the peripheral blood. Nevertheless, viable, resistant cells were found to reside in the tumor tissue and spleen. This peripheral depletion phase was associated with high systemic levels of granulocyte colony-stimulating factor and KC and enhanced splenic production of Ly-6G(+) cells. Even under sustained treatment with either αGr-1 or αLy-6G antibodies, peripheral blood depletion ended after approximately 1 wk and was followed by reappearance of immature Ly-6G(+) cells with an immunoregulatory phenotype. Reappearance of these depletion-resistant immature cells was enhanced in tumor-bearing, compared with naïve, control mice. Collectively, our data suggest that depletion of Ly-6G(+) myeloid cells in tumor-bearing mice is counteracted by the persistence of intratumoral cells, enhanced extramedullary granulopoiesis, and accelerated reappearance of immature cells. Hence, extensive monitoring of in vivo kinetics and tissue distribution of Ly-6G(+) cells is required in depletion studies. PMID:26819319

  11. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway.

    PubMed

    Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

    2016-04-29

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. PMID:27003260

  12. Tumoral Vitamin D Synthesis by CYP27B1 1-α-Hydroxylase Delays Mammary Tumor Progression in the PyMT-MMTV Mouse Model and Its Action Involves NF-κB Modulation.

    PubMed

    Li, Jiarong; Luco, Aimée-Lee; Ochietti, Benoît; Fadhil, Ibtihal; Camirand, Anne; Reinhardt, Timothy A; St-Arnaud, René; Muller, William; Kremer, Richard

    2016-06-01

    Biologically active vitamin D (1,25-dihydroxycholecalciferol or 1,25(OH)2D) is synthetized from inactive prohormone 25-hydroxycholecalciferol (25(OH)D) by the enzyme CYP27B1 1-α-hydroxylase in kidney and several extrarenal tissues including breast. Although the development of breast cancer has been linked to inadequate vitamin D status, the importance of bioactive vitamin D production within tumors themselves is not fully understood. To investigate the role of tumoral vitamin D production in mammary epithelial cell progression to breast cancer, we conducted a Cre-loxP-mediated Cyp27b1 gene ablation in the mammary epithelium of the polyoma middle T antigen-mouse mammary tumor virus (PyMT-MMTV) mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous mammary tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression, and survival markers were up-regulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. AK thymoma (AKT) phosphorylation and expression of several components of nuclear factor κB (NF-κB), integrin, and signal transducer and activator of transcription 3 (STAT3) signaling pathways were increased in Cyp27b1-ablated tumors compared with nonablated controls. In vitro, 1,25(OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and nonablated mice, accompanied by rapid disappearance of NF-κB p65 from the nucleus and segregation in the cytoplasm. In contrast, treatment with the metabolic precursor 25(OH)D was only effective against cells from nonablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-κB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1-α-hydroxylase activity plays a crucial role in controlling early oncogene-mediated mammary carcinogenesis events, at least in part by modulating tumoral cell NF-κB p65 nuclear translocation. PMID:27119753

  13. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: feasible and efficacious

    PubMed Central

    Ramaswamy, Anant; Pande, Nikhil; Shetty, Omshree; Shetty, Nitin; Gupta, Sudeep

    2016-01-01

    Background A median progression free survival (PFS) of 18–20 months and median overall survival (OS) of 51–57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. Methods All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed. Patients were assessed for response with CT or PET CT scans. Patients continued pazopanib until progression or unacceptable toxicity. Survival was evaluated by Kaplan Meier product method. Results A total of 11 consecutive patients were included in our study. Median duration of follow up was seven months. The median lines of prior therapy was 2 [1-5]. Partial response (PR) was observed in seven patients and two had stable disease (SD). Two patients died within one month of start of pazopanib. Five of ten patients had progressed during the study with eight patients still alive. The median PFS was 11.9 months and the median OS was not reached. Common adverse events seen were hand-foot-syndrome (HFS) in four patients, anemia in four patients and fatigue in three patients. Grade 3/4 adverse events were uncommon. Three patients required dose modification of pazopanib. Conclusions Pazopanib is a reasonably efficacious well tolerated TKI and can be explored as a treatment option in advanced GIST that has progressed on imatinib. PMID:27563456

  14. Chemopreventive Efficacy of Inositol Hexaphosphate against Prostate Tumor Growth and Progression in TRAMP Mice

    PubMed Central

    Raina, Komal; Rajamanickam, Subapriya; Singh, Rana P.; Agarwal, Rajesh

    2010-01-01

    Purpose Herein, for the first time, we evaluated in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high fiber containing diets, against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Experimental Design Beginning 4 weeks of age, male TRAMP mice were fed with 2% (w/v) IP6 in drinking water or only drinking water till 24 weeks of age, and then sacrificed. Prostate tissue was subjected to histopathology, and immunohistochemical analyses for proliferation and apoptosis. Results IP6 feeding did not show any adverse effect on fluid and diet consumption, and body weight. There was a significant reduction (40%, P<0.01) in the weight of lower urogenital tract organs in the IP6-fed mice. IP6 inhibited prostate cancer (PCa) progression at prostatic intraepithelial neoplasia (PIN) stage and strongly reduced the incidence of adenocarcinoma (PIN:adenocarcinoma, 75:25% mice in IP6 group versus 39:61% in control group, P<0.05). The incidences of well differentiated and poorly differentiated adenocarcinomas in IP6-fed group were reduced by 44% and 62%, respectively. Immunohistochemical analysis of prostate tissue showed 26% (P<0.05) decrease in proliferation cell nuclear antigen (PCNA)-positive cells, and 3.5-fold increase in apoptotic cells with no effect on Tag expression by IP6. Conclusions These findings are both novel and highly significant in establishing for the first time that oral IP6 feeding, without any toxicity, suppresses prostate tumor growth and progression at the neoplastic stage thereby reducing the incidence of adenocarcinoma involving anti-proliferative and pro-apoptotic effects, and thus could have potential against human PCa. PMID:18483386

  15. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    PubMed

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  16. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

    PubMed Central

    Ibrahim, Safaa A.; Katara, Gajendra K.; Kulshrestha, Arpita; Jaiswal, Mukesh K.; Amin, Magdy A.; Beaman, Kenneth D.

    2015-01-01

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  17. Circulating tumor cells are correlated with disease progression and treatment response in an orthotopic hepatocellular carcinoma model.

    PubMed

    Yan, Jun; Fan, Zhichao; Wu, Xiufeng; Xu, Min; Jiang, Jiahao; Tan, Changjun; Wu, Weizhong; Wei, Xunbin; Zhou, Jian

    2015-11-01

    Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by rapid progression, poor prognosis, and frequent hematogenous metastasis. A minimally invasive diagnostic biomarker that can predict disease progression and treatment response would be of extraordinary benefit. Therefore, we have investigated whether the number of circulating tumor cells (CTCs) is correlated with disease progression and treatment response in HCC. Here we report that the number of CTCs, monitored by in vivo flow cytometry (IVFC), is strongly correlated with disease progression and treatment response in a highly metastatic orthotopic nude mouse model of green fluorescent protein (GFP)-labeled HCC. Sorafenib treatment reduces the number of CTCs significantly. The decreased number of CTCs is consistent with low lung metastasis. This study has demonstrated a considerable clinical value of CTCs as a biomarker in predicting disease progression and monitoring therapeutic efficacy in patients with HCC. PMID:26355643

  18. High Milk Consumption Does Not Affect Prostate Tumor Progression in Two Mouse Models of Benign and Neoplastic Lesions

    PubMed Central

    Boutillon, Florence; Verkarre, Virginie; Camparo, Philippe; Viltard, Mélanie; Méjean, Arnaud; Oudard, Stéphane; Souberbielle, Jean-Claude; Friedlander, Gérard; Goffin, Vincent

    2015-01-01

    Epidemiological studies that have investigated whether dairy (mainly milk) diets are associated with prostate cancer risk have led to controversial conclusions. In addition, no existing study clearly evaluated the effects of dairy/milk diets on prostate tumor progression, which is clinically highly relevant in view of the millions of men presenting with prostate pathologies worldwide, including benign prostate hyperplasia (BPH) or high-grade prostatic intraepithelial neoplasia (HGPIN). We report here a unique interventional animal study to address this issue. We used two mouse models of fully penetrant genetically-induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia (probasin-Prl mice, Pb-Prl) or pre-cancerous PIN lesions (KIMAP mice). Mice were fed high milk diets (skim or whole) for 15 to 27 weeks of time depending on the kinetics of prostate tumor development in each model. Prostate tumor progression was assessed by tissue histopathology examination, epithelial proliferation, stromal inflammation and fibrosis, tumor invasiveness potency and expression of various tumor markers relevant for each model (c-Fes, Gprc6a, activated Stat5 and p63). Our results show that high milk consumption (either skim or whole) did not promote progression of existing prostate tumors when assessed at early stages of tumorigenesis (hyperplasia and neoplasia). For some parameters, and depending on milk type, milk regimen could even exhibit slight protective effects towards prostate tumor progression by decreasing the expression of tumor-related markers like Ki-67 and Gprc6a. In conclusion, our study suggests that regular milk consumption should not be considered detrimental for patients presenting with early-stage prostate tumors. PMID:25938513

  19. miR-221/222 control luminal breast cancer tumor progression by regulating different targets

    PubMed Central

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3′UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted “normal” breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy. PMID:24736554

  20. An Examination of the Impact of Accelerating Community College Students' Progression through Developmental Education

    ERIC Educational Resources Information Center

    Hodara, Michelle; Jaggars, Shanna Smith

    2014-01-01

    In an effort to improve developmental education students' outcomes, community colleges have been experimenting with acceleration strategies. Models of acceleration allow students to complete their developmental requirements in a shorter amount of time. However, there has been limited empirical research on the effects of accelerating students'…

  1. Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

    PubMed Central

    Zhang, Jin; Xu, Enshun; Ren, Cong; Yan, Wensheng; Zhang, Min; Chen, Mingyi; Cardiff, Robert D.; Imai, Denise M.; Wisner, Erik; Chen, Xinbin

    2014-01-01

    RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression. PMID:25512531

  2. A comparative study of two prediction models for brain tumor progression

    NASA Astrophysics Data System (ADS)

    Zhou, Deqi; Tran, Loc; Wang, Jihong; Li, Jiang

    2015-03-01

    MR diffusion tensor imaging (DTI) technique together with traditional T1 or T2 weighted MRI scans supplies rich information sources for brain cancer diagnoses. These images form large-scale, high-dimensional data sets. Due to the fact that significant correlations exist among these images, we assume low-dimensional geometry data structures (manifolds) are embedded in the high-dimensional space. Those manifolds might be hidden from radiologists because it is challenging for human experts to interpret high-dimensional data. Identification of the manifold is a critical step for successfully analyzing multimodal MR images. We have developed various manifold learning algorithms (Tran et al. 2011; Tran et al. 2013) for medical image analysis. This paper presents a comparative study of an incremental manifold learning scheme (Tran. et al. 2013) versus the deep learning model (Hinton et al. 2006) in the application of brain tumor progression prediction. The incremental manifold learning is a variant of manifold learning algorithm to handle large-scale datasets in which a representative subset of original data is sampled first to construct a manifold skeleton and remaining data points are then inserted into the skeleton by following their local geometry. The incremental manifold learning algorithm aims at mitigating the computational burden associated with traditional manifold learning methods for large-scale datasets. Deep learning is a recently developed multilayer perceptron model that has achieved start-of-the-art performances in many applications. A recent technique named "Dropout" can further boost the deep model by preventing weight coadaptation to avoid over-fitting (Hinton et al. 2012). We applied the two models on multiple MRI scans from four brain tumor patients to predict tumor progression and compared the performances of the two models in terms of average prediction accuracy, sensitivity, specificity and precision. The quantitative performance metrics were

  3. Dysregulation of JAM-A plays an important role in human tumor progression

    PubMed Central

    Zhao, Chen; Lu, Funian; Chen, Hongxia; Zhao, Xianda; Sun, Jun; Chen, Honglei

    2014-01-01

    Junctional adhesion molecule A (JAM-A) is a transmembrane protein that belongs to the immunoglobulin (Ig) superfamily. Evidence determines that JAM-A plays a role in numerous cellular processes, including tight junction assembly, leukocyte migration, platelet activation, angiogenesis and virus binding. Recent research suggests that JAM-A is dysregulated in various cancers and is vital for tumor progression. JAM-A is implicated in carcinogenesis via different signal pathways such as TGF-β1 signaling. Furthermore, JAM-A expression in cancers is usually associated with certain outcome of patients and might be a prognostic indicator. In this review, the correlation between JAM-A expression and human cancers will be described. PMID:25400822

  4. FGF19 Contributes to Tumor Progression in Gastric Cancer by Promoting Migration and Invasion.

    PubMed

    Wang, Shuang; Zhao, Daqi; Tian, Ruihua; Shi, Hailong; Chen, Xiangming; Liu, Wenzhi; Wei, Lin

    2016-01-01

    Gastric cancer is the fourth most common type of cancer and second leading cause of cancer-related death in the world. Since patients are often diagnosed at a late stage, very few effective therapies are left in the arsenal. FGF19, as a hormone, has been reported to promote tumor growth in various types of cancer; however, its function in gastric cancer remains unknown. In the current study, we showed that FGF19 is overexpressed in gastric cancer and is associated with depth of invasion, lymph node metastasis, and TNM stage. In addition, in vitro experiments demonstrated that FGF19 is able to enhance migration and invasion abilities of gastric cancer cells. Given its great potency in gastric cancer progression, FGF19 may be an effective target of treatment for advanced gastric cancer patients. PMID:27053348

  5. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease. PMID:25713992

  6. Targeted tumor delivery and controlled release of neuronal drugs with ferritin nanoparticles to regulate pancreatic cancer progression.

    PubMed

    Lei, Yifeng; Hamada, Yoh; Li, Jun; Cong, Liman; Wang, Nuoxin; Li, Ying; Zheng, Wenfu; Jiang, Xingyu

    2016-06-28

    Pancreatic cancer is a lethal malignancy whose progression is highly dependent on the nervous microenvironment. This study develops neural drug-loaded ferritin nanoparticles (Ft NPs) to regulate the nervous microenvironment, in order to control the pancreatic cancer progression. The drug-loaded Ft NPs can target pancreatic tumors via passive targeting of EPR effects of tumors and active targeting via transferrin receptor 1 (TfR1) binding on cancer cells, with a triggered drug release in acidic tumor environment. Two drugs, one activates neural activity (carbachol), the other impairs neural activity (atropine), are encapsulated into the Ft NPs to form two kinds of nano drugs, Nano-Cab NPs and Nano-Ato NPs, respectively. The activation of the nervous microenvironment by Nano-Cab NPs significantly promotes the pancreatic tumor progression, whereas the blockage of neural niche by Nano-Ato NPs remarkably impairs the neurogenesis in tumors and the progression of pancreatic cancer. The Ft-based nanoparticles thus comprise an effective and safe route of delivery of neural drugs for novel anti-cancer therapy. PMID:27046157

  7. Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats.

    PubMed

    Deminice, Rafael; Cella, Paola Sanches; Padilha, Camila S; Borges, Fernando H; da Silva, Lilian Eslaine Costa Mendes; Campos-Ferraz, Patrícia L; Jordao, Alceu Afonso; Robinson, Jason Lorne; Bertolo, Robert F; Cecchini, Rubens; Guarnier, Flávia Alessandra

    2016-08-01

    The purpose of this study was to investigate (1) the impact of tumor growth on homocysteine (Hcy) metabolism, liver oxidative stress and cancer cachexia and, (2) the potential benefits of creatine supplementation in Walker-256 tumor-bearing rats. Three experiments were conducted. First, rats were killed on days 5 (D5), 10 (D10) and 14 (D14) after tumor implantation. In experiment 2, rats were randomly assigned to three groups designated as control (C), tumor-bearing (T) and tumor-bearing supplemented with creatine (TCr). A life span experiment was conducted as the third experiment. Creatine was supplied in drinking water for 21 days (8 g/L) in all cases. Tumor implantation consisted of a suspension of Walker-256 cells (8.0 × 10(7) cells in 0.5 mL of PBS). The progressive increase (P < 0.05) in tumor mass coincided with a progressively lower body weight and higher hepatic oxidative stress; plasma Hcy concentration was 80 % higher (P < 0.05) by 10 days of tumor implantation. Impaired Hcy metabolism was evidenced by decreased hepatic betaine-homocysteine methyltransferase (Bhmt), glycine N-methyltransferase (Gnmt) and cystathionine beta synthase (CBS) gene expression. In contrast, creatine supplementation promoted a 28 % reduction of tumor weight (P < 0.05). Plasma Hcy (C 6.1 ± 0.6, T 10.3 ± 1.5, TCr 6.3 ± 0.9, µmol/L) and hepatic oxidative stress were lower in the TCr group compared to T. Creatine supplementation was unable to decrease Hcy concentration and to increase SAM/SAH ratio in tumor tissue. These data suggest that creatine effects on hepatic impaired Hcy metabolism promoted by tumor cell inoculation are responsible to decrease plasma Hcy in tumor-bearing rats. In conclusion, Walker-256 tumor growth is associated with progressive hyperhomocysteinemia, body weight loss and liver oxidative stress in rats. Creatine supplementation, however, prevented these tumor-associated perturbations. PMID:26781304

  8. YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

    PubMed Central

    Somasekharan, Syam Prakash; El-Naggar, Amal; Leprivier, Gabriel; Cheng, Hongwei; Hajee, Shamil; Grunewald, Thomas G.P.; Zhang, Fan; Ng, Tony; Delattre, Olivier; Evdokimova, Valentina; Wang, Yuzhuo; Gleave, Martin

    2015-01-01

    Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression. PMID:25800057

  9. Expression of Neuropilin-2 in salivary adenoid cystic carcinoma: its implication in tumor progression and angiogenesis.

    PubMed

    Cai, Yu; Wang, Rong; Zhao, Yi-Fang; Jia, Jun; Sun, Zhi-Jun; Chen, Xin-Ming

    2010-12-15

    Neuropilin-2(Nrp2), which is a nontyrosine kinase transmembrane glycoprotein, can promote angiogenesis and is a poor prognostic factor in some human cancers. In the present study, to explore the expression and potential function of Nrp2 in salivary adenoid cystic carcinoma (SACC), immunohistochemistry was used to examine the Nrp2 expression in 50 SACCs and 20 normal salivary gland tissues nearby SACCs. The result showed that immunoreactivity for Nrp2 was detected in 47 of 50 SACCs, and its expression level had significant correlations with microvessel density, tumor size, TMN clinical stage, vascular invasion, and metastasis (P<0.05) of SACCs. In addition, inhibition of Nrp2 function by the receptor-ligand interaction-blocking antibody decreased cell migration, invasion, and angiogenic promotion without influences on the cell proliferation of Acc-3 cells. Taken together, the expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in SACCs. These results suggest that Nrp2 may be a potential therapeutic target for SACCs. PMID:20851535

  10. Heme oxygenase-1 promotes tumor progression and metastasis of colorectal carcinoma cells by inhibiting antitumor immunity

    PubMed Central

    Seo, Geom Seog; Jiang, Wen-Yi; Chi, Jin Hua; Jin, Hao; Park, Won-Chul; Sohn, Dong Hwan; Park, Pil-Hoon; Lee, Sung Hee

    2015-01-01

    Heme oxygenase-1 (HO-1) is upregulated in colorectal carcinoma (CRC) cells. However, the role of HO-1 in the metastatic potential of CRC remains to be elucidated. In this study, we investigated the potential of HO-1 to control the antitumor immunity of CRC. Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the immune surveillance system. Hemin-induced HO-1 expression suppressed the expression of ICAM-1 in human CRC cells. HO-1 regulated ICAM-1 expression via tristetraprolin, an mRNA-binding protein, at the posttranscriptional level in CRC cells. The upregulated HO-1 expression in CRC cells markedly decreased the adhesion of peripheral blood mononuclear lymphocytes (PBMLs) to CRC cells and PBML-mediated cytotoxicity against CRC cells. Production of CXCL10, an effector T cell-recruiting chemokine, was significantly reduced by the increased HO-1 expression. The expression of the CXCL10 receptor, CXCR3, decreased significantly in PBMLs that adhered to CRC cells. HO-1 expression correlated negatively, although nonsignificantly, with ICAM-1 and CXCL10 expression in xenograft tumors. Taken together, our data suggest that HO-1 expression is functionally linked to the mediation of tumor progression and metastasis of CRC cells by inhibiting antitumor immunity. PMID:26087182

  11. Involvement of 14-3-3 Proteins in Regulating Tumor Progression of Hepatocellular Carcinoma.

    PubMed

    Wu, Yi-Ju; Jan, Yee-Jee; Ko, Bor-Sheng; Liang, Shu-Man; Liou, Jun-Yang

    2015-01-01

    There are seven mammalian isoforms of the 14-3-3 protein, which regulate multiple cellular functions via interactions with phosphorylated partners. Increased expression of 14-3-3 proteins contributes to tumor progression of various malignancies. Several isoforms of 14-3-3 are overexpressed and associate with higher metastatic risks and poorer survival rates of hepatocellular carcinoma (HCC). 14-3-3β and 14-3-3ζ regulate HCC cell proliferation, tumor growth and chemosensitivity via modulating mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 signal pathways. Moreover, 14-3-3ε suppresses E-cadherin and induces focal adhesion kinase (FAK) expression, thereby enhancing epithelial-mesenchymal transition (EMT) and HCC cell migration. 14-3-3ζ forms complexes with αB-crystallin, which induces EMT and is the cause of sorafenib resistance in HCC. Finally, a recent study has indicated that 14-3-3σ induces heat shock protein 70 (HSP70) expression, which increases HCC cell migration. These results suggest that selective 14-3-3 isoforms contribute to cell proliferation, EMT and cell migration of HCC by regulating distinct targets and signal pathways. Targeting 14-3-3 proteins together with specific downstream effectors therefore has potential to be therapeutic and prognostic factors of HCC. In this article, we will overview 14-3-3's regulation of its downstream factors and contributions to HCC EMT, cell migration and proliferation. PMID:26083935

  12. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    PubMed

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P = 0.001) and had poorer disease-free survival (DFS) and overall survival (OS) compared to normal SOX17 expression (P = 0.002 and 0.001, respectively). Univariate and multivariate analyses indicated that lower SOX17 expression was an independent prognostic factor for DFS (P = 0.007; HR = 2.854; 95 % CI 1.326-6.147) and OS (P = 0.005; HR = 5.035; 95 % CI 1.648-15.385) for breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer. PMID:25971583

  13. Pretreatment serum interleukin-1β, interleukin-6, and tumor necrosis factor-α levels predict the progression of colorectal cancer.

    PubMed

    Chang, Pei-Hung; Pan, Yi-Ping; Fan, Chung-Wei; Tseng, Wen-Ko; Huang, Jen-Seng; Wu, Tsung-Han; Chou, Wen-Chi; Wang, Cheng-Hsu; Yeh, Kun-Yun

    2016-03-01

    The correlations of pretreatment serum concentrations of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα) with the clinicopathologic features and progression of colorectal cancer (CRC) were investigated. The pretreatment serum levels of IL-1β, IL-6, and TNFα were measured in 164 CRC patients before treatment. The relationships between changes in proinflammatory cytokine and C-reactive protein (CRP) levels and both clinicopathologic variables and disease progression were examined by univariate and multivariate analysis. Advanced tumor stage was associated with a poorer histologic differentiation, higher CRP level, lower albumin level, and inferior progression-free survival rate (PFSR). Furthermore, high levels of CRP (>5 mg/L) were associated with proinflammatory cytokine intensity, defined according to the number of proinflammatory cytokines with levels above the median level (IL-1β ≥10 pg/mL; IL-6 ≥ 10 pg/mL; and TNFα ≥55 pg/mL). Under different inflammation states, proinflammatory cytokine intensity, in addition to tumor stage, independently predicted PFSR in patients with CRP <5 mg/L, whereas tumor stage was the only independent predictor of PFSR in patients with CRP ≥5 mg/L. Proinflammatory cytokine intensity and the CRP level are clinically relevant for CRC progression. Measurement of IL-1β, IL-6, and TNFα serum levels may help identify early cancer progression among patients with CRP <5 mg/L in routine practice. PMID:26799163

  14. Cytoskeletal protein flightless I inhibits apoptosis, enhances tumor cell invasion and promotes cutaneous squamous cell carcinoma progression

    PubMed Central

    Kopecki, Zlatko; Yang, Gink N.; Jackson, Jessica E.; Melville, Elizabeth L.; Cal1ey, Matthew P.; Murrell, Dedee F.; Darby, Ian A.; O'Toole, Edel A.; Samuel, Michael S.; Cowin, Allison J.

    2015-01-01

    Flightless I (Flii) is an actin remodeling protein that affects cellular processes including adhesion, proliferation and migration. In order to determine the role of Flii during carcinogenesis, squamous cell carcinomas (SCCs) were induced in Flii heterozygous (Flii+/−), wild-type and Flii overexpressing (FliiTg/Tg) mice by intradermal injection of 3-methylcholanthrene (MCA). Flii levels were further assessed in biopsies from human SCCs and the human SCC cell line (MET-1) was used to determine the effect of Flii on cellular invasion. Flii was highly expressed in human SCC biopsies particularly by the invading cells at the tumor edge. FliiTg/Tg mice developed large, aggressive SCCs in response to MCA. In contrast Flii+/− mice had significantly smaller tumors that were less invasive. Intradermal injection of Flii neutralizing antibodies during SCC initiation and progression significantly reduced the size of the tumors and, in vitro, decreased cellular sphere formation and invasion. Analysis of the tumors from the Flii overexpressing mice showed reduced caspase I and annexin V expression suggesting Flii may negatively regulate apoptosis within these tumors. These studies therefore suggest that Flii enhances SCC tumor progression by decreasing apoptosis and enhancing tumor cell invasion. Targeting Flii may be a potential strategy for reducing the severity of SCCs. PMID:26497552

  15. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  16. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  17. Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma.

    PubMed

    Gao, Shan; Tu, Dan-Na; Li, Heng; Jiang, Jian-Xin; Cao, Xin; You, Jin-Bin; Zhou, Xiao-Qin

    2016-07-01

    Reprogrammed energy metabolism is an emerging hallmark of cancer. Lactate dehydrogenase A (LDHA), a key enzyme involved in anaerobic glycolysis, is frequently deregulated in human malignancies. However, limited knowledge is known about its roles in the progression of osteosarcoma (OS). In this study, we found that LDHA is commonly upregulated in four OS cell lines compared with the normal osteoblast cells (hFOB1.19). Treatment with FX11, a specific inhibitor of LDHA, significantly reduced LDHA activity, and inhibited cell proliferation and invasive potential in a dose dependent manner. Genetic silencing of LDHA resulted in a decreased lactate level in the culture medium, reduced cell viability and decreased cell invasion ability. Meanwhile, silencing of LDHA also compromised tumorigenesis in vivo. Furthermore, knockdown of LDHA remarkably reduced extracellular acidification rate (ECAR) as well as glucose consumption. In the presence of 2-DG, a glycolysis inhibitor, LDHA-mediated cell proliferation and invasion were completely blocked, indicating the oncogenic activities of LDHA may dependent on Warburg effect. Finally, pharmacological inhibition of c-Myc or HIF1α significantly attenuated LDHA expression. Taken together, upregulated LDHA facilitates tumor progression of OS and might be a potential target for OS treatment. PMID:27261617

  18. Phase II Study of Intraventricular Methotrexate in Children With Recurrent or Progressive Malignant Brain Tumors

    ClinicalTrials.gov

    2016-06-30

    Recurrent Childhood Medulloblastoma; Recurrent Childhood Ependymoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Embryonal Tumor With Abundant Neuropil and True Rosettes; Metastatic Malignant Neoplasm to the Leptomeninges

  19. An Examination of the Impact of Accelerating Community College Students' Progression through Developmental Education

    ERIC Educational Resources Information Center

    Hodara, Michelle; Jaggars, Shanna Smith

    2014-01-01

    In an effort to improve developmental education students' outcomes, community colleges have been experimenting with acceleration strategies. Models of acceleration allow students to complete their developmental requirements in a shorter amount of time. However, there has been limited empirical research on the effects of accelerating…

  20. Determinants of Local Progression After Computed Tomography-Guided Percutaneous Radiofrequency Ablation for Unresectable Lung Tumors: 9-Year Experience in a Single Institution

    SciTech Connect

    Okuma, Tomohisa Matsuoka, Toshiyuki; Yamamoto, Akira; Oyama, Yoshimasa; Hamamoto, Shinichi; Toyoshima, Masami; Nakamura, Kenji; Miki, Yukio

    2010-08-15

    The purpose of this study was to retrospectively determine the local control rate and contributing factors to local progression after computed tomography (CT)-guided radiofrequency ablation (RFA) for unresectable lung tumor. This study included 138 lung tumors in 72 patients (56 men and 16 women; age 70.0 {+-} 11.6 years (range 31-94); mean tumor size 2.1 {+-} 1.2 cm [range 0.2-9]) who underwent lung RFA between June 2000 and May 2009. Mean follow-up periods for patients and tumors were 14 and 12 months, respectively. The local progression-free rate and survival rate were calculated to determine the contributing factors to local progression. During follow-up, 44 of 138 (32%) lung tumors showed local progression. The 1-, 2-, 3-, and 5-year overall local control rates were 61, 57, 57, and 38%, respectively. The risk factors for local progression were age ({>=}70 years), tumor size ({>=}2 cm), sex (male), and no achievement of roll-off during RFA (P < 0.05). Multivariate analysis identified tumor size {>=}2 cm as the only independent factor for local progression (P = 0.003). For tumors <2 cm, 17 of 68 (25%) showed local progression, and the 1-, 2-, and 3-year overall local control rates were 77, 73, and 73%, respectively. Multivariate analysis identified that age {>=}70 years was an independent determinant of local progression for tumors <2 cm in diameter (P = 0.011). The present study showed that 32% of lung tumors developed local progression after CT-guided RFA. The significant risk factor for local progression after RFA for lung tumors was tumor size {>=}2 cm.

  1. KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis

    PubMed Central

    Narla, Goutham; DiFeo, Analisa; Fernandez, Yolanda; Dhanasekaran, Saravana; Huang, Fei; Sangodkar, Jaya; Hod, Eldad; Leake, Devin; Friedman, Scott L.; Hall, Simon J.; Chinnaiyan, Arul M.; Gerald, William L.; Rubin, Mark A.; Martignetti, John A.

    2008-01-01

    Metastatic prostate cancer (PCa) is one of the leading causes of death from cancer in men. The molecular mechanisms underlying the transition from localized tumor to hormone-refractory metastatic PCa remain largely unknown, and their identification is key for predicting prognosis and targeted therapy. Here we demonstrated that increased expression of a splice variant of the Kruppel-like factor 6 (KLF6) tumor suppressor gene, known as KLF6-SV1, in tumors from men after prostatectomy predicted markedly poorer survival and disease recurrence profiles. Analysis of tumor samples revealed that KLF6-SV1 levels were specifically upregulated in hormone-refractory metastatic PCa. In 2 complementary mouse models of metastatic PCa, KLF6-SV1–overexpressing PCa cells were shown by in vivo and ex vivo bioluminescent imaging to metastasize more rapidly and to disseminate to lymph nodes, bone, and brain more often. Interestingly, while KLF6-SV1 overexpression increased metastasis, it did not affect localized tumor growth. KLF6-SV1 inhibition using RNAi induced spontaneous apoptosis in cultured PCa cell lines and suppressed tumor growth in mice. Together, these findings demonstrate that KLF6-SV1 expression levels in PCa tumors at the time of diagnosis can predict the metastatic behavior of the tumor; thus, KLF-SV1 may represent a novel therapeutic target. PMID:18596922

  2. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    PubMed

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  3. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    PubMed Central

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  4. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Tumor progression locus 2 (TPL2), a serine threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unkn...

  5. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    PubMed

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX. PMID:26071407

  6. Accelerated tumor invasion under non-isotropic cell dispersal in glioblastomas

    NASA Astrophysics Data System (ADS)

    Fort, Joaquim; Solé, Ricard V.

    2013-05-01

    Glioblastomas are highly diffuse, malignant tumors that have so far evaded clinical treatment. The strongly invasive behavior of cells in these tumors makes them very resistant to treatment, and for this reason both experimental and theoretical efforts have been directed toward understanding the spatiotemporal pattern of tumor spreading. Although usual models assume a standard diffusion behavior, recent experiments with cell cultures indicate that cells tend to move in directions close to that of glioblastoma invasion, thus indicating that a biased random walk model may be much more appropriate. Here we show analytically that, for realistic parameter values, the speeds predicted by biased dispersal are consistent with experimentally measured data. We also find that models beyond reaction-diffusion-advection equations are necessary to capture this substantial effect of biased dispersal on glioblastoma spread.

  7. Structure and function of IQ-domain GTPase-activating protein 1 and its association with tumor progression (Review)

    PubMed Central

    WU, YAN; CHEN, YONG-CHANG

    2014-01-01

    IQ-domain GTPase-activating proteins (IQGAPs) are evolutionary conserved multidomain proteins that are found in numerous organisms, from yeast to mammals. To date, three IQGAP proteins have been identified in humans, of which IQGAP1 is the best characterized. As a scaffold protein, IQGAP1 contains multiple protein-interacting domains, which modulate binding to target proteins. Recent mounting studies demonstrated a role for IQGAP1 in tumor progression, supported by the altered expression and subcellular distribution of IQGAP1 in tumors. The contribution of IQGAP1 to tumor progression appears to involve a complex interplay of cell functions by integrating diverse signal transduction pathways and coordinating activities, such as cell adhesion, migration, invasion, proliferation and angiogenesis. PMID:24649059

  8. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures

    PubMed Central

    Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

    2014-01-01

    Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49fhi/CD90lo cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49fhi/CD90lo cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID:24802970

  9. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures.

    PubMed

    Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

    2014-08-01

    Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49f(hi) /CD90(lo) cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49f(hi) /CD90(lo) cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID:24802970

  10. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

    PubMed Central

    Vercherat, Cécile; Blanc, Martine; Lepinasse, Florian; Gadot, Nicolas; Couderc, Christophe; Poncet, Gilles; Walter, Thomas; Joly, Marie-Odile; Hervieu, Valérie; Scoazec, Jean-Yves; Roche, Colette

    2015-01-01

    Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs. SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways. This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy. PMID:26447612

  11. Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation

    PubMed Central

    Stice, Camilla P.; Hussain, Sajid; Liu, Chun; Ausman, Lynne M.

    2016-01-01

    Background The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation. Methods Male TPL2−/− knockout (TPL2KO) mice and TPL2+/+ wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined. Results Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls. Conclusions The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD. PMID:26904554

  12. Persistent Uroplakin Expression in Advanced Urothelial Carcinomas: Implications in Urothelial Tumor Progression and Clinical Outcome

    PubMed Central

    Huang, Hong-Ying; Shariat, Shahrokh F.; Sun, Tung-Tien; Lepor, Herbert; Shapiro, Ellen; Hsieh, Jer-Tsong; Ashfaq, Raheela; Lotan, Yair; Wu, Xue-Ru

    2007-01-01

    As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathological parameter, tumor’s biological behavior or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or non-tumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63/74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104/202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33/50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including micro-luminal, basal-laminal, cytoplasmic or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence and bladder cancer-specific mortality (p=0.042, p=0.035, p=0.023 and p=0.022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27 and cyclin D1, thus excluding a functional link between these two groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and –negative carcinomas

  13. Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

    PubMed Central

    Bowser, Jessica L.; Blackburn, Michael R.; Shipley, Gregory L.; Molina, Jose G.; Dunner, Kenneth; Broaddus, Russell R.

    2015-01-01

    Ecto-5′-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell–mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization–dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42–dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na+K+ ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described. PMID:26642367

  14. Progress in radiocarbon dating with the Chalk River MP tandem accelerator

    SciTech Connect

    Andrews, H.R.; Ball, G.C.; Brown, R.M.; Davies, W.G.; Imahori, Y.; Milton, J.C.D.

    1980-01-01

    The evolution of a tandem accelerator /sup 14/C dating system at Chalk River is recounted. Background problems and sources of instability are discussed and solutions are described. Details of sample chemistry and source preparation are presented.

  15. Real-World Study of Everolimus in Advanced Progressive Neuroendocrine Tumors

    PubMed Central

    Panzuto, Francesco; Rinzivillo, Maria; Fazio, Nicola; de Braud, Filippo; Luppi, Gabriele; Zatelli, Maria Chiara; Lugli, Francesca; Tomassetti, Paola; Riccardi, Ferdinando; Nuzzo, Carmen; Brizzi, Maria Pia; Faggiano, Antongiulio; Zaniboni, Alberto; Nobili, Elisabetta; Pastorelli, Davide; Cascinu, Stefano; Merlano, Marco; Chiara, Silvana; Antonuzzo, Lorenzo; Funaioli, Chiara; Spada, Francesca; Pusceddu, Sara; Fontana, Annalisa; Ambrosio, Maria Rosaria; Cassano, Alessandra; Campana, Davide; Cartenì, Giacomo; Appetecchia, Marialuisa; Berruti, Alfredo; Colao, Annamaria; Falconi, Massimo

    2014-01-01

    Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3–4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3–4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs. PMID:25117065

  16. Regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor-α genetic variations

    PubMed Central

    LIU, YANGZHOU; HAN, NING; LI, QINCHUAN; LI, ZENGCHUN

    2016-01-01

    The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software. An integrated miRNA-DEG network was constructed using the Cytoscape software, based on the interactions between the DEGs, as identified using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the correlation between miRNAs and their target genes. Furthermore, Gene Ontology and pathway enrichment analyses were conducted for the DEGs using the Database for Annotation, Visualization and Integrated Discovery and the KEGG Orthology Based Annotation System, respectively. A total of 390 DEGS between the WT and MUT samples, along with 11 -associated miRNAs, were identified. The integrated miRNA-DEG network consisted of 38 DEGs and 11 miRNAs. Within this network, COPS2 was found to be associated with transcriptional functions, while FUS was found to be involved in mRNA metabolic processes. Other DEGs, including FBXW7 and CUL3, were enriched in the ubiquitin-mediated proteolysis pathway. In addition, miR-15 was predicted to target COPS2 and CUL3. The results of the present study suggested that COPS2, FUS, FBXW7 and CUL3 may be associated with sepsis in patients with TNF-α genetic variations. In the progression of sepsis, FBXW7 and CUL3 may participate in the ubiquitin-mediated proteolysis pathway, whereas COPS2 may regulate the phosphorylation and ubiquitination of the FUS protein. Furthermore, COPS2 and CUL3 may be novel targets of miR-15. PMID:27347057

  17. Real-world study of everolimus in advanced progressive neuroendocrine tumors.

    PubMed

    Panzuto, Francesco; Rinzivillo, Maria; Fazio, Nicola; de Braud, Filippo; Luppi, Gabriele; Zatelli, Maria Chiara; Lugli, Francesca; Tomassetti, Paola; Riccardi, Ferdinando; Nuzzo, Carmen; Brizzi, Maria Pia; Faggiano, Antongiulio; Zaniboni, Alberto; Nobili, Elisabetta; Pastorelli, Davide; Cascinu, Stefano; Merlano, Marco; Chiara, Silvana; Antonuzzo, Lorenzo; Funaioli, Chiara; Spada, Francesca; Pusceddu, Sara; Fontana, Annalisa; Ambrosio, Maria Rosaria; Cassano, Alessandra; Campana, Davide; Cartenì, Giacomo; Appetecchia, Marialuisa; Berruti, Alfredo; Colao, Annamaria; Falconi, Massimo; Delle Fave, Gianfranco

    2014-09-01

    Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs. PMID:25117065

  18. Cavin-2 in oral cancer: A potential predictor for tumor progression.

    PubMed

    Unozawa, Motoharu; Kasamatsu, Atsushi; Higo, Morihiro; Fukumoto, Chonji; Koyama, Tomoyoshi; Sakazume, Tomomi; Nakashima, Dai; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-06-01

    Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc. PMID:26086332

  19. Haploinsufficiency in the prometastasis Kiss1 Receptor Gpr54 delays breast tumor initiation, progression and lung metastasis

    PubMed Central

    Cho, Sung-Gook; Wang, Ying; Rodriguez, Melissa; Tan, Kunrong; Zhang, Wenzheng; Luo, Jian; Li, Dali; Liu, Mingyao

    2016-01-01

    Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1-induced KISS1R signaling is known to inhibit tumor angiogenesis and metastasis. However, roles of KISS1 and KISS1R in earlier stages of tumor progression and metastasis in vivo are still unknown. In this study, we demonstrate a critical role for Kiss1r in early stages of tumor progression using mouse tumor models. PyMT/Kiss1r mice with different Kiss1r genotypes were obtained by crossing MMTV-PyMT transgenic mouse with Kiss1r heterozygous mouse (Kiss1r+/−). Kiss1r heterozygosity attenuated breast tumor initiation, growth, latency, multiplicity and metastasis in MMTV-PyMT/Kiss1r+/− mouse models. To confirm the effects of Kiss1r in tumor progression and limit any effect of endogenous hormones, we isolated primary tumor cells from PyMT/Kiss1r+/+ or PyMT/Kiss1r+/− mice and performed in vitro and in vivo tumorigenesis assays. Kiss1r heterozygosity inhibited PyMT-induced in vitro tumorigeneity and in vivo tumor growth in NOD.SCID/NCr mice. To understand the underlying mechanism, we showed that activation of KISS1R by kisspeptin-10 led to RhoA activation and RhoA-dependent gene expression through Gαq-p63RhoGEF signaling pathway. Furthermore, anchorage-independent growth was tightly linked to the dosage-dependent regulation of RhoA by KISS1R. When MCF10A cells overexpressing H-RasV12 were subjected to in vitro tumorigenesis assays, knockdown of KISS1R or inactivation of RhoA in MCF10A cells reduced Ras-induced anchorage-independent growth, similar to our data obtained from PyMT-Kiss1r+/− mouse models. Altogether, we conclude that Kiss1r haploinsufficiency delays breast tumor initiation, progression and metastasis through its downstream Gαq-p63RhoGEF-RhoA signaling pathway. PMID:21852382

  20. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression

    PubMed Central

    Li, Zhaoyang; Pang, Yanli; Gara, Sudheer Kumar; Achyut, B.R.; Heger, Christopher; Goldsmith, Paul K.; Lonning, Scott; Yang, Li

    2012-01-01

    One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells (MDSCs) are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the anti-tumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines & Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β targeted therapy. PMID:22487809

  1. 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

  2. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression.

    PubMed

    Ruebel, Katharina; Leontovich, Alexey A; Stilling, Gail A; Zhang, Shuya; Righi, Alberto; Jin, Long; Lloyd, Ricardo V

    2010-03-01

    MicroRNAs (miRNAs) are involved in cell proliferation, differentiation, and apoptosis and can function as tumor suppressor genes or oncogenes. The role of miRNAs in neuroendocrine tumors such as ileal carcinoids is largely unknown. We examined the differential expression of 95 miRNAs by RT-PCR using the QuantiMir System in eight matching primary and metastatic carcinoid tumors from the ileum. All miRNAs chosen for the QuantiMir System array were based on their potential functions related to cancer biology, cell development, and apoptosis. The expression of miRNAs for the samples was normalized to miRNA-197, and the matching primary and metastatic tumors were compared. There was downregulation of miRNA-133a, -145, -146, -222, and -10b in all samples between the primary and matching metastatic tumors and upregulation of miRNA-183, -488, and -19a+b in six of eight metastatic carcinoids compared to the primary tumors. miRNA-133a was further analyzed by TaqMan real-time RT-PCR and northern hybridization using six additional matching primary and metastatic samples, which supported the PCR array findings. There were significant differences in miRNA-133a expression with downregulation in the metastasis compared to the primary in the eight original cases (P<0.009) and in the six additional cases used for validation (P<0.014). Laser capture microdissection and real-time RT-PCR analysis using normal ileum found miRNA-133a expression in normal enterochromaffin cells. In situ hybridization in normal ileum showed that some of the mucosal endocrine cells expressed miRNA-133a. Both primary and metastatic ileal carcinoid tumors expressed miRNA-133a by in situ hybridization. These results provide information about novel marker miRNAs that may be used as biomarkers and/or therapeutic targets in intestinal carcinoid tumors. PMID:20037573

  3. THE ROLE OF TUMOR PROGRESSION LOCUS 2 (TPL-2) PROTEIN KINASE IN GLIAL INFLAMMATORY RESPONSE

    PubMed Central

    Hirschhorn, Joshua; Mohanty, Sangeeta; Bhat, Narayan R.

    2013-01-01

    Tumor progression locus 2 (Tpl2)/Cot kinase is a newer member of MAP3K family that is now known for its essential role in TNFα expression in macrophages, but its proinflammatory signaling, if any, in glia is unknown. When cultures of murine microglia and astrocytes were exposed to lipopolysaccharide, there was a rapid activation (i.e., phosphorylation) of Tpl2 in parallel to the activation of down-stream effector MAPKs i.e., ERK, p38 MAPK and JNK. Pre-incubation of the cultures with a Tpl2 inhibitor selectively suppressed the activation of the primary down-stream target i.e., ERK relative to p38 MAPK and JNK. That Tpl2 activation was functionally involved in glial inflammatory response was indicated by a reduced release of the cytokines i.e., TNFα and the expression of inducible nitric oxide synthase (iNOS) in the presence of the kinase inhibitor. Further, overexpression of a wild-type Tpl2 construct in C-6 glia resulted in an enhanced transcriptional activation of iNOS while transfection with a dominant negative form of Tpl-2 had the opposite effect. The findings assign an important proinflammatory signaling function for Tpl2 pathway in glial cells. PMID:24188160

  4. Imbalance of tumor necrosis factor receptors during progression in bovine leukemia virus infection

    SciTech Connect

    Konnai, Satoru . E-mail: konnai@vetmed.hokudai.ac.jp; Usui, Tatsufumi; Ikeda, Manabu; Kohara, Junko; Hirata, Toh-ichi; Okada, Kosuke; Ohashi, Kazuhiko; Onuma, Misao

    2005-09-01

    Previously, we found an up-regulation of tumor necrosis factor alpha (TNF)-{alpha} and an imbalance of TNF receptors in sheep experimentally infected with bovine leukemia virus (BLV). In order to investigate the different TNF-{alpha}-induced responses, in this study we examined the TNF-{alpha}-induced proliferative response and the expression levels of two distinct TNF receptors on peripheral blood mononuclear cells (PBMC) derived from BLV-uninfected cattle and BLV-infected cattle that were aleukemic (AL) or had persistent lymphocytosis (PL). The proliferative response of PBMC isolated from those cattle with PL in the presence of recombinant bovine TNF-{alpha} (rTNF-{alpha}) was significantly higher than those from AL cattle and uninfected cattle and the cells from PL cattle expressed significantly higher mRNA levels of TNF receptor type II (TNF-RII) than those from AL and BLV-uninfected cattle. No difference was found in TNF-RI mRNA levels. Most cells expressing TNF-RII in PL cattle were CD5{sup +} or sIgM{sup +} cells and these cells showed resistance to TNF-{alpha}-induced apoptosis. Additionally, there were significant positive correlations between the changes in provirus load and TNF-RII mRNA levels, and TNF-{alpha}-induced proliferation and TNF-RII mRNA levels. These data suggest that imbalance in the expression of TNF receptors could at least in part contribute to the progression of lymphocytosis in BLV infection.

  5. Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma

    PubMed Central

    Mai, Shi-Juan; Wang, Meng-He; Zhang, Mei-Yin; Zheng, X.F. Steven; Wang, Hui-Yun

    2016-01-01

    Histone deacetylases (HDACs) mediate histone deacetylation, leading to transcriptional repression, which is involved in many diseases, including age-related tissue degeneration, heart failure and cancer. In this study, we were aimed to investigate the expression, clinical significance and biological function of HDAC4 in esophageal carcinoma (EC). We found that HDAC4 mRNA and protein are overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. HDAC4 overexpression is associated with higher tumor grade, advanced clinical stage and poor survival. Mechanistically, HDAC4 promotes proliferation and G1/S cell cycle progression in EC cells by inhibiting cyclin-dependent kinase (CDK) inhibitors p21 and p27 and up-regulating CDK2/4 and CDK-dependent Rb phosphorylation. HDAC4 also enhances ESCC cell migration. Furthermore, HDAC4 positively regulates epithelial-mesenchymal transition (EMT) by increasing the expression of Vimentin and decreasing the expression of E-Cadherin/α-Catenin. Together, our study shows that HDAC4 overexpression is important for the oncogenesis of EC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy. PMID:27295551

  6. β-Catenin Signaling Increases during Melanoma Progression and Promotes Tumor Cell Survival and Chemoresistance

    PubMed Central

    Sinnberg, Tobias; Menzel, Moritz; Ewerth, Daniel; Sauer, Birgit; Schwarz, Michael; Schaller, Martin; Garbe, Claus; Schittek, Birgit

    2011-01-01

    Beta-catenin plays an important role in embryogenesis and carcinogenesis by controlling either cadherin-mediated cell adhesion or transcriptional activation of target gene expression. In many types of cancers nuclear translocation of beta-catenin has been observed. Our data indicate that during melanoma progression an increased dependency on the transcriptional function of beta-catenin takes place. Blockade of beta-catenin in metastatic melanoma cell lines efficiently induces apoptosis, inhibits proliferation, migration and invasion in monolayer and 3-dimensional skin reconstructs and decreases chemoresistance. In addition, subcutaneous melanoma growth in SCID mice was almost completely inhibited by an inducible beta-catenin knockdown. In contrast, the survival of benign melanocytes and primary melanoma cell lines was less affected by beta-catenin depletion. However, enhanced expression of beta-catenin in primary melanoma cell lines increased invasive capacity in vitro and tumor growth in the SCID mouse model. These data suggest that beta-catenin is an essential survival factor for metastatic melanoma cells, whereas it is dispensable for the survival of benign melanocytes and primary, non-invasive melanoma cells. Furthermore, beta-catenin increases tumorigenicity of primary melanoma cell lines. The differential requirements for beta-catenin signaling in aggressive melanoma versus benign melanocytic cells make beta-catenin a possible new target in melanoma therapy. PMID:21858114

  7. MicroRNA-202 inhibits tumor progression by targeting LAMA1 in esophageal squamous cell carcinoma.

    PubMed

    Meng, Xiangrui; Chen, Xiaoqi; Lu, Peng; Ma, Wang; Yue, Dongli; Song, Lijie; Fan, Qingxia

    2016-05-13

    Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in the gastrointestinal tract. Emerging studies have indicated that microRNAs (miRNAs) are strongly implicated in the development and progression of ESCC. Here, we focused on the function and the underlying molecular mechanism of miR-202 in ESCC. The results showed that miR-202 was significantly down-regulated in ESCC tissues and cell lines. Overexpression of miR-202 in ECa-109 and KYSE-510 cells markedly suppressed cell proliferation and cell migration, and induced cell apoptosis. Furthermore, laminin α1 (LAMA1) expression was frequently positive in ESCC tissues and inversely correlated with miR-202 expression. Then we demonstrated that miR-202 targeted 3'-untranslated region (UTR) of LAMA1 and inhibited its protein expression. Additionally, LAMA1 overexpression rescued the proliferation inhibition and cell apoptosis elevation induced by miR-202. MiR-202 also inhibited the protein expression of p-FAK and p-Akt, which were all reversed by LAMA1 overexpression. Taken together, these findings suggest that miR-202 may function as a novel tumor suppressor in ESCC by repressing cell proliferation and migration, and its biological effects may attribute the inhibition of LAMA1-mediated FAK-PI3K-Akt signaling. PMID:27045085

  8. Registered report: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.

    PubMed

    Bhargava, Ajay; Anant, Madan; Mack, Hildegard

    2016-01-01

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF" by Heidorn and colleagues, published in Cell in 2010 (Heidorn et al., 2010). The experiments to be replicated are those reported in Figures 1A, 1B, 3A, 3B, and 4D. Heidorn and colleagues report that paradoxical activation of the RAF-RAS-MEK-ERK pathway by BRAF inhibitors when applied to BRAF(WT) cells is a result of BRAF/CRAF heterodimer formation upon inactivation of BRAF kinase activity, and occurs only in the context of active RAS. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID:26885666

  9. Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis

    PubMed Central

    Ito, Hiromitsu; Tanaka, Shinji; Akiyama, Yoshimitsu; Shimada, Shu; Adikrisna, Rama; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Yamaoka, Shoji; Tanabe, Minoru

    2016-01-01

    Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer. PMID:26764906

  10. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment.

    PubMed

    Poczobutt, Joanna M; Nguyen, Teresa T; Hanson, Dwight; Li, Howard; Sippel, Trisha R; Weiser-Evans, Mary C M; Gijon, Miguel; Murphy, Robert C; Nemenoff, Raphael A

    2016-01-15

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  11. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment

    PubMed Central

    Poczobutt, Joanna M.; Nguyen, Teresa T.; Hanson, Dwight; Li, Howard; Sippel, Trisha R.; Weiser-Evans, Mary C. M.; Gijon, Miguel; Murphy, Robert C.

    2016-01-01

    Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer. PMID:26663781

  12. Bioluminescence-Based Tumor Quantification Method for Monitoring Tumor Progression and Treatment Effects in Mouse Lymphoma Models.

    PubMed

    Cosette, Jeremie; Ben Abdelwahed, Rym; Donnou-Triffault, Sabrina; Sautès-Fridman, Catherine; Flaud, Patrice; Fisson, Sylvain

    2016-01-01

    Although bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. Here we describe a method for bioluminescence imaging to obtain a semi-quantitative analysis of tumor burden and treatment response. This method is based on the calculation of a luminoscore, a value that allows comparisons of two animals from the same or different experiments. Current BLI instruments enable the calculation of this luminoscore, which relies mainly on the acquisition conditions (back and front acquisitions) and the drawing of the region of interest (manual markup around the mouse). Using two previously described mouse lymphoma models based on cell engraftment, we show that the luminoscore method can serve as a noninvasive way to verify successful tumor cell inoculation, monitor tumor burden, and evaluate the effects of in situ cancer treatment (CpG-DNA). Finally, we show that this method suits different experimental designs. We suggest that this method be used for early estimates of treatment response in preclinical small-animal studies. PMID:27501019

  13. NOK/STYK1 promotes the genesis and remodeling of blood and lymphatic vessels during tumor progression.

    PubMed

    Liu, Yue; Li, Tianqi; Hu, Dan; Zhang, Shuping

    2016-09-01

    Previous studies have indicated that the overexpression of NOK, also named STYK1, led to tumorigenesis and metastasis. Here, we provide evidence that increased expression of NOK/STYK1 caused marked alterations in the overall and inner structures of tumors and substantially facilitates the genesis and remodeling of the blood and lymphatic vessels during tumor progression. In particular, NOK-expressed HeLa stable cells (HeLa-K) significantly enhanced tumor growth and metastasis in xenografted nude mice. Hematoxylin and eosin (HE) staining demonstrated that the tumor tissues generated by HeLa-K cells were much more ichorous and had more interspaces than those generated by control HeLa cells (HeLa-C). The fluorescent areas stained with cluster of differentiation 31 (CD31), a marker protein for blood vessels, appeared to be in different patterns. The total blood vessels, especially the ring patterns, within the tumors of the HeLa-K group were highly enriched compared with those in the HeLa-C group. NOK-HA was demonstrated to be well colocalized with CD31 in the wall of the tubular structures within tumor tissues. Interestingly, antibody staining of the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) further revealed the increase in ring (oratretic strip-like) lymphatic vessels in either the peritumoral or intratumoral areas in the HeLa-K group compared with the HeLa-C group. Consistently, the analysis of human cancerous tissue also showed that NOK was highly expressed in the walls of tubular structures. Thus, our results reveal a novel tumorigenic function of NOK to mediate the genesis and remodeling of blood and lymphatic vessels during tumor progression. PMID:27444381

  14. Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20.

    PubMed

    Boisson, Sophie; Engels, Dirk; Gordon, Bruce A; Medlicott, Kate O; Neira, Maria P; Montresor, Antonio; Solomon, Anthony W; Velleman, Yael

    2016-03-01

    Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind. PMID:26940305

  15. B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer.

    PubMed

    Tang, Alexandre; Dadaglio, Gilles; Oberkampf, Marine; Di Carlo, Selene; Peduto, Lucie; Laubreton, Daphné; Desrues, Belinda; Sun, Cheng-Ming; Montagutelli, Xavier; Leclerc, Claude

    2016-09-15

    Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient μMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in μMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines. PMID:27130719

  16. Identifying the Real Seed Population for Shock Accelerated Energetic Particles: Recent Observational Progress

    NASA Astrophysics Data System (ADS)

    Mason, G. M.; Mazur, J. E.; Desai, M. I.; Dwyer, J. R.

    2002-12-01

    Gradual solar energetic particle events, traveling interplanetary shocks, and corotating interaction regions are examples of shock acceleration of particles in the heliosphere. Although shock acceleration of particles has long been the subject of theoretical investigation, nevertheless key energetic particle properties such as intensity and spectral index are only roughly correlated with predictions of the theories. This may be due to limitations of the theories, but it may also be due to a lack of understanding of properties of the seed population. Recent measurements have shown that trace elements in the thermal plasma (e.g. singly ionized He, and 3He) often show dramatic enhancements in the energetic particle population. Although the observational picture is far from complete, it appears that the injection threshold in these events is about 1.5-2 times the solar wind speed. In this range, multiple particle sources are present, including solar wind suprathermals, pick up ions, and remnant material from prior shocks and impulsive events. Thus, the enhancements are not due to properties of the shock acceleration, but rather are primarily due to the properties of the seed population. This points to new opportunities for theoretical and experimental investigations to quantitatively model shock accelerated particle populations using realistic seed populations.

  17. High Energy Accelerator and Colliding Beam User Group: Progress report, March 1, 1988--February 28, 1989

    SciTech Connect

    Not Available

    1988-09-01

    This report discusses work carried out by the High Energy Accelerator and Colliding Beam User Group at the University of Maryland. Particular topics discussed are: OPAL experiment at LEP; deep inelastic muon interactions; B physics with the CLEO detector at CESR; further results from JADE; and search for ''small'' violation of the Pauli principle. (LSP)

  18. SOUTHERN HIGH SCHOOL PROGRAMS FOR ADVANCED STANDING AND ACCELERATED COLLEGE PROGRESSION.

    ERIC Educational Resources Information Center

    ALBRIGHT, A.D.; AND OTHERS

    APPROACHES TO EDUCATING ABLE STUDENTS OF 45 HIGH SCHOOLS WERE PRESENTED. MOST OF THE SPECIAL PROGRAMS FALL INTO ONE OF TWO CATEGORIES--SPECIAL CLASSES ORGANIZED IN PLACE OF REGULAR ONES, AND ATTEMPTS TO ENRICH OR ACCELERATE THOSE CLASSES ALREADY SCHEDULED. THE CURRICULUM OF MOST OF THE SCHOOLS FOR THESE STUDENTS INCLUDED ENGLISH, PHYSICAL SCIENCE,…

  19. Lenalidomide in Treating Young Patients With Recurrent, Progressive, or Refractory CNS Tumors

    ClinicalTrials.gov

    2013-09-27

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Mixed Glioma; Childhood Oligodendroglioma; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  20. [Progress in study of chemical constituents and anti-tumor activities of Cnidium monnieri].

    PubMed

    Zhou, Ze-wei; Liu, Pei-xun

    2005-09-01

    The main pharmacological constituents of Chinese traditional medicine herb Cnidium monnieri are coumarin compounds and volatile oil. In addition, it contains monoterpene polyols, glucides, as well as recently discovered sesquiterpene components. In recent years, rather active investigations of its anti-tumor were performed at home and abroad. C. monnieri possesses multi-aspect and comprehensive anti-tumor functions, involving directly tumor-inhibitory activity, anti-mutagenicity, reversing multi-drug tolerance of tumor, as well as improving immune functions and so on. In this review, chemical constituents, anti-tumor activities and relevant investigations of Fructus Cnidii were summarized recent decade. PMID:16323535

  1. Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.

    PubMed

    Hirata, Hidenari; Sugimachi, Keishi; Komatsu, Hisateru; Ueda, Masami; Masuda, Takaaki; Uchi, Ryutaro; Sakimura, Shotaro; Nambara, Sho; Saito, Tomoko; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Ito, Shuhei; Terashima, Kotaro; Sakamoto, Katsumi; Hirakawa, Masakazu; Honda, Hiroshi; Mimori, Koshi

    2016-06-01

    Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is reduced in expression in certain cancers where it has been hypothesized to act as a tumor suppressor, including in hepatocellular carcinoma (HCC). Here, we report functional evidence supporting this hypothesis, providing a preclinical rationale to develop FBP1 as a therapeutic target for HCC treatment. Three independent cohorts totaling 594 cases of HCC were analyzed to address clinical significance. Lower FBP1 expression associated with advanced tumor stage, poor overall survival, and higher tumor recurrence rates. In HCC cell lines, where endogenous FBP1 expression is low, engineering its ectopic overexpression inhibited tumor growth and intracellular glucose uptake by reducing aerobic glycolysis. In patient specimens, promoter methylation and copy-number loss of FBP1 were independently associated with decreased FBP1 expression. Similarly, FBP1 downregulation in HCC cell lines was also associated with copy-number loss. HCC specimens exhibiting low expression of FBP1 had a highly malignant phenotype, including large tumor size, poor differentiation, impaired gluconeogenesis, and enhanced aerobic glycolysis. The effects of FBP1 expression on prognosis and glucose metabolism were confirmed by gene set enrichment analysis. Overall, our findings established that FBP1 downregulation in HCC contributed to tumor progression and poor prognosis by altering glucose metabolism, and they rationalize further study of FBP1 as a prognostic biomarker and therapeutic target in HCC patients. Cancer Res; 76(11); 3265-76. ©2016 AACR. PMID:27197151

  2. Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

    PubMed Central

    Sarin, Hemant

    2009-01-01

    Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof. PMID:19723323

  3. Application of Circulating Tumor DNA as a Non-Invasive Tool for Monitoring the Progression of Colorectal Cancer

    PubMed Central

    Guan, Yanfang; Yang, Ling; Xia, Xuefeng; Cui, Liqiang; Yi, Xin; Lin, Guole

    2016-01-01

    Background Liquid biopsy has been proposed to be a promising noninvasive tool to obtain information on tumor progression. Through a clinical observation of a case series of 6 consecutive patients, we aim to determine the value of circulating tumor DNA (ctDNA) for monitoring the tumor burden during the treatment of colorectal cancer (CRC). Materials and Methods We used capture sequencing of 545 genes to identify somatic alternations in primary tumor tissues of the six CRC patients who underwent radical surgery and in 23 plasma samples collected at serial time points. We compared the mutation patterns and variant allele frequencies (VAFs) between the matched tissue and the plasma samples and evaluated the potential advantage of using ctDNA as a better tumor load indicator to detect disease relapse over carcinoembryonic antigen (CEA), cancer antigen (CA) 19–9 and imaging studies. Results We identified low-frequency mutations with a mean VAF of 0.88% (corresponding to a mean tumor burden of 0.20ng/mL) in the preoperative plasmas of four patients with locally advanced CRC and a subset of mutations shared by their primary tumors. The tumor loads appeared a sudden decrease upon surgery or other adjuvant treatments and then generally maintained at low levels (0.092ng/mL) until disease recurred. ctDNA increased by 13-fold when disease relapsed in one patient while the CEA and CA 19–9 levels remained normal. In this patient, all six somatic mutations identified in the preoperative plasma were detected in the recrudescent plasma again, with five mutations showing allele fraction increase. Conclusions We described a multi-time-point profile of ctDNA of CRC patients during the course of comprehensive treatment and observed a correlation of ctDNA level with the clinically evaluated tumor progression. This demonstrated a new strategy by analyzing the heterogeneous ctDNA to evaluate and monitor the tumor burden in the treatment and follow-up of CRC patients, with potentially

  4. Upregulated microRNA-301a in osteosarcoma promotes tumor progression by targeting CDC14A.

    PubMed

    Ni, Z; Shang, X F; Wang, Y F; Sun, Y J; Fu, D J

    2016-01-01

    MicroRNAs (miRs) are associated with tumor progression in various cancers, such as gastric and hepatic carcinomas, and lung cancer. miR-301a is overexpressed and displays oncogenic activity in cancers. We investigated the biological involvement of miR-301a in osteosarcoma (OS). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze expression levels of miR-301a in 24 OS and matched adjacent non-tumor tissues. A miR-301a mimic was transferred into OS cell lines U-2 OS and MG-63 to upregulate miR-301a. The effects of miR-301a were investigated by examining cell proliferation, migration, and the cell cycle. The miR-301 target was predicted by TargetScan and confirmed by western blotting and qRT-PCR. The expression of miR-301a was significantly higher in OS tissues compared with the matched adjacent non-tumor tissues (0.959 ± 0.39 vs 3.9516 ± 1.18). Upregulated miR-301a significantly increased proliferation at 48 and 72 h compared to the negative control (U-2 OS: 2.11 ± 0.21 vs 2.88 ± 0.24; 2.70 ± 0.26 vs 3.71 ± 0.24; MG-63: 2.19 ± 0.20 vs 3.19 ± 0.22; 3.1 ± 0.25 vs 4.01 ± 0.27) and migration capability (U-2 OS: 100 ± 20.19 vs 150.68 ± 32.83; MG-63: 100 ± 17.20 vs 133.35 ± 26.26), and decreased apoptosis in both U-2 OS (10.87 ± 2.53 vs 4.01 ± 2.23) and MG-63 (15.26 ± 2.15 vs 8.25 ± 3.07). The cell cycle studies revealed that miR-301a caused an increase of the G2 population in U-2 OS (38.6 ± 6.58 vs 47.2 ± 7.27) and MG-63 (44.01 ± 5.28 vs 57.9 ± 4.25). Additional experiments indicated that CDC14A was upregulated by miR-301a (0.63 ± 0.06 vs 0.98 ± 0.06; 1.49 ± 0.25 vs 2.99 ± 0.14). Overexpressed miR-301a may increase CDC14A expression and promote cell proliferation and migration in OS cells. Therefore, miR- 301a may be useful for osteosarcoma diagnosis and therapy. PMID:27323075

  5. Risk assessment of multistate progression of breast tumor with state-dependent genetic and environmental covariates.

    PubMed

    Wu, Yi-Ying; Yen, Ming-Fang; Yu, Cheng-Ping; Chen, Hsiu-Hsi

    2014-02-01

    Few studies have focused on the different roles risk factors play in the multistate temporal natural course of breast cancer. We proposed a three-state Markov regression model to predict the risk from free of breast cancer (FBC) to the preclinical screen-detectable phase (PCDP) and from the PCDP to the clinical phase (CP). We searched the initiators and promoters affecting onset and subsequent progression of breast tumor to build up a three-state temporal natural history model with state-dependent genetic and environmental covariates. This risk assessment model was applied to a 1 million Taiwanese women cohort. The proposed model was verified by external validation with another independent data set. We identified three kinds of initiators, including the BRCA gene, seven single nucleotides polymorphism, and breast density. ER, Ki-67, and HER-2 were found as promoters. Body mass index and age at first pregnancy both played a role. Among women carrying the BRCA gene, the 10-year predicted risk for the transition from FBC to CP was 25.83%, 20.31%, and 13.84% for the high-, intermediate-, and low-risk group, respectively. The corresponding figures were 1.55%, 1.22%, and 0.76% among noncarriers. The mean sojourn time of staying at the PCDP ranged from 0.82 years for the highest risk group to 6.21 years for the lowest group. The lack of statistical significance for external validation (x(4)2=5.30,p=0.26) revealed the adequacy of our proposed model. The three-state model with state-dependent covariates of initiators and promoters was proposed for achieving individually tailored screening and also for personalized clinical surveillance of early breast cancer. PMID:24111840

  6. Translation factors and ribosomal proteins control tumor onset and progression: how?

    PubMed

    Loreni, F; Mancino, M; Biffo, S

    2014-04-24

    Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus. PMID:23644661

  7. Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence

    PubMed Central

    GAO, JIAN-ZHI; LI, JIA; DU, JING-LI; LI, XIAO-LEI

    2016-01-01

    The present study aimed to investigate the expression level of HOX transcript antisense RNA (HOTAIR) in hepatocellular carcinoma (HCC) and its association with various clinicopathological characteristics, and to further explore the molecular mechanisms of HOTAIR function in HCC. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression level of HOTAIR in 60 paired fresh HCC samples and adjacent normal liver tissue samples. The association between HOTAIR expression and clinicopathological parameters was analyzed. Lentivirus-mediated HOTAIR-specific small hairpin RNA vectors were transfected into HepG2 cells. Cell proliferation and invasion in vitro were examined by MTT and Transwell assays, respectively. A xenograft model was used to analyze the tumorigenesis of liver cancer cells in vivo. In addition, semi-quantitative RT-PCR was used to detect the expression level of Wnt/β-catenin signaling molecules under the condition of HOTAIR inhibition. The results revealed that the expression level of HOTAIR in HCC tissues was higher than that in adjacent non-cancerous tissues. HOTAIR expression was significantly associated with poor tumor differentiation (P=0.002), metastasis (P=0.002) and early recurrence (P=0.001). In vitro, the inhibition of HOTAIR in liver cancer cells resulted in the suppression of cell proliferation and invasion. HOTAIR depletion significantly inhibited the rate of growth of liver cancer cells in vivo. Furthermore, the expression levels of Wnt and β-catenin were downregulated when HOTAIR expression was suppressed. In conclusion, HOTAIR is important in the progression and recurrence of HCC, partly through the regulation of the Wnt/β-catenin signaling pathway. Targeting HOTAIR may be a novel therapeutic strategy for HCC. PMID:26998078

  8. Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice.

    PubMed

    Mercer, Kelly E; Pulliam, Casey; Hennings, Leah; Lai, Keith; Cleves, Mario; Jones, Ellen; Drake, Richard R; Ronis, Martin

    2016-06-01

    In this study, diethylnitrosamine-treated male mice were assigned to three groups: (i) a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, (ii) the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SPI), (iii) and a chow group. EtOH feeding continued for 16 weeks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared with the chow group, P < 0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared with the EtOH and EtOH/SPI group (P < 0.05). Tumor reduction in the EtOH/SPI group corresponded to reduced liver injury associated with decreased hepatic Tnfα and Cd14 antigen (Cd14) expression and decreased nuclear accumulation of NF-κB1 protein compared with the EtOH group (P < 0.05). Detection of sphingolipids using high-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, and sphingosine-1-phosphate (S1P) in the EtOH group that were significantly reduced in the EtOH/SPI group. Chronic EtOH feeding also increased mRNA expression of β-catenin transcriptional targets, including cyclin D1 (Ccnd1), matrix metallopeptidase 7 (Mmp7), and glutamine synthetase (Glns), which were reduced in the EtOH/SPI group (P < 0.05). We conclude that soy prevents tumorigenesis by reducing proinflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of β-catenin signaling. These mechanisms may involve changes in sphingolipid signaling. Cancer Prev Res; 9(6); 466-75. ©2016 AACR. PMID:27006377

  9. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression

    PubMed Central

    Yang, H; Pellegrini, L; Napolitano, A; Giorgi, C; Jube, S; Preti, A; Jennings, C J; De Marchis, F; Flores, E G; Larson, D; Pagano, I; Tanji, M; Powers, A; Kanodia, S; Gaudino, G; Pastorino, S; Pass, H I; Pinton, P; Bianchi, M E; Carbone, M

    2015-01-01

    High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information. PMID:26068794

  10. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.

    PubMed

    Yang, H; Pellegrini, L; Napolitano, A; Giorgi, C; Jube, S; Preti, A; Jennings, C J; De Marchis, F; Flores, E G; Larson, D; Pagano, I; Tanji, M; Powers, A; Kanodia, S; Gaudino, G; Pastorino, S; Pass, H I; Pinton, P; Bianchi, M E; Carbone, M

    2015-01-01

    High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information. PMID:26068794

  11. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    PubMed

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations. PMID:25088201

  12. Ascorbate as a Co-Factor for Fe- and 2-Oxoglutarate Dependent Dioxygenases: Physiological Activity in Tumor Growth and Progression

    PubMed Central

    Kuiper, Caroline; Vissers, Margreet C. M.

    2014-01-01

    Ascorbate is a specific co-factor for a large family of enzymes known as the Fe- and 2-oxoglutarate-dependent dioxygenases. These enzymes are found throughout biology and catalyze the addition of a hydroxyl group to various substrates. The proline hydroxylase that is involved in collagen maturation is well known, but in recent times many new enzymes and functions have been uncovered, including those involved in epigenetic control and hypoxia-inducible factor (HIF) regulation. These discoveries have provided crucial mechanistic insights into how ascorbate may affect tumor biology. In particular, there is growing evidence that HIF-1-dependent tumor progression may be inhibited by increasing tumor ascorbate levels. However, rigorous clinical intervention studies are lacking. This review will explore the physiological role of ascorbate as an enzyme co-factor and how this mechanism relates to cancer biology and treatment. The use of ascorbate in cancer should be informed by clinical studies based on such mechanistic hypotheses. PMID:25540771

  13. Dynamical Observation on Biological Progression of VX2 Liver Tumors to Identify the Optimal Time for Intervention in Animal Models

    PubMed Central

    Wang, Zhenguang; Yang, Guangjie; Nie, Pei; Fu, Junhua; Wang, Xufu; Liu, Dan

    2013-01-01

    Purpose Based on practice guideline of “management of hepatocellular carcinoma (HCC): update” published by American Association for the Study of Liver Diseases (AASLD) and “Barcelona Clinic Liver Cancer staging system (BCLC),” this study investigated how to enroll the optimal VX2 liver tumor model for HCC researches by dynamically observing the biological progression of the tumor. Materials Thirty-two healthy New Zealand white rabbits were implanted VX2 liver tumor by cell suspension method (n=24) and tissue fragment method (n=8). All the rabbits underwent CT scans on day 7, 14, 21 and 28 after implantation to observe the size of the tumors, the time when metastases and ascites occurred and the survival time. Appropriate intervention times were estimated corresponding to different clinical HCC stages by using tumor diameter-time curve. Results The VX2 liver tumors grew rapidly within 28 days after implantation. And the tumors in the cell suspension group grew faster than those of the tissue fragment group. The appropriate intervention time corresponding to very early stage, early stage and intermediate stage were <11 days, 11–16.9 days and >16.9 days, respectively in the cell suspension group, and <19.9 days, 19.9–25.5 days and >25.5 days, respectively in the tissue fragment group. Conclusion Preclinical animal research needs to improve on different levels to yield best predictions for human patients. Researchers should seek for an individualized proposal to select optimal VX2 liver tumor models for their experiments. This approach may lead to a more accurate determination of therapeutic outcomes. PMID:23977399

  14. The Radiological Research Accelerator Facility. Progress report, December 1, 1992--November 30, 1993

    SciTech Connect

    Hall, E.J.; Marino, S.A.

    1993-05-01

    The Radiological Research Accelerator Facility (RARAF) is based on a 4-MV Van de Graaff accelerator, which is used to generate a variety of well-characterized radiation beams for research in radiobiology, radiological physics, and radiation chemistry. It is part of the Center for Radiological Research (CRR) - formerly the Radiological Research Laboratory of Columbia University, and its operation is supported as a National Facility by the US Department of Energy (DOE). As such, RARAF is available to all potential users on an equal basis and scientists outside the CRR are encouraged to submit proposals for experiments at RARAF. The operation of the Van de Graaff is supported by the DOE, but the research projects themselves must be supported separately. This report provides a listing and brief description of experiments performed at RARAF during the May 1, 1992 through April 30, 1993.

  15. Progress In Plasma Accelerator Development for Dynamic Formation of Plasma Liners

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Eskridge, Richard; Martin, Adam; Smith, James; Lee, Michael; Cassibry, Jason T.; Griffin, Steven; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    An experimental plasma accelerator for magnetic target fusion (MTF) applications under development at the NASA Marshall Space Flight Center is described. The accelerator is a coaxial pulsed plasma thruster (Figure 1). It has been tested experimentally and plasma jet velocities of approx.50 km/sec have been obtained. The plasma jet has been photographed with 10-ns exposure times to reveal a stable and repeatable plasma structure (Figure 2). Data for velocity profile information has been obtained using light pipes and magnetic probes embedded in the gun walls to record the plasma and current transit respectively at various barrel locations. Preliminary spatially resolved spectral data and magnetic field probe data are also presented. A high speed triggering system has been developed and tested as a means of reducing the gun "jitter". This jitter is being characterized and future work for second generation "ultra-low jitter" gun development is being identified.

  16. Recent Progress in the Development of a Circular Ion Induction Accelerator for Space Charge Dominated Beams

    NASA Astrophysics Data System (ADS)

    Ahle, L.; Sangster, T. C.; Autrey, D.; Barnard, J.; Craig, G.; Friedman, A.; Grote, D. P.; Halaxa, E.; Hanks, R. L.; Hernandez, M.; Kirbie, H. C.; Logan, B. G.; Lund, S. M.; Mant, G.; Molvik, A.; Sharp, W.; Berners, D.; Eylon, S.; Judd, D. L.; Reginato, L.; Debeling, A.; Fritz, W.

    1998-11-01

    The Heavy Ion Fusion Group at Lawrence Livermore National Laboratory has been developing the world's first ion induction accelerator. This machine has recently been extended to 90 degress, or 10 half-lattice periods(HLP) with full beam transport. As part of this extension, two new diagnostic systems have been fully enabled, the Capacitive Beam Probes(C-probes) and the Gated Beam Imager(GBI). The C-probes measure the charge centroid of the beam in each HLP and the GBI measures emittance in both transverse planes. Output from both diagnostics will be presented. In addition, induction cores have been installed on five of the HLP's, in anticipation of the first attempts at acceleration. The status of these attempts will also be discussed.

  17. The Radiological Research Accelerator Facility. Progress report, December 1, 1993--November 30, 1994

    SciTech Connect

    Hall, E.J.; Marino, S.A.

    1994-04-01

    This document begins with a general description of the facility to include historical and up-to-date aspects of design and operation. A user`s guide and a review of research using the facility follows. Next the accelerator utilization and operation and the development of the facilities is given. Personnel currently working at the facility are listed. Lastly, recent publications and literature cited are presented.

  18. Margin Size is an Independent Predictor of Local Tumor Progression After Ablation of Colon Cancer Liver Metastases

    SciTech Connect

    Wang Xiaodong; Sofocleous, Constantinos T. Erinjeri, Joseph P.; Petre, Elena N.; Gonen, Mithat; Do, Kinh G.; Brown, Karen T.; Covey, Anne M.; Brody, Lynn A.; Alago, William; Thornton, Raymond H.; Kemeny, Nancy E.; Solomon, Stephen B.

    2013-02-15

    This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM). An institutional review board-approved, HIPPA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4-8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1-5, 6-10, and 11-15 mm. Follow-up included CT every 2-4 months. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP. Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1-5 mm, 6-10 mm, 11-15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %. An ablation zone with a minimal margin uniformly larger than 5 mm 4-8 weeks postablation CT is associated with the best local tumor control.

  19. TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression

    PubMed Central

    Tang, Binwu; Vu, Mary; Booker, Timberly; Santner, Steven J.; Miller, Fred R.; Anver, Miriam R.; Wakefield, Lalage M.

    2003-01-01

    The TGF-β signaling network plays a complex role in carcinogenesis because it has the potential to act as either a tumor suppressor or a pro-oncogenic pathway. Currently, it is not known whether TGF-β can switch from tumor suppressor to pro-oncogenic factor during the course of carcinogenic progression in a single cell lineage with a defined initiating oncogenic event or whether the specific nature of the response is determined by cell type and molecular etiology. To address this question, we have introduced a dominant negative type II TGF-β receptor into a series of genetically related human breast–derived cell lines representing different stages in the progression process. We show that decreased TGF-β responsiveness alone cannot initiate tumorigenesis but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic cell line histologically and proliferatively more aggressive. In a high-grade tumorigenic cell line, however, reduced TGF-β responsiveness has no effect on primary tumorigenesis but significantly decreases metastasis. Our results demonstrate a causal role for loss of TGF-β responsiveness in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but nonmetastatic disease and suggest that at that point TGF-β switches from tumor suppressor to prometastatic factor. PMID:14523048

  20. Progress report on the accelerator production of tritium materials irradiation program

    SciTech Connect

    Maloy, S.A.; Sommer, W.F.; Brown, R.D.; Roberts, J.E.

    1997-05-01

    The Accelerator Production of Tritium (APT) project is developing an accelerator and a spoliation neutron source capable of producing tritium through neutron capture on He-3. A high atomic weight target is used to produce neutrons that are then multiplied and moderated in a blanket prior to capture. Materials used in the target and blanket region of an APT facility will be subjected to several different and mixed particle radiation environments; high energy protons (1-2 GeV), protons in the 20 MeV range, high energy neutrons, and low energy neutrons, depending on position in the target and blanket. Flux levels exceed 10{sup 14}/cm{sup 2}s in some areas. The APT project is sponsoring an irradiation damage effects program that will generate the first data-base for materials exposed to high energy particles typical of spallation neutron sources. The program includes a number of candidate materials in small specimen and model component form and uses the Los Alamos Spallation Radiation Effects Facility (LASREF) at the 800 MeV, Los Alamos Neutron Science Center (LANSCE) accelerator.

  1. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma.

    PubMed

    Xiao, Zhenyu; Chung, Haniee; Banan, Babak; Manning, Pamela T; Ott, Katherine C; Lin, Shin; Capoccia, Benjamin J; Subramanian, Vijay; Hiebsch, Ronald R; Upadhya, Gundumi A; Mohanakumar, Thalachallour; Frazier, William A; Lin, Yiing; Chapman, William C

    2015-05-01

    Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα. Further, CD47 blockade inhibited tumor growth in both heterotopic and orthotopic models of HCC, and promoted the migration of macrophages into the tumor mass. Our results demonstrate that targeting CD47 by specific antibodies has potential immunotherapeutic efficacy in human HCC. PMID:25721088

  2. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma

    PubMed Central

    Xiao, Zhenyu; Chung, Haniee; Banan, Babak; Manning, Pamela T.; Ott, Katherine C.; Lin, Shin; Capoccia, Benjamin J.; Subramanian, Vijay; Hiebsch, Ronald R.; Upadhya, Gundumi A.; Mohanakumar, Thalachallour; Frazier, William A.; Lin, Yiing; Chapman, William C.

    2016-01-01

    Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα. Further, CD47 blockade inhibited tumor growth in both heterotopic and orthotopic models of HCC, and promoted the migration of macrophages into the tumor mass. Our results demonstrate that targeting CD47 by specific antibodies has potential immunotherapeutic efficacy in human HCC. PMID:25721088

  3. 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

  4. Heart failure progression is accelerated following myocardial infarction in type II diabetic rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients and following an infarction, diabetes is associated with an increased risk for the development of left ventricular dysfunction and heart failure. The goal of this study was to determine if the progression o...

  5. Co-evolution of solid stress and interstitial fluid pressure in tumors during progression: Implications for vascular collapse

    PubMed Central

    Stylianopoulos, Triantafyllos; Martin, John D.; Snuderl, Matija; Mpekris, Fotios; Jain, Saloni R.; Jain, Rakesh K.

    2013-01-01

    The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently demonstrated that growth-induced solid stress is on the order of 1.3–13.0 kPa (10–100 mmHg) - high enough to cause compression of fragile blood vessels resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress and fluid pressure. First, we performed in vivo experiments and found that growth-induced stress is related to tumor volume through a bi-exponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared to the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histological sections of human cancers that demonstrate such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels. Major Findings. Growth-induced solid stress is accumulated in

  6. Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

    PubMed Central

    Foronda, Miguel; Martínez, Paula; Schoeftner, Stefan; Gómez-López, Gonzalo; Schneider, Ralph; Flores, Juana M.; Pisano, David G.; Blasco, Maria A.

    2016-01-01

    Summary Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO) in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer. PMID:25043184

  7. The deficiency of tumor suppressor prep1 accelerates the onset of meis1- hoxa9 leukemogenesis.

    PubMed

    Dardaei, Leila; Modica, Livia; Iotti, Giorgio; Blasi, Francesco

    2014-01-01

    Prep1 and Meis1 ortholog TALE transcription factors have opposing roles in tumorigenesis: Meis1 serves as an oncogene, Prep1 as a tumor suppressor. We now report that, Meis1 overexpression in primary Prep1-deficient (Prep1i/i) embryonic hematopoietic cells increases self-renewal potential of cells in vitro but not in vivo, whereas leukemia is instead obtained when Meis1 is combined with another oncogene, HoxA9. Prep1i/i Meis1-HoxA9-generated leukemic cells are less differentiated and grow more aggressively after the second passage in the mouse. These data indicate that Prep1 represents a barrier to the transforming activity of Meis1 in vitro, but its absence is not sufficient to induce early leukemogenesis. On the other hand, the Prep1i/i background appears to favor the insurgence of mutations that cause a more aggressive Meis1-HoxA9-generated leukemia. Indeed, the Prep1i/i leukemic cells upregulate the Polycomb protein Bmi-1 and expectedly down-regulate the Ink4a/Arf locus products. Finally, an important feature contributed by the Prep1i/i background is the post-transcriptional increase in Meis1 protein level. PMID:24809472

  8. Accelerated Tumor Growth Mediated by Sub-lytic Levels of Antibody-Induced Complement Activation is Associated with Activation of the PI3K/AKT Survival Pathway

    PubMed Central

    Wu, Xiaohong; Ragupathi, Govind; Panageas, Katherine; Hong, Feng; Livingston, Philip O.

    2013-01-01

    Purpose We addressed the possibility that low levels of tumor cell bound antibodies targeting gangliosides might accelerate tumor growth. Experimental Design To test this hypothesis, we treated mice with a range of mAb doses against GM2, GD2, GD3 and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in-vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it. Results Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2-expressing cell lines both in-vitro and in a SCID mouse model, while very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM antibodies targeting GM2 but consistent against IgG-mAb targeting GD3 as well. These findings were mirrored by in-vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the PI3K/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K-activation and accelerated tumor growth in-vitro and in-vivo are eliminated by PI3K-inhibitors NVP-BEZ235 and Wortmannin. These PI3K-inhibitors also significantly increased efficacy of high doses of these 4 mAbs. Conclusion Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced-antibodies targeting a variety of tumor-cell-surface-antigens. PMID:23833306

  9. 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

  10. Progress estimating incidence rates of tumors and deformities in St. Louis River white sucker

    EPA Science Inventory

    The St. Louis River Area of Concern (AOC) was listed for the Beneficial Use Impairment (BUI) of Fish Tumors and Other Deformities without the benefit of histological information. Information on the fish tumor incidence rate is important for the future removal of the BUI. Two year...

  11. Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity.

    PubMed

    Mirković, Bojana; Markelc, Boštjan; Butinar, Miha; Mitrović, Ana; Sosič, Izidor; Gobec, Stanislav; Vasiljeva, Olga; Turk, Boris; Čemažar, Maja; Serša, Gregor; Kos, Janko

    2015-08-01

    Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models. Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro. Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment. PMID:25848918

  12. LYSOPHOSPHATIDIC ACID INHIBITS CD8 T CELL ACTIVATION AND CONTROL OF TUMOR PROGRESSION

    PubMed Central

    Oda, Shannon K.; Strauch, Pamela; Fujiwara, Yuko; Al-Shami, Amin; Oravecz, Tamas; Tigyi, Gabor; Pelanda, Roberta; Torres, Raul M.

    2013-01-01

    CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immune surveillance. However, multiple inhibitory mechanisms within the tumor microenvironment have been described that impede tumor rejection by CD8 T cells, including increased signaling by inhibitory receptors. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that has been shown repeatedly to promote diverse cellular processes benefiting tumorigenesis. Accordingly, the increased expression of LPA and LPA receptors is a common feature of diverse tumor cell lineages and can result in elevated systemic LPA levels. LPA is recognized by at least 6 distinct G-protein-coupled receptors and several of which are expressed by T cells, although the precise role of LPA signaling in CD8 T cell activation and function has not been defined. Here, we demonstrate that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells. Together, these data suggest that the production of LPA by tumors serves not only in an autocrine manner to promote tumorigenesis but also as a mechanism to suppress adaptive immunity and highlights a potential novel target for cancer treatment. PMID:24455753

  13. Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression.

    PubMed

    Oda, Shannon K; Strauch, Pamela; Fujiwara, Yuko; Al-Shami, Amin; Oravecz, Tamas; Tigyi, Gabor; Pelanda, Roberta; Torres, Raul M

    2013-10-01

    CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immune surveillance. However, multiple inhibitory mechanisms within the tumor microenvironment have been described that impede tumor rejection by CD8 T cells, including increased signaling by inhibitory receptors. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that has been shown repeatedly to promote diverse cellular processes benefiting tumorigenesis. Accordingly, the increased expression of LPA and LPA receptors is a common feature of diverse tumor cell lineages and can result in elevated systemic LPA levels. LPA is recognized by at least 6 distinct G-protein-coupled receptors and several of which are expressed by T cells, although the precise role of LPA signaling in CD8 T cell activation and function has not been defined. Here, we demonstrate that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells. Together, these data suggest that the production of LPA by tumors serves not only in an autocrine manner to promote tumorigenesis but also as a mechanism to suppress adaptive immunity and highlights a potential novel target for cancer treatment. PMID:24455753

  14. Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis.

    PubMed

    Georgoudaki, Anna-Maria; Prokopec, Kajsa E; Boura, Vanessa F; Hellqvist, Eva; Sohn, Silke; Östling, Jeanette; Dahan, Rony; Harris, Robert A; Rantalainen, Mattias; Klevebring, Daniel; Sund, Malin; Brage, Suzanne Egyhazi; Fuxe, Jonas; Rolny, Charlotte; Li, Fubin; Ravetch, Jeffrey V; Karlsson, Mikael C I

    2016-05-31

    Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming TAM populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, FcγRIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment. PMID:27210762

  15. High energy accelerator and colliding beam user group: Progress report, March 1, 1987-February 29, 1988

    SciTech Connect

    Not Available

    1987-09-01

    Progress is reported on the OPAL experiment at LEP, including construction and assembly of the hadron calorimeter and development of OPAL software. Progress on the JADE experiment, which examines e/sup +/e/sup -/ interactions at PETRA, and of the PLUTO collaboration are also discussed. Experiments at Fermilab are reported, including deep inelastic muon scattering at TeV II, the D0 experiment at TeV I, and hadron jet physics. Neutrino-electron elastic scattering and a search for point-sources of ultra-high energy cosmic rays are reported. Other activities discussed include polarization in electron storage rings, participation in studies for the SSC and LEP 200, neutron-antineutron oscillations, and the work of the electronics support group. High energy physics computer experience is also discussed. 158 refs. (LEW)

  16. Magnetic resonance imaging of brain tumors: measurement of T1: work in progress

    SciTech Connect

    Araki, T.; Inouye, T.; Suzuki, H.; Machida, T.; Iio, M.

    1984-01-01

    Longitudinal relaxation times (T1) of 20 brain tumors were calculated in vivo using a whole-body magnetic resonance unit with a 0.15-T resistive magnet. Images employing standard inversion recovery pulse sequences with different intervals between the 180)2) pulse and selective excitation pulses were compared on every point of the 256 x 256 pixel matrix. Tumor, white matter, and gray matter were sampled from each patient from the computed T1 image for T1 measurement. Astrocytomas, neurinomas, and metastatic tumors showed longer T1 values than did meningiomas. Lipomas had the shortest T1s. It is concluded that it is difficult to predict histological types of brain tumors by the measurement of T1 alone because of the wide variation in relaxation times, but measurement of T1 can be helpful in differentiating brain tumors when additional information about the patient's condition is known.

  17. Regulator of G protein signaling 2 (RGS2) deficiency accelerates the progression of kidney fibrosis.

    PubMed

    Jang, Hee-Seong; Kim, Jee In; Noh, Mira; Rhee, Man Hee; Park, Kwon Moo

    2014-09-01

    The regulator of G protein signaling 2 (RGS2) is a potent negative regulator of Gq protein signals including the angiotensin II (AngII)/AngII receptor signal, which plays a critical role in the progression of fibrosis. However, the role of RGS2 on the progression of kidney fibrosis has not been assessed. Here, we investigated the role of RGS2 in kidney fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO resulted in increased expression of RGS2 mRNA and protein in the kidney along with increases of AngII and its type 1 receptor (AT1R) signaling and fibrosis. Furthermore, UUO increased the levels of F4/80, Ly6G, myeloperoxidase, and CXCR4 in the kidneys. RGS2 deficiency significantly enhanced these changes in the kidney. RGS2 deletion in the bone marrow-derived cells by transplanting the bone marrow of RGS2 knock-out mice into wild type mice enhanced UUO-induced kidney fibrosis. Overexpression of RGS2 in HEK293 cells, a human embryonic kidney cell line, and RAW264.7 cells, a monocyte/macrophage line, inhibited the AngII-induced activation of ERK and increase of CXCR4 expression. These findings provide the first evidence that RGS2 negatively regulates the progression of kidney fibrosis following UUO, likely by suppressing fibrogenic and inflammatory responses through the inhibition of AngII/AT1R signaling. PMID:24973550

  18. Modeling Freedom From Progression for Standard-Risk Medulloblastoma: A Mathematical Tumor Control Model With Multiple Modes of Failure

    SciTech Connect

    Brodin, N. Patrik; Vogelius, Ivan R.; Björk-Eriksson, Thomas; Munck af Rosenschöld, Per; Bentzen, Søren M.

    2013-10-01

    Purpose: As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data. Methods and Materials: Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data. Results: The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range. Conclusions: Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available.

  19. Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras–initiated leukemia

    PubMed Central

    Chiang, Mark Y.; Xu, Lanwei; Shestova, Olga; Histen, Gavin; L’Heureux, Sarah; Romany, Candice; Childs, M. Eden; Gimotty, Phyllis A.; Aster, Jon C.; Pear, Warren S.

    2008-01-01

    Gain-of-function NOTCH1 mutations are found in 50%–70% of human T cell acute lymphoblastic leukemia/lymphoma (T-ALL) cases. Gain-of-function NOTCH1 alleles that initiate strong downstream signals induce leukemia in mice, but it is unknown whether the gain-of-function NOTCH1 mutations most commonly found in individuals with T-ALL generate downstream signals of sufficient strength to induce leukemia. We addressed this question by expressing human gain-of-function NOTCH1 alleles of varying strength in mouse hematopoietic precursors. Uncommon gain-of-function NOTCH1 alleles that initiated strong downstream signals drove ectopic T cell development and induced leukemia efficiently. In contrast, although gain-of-function alleles that initiated only weak downstream signals also induced ectopic T cell development, these more common alleles failed to efficiently initiate leukemia development. However, weak gain-of-function NOTCH1 alleles accelerated the onset of leukemia initiated by constitutively active K-ras and gave rise to tumors that were sensitive to Notch signaling pathway inhibition. These data show that induction of leukemia requires doses of Notch1 greater than those needed for T cell development and that most NOTCH1 mutations found in T-ALL cells do not generate signals of sufficient strength to initiate leukemia development. Furthermore, low, nonleukemogenic levels of Notch1 can complement other leukemogenic events, such as activation of K-ras. Even when Notch1 participates secondarily, the resulting tumors show “addiction” to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia. PMID:18677410

  20. 3-D photoacoustic and pulse echo imaging of prostate tumor progression in the mouse window chamber

    NASA Astrophysics Data System (ADS)

    Bauer, Daniel R.; Olafsson, Ragnar; Montilla, Leonardo G.; Witte, Russell S.

    2011-02-01

    Understanding the tumor microenvironment is critical to characterizing how cancers operate and predicting their response to treatment. We describe a novel, high-resolution coregistered photoacoustic (PA) and pulse echo (PE) ultrasound system used to image the tumor microenvironment. Compared to traditional optical systems, the platform provides complementary contrast and important depth information. Three mice are implanted with a dorsal skin flap window chamber and injected with PC-3 prostate tumor cells transfected with green fluorescent protein. The ensuing tumor invasion is mapped during three weeks or more using simultaneous PA and PE imaging at 25 MHz, combined with optical and fluorescent techniques. Pulse echo imaging provides details of tumor structure and the surrounding environment with 100-μm3 resolution. Tumor size increases dramatically with an average volumetric growth rate of 5.35 mm3/day, correlating well with 2-D fluorescent imaging (R = 0.97, p < 0.01). Photoacoustic imaging is able to track the underlying vascular network and identify hemorrhaging, while PA spectroscopy helps classify blood vessels according to their optical absorption spectrum, suggesting variation in blood oxygen saturation. Photoacoustic and PE imaging are safe, translational modalities that provide enhanced depth resolution and complementary contrast to track the tumor microenvironment, evaluate new cancer therapies, and develop molecular contrast agents in vivo.

  1. 3-D photoacoustic and pulse echo imaging of prostate tumor progression in the mouse window chamber

    PubMed Central

    Bauer, Daniel R.; Olafsson, Ragnar; Montilla, Leonardo G.; Witte, Russell S.

    2011-01-01

    Understanding the tumor microenvironment is critical to characterizing how cancers operate and predicting their response to treatment. We describe a novel, high-resolution coregistered photoacoustic (PA) and pulse echo (PE) ultrasound system used to image the tumor microenvironment. Compared to traditional optical systems, the platform provides complementary contrast and important depth information. Three mice are implanted with a dorsal skin flap window chamber and injected with PC-3 prostate tumor cells transfected with green fluorescent protein. The ensuing tumor invasion is mapped during three weeks or more using simultaneous PA and PE imaging at 25 MHz, combined with optical and fluorescent techniques. Pulse echo imaging provides details of tumor structure and the surrounding environment with 100-μm3 resolution. Tumor size increases dramatically with an average volumetric growth rate of 5.35 mm3∕day, correlating well with 2-D fluorescent imaging (R = 0.97, p < 0.01). Photoacoustic imaging is able to track the underlying vascular network and identify hemorrhaging, while PA spectroscopy helps classify blood vessels according to their optical absorption spectrum, suggesting variation in blood oxygen saturation. Photoacoustic and PE imaging are safe, translational modalities that provide enhanced depth resolution and complementary contrast to track the tumor microenvironment, evaluate new cancer therapies, and develop molecular contrast agents in vivo. PMID:21361696

  2. The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Gladman, Stacy; Biggio, Maria Luigia; Marino, Marianna; Jayasinghe, Maduka; Ullah, Farhan; Dyall, Simon C.; Malaspina, Andrea; Bendotti, Caterina; Michael-Titus, Adina

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients. PMID:23620776

  3. Overview of progress on the improvement projects for the LANSCE accelerator and target facilities

    SciTech Connect

    Macek, R.J.; Browne, J.; Brun, T.; Donahue, J.B.; Fitzgerald, D.H.; Hoffman, E.; Pynn, R.; Schriber, S.; Weinacht, D.

    1997-06-01

    Three projects have been initiated since 1994 to improve the performance of the accelerator and target facilities for the Los Alamos Neutron Science Center (LANSCE). The LANSCE Reliability Improvement Project (LRIP) was separated into two phases. Phase 1, completed in 1995, targeted near-term improvements to beam reliability and availability that could be completed in one-year`s time. Phase 2, now underway and scheduled for completion in May 1998, consists of two projects: (a) implementation of direct H-injection for the Proton Storage Ring (PSR) and (b) an upgrade of the target/moderator system for the short pulse spallation neutron (SPSS) source. The latter will reduce the target change-out time from about 10 months to about three weeks. The third project, the SPSS Enhancement Project, is aimed at increasing the PSR output beam current to 200 {micro}A at 30 Hz and providing up to seven new neutron scattering instruments.

  4. Progress on the accelerator based SPES-BNCT project at INFN Legnaro

    SciTech Connect

    Esposito, J.; Colautti, P.; Pisent, A.; Conte, V.; Moro, D.; De Nardo, L.; Agosteo, S.; Rosi, G.

    2007-02-12

    In the framework of an advanced Exotic Ion Beam facility, named SPES (Study and Production of Exotic Species), that will allow a frontier program both in nuclear and interdisciplinary physics, an intense thermal neutron beam facility, devoted to perform Boron Neutron Capture Therapy (BNCT) experimental treatments on skin melanoma tumor, is currently under construction based on the SPES proton driver. A vast radiobiological investigation in vitro and in vivo has started with the new 10B carriers developed. Special microdosimetric detectors have been constructed to properly measure all the BNCT dose components and their qualities. Both microdosimetric and radiobiological measurements are being performed at the new HYTHOR beam shaping assembly at the Enea-Casaccia TAPIRO reactor.

  5. AZD2171 in Treating Young Patients With Recurrent, Progressive, or Refractory Primary CNS Tumors

    ClinicalTrials.gov

    2016-03-04

    Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Cerebral Anaplastic Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood Infratentorial Ependymoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway Glioma

  6. [Research progress of tumor cell migration strategy and the migration transition mechanism].

    PubMed

    Wang, Hongbing; Tan, Qiaoyan; Yang, Ben Yanzi; Zou, Xiaobing; Yang, Li

    2011-12-01

    Tumor cells exhibit two main different migration strategies when invading in 3D environment, i. e. mesenchymal migration and amoeboid migration. This review summarizes the internal reasons and characteristics on various modes of migration adaptation to the microenvironment, and the molecular mechanisms in particular environment where they are mutually interchangeable. A study of the mechanisms that may possibly trigger mesenchymal-amoeboid transition/amoeboid-mesenchymal transition help us to understand the change and the plasticity in the migration strategies of tumor cells. These are important for the development of a cancer treatment, which would efficiently suppress tumor cell invasiveness. PMID:22295724

  7. Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression.

    PubMed

    Bon, Giulia; Di Carlo, Selene E; Folgiero, Valentina; Avetrani, Paolo; Lazzari, Chiara; D'Orazi, Gabriella; Brizzi, Maria Felice; Sacchi, Ada; Soddu, Silvia; Blandino, Giovanni; Mottolese, Marcella; Falcioni, Rita

    2009-07-15

    Increased expression of alpha(6)beta(4) integrin in several epithelial cancers promotes tumor progression; however, the mechanism underlying its transcriptional regulation remains unclear. Here, we show that depletion of homeodomain-interacting protein kinase 2 (HIPK2) activates beta(4) transcription that results in a strong increase of beta(4)-dependent mitogen-activated protein kinase and Akt phosphorylation, anchorage-independent growth, and invasion. In contrast, stabilization of HIPK2 represses beta(4) expression in wild-type p53 (wtp53)-expressing cells but not in p53-null cells or cells expressing mutant p53, indicating that HIPK2 requires a wtp53 to inhibit beta(4) transcription. Consistent with our in vitro findings, a strong correlation between beta(4) overexpression and HIPK2 inactivation by cytoplasmic relocalization was observed in wtp53-expressing human breast carcinomas. Under loss of function of HIPK2 or p53, the p53 family members TAp63 and TAp73 strongly activate beta(4) transcription. These data, by revealing that beta(4) expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair beta(4)-dependent tumor progression, suggest that loss of p53 function favors the formation of coactivator complex with the TA members of the p53 family to allow beta(4) transcription. PMID:19567674

  8. Carboxymethyl Chitosan-Modified Polyamidoamine Dendrimer Enables Progressive Drug Targeting of Tumors via pH-Sensitive Charge Inversion.

    PubMed

    Qi, Xiaole; Qin, Jiayi; Fan, Yuchao; Qin, Xiaoxue; Jiang, Yujie; Wu, Zhenghong

    2016-04-01

    Polyamidoamine dendrimers are potential candidates for drug delivery systems due to their remarkable cell-penetrating power that results from their strong positive surface charge. However, the positively charged surfaces always lead to serious cytotoxicity and the rapid clearance of polyamidoamine in vivo, which limit the application of these dendrimers. To overcome these drawbacks, we developed a carboxymethyl chitosan-modified polyamidoamine dendrimer to achieve progressive drug targeting of tumors via pH-sensitive charge inversion. With the shielding of carboxymethyl chitosan, the complex was negatively charged at physiological conditions (pH 7.4) and prone to enrich at tumor sites due to the enhanced permeation and retention effect; however, it regained a positive charge via the removal of the carboxymethyl chitosan coating under tumor-acidic conditions (pH 6.5) and achieved high intracellular uptake in tumor cells through electrostatic adsorptive endocytosis. In this study, these dendrimers exhibited 1.99- and 1.76-times higher cellular uptake efficiencies at pH 7.4 in MCF-7 or A549 cells, respectively, compared with efficiencies at pH 6.5, indicating an effective pH-dependent accumulation; the fluorescence intensities of these cells exposed to the dendrimers at pH 6.5 were also 16.45- and 9.27-fold greater, respectively, than those of free doxorubicin. After intravenous administration in mice bearing H22 tumors, doxorubicin-loaded dendrimers exhibited a 1.50-fold greater antitumor activity and presented no obvious systematic toxicity based on histological analysis compared with free drugs. Overall, a simple decoration of carboxymethyl chitosan demonstrated to be a promising way for cationic nanocarriers to achieve pH-sensitive drug release and charge conversion response to tumor microenvironment pH and enhance the antitumor therapy efficiency of anticancer drugs. PMID:27301193

  9. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

    PubMed Central

    Ward, Kristy K.; Tancioni, Isabelle; Lawson, Christine; Miller, Nichol L.G.; Jean, Christine; Chen, Xiao Lei; Uryu, Sean; Kim, Josephine; Tarin, David; Stupack, Dwayne G.; Plaxe, Steven C.; Schlaepfer, David D.

    2013-01-01

    Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer. PMID:23275034

  10. Research progress on the reproductive and non-reproductive endocrine tumors by estrogen-related receptors.

    PubMed

    Xu, Zhixiang; Liu, Jun; Gu, Lipeng; Ma, Xiaodong; Huang, Bin; Pan, Xuejun

    2016-04-01

    Oncologists have traditionally considered that tumorigenesis are closely related to classical nuclear estrogen receptors (ERs), such as estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), through the ligands binding and target gene transcription induction. Estrogen-related receptors (ERRs) have similar structures with ERs, which are also gradually thought to be relevant to reproductive endocrine tumor diseases, even non-reproductive endocrine tumors. In this review, different subtypes of ERRs and their structures firstly will be introduced, then the expression patterns in gynecological oncology (i.e., breast cancer, endometrial cancer, and ovarian cancer), male genitourinary system malignancy especially prostatic cancer along with other non-reproductive endocrine tumors (i.e., lung cancer, colorectal cancer, and liver cancer) will be described, and simultaneously the role of tumorigenesis related to ERRs will be discussed. Therefore, the review is benefit to explore the way of tumor prevention and treatment. PMID:26802897

  11. PHLPP is a Negative Regulator of RAF1 that Reduces Colorectal Cancer Cell Motility and Prevents Tumor Progression in Mice

    PubMed Central

    Li, Xin; Stevens, Payton D.; Liu, Jianyu; Yang, Haihua; Wang, Wei; Wang, Chi; Zeng, Zheng; Schmidt, Micheal D.; Yang, Mike; Lee, Eun Y.; Gao, Tianyan

    2014-01-01

    BACKGROUND & AIMS Hyperactivation of the RAS-RAF signaling pathway in colorectal tumors is associated with metastasis and poor outcomes of patients. Little is known about how RAS–RAF signaling is turned off once activated. We investigated how the pH domain and leucine-rich repeat protein phosphatases (PHLPPs) control RAS–RAF signaling and colorectal cancer (CRC) development. METHODS We used co-immunoprecipitation assays to identify substrates of PHLPP1 and PHLPP2.We studied phosphorylation of RAF1 in CRC cells that express transgenic PHLPP1 or PHLPP2, or lentiviral-based small hairpin (sh)RNAs against their transcripts; we measured effects on cell motility, migration, and invasion in vitro. Tumor progression and survival were analyzed in Phlpp1−/− mice, ApcMin mice, and ApcMin/Phlpp1−/− mice. Microarray data sets of colorectal tumor and non-tumor tissues were analyzed for PHLPP gene expression. RESULTS PHLPP1 and 2 were found to dephosphorylate RAF1 at S338, inhibiting its kinase activity in vitro and in CRC cells. In cells, shRNA knockdown of PHLPP1 or PHLPP2 increased the amplitude and duration of RAF-MEK-ERK signaling downstream of EGFR and KRAS, whereas overexpression had the opposite effect. Knockdown of PHLPP1 or PHLPP2 caused CRC cells to express markers of the epithelial-mesenchymal transition (EMT), and increased migration and invasion in vitro. ApcMin/Phlpp1−/− mice had decreased survival and developed larger intestinal and colon tumors than ApcMin mice, which developed mostly low-grade adenomas; in contrast, 20% of the tumors that developed in ApcMin/Phlpp1−/− mice were invasive adenocarcinomas. Normal villi and adenomas of ApcMin/Phlpp1−/− mice had significantly fewer apoptotic cells than ApcMin mice. Human CRC patient microarray data revealed that the expression of PHLPP1 or PHLPP2 is positively correlated with CDH1. CONCLUSIONS PHLPP1 and 2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory

  12. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients.

    PubMed

    Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Takako; Kimura, Madoka; Oba, Shigeyuki; Imamura, Fumio

    2016-01-01

    Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5-100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies. PMID:27381430

  13. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients

    PubMed Central

    Kato, Kikuya; Uchida, Junji; Kukita, Yoji; Kumagai, Toru; Nishino, Kazumi; Inoue, Takako; Kimura, Madoka; Oba, Shigeyuki; Imamura, Fumio

    2016-01-01

    Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies. PMID:27381430

  14. Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

    ClinicalTrials.gov

    2016-05-26

    Childhood Choroid Plexus Tumor; Childhood Ependymoblastoma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

  15. Tumor-Associated Glycans and Their Role in Gynecological Cancers: Accelerating Translational Research by Novel High-Throughput Approaches

    PubMed Central

    Pochechueva, Tatiana; Jacob, Francis; Fedier, Andre; Heinzelmann-Schwarz, Viola

    2012-01-01

    Glycans are important partners in many biological processes, including carcinogenesis. The rapidly developing field of functional glycomics becomes one of the frontiers of biology and biomedicine. Aberrant glycosylation of proteins and lipids occurs commonly during malignant transformation and leads to the expression of specific tumor-associated glycans. The appearance of aberrant glycans on carcinoma cells is typically associated with grade, invasion, metastasis and overall poor prognosis. Cancer-associated carbohydrates are mostly located on the surface of cancer cells and are therefore potential diagnostic biomarkers. Currently, there is increasing interest in cancer-associated aberrant glycosylation, with growing numbers of characteristic cancer targets being detected every day. Breast and ovarian cancer are the most common and lethal malignancies in women, respectively, and potential glycan biomarkers hold promise for early detection and targeted therapies. However, the acceleration of research and comprehensive multi-target investigation of cancer-specific glycans could only be successfully achieved with the help of a combination of novel high-throughput glycomic approaches. PMID:24957768

  16. Targeting matriptase in breast cancer abrogates tumor progression via impairment of stromal-epithelial growth factor signaling

    PubMed Central

    Zoratti, Gina L.; Tanabe, Lauren M.; Varela, Fausto A.; Murray, Andrew S.; Bergum, Christopher; Colombo, Eloic; Lang, Julie; Molinolo, Alfredo A.; Leduc, Richard; Marsault, Eric; Boerner, Julie; List, Karin

    2015-01-01

    Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years due to its consistent dysregulation in human epithelial tumors, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumor formation and blunted tumor growth. The abated tumor growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signaling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer. PMID:25873032

  17. Monitoring disease progression and treatment efficacy with circulating tumor cells in esophageal squamous cell carcinoma: A case report

    PubMed Central

    Qiao, Yuan-Yuan; Lin, Kai-Xuan; Zhang, Ze; Zhang, Da-Jin; Shi, Cheng-He; Xiong, Ming; Qu, Xiu-Hua; Zhao, Xiao-Hang

    2015-01-01

    This study investigated whether changes in circulating tumor cell (CTC) numbers reflect tumor progression and treatment efficacy in esophageal squamous cell carcinoma (ESCC). A 47-year-old male patient with ESCC is presented in this case study. The patient was evaluated for a series of serum tumor markers and subjected to radiological examinations before and after surgery and during follow-up over the course of five years. In addition, the CTCs in 7.5 mL of peripheral blood were enriched by magnetic-activated cell sorting negative selection and identified by immunofluorescence staining. Serum tumor markers remained within normal ranges and were discordant with imaging scans during the follow-up. Initially, one CTC was detected in the peripheral blood sample, and 14 were observed seven days after the operation. After 12 wk, subcutaneous metastases and bone metastases occurred, and the number of CTCs increased to 84. After 48 wk, lung metastases were noted, and the CTC level was 21. At 104 wk, the number of CTCs was 14, and disease recurrence was detected by positron emission tomography-computed tomography. The CTC counts were in accord with the imaging studies at several time points. The additional information provided by CTC enumeration could thus facilitate monitoring of disease status and treatment efficacy and provide support for treatment decisions. PMID:26167094

  18. Functional Relationship between Tumor-Associated Macrophages and Macrophage Colony-Stimulating Factor as Contributors to Cancer Progression

    PubMed Central

    Laoui, Damya; Van Overmeire, Eva; De Baetselier, Patrick; Van Ginderachter, Jo A.; Raes, Geert

    2014-01-01

    The current review article describes the functional relationship between tumor-associated macrophages (TAM) as key cellular contributors to cancer malignancy on the one hand and macrophage-colony-stimulating factor (M-CSF or CSF-1) as an important molecular contributor on the other. We recapitulate the available data on expression of M-CSF and the M-CSF receptor (M-CSFR) in human tumor tissue as constituents of a stromal macrophage signature and on the limits of the predictive and prognostic value of plasma M-CSF levels. After providing an update on current insights into the nature of TAM heterogeneity at the level of M1/M2 phenotype and TAM subsets, we give an overview of experimental evidence, based on genetic, antibody-mediated, and pharmacological disruption of M-CSF/M-CSFR signaling, for the extent to which M-CSFR signaling can not only determine the TAM quantity, but can also contribute to shaping the phenotype and heterogeneity of TAM and other related tumor-infiltrating myeloid cells (TIM). Finally, we review the accumulating information on the – sometimes conflicting – effects blocking M-CSFR signaling may have on various aspects of cancer progression such as tumor growth, invasion, angiogenesis, metastasis, and resistance to therapy and we thereby discuss in how far these different effects actually reflect a contribution of TAM. PMID:25339957

  19. Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer.

    PubMed

    Miar, Ana; Hevia, David; Muñoz-Cimadevilla, Henar; Astudillo, Aurora; Velasco, Julio; Sainz, Rosa M; Mayo, Juan C

    2015-08-01

    The role of manganese-dependent superoxide dismutase (SOD2/MnSOD) during tumor progression has been studied for several decades with controversial results. While SOD2 downregulation was initially associated with tumor initiation and was proposed as a tumor suppressor gene, recent studies have reported that SOD2 might favor tumor progression and dissemination. To our knowledge this is the first time that changes in SOD2 expression in three different types of tumors, i.e., prostate, lung, and colon cancer, are studied by analyzing both SOD2 mRNA and protein levels in a total of 246 patients' samples. In prostate samples, SOD2 protein levels were also increased, especially in middle stage tumors. In the case of colon and lung tumors both mRNA and protein SOD2 levels were increased in malignant tissues compared to those in nontumor samples. More importantly, all metastases analyzed showed increased levels of SOD2 when compared to those of normal primary tissue and healthy adjacent tissue. Together, these results suggest that a common redox imbalance in these three types of tumor occurs at intermediate stages which then might favor migration and invasion, leading to a more aggressive cancer type. Consequently, the ratios SOD2/catalase and SOD2/Gpx1 could be considered as potential markers during progression from tumor growth to metastasis. PMID:25866291

  20. Academic affairs and global health: how global health electives can accelerate progress towards ACGME milestones.

    PubMed

    Hayward, Alison Schroth; Jacquet, Gabrielle A; Sanson, Tracy; Mowafi, Hani; Hansoti, Bhakti

    2015-12-01

    Global health electives (GHEs) have become a standard offering in many residency programs. Residency electives should aid residents in achieving outcomes in the Accreditation Council for Graduate Medical Education (ACGME) competency domains. In this paper, the authors review existing literature and provide expert opinion to highlight how global health electives can complement traditional training programs to assist residents in achieving ACGME milestones, using emergency medicine residency as an example. Recommendations are provided for identifying exemplary global health electives and for the development of institutional global health elective curricula in order to facilitate milestone achievement. Global health electives can advance progress towards ACGME milestones; however, they may vary greatly in terms of potential for learner advancement. Electives should thus be rigorously vetted to ensure they meet standards that will facilitate this process. Given that milestones are a newly introduced tool for assessing resident educational achievement, very little research is available currently to directly determine impacts, and further study will be needed. PMID:26628320

  1. The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth.

    PubMed

    Palazzo, E; Kellett, M; Cataisson, C; Gormley, A; Bible, P W; Pietroni, V; Radoja, N; Hwang, J; Blumenberg, M; Yuspa, S H; Morasso, M I

    2016-06-16

    Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis. PMID:26522723

  2. Progress of laser ablation for accelerator mass spectroscopy at ATLAS utilizing an ECRIS

    NASA Astrophysics Data System (ADS)

    Scott, R.; Palchan, T.; Pardo, R.; Vondrasek, R.; Kondev, F.; Nusair, O.; Peters, C.; Paul, M.; Bauder, W.; Collon, P.

    2014-02-01

    Beams of ions from the laser ablation method of solid materials into an electron cyclotron resonance ion source (ECRIS) plasma have been used for the first time in experiments at ATLAS. Initial accelerator mass spectroscopy experiments using laser ablation for actinides and samarium have been performed. Initial results of coupling the laser system to the ECR source have guided us in making a number of changes to the original design. The point of laser impact has been moved off axis from the center of the ECR injection side. Motor control of the laser positioning mirror has been replaced with a faster and more reliable piezo-electric system, and different raster scan patterns have been tested. The use of the laser system in conjunction with a multi-sample changer has been implemented. Two major problems that are being confronted at this time are beam stability and total beam intensity. The status of the development will be presented and ideas for further improvements will be discussed.

  3. Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress.

    PubMed

    Lyon, Gholson J; Wang, Kai

    2012-01-01

    The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine. PMID:22830651

  4. Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress

    PubMed Central

    2012-01-01

    The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine. PMID:22830651

  5. Mainstream cigarette smoke accelerates the progression of nonalcoholic steatohepatitis by modulating Kupffer cell-mediated hepatocellular apoptosis in adolescent mice.

    PubMed

    Park, Surim; Kim, Jong Won; Yun, Hyejin; Choi, Seong-Jin; Lee, Sang-Hyub; Choi, Kyung-Chul; Lim, Chae Woong; Lee, Kyuhong; Kim, Bumseok

    2016-08-10

    Cigarette smoking in adolescents is considered to be a major cause of preventable morbidity and mortality. The purpose of this study is to investigate the role of mainstream cigarette smoke (MSCS) on the progression of nonalcoholic steatohepatitis in adolescents. Three-week-old C57BL/6 mice were fed either a methionine and choline-deficient plus high fat (MCDHF) diet for 6 weeks. Each group was exposed to MSCS (300, 600 ug/L) or fresh air for 2h per day during the first 3 weeks of MCDHF diet feeding. MSCS increased MCDHF diet-induced NASH by increasing serum ALT/AST levels, steatosis, inflammation, and fibrosis. Furthermore, MSCS was associated with the degree of oxidative stress and hepatocellular apoptosis in NASH mice, but not prominent in controls. In vitro, cigarette smoke extract (CSE) activated Kupffer cells (KCs) to release inflammatory cytokines and oxidative stress, which induced hepatocellular apoptosis. In conclusion, MSCS exposure accelerates the progression and severity of NASH by modulating KC-mediated hepatocellular apoptosis. Our results support the regulation of CS in adolescents with steatohepatitis. PMID:27180087

  6. Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice.

    PubMed

    Ru, Ding; Zhiqing, He; Lin, Zhu; Feng, Wu; Feng, Zhang; Jiayou, Zhang; Yusheng, Ren; Min, Fan; Chun, Liang; Zonggui, Wu

    2015-05-01

    High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox-HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox-HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox-HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox-HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox-HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox-HDL, (iii) the pro-atherosclerotic effects of ox-HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro-atherosclerosis effects of ox-HDL. PMID:25912129

  7. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    DOE PAGESBeta

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hung, Ming -Szu; Hsieh, David; Au, Alfred; Jablons, David M.; You, Liang

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods:more » Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.« less

  8. Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene

    SciTech Connect

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; Hung, Ming -Szu; Hsieh, David; Au, Alfred; Jablons, David M.; You, Liang

    2015-06-08

    Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Methods: Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. Results: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. Conclusion: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

  9. Distribution of cytokeratin polypeptides in human transitional cell carcinomas, with special emphasis on changing expression patterns during tumor progression.

    PubMed Central

    Schaafsma, H. E.; Ramaekers, F. C.; van Muijen, G. N.; Lane, E. B.; Leigh, I. M.; Robben, H.; Huijsmans, A.; Ooms, E. C.; Ruiter, D. J.

    1990-01-01

    The expression of cytokeratin (CK) polypeptides was studied in 59 transitional cell carcinomas (TCC) of the urinary tract of different grade and stage. Using a panel of 14 polypeptide-specific monoclonal CK-antibodies we identified immunohistochemically 8 different CKs separately, ie, CKs 4, 7, 8, 10, 13, 14, 18, and 19, while in immunoblotting studies CK5 expression was detected indirectly by using the antibody RCK102, recognizing CK5 + 8. In low-grade TCCs (G1-G2), the CK distribution was comparable to that in normal urothelium, however with a variable expression of CK13 in the different tumors and a uniform distribution of CK7. In higher-grade TCCs (G3), a decrease in CK13 expression was observed, particularly in the areas of muscle invasion. Furthermore, the appearance and increasing expression of CK14 (not present in normal urothelium or G1 TCCs) with higher grade and stage was striking. With tumor progression changes in epitope configurations of CK8 and CK18 were detected, as concluded from immunohistochemical assays with the panel of monoclonal antibodies for each of these two CKs. In extreme cases this resulted in differential staining patterns of the invasive and noninvasive components within one tumor. In 7 of 32 G3 TCCs, some of which showed areas with evident squamous differentiation, a decrease in the expression of CK7 and/or CK8 was seen. We conclude that tumor progression in TCCs is associated with discrete changes of CK expression, which can be detected using monoclonal antibodies. Images Figure 1 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:1689541

  10. Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer

    PubMed Central

    Wen, Wei; Liang, Wei; Wu, Jun; Kowolik, Claudia M.; Buettner, Ralf; Scuto, Anna; Hsieh, Meng-Yin; Hong, Hao; Brown, Christine E.; Forman, Stephen J.; Horne, David; Morgan, Robert; Wakabayashi, Mark; Dellinger, Thanh H.; Han, Ernest S.; Yim, John H.; Jove, Richard

    2015-01-01

    JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine-cytokine loop involving the IL-6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL-6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL-6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer. PMID:25319391

  11. Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis

    PubMed Central

    Barros, Rita; Gomes, Catarina; de Matos, Augusto J.; Reis, Celso A.; Rutteman, Gerard R.; Gärtner, Fátima

    2015-01-01

    The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness. PMID:26222311

  12. Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis.

    PubMed

    de Oliveira, Joana T; Ribeiro, Cláudia; Barros, Rita; Gomes, Catarina; de Matos, Augusto J; Reis, Celso A; Rutteman, Gerard R; Gärtner, Fátima

    2015-01-01

    The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness. PMID:26222311

  13. Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice.

    PubMed

    Liu, Hui; Xia, Yanfei; Li, Beibei; Pan, Jinyu; Lv, Mei; Wang, Xuyang; An, Fengshuang

    2016-04-22

    PHD3 belongs to the family of 2-oxoglutarate and iron-dependent dioxygenases and is a critical regulator of HIF-1α. Its expression is increased in cardiovascular diseases such as cardiomyopathy, myocardial ischemia-reperfusion injury, and congestive heart failure. However, the association between PHD3 and atherosclerosis has not been clearly elucidated. In the present study, we investigated the potential effect and mechanism of PHD3 in apolipoprotein E-deficient (ApoE-/-) mice. Murine PHD3 lentivirus and shRNA -PHD3 lentivirus were constructed and injected intravenously into ApoE-/- mice fed on a high fat diet. The aortic atherosclerotic lesion area was larger with PHD3 over-expression. With increased PHD3 levels, macrophages and smooth muscle cells were enhanced. The apoptosis of atherosclerotic plaques revealed an increase when PHD3 was elevated. Furthermore, the expression of intercellular cell adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), monocyte chemotactic protein 1 (MCP-1), interleukin-1beta (IL-1β) and tumor necrosis factor-α(TNF-α) were upregulated with PHD3 over-expression. In vitro, we explored the specific signaling pathway of PHD3 in HUVECs. PHD3 over-expression is associated with activation of ERK1/2 and JNK phosphorylation of MAPK signaling pathway. PHD3 inhibition decreased the apoptosis of HUVECs treated with ox-LDL (50 μg/ml). Our study suggests that PHD3 is not only a regulator of HIF-1α but also an active participant in atherogenesis. PMID:26995088

  14. Tectonic 1 accelerates gastric cancer cell proliferation and cell cycle progression in vitro.

    PubMed

    Wang, Xinbao; Yu, Qiming; Zhang, Yingli; Ling, Zhiqiang; Yu, Pengfei

    2015-10-01

    Hedgehog (Hh) pathway is important in development and cancer. Hh signaling is constitutively active in gastric cancer. Recently, tectonic 1 (TCTN1) was identified as one regulator of the Hh pathway. In the present study, the biological role of TCTN1 was examined in gastric cancer via an RNA interference lentivirus system. The constructed lentivirus efficiently suppressed TCTN1 expression in three gastric cancer cell lines. The proliferation of gastric cancer cells was significantly inhibited in TCTN1 knockdown cells, as determined by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide and colony formation assays. Furthermore, in order to determine the underlying mechanism, the cell cycle progression of MGC80‑3 cells was analyzed by flow cytometry. Knockdown of TCTN1 led to cell cycle arrest at the G2/M phase, which contributed to inhibition of growth. In conclusion, the results demonstrated that TCTN1 was essential in the growth of gastric cancer cells in vitro, suggesting TCTN1 as a potential target candidate for the treatment of gastric cancer. PMID:26252641

  15. Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice

    PubMed Central

    Huang, Jin; Filipe, Anne; Rahuel, Cécile; Bonnin, Philippe; Mesnard, Laurent; Guérin, Coralie; Wang, Yu; Le Van Kim, Caroline; Colin, Yves; Tharaux, Pierre-Louis

    2014-01-01

    Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury. PMID:24429403

  16. [Application Progress of CRISPR/Cas9 System for Gene Editing in Tumor Research].

    PubMed

    Liu, Chao; Li, Zhiwei; Zhang, Yanqiao

    2015-09-20

    TCRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR-associated nuclease 9) gene editing system is a new type of gene editing technology developed based on the immune mechanism of archaea resisting the invasion of exogenous nucleic acid. Compared with traditional gene editing system, CRISPR/Cas9 system is more efficient, easier operating, and less cytotoxic. Currently, CRISPR/Cas9 gene editing technology has been applied to many aspects of cancer research, including research on cancer genes, constructing animal tumor models, screening tumor resistance-associated and phenotypic-related genes and cancer gene therapy. In this review, the application of the CRISPR/Cas9 system in tumor research were introduced. PMID:26383982

  17. The hypoxic tumor microenvironment: A driving force for breast cancer progression.

    PubMed

    Semenza, Gregg L

    2016-03-01

    Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. PMID:26079100

  18. Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer

    PubMed Central

    Argiris, Athanassios; Duffy, Austin G.; Kummar, Shivaani; Simone, Nicole L.; Arai, Yoshio; Kim, Seungwon W.; Rudy, Susan. F.; Kannabiran, Vishnu. R.; Yang, Xinping; Jang, Minyoung; Chen, Zhong; Suksta, Nanette; Cooley-Zgela, Theresa; Ramanand, Susmita G.; Ahsan, Aarif; Nyati, Mukesh. K.; Wright, John J.; Van Waes, Carter

    2011-01-01

    PURPOSE A phase I clinical trial and molecular correlative studies were performed to evaluate preclinical evidence for combinatorial activity of proteasome inhibitor bortezomib, epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. EXPERIMENTAL DESIGN Patients with radiotherapy-naïve stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0 and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity modulated radiotherapy (IMRT), delivered in 2Gy fractions to 70-74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens, and the cell line UMSCC-1. RESULTS Seven patients were accrued before the study was terminated when 5/6 previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (PFS =4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; 1 patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease. Expected grade 3 toxicities included radiation mucositis (n=4), dermatitis (n=1), and rash (n=1). SCCHN-related cytokines increased in serial serum specimens of patients developing progressive disease (P=0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. CONCLUSIONS Combining bortezomib with cetuximab and radiation therapy demonstrated unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling and SCCHN cytokine expression, warranting avoidance of this combination. PMID:21750205

  19. Targeting Chemokine Receptor CXCR4 for Treatment of HIV-1 Infection, Tumor Progression, and Metastasis

    PubMed Central

    Choi, Won-Tak; Yang, Yilei; Xu, Yan; An, Jing

    2015-01-01

    The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and for the development and dissemination of various types of cancers, including gastrointestinal, cutaneous, head and neck, pulmonary, gynecological, genitourinary, neurological, and hematological malignancies. The T-cell (T)-tropic HIV-1 strains use CXCR4 as the entry coreceptor; consequently, multiple CXCR4 antagonistic inhibitors have been developed for the treatment of acquired immune deficiency syndrome (AIDS). However, other potential applications of CXCR4 antagonists have become apparent since its discovery in 1996. In fact, increasing evidence demonstrates that epithelial and hematopoietic tumor cells exploit the interaction between CXCR4 and its natural ligand, stromal cell-derived factor (SDF)-1α, which normally regulates leukocyte migration. The CXCR4 and/or SDF-1α expression patterns in tumor cells also determine the sites of metastatic spread. In addition, the activation of CXCR4 by SDF-1α promotes invasion and proliferation of tumor cells, enhances tumor-associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane. As such, the evaluation of CXCR4 and/or SDF-1α expression levels has a significant prognostic value in various types of malignancies. Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy. PMID:25159167

  20. Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

    PubMed Central

    Karakashev, Sergey V; Reginato, Mauricio J

    2015-01-01

    Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance. PMID:26316817

  1. Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

    PubMed Central

    Abbate, Mauro; Zoja, Carla; Corna, Daniela; Rottoli, Daniela; Zanchi, Cristina; Azzollini, Nadia; Tomasoni, Susanna; Berlingeri, Silvia; Noris, Marina; Morigi, Marina; Remuzzi, Giuseppe

    2008-01-01

    Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload–induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell–derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease. PMID:18354030

  2. Progress in AMS measurements at the LLNL spectrometer. [Accelerator Mass Spectroscopy (AMS)

    SciTech Connect

    Southon, J.R.; Vogel, J.S.; Trumbore, S.E.; Davis, J.C.; Roberts, M.L.; Caffee, M.; Finkel, R.; Proctor, I.D.; Heikkinen, D.W.; Berno, A.J.; Hornady, R.S.

    1991-06-01

    The AMS measurement program at LLNL began in earnest in late 1989, and has initially concentrated on {sup 14}C measurements for biomedical and geoscience applications. We have now begun measurements on {sup 10}Be and {sup 36}Cl, are presently testing the spectrometer performance for {sup 26}Al and {sup 3}H, and will begin tests on {sup 7}Be, {sup 41}Ca and {sup 129}I within the next few months. Our laboratory has a strong biomedical AMS program of {sup 14}C tracer measurements involving large numbers of samples (sometimes hundreds in a single experiment) at {sup 14}C concentrations which are typically .5--5 times Modern, but are occasionally highly enriched. The sample preparation techniques required for high throughput and low cross-contamination for this work are discussed elsewhere. Similar demands are placed on the AMS measurement system, and in particular on the ion source. Modifications to our GIC 846 ion source, described below, allow us to run biomedical and geoscience or archaeological samples in the same source wheel with no adverse effects. The source has a capacity for 60 samples (about 45 unknown) in a single wheel and provides currents of 30--60{mu}A of C{sup {minus}} from hydrogen-reduced graphite. These currents and sample capacity provide high throughput for both biomedical and other measurements: the AMS system can be started up, tuned, and a wheel of carbon samples measured to 1--1.5% in under a day; and 2 biomedical wheels can be measured per day without difficulty. We report on the present status of the Lawrence Livermore AMS spectrometer, including sample throughput and progress towards routine 1% measurement capability for {sup 14}C, first results on other isotopes, and experience with a multi-sample high intensity ion source. 5 refs.

  3. Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.

    PubMed

    Sheldon, Ryan D; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Rector, R Scott

    2015-03-15

    The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity. PMID:25573175

  4. [A clinical trial of neutron capture therapy for brain tumors]. Technical progress report 1988

    SciTech Connect

    Zamenhof, R.G.

    1988-12-31

    This report describes progress made in refining of neutron-induced alpha tract autoradiography, in designing epithermal neutron bean at MITR-II and in planning treatment dosimetry using Monte Carlo techniques.

  5. Changes in tumor-antigen expression profile as human small-cell lung cancers progress

    PubMed Central

    Ge, Li-Sheng; Hoa, Neil T.; Lambrecht, Nils; Dacosta-Iyer, Maria; Ouyang, Yi; Abolhoda, Amir; Jadus, Martin R.

    2015-01-01

    Objective Our group has previously observed that in patients with small-cell lung cancers (SCLCs), the expression of a tumor antigen, glioma big potassium (gBK) ion channel, is higher at the time of death than when the cancer is first treated by surgical resection. This study aimed to determine whether this dichotomy was common in other potential lung tumor antigens by examining the same patient samples using our more extensive profile analysis of tumor-antigen precursor protein (TAPP). We then tested the hypothesis that therapeutic intervention may inadvertently cause this increased gBK production. Methods SCLC samples (eight surgical resections and three autopsy samples) and three control lungs were examined by quantitative real-time polymerase chain reaction for 42 potential TAPPs that represent potential T-cell-mediated immunological targets. Results Twenty-two TAPP mRNAs displayed the same profile as gBK, i.e., more mRNAs were expressed at autopsy than in their surgical counterparts. B-cyclin and mouse double minute 2, human homolog of P53-binding protein were elevated in both autopsy and surgical specimens above the normal-lung controls. When HTB119 cells were incubated with doxorubicin, gBK was strongly induced, as confirmed by intracellular flow cytometry with a gBK-specific antibody. Conclusion Our findings suggested that more immunological targets became available as the tumor responded to chemotherapy and proceeded toward its terminal stages. PMID:26175925

  6. Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis

    PubMed Central

    2010-01-01

    Introduction To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years. Methods In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years. Results 68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage. Conclusions In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year. PMID:20482894

  7. The progress in the laser-driven proton acceleration experiment JAEA with table-tip Ti:Sappire laser system

    NASA Astrophysics Data System (ADS)

    Nishiuchi, M.; Ogura, K.; Pirozhkov, A. S.; Tanimoto, T.; Yogo, A.; Sakaki, H.; Hori, T.; Fukuda, Y.; Kanasaki, M.; Sagisaka, A.; Tampo, M.; Kiriyama, H.; Shimomura, T.; Kondo, K.; Kawanishi, S.; Brenner, C.; Neely, D.

    2011-05-01

    This paper presents the experimental investigation of laser-driven proton acceleration using a table top Ti:Sapphire laser system interacting with the thin-foil targets during the course of medical application of the laser-driven proton beam. The proton beam with maximum energy of upto 14~MeV is generated in 60 TW mode. The number of protons at ~10 MeV is estimated to be over 105 proton/sr/MeV/shot with beam having half divergence angle of 5~degree. If 10 Hz operation is assumed 2 Gy dose is possible to irradiate during 10 min onto a ~1 mm tumor just under the skin. In contrast to the previous condition of our apparatus with which we demonstrated the DNA double-strand breaking by irradiating the laser-driven proton beam onto the human cancer cells in-vitro test, the result reported here has significant meaning in the sense that pre-clinical in-vivo test can be started by irradiating the laser-driven proton beam onto the skin of the mouse, which is unavoidable step before the real radiation therapy.

  8. Overexpression of ADAMTS-7 leads to accelerated initiation and progression of collagen-induced arthritis in mice

    PubMed Central

    Zhang, Yuying; Wei, Fanhua; Liu, Chuan-ju

    2015-01-01

    The aim of the present study is to determine whether ADAMTS-7 contributes to the onset and severity of joint inflammation in the pathogenesis of inflammatory arthritis. ADAMTS-7 was found to be elevated in the course of collagen-induced arthritis (CIA).. ADAMTS-7 transgenic (TG) mice were more susceptible to the induction of CIA. The onset of CIA was accelerated and the arthritic severity was increased in TG mice compared to wild type mice. The overall incidence was also significantly higher in TG mice. In addition, arthritic TG mice displayed significantly higher clinical and histological arthritis scores. The COMP degradative fragments were significantly elevated in articular cartilage and sera in CIA models of TG mice. Furthermore, the production of tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) were also increased in serum and draining lymph nodes of arthritic TG mice. Therefore, these data provided the in vivo evidence, suggesting that ADAMTS-7 may play an important role in the pathogenesis of inflammatory arthritis, and that inhibition of ADAMTS-7 may be a potential target to ameliorate the severity of inflammatory arthritis. PMID:25742929

  9. A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth

    PubMed Central

    Xiao, Nan; Cao, Hongbin; Chen, Che-Hong; Kong, Christina S.; Ali, Rehan; Chan, Cato; Sirjani, Davud; Graves, Edward; Koong, Albert; Giaccia, Amato; Mochly-Rosen, Daria; Le, Quynh-Thu

    2013-01-01

    Purpose To determine the effect of Alda-89 (an ALDH3 activitor) on (1) the function of irradiated (RT) submandibular gland (SMG) in mice, (2) its toxicity profile and (3) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo. Experimental Design Adult mice were infused with Alda-89 or vehicle before, during and after RT. Saliva secretion was monitored weekly. Hematology, metabolic profile and post-mortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and SCID mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 HNC patients and correlated to freedom from relapse (FFR) and overall survival (OS). Results Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after RT compared to vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared to vehicle control, Alda-89 treatment did not accelerate HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without RT. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either HPV-positive or HPV-negative group. Conclusion Alda-89 preserves salivary function after RT without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate RT-related xerostomia. PMID:23812668

  10. Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

    PubMed Central

    Chi, Jhih-Ying; Hsiao, Yu-Wei; Li, Chien-Feng; Lo, Yu-Chih; Lin, Zu-Yau; Hong, Jhen-Yi; Liu, Yang-Ming; Han, Xiu; Wang, Shao-Ming; Chen, Ben-Kuen; Tsai, Kelvin K.; Wang, Ju-Ming

    2015-01-01

    The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers. PMID:26124179

  11. Laricitrin suppresses increased benzo(a)pyrene-induced lung tumor-associated monocyte-derived dendritic cell cancer progression

    PubMed Central

    CHANG, WEI-AN; HUNG, JEN-YU; TSAI, YING-MING; HSU, YA-LING; CHIANG, HUNG-HSING; CHOU, SHAH-HWA; HUANG, MING-SHYAN; KUO, PO-LIN

    2016-01-01

    Benzo(a)pyrene (BaP) stimulates lung cancer cells, promoting monocyte-derived dendritic cells to secrete soluble factors, including heparin binding-epidermal growth factor and C-X-C motif chemokine 5. The secretions from monocyte-derived dendritic cells stimulate the progression of lung cancer cells, including the migration and invasion of cells. To the best of our knowledge, these secretions remain unknown, and require additional study. The present study identified that treatment with BaP-H1395-tumor-associated dendritic cell-conditioned medium had the most marked effect on cell migration and invasion. This result may be associated with the female gender, stage 2 adenocarcinoma or mutation of the proto-oncogene B-Raf (BRAF), according to the cell line background. Laricitrin, a dietary flavonoid derivative present in grapes and red wine, suppresses certain factors and decreases the progression of lung cancer cells that are promoted by BaP in the lung cancer tumor microenvironment. The results of the present study suggest that prolonged exposure to BaP exacerbates lung cancer, particularly in female lung cancer patients with the BRAF mutation, but that laricitrin may ameliorate this effect. PMID:26998077

  12. A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.

    PubMed

    Nam, Seungyoon; Chang, Hae Ryung; Jung, Hae Rim; Gim, Youme; Kim, Nam Youl; Grailhe, Regis; Seo, Haeng Ran; Park, Hee Seo; Balch, Curt; Lee, Jinhyuk; Park, Inhae; Jung, So Youn; Jeong, Kyung-Chae; Powis, Garth; Liang, Han; Lee, Eun Sook; Ro, Jungsil; Kim, Yon Hui

    2015-01-28

    Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance. PMID:25449779

  13. Estrogen deprivation and excess energy supply accelerate 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice

    PubMed Central

    Kim, Jin; Lee, Yoon Hee; Park, Jung Han Yoon

    2015-01-01

    BACKGROUND/OBJECTIVES Obesity is a risk factor of breast cancer in postmenopausal women. Estrogen deprivation has been suggested to cause alteration of lipid metabolism thereby creating a cellular microenvironment favoring tumor growth. The aim of this study is to investigate the effects of estrogen depletion in combination with excess energy supply on breast tumor development. MATERIALS/METHODS Ovariectomized (OVX) or sham-operated C3H/HeN mice at 4 wks were provided with either a normal diet or a high-fat diet (HD) for 16 weeks. Breast tumors were induced by administration of 7,12-dimethylbenz(a)anthracene once a week for six consecutive weeks. RESULTS Study results showed higher serum concentrations of free fatty acids and insulin in the OVX+HD group compared to other groups. The average tumor volume was significantly larger in OVX+HD animals than in other groups. Expressions of mammary tumor insulin receptor and mammalian target of rapamycin proteins as well as the ratio of pAKT/AKT were significantly increased, while pAMPK/AMPK was decreased in OVX+HD animals compared to the sham-operated groups. Higher relative expression of liver fatty acid synthase mRNA was observed in OVX+HD mice compared with other groups. CONCLUSIONS These results suggest that excess energy supply affects the accelerated mammary tumor growth in estrogen deprived mice. PMID:26634052

  14. PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction, increased apoptosis and impaired neovascularisation

    PubMed Central

    Levesque, Christine; Couture, Frédéric; Kwiatkowska, Anna; Desjardins, Roxane; Guérin, Brigitte; Neugebauer, Witold A.; Day, Robert

    2015-01-01

    Prostate cancer is the leading cancer in North American men. Current pharmacological treatments are limited to anti-androgen strategies and the development of new therapeutic approaches remains a challenge. As a fundamentally new approach, we propose the inhibition of PACE4, a member of the proprotein convertases family of enzymes, as a therapeutic target in prostate cancer. We developed an inhibitor named the Multi-Leu peptide, with potent in vitro anti-proliferative effects. However, the Multi-Leu peptide has not been tested under in vivo conditions and its potency under such conditions is most likely limited, due to the labile characteristics of peptides in general. Using a peptidomimetic approach, we modified the initial scaffold, generating the analog Ac-[DLeu]LLLRVK-Amba, which demonstrates increased inhibitory potency and stability. The systemic administration of this peptidomimetic significantly inhibits tumor progression in the LNCaP xenograft model of prostate cancer by inducing tumor cell quiescence, increased apoptosis and neovascularization impairment. Pharmacokinetic and biodistribution profiles of this inhibitor confirm adequate tumor delivery properties of the compound. We conclude that PACE4 peptidomimetic inhibitors could result in stable and potent drugs for a novel therapeutic strategy for prostate cancer. PMID:25682874

  15. SPOP promotes tumor progression via activation of β-catenin/TCF4 complex in clear cell renal cell carcinoma.

    PubMed

    Zhao, Wencai; Zhou, Jiancheng; Deng, Zhuo; Gao, Yang; Cheng, Yongyi

    2016-09-01

    Renal cell carcinoma (RCC) is the most common type of kidney cancer, about one third of the cases are diagnosed at advanced stages with metastases and effective treatments for metastatic RCC are lacking. The molecular events supporting RCC progression remain poorly understood. SPOP, an E3 ubiquitin ligase component, was recently showed to sufficiently promote RCC tumorigenesis, however, other potential functions of SPOP in RCC have not been studied. In the present investigation, by assessing the immunohistochemical staining of SPOP in urological tumors, we found the protein was highly expressed in RCC, in particular, it was specifically expressed in clear cell RCC. cDNA microarray data showed that SPOP mRNA level was significantly increased in clear cell RCC compared to normal kidney tissues, which might be the result of the abnormal DNA copy number of this gene. More interestingly, SPOP was positive in tumors with local invasion or metastasis, and it was associated with tumor recurrence-free survival of clear cell RCC patients. Further in vitro assays demonstrated that SPOP drove RCC epithelial-mesenchymal transition (EMT) and promoted cell invasion. Mechanistically, SPOP enhanced β-catenin protein expression as well as its nuclear translocation, and elevated TCF4 expression. Both β-catenin and TCF4 upregulated the critical EMT-inducing transcription factor ZEB1, which functioned as an effector of β-catenin/TCF4 signaling in RCC invasion. These data identified SPOP as a new marker and prognostic factor for clear cell RCC, and its functions provide new insight into the molecular mechanisms of RCC progression, in which SPOP appears to be an EMT activator. PMID:27572476

  16. BCL2 accelerates inflammation-induced BALB/c plasmacytomas and promotes novel tumors with coexisting T(12;15) and T(6;15) translocations.

    PubMed

    Silva, Santiago; Kovalchuk, Alexander L; Kim, Joong Su; Klein, George; Janz, Siegfried

    2003-12-15

    Previous studies on peritoneal plasmacytomas (PCTs) in BALB/c (C) mice suggested that the enforced expression of the death repressor BCL2 in B cells might facilitate the malignant transformation of aberrant B cells containing Myc-activating T(12;15) translocations, generating an improved model of plasmacytomagenesis. To investigate this hypothesis, we backcrossed a human BCL2 transgene onto strain C and performed a PCT induction study with pristane in the newly generated C.BCL2 congenics. In specific pathogen-free-maintained C.BCL2 mice, PCT incidence (19 of 34, 56%) was 24 times higher than in specific pathogen-free-maintained C mice (1 of 44, 2.3%), and tumor onset (113 days) was half that of conventionally maintained C mice (220 days). BCL2 transgenic PCT harbored T(12;15) translocations (12 of 12 tumors) with an unusual clustering of translocation breakpoints in the near 5' flank of Myc (4 of 5 tumors, 80%). Five tumors contained coexisting T(12;15) and T(6;15) translocations (not observed in >300 karyotyped PCTs from conventionally maintained C mice). BCL2 transgenic C57BL/6 mice exclusively developed B lymphomas (11 of 20, 55%) that also contained T(12;15) translocations (11 of 11 cases) with breakpoints in the near 5' flank of Myc (five of five tumors). We conclude that BCL2 accelerates PCT with novel Myc-activating translocations independently of environmental antigen stimulation. Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenström's macroglobulinemia and multiple myeloma. PMID:14695177

  17. Biology of MET: a double life between normal tissue repair and tumor progression

    PubMed Central

    2015-01-01

    MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer. PMID:25992381

  18. The anti-angiogenic activities of glycyrrhizic acid in tumor progression.

    PubMed

    Kim, Kil-Jung; Choi, Jae-Sun; Kim, Kyu-Won; Jeong, Joo-Won

    2013-06-01

    Glycyrrhizic acid (GA) is the bioactive compound of licorice and has been used as a herbal medicine because of its anti-viral, anti-cancer, and anti-inflammatory properties. This study was designed to investigate the effects of GA on tumor growth, angiogenesis, and the mechanisms underlying the anti-angiogenic activities of GA. We observed that GA inhibited tumor growth and angiogenesis in mice. GA decreased angiogenic activities, such as the migration, invasion, and tube formation of endothelial cells. We also demonstrated that GA reduced the production of reactive oxygen species and activation of ERK in endothelial cells. Our findings suggest that GA is a promising anti-angiogenic therapeutic agent that targets the ERK pathway. Considering that angiogenesis is highly stimulated in the majority of cancers, GA could offer a potent therapeutic agent for cancer. PMID:22899320

  19. Lung Cancer: A Classic Example of Tumor Escape and Progression While Providing Opportunities for Immunological Intervention

    PubMed Central

    Jadus, Martin R.; Natividad, Josephine; Mai, Anthony; Ouyang, Yi; Lambrecht, Nils; Szabo, Sandor; Ge, Lisheng; Hoa, Neil; Dacosta-Iyer, Maria G.

    2012-01-01

    Lung cancers remain one of the most common and deadly cancers in the world today (12.5% of newly diagnosed cancers) despite current advances in chemo- and radiation therapies. Often, by the time these tumors are diagnosed, they have already metastasized. These tumors demonstrate the classic hallmarks of cancer in that they have advanced defensive strategies allowing them to escape various standard oncological treatments. Immunotherapy is making inroads towards effectively treating other fatal cancers, such as melanoma, glioblastoma multiforme, and castrate-resistant prostate cancers. This paper will cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. We also review the history of immunotherapy directed towards lung cancers. PMID:22899945

  20. Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

    PubMed

    Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

    2012-01-01

    The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence. PMID:23061906

  1. Role of tumor-associated glycoprotein-72 in the progression of endometrial adenocarcinoma: a proposed study.

    PubMed

    Kristofic, Ines; Redzovic, Arnela; Laskarin, Gordana; Eminovic, Senija; Haller, Herman; Rukavina, Daniel

    2015-05-01

    Endometrial adenocarcinoma is on the basis of the molecular, immunohistological and clinicopathologic features broadly divided into two groups, referred as type I and type II. Type I appears more frequently and in principle patients have a good prognosis; however a significant number of patients develop local recurrences. We hypothesize that TAG-72, expressed on endometrial carcinoma binds and internalizes endocytic pattern recognition receptors on surrounding tissue antigen presenting cells (dendritic cells and macrophages), powers their anti-inflammatory maturation program and make them capable to elicit or modulated tolerogenic immune response mediated by local T and NK effectors. This could support uncontrolled local tumor growth, deeper tumor invasion into surrounding tissues, frequent local recurrences and/or lymph node metastasis. To test this hypothesis, we propose a semi-quantitative immunohistochemical analysis of TAG-72 expression in endometrial adenocarcinoma samples and to correlate the results with clinical and pathological parameters (age, type and histological grade of the tumor, estrogen and progesterone receptor expression, invasion into the myometrium and capillaries, presence of lymph node metastases, FIGO stage, and TNM classification). It would be worthwhile to investigate the local tissue immune response in the tumor environment using tissue samples removed during surgery. These studies could elucidate the underlying immunopathological mechanisms that govern the early recurrence and possibly distant metastases of TAG-72-expressing adenocarcinomas and might help in deciding the type of treatment to be applied in a selected group of cancer patients including application of biological therapy with anti-TAG-72 antibodies, according the principle of personalized oncology treatments. PMID:25769704

  2. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1#

    PubMed Central

    Zhang, Huabing; Ramakrishnan, Sadeesh K.; Triner, Daniel; Centofanti, Brook; Maitra, Dhiman; Győrffy, Balázs; Sebolt-Leopold, Judith S.; Dame, Michael K.; Varani, James; Brenner, Dean E.; Fearon, Eric R.; Omary, M. Bishr; Shah, Yatrik M.

    2016-01-01

    Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1- activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. Here, we found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetic or chemical-induced mouse models of CRC, in patient-derived xenografts and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viabilty of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells in hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death; whereas culturing cells in normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers. PMID:26443705

  3. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells

    PubMed Central

    ZHAO, LU; ZHAO, YUE; SCHWARZ, BETTINA; MYSLIWIETZ, JOSEF; HARTIG, ROLAND; CAMAJ, PETER; BAO, QI; JAUCH, KARL-WALTER; GUBA, MAKUS; ELLWART, JOACHIM WALTER; NELSON, PETER JON; BRUNS, CHRISTIANE JOSEPHINE

    2016-01-01

    Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multi-drug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density. PMID:27177126

  4. Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells.

    PubMed

    Zhao, Lu; Zhao, Yue; Schwarz, Bettina; Mysliwietz, Josef; Hartig, Roland; Camaj, Peter; Bao, Qi; Jauch, Karl-Walter; Guba, Makus; Ellwart, Joachim Walter; Nelson, Peter Jon; Bruns, Christiane Josephine

    2016-07-01

    Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multidrug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density. PMID:27177126

  5. Tumor suppressive microRNA-137 negatively regulates Musashi-1 and colorectal cancer progression

    PubMed Central

    Smith, Amber R.; Marquez, Rebecca T.; Tsao, Wei-Chung; Pathak, Surajit; Roy, Alexandria; Ping, Jie; Wilkerson, Bailey; Lan, Lan; Meng, Wenjian; Neufeld, Kristi L.; Sun, Xiao-Feng; Xu, Liang

    2015-01-01

    Stem cell marker, Musashi-1 (MSI1) is over-expressed in many cancer types; however the molecular mechanisms involved in MSI1 over-expression are not well understood. We investigated the microRNA (miRNA) regulation of MSI1 and the implications this regulation plays in colorectal cancer. MicroRNA miR-137 was identified as a MSI1-targeting microRNA by immunoblotting and luciferase reporter assays. MSI1 protein was found to be highly expressed in 79% of primary rectal tumors (n=146), while miR-137 expression was decreased in 84% of the rectal tumor tissues (n=68) compared to paired normal mucosal samples. In addition to reduced MSI1 protein, exogenous expression of miR-137 inhibited cell growth, colony formation, and tumorsphere growth of colon cancer cells. Finally, in vivo studies demonstrated that induction of miR-137 can decrease growth of human colon cancer xenografts. Our results demonstrate that miR-137 acts as a tumor-suppressive miRNA in colorectal cancers and negatively regulates oncogenic MSI1. PMID:25940441

  6. Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression

    PubMed Central

    Rupaimoole, Rajesha; Ivan, Cristina; Yang, Da; Gharpure, Kshipra M.; Wu, Sherry Y.; Pecot, Chad V.; Previs, Rebecca A.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N; McGuire, Michael; Pradeep, Sunila; Mangala, Lingegowda S.; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Zhang, Wei; Lopez-Berestein, Gabriel; Calin, George A.; Sood, Anil K.

    2015-01-01

    MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer, and resulting in increased tumor growth and metastasis. Here, we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using DOPC nanoliposomes resulted in increased tumor growth and metastasis and decreased Dicer ex