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Sample records for affect tumor growth

  1. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.

    PubMed Central

    Cornil, I; Theodorescu, D; Man, S; Herlyn, M; Jambrosic, J; Kerbel, R S

    1991-01-01

    It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites. PMID:2068080

  2. SIRT3-dependent GOT2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

    PubMed Central

    Yang, Hui; Zhou, Lisha; Shi, Qian; Zhao, Yuzheng; Lin, Huaipeng; Zhang, Mengli; Zhao, Shimin; Yang, Yi; Ling, Zhi-Qiang; Guan, Kun-Liang; Xiong, Yue; Ye, Dan

    2015-01-01

    The malate–aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate–aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD+ redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate–aspartate NADH shuttle activity and oxidative protection. PMID:25755250

  3. Factors affecting bone growth.

    PubMed

    Gkiatas, Ioannis; Lykissas, Marios; Kostas-Agnantis, Ioannis; Korompilias, Anastasios; Batistatou, Anna; Beris, Alexandros

    2015-02-01

    Bone growth and development are products of the complex interactions of genetic and environmental factors. Longitudinal bone growth depends on the growth plate. The growth plate has 5 different zones-each with a different functional role-and is the final target organ for longitudinal growth. Bone length is affected by several systemic, local, and mechanical factors. All these regulation systems control the final length of bones in a complicated way. Despite its significance to bone stability, bone growth in width has not been studied as extensively as longitudinal bone growth. Bone growth in width is also controlled by genetic factors, but mechanical loading regulates periosteal apposition. In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases and fracture risk.

  4. Phyllodes tumor showing intraductal growth.

    PubMed

    Makidono, Akari; Tsunoda, Hiroko; Mori, Miki; Yagata, Hiroshi; Onoda, Yui; Kikuchi, Mari; Nozaki, Taiki; Saida, Yukihisa; Nakamura, Seigo; Suzuki, Koyu

    2013-07-01

    Phyllodes tumor of the breast is a rare fibroepithelial lesion and particularly uncommon in adolescent girls. It is thought to arise from the periductal rather than intralobular stroma. Usually, it is seen as a well-defined mass. Phyllodes tumor showing intraductal growth is extremely rare. Here we report a girl who has a phyllodes tumor with intraductal growth.

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

    PubMed Central

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

    2016-01-01

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

  6. The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines

    SciTech Connect

    Mack, Hildegard I.D.; Munger, Karl

    2013-11-15

    Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis. However, most lesions caused by high-risk HPV infections do not progress to cancer. Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown. Based on a previous study that reported an association between liver kinase B1 (LKB1) tumor suppressor loss and poor outcome in cervical cancer, we sought to determine the molecular basis for this observation. LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1-regulated processes including inhibition of cell proliferation and elevated resistance to energy stress. Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines. Thus, our results suggest that LKB1 may be a cell-type specific tumor suppressor. - Highlights: • LKB1 is a tumor suppressor that is linked to Peutz-Jeghers syndrome. • Peutz-Jeghers syndrome patients have a high incidence of cervical cancer. • Cervical cancer is caused by HPV infections. • This study investigates LKB1 tumor suppressor activity in cervical cancer.

  7. Mesoscopic model for tumor growth.

    PubMed

    Izquierdo-Kulich, Elena; Nieto-Villar, José Manuel

    2007-10-01

    In this work, we propose a mesoscopic model for tumor growth to improve our understanding of the origin of the heterogeneity of tumor cells. In this sense, this stochastic formalism allows us to not only to reproduce but also explain the experimental results presented by Brú. A significant aspect found by the model is related to the predicted values for beta growth exponent, which capture a basic characteristic of the critical surface growth dynamics. According to the model, the value for growth exponent is between 0,25 and 0,5, which includes the value proposed by Kadar-Parisi-Zhang universality class (0,33) and the value proposed by Brú (0,375) related to the molecular beam epitaxy (MBE) universality class. This result suggests that the tumor dynamics are too complex to be associated to a particular universality class.

  8. Platelets effects on tumor growth.

    PubMed

    Goubran, Hadi A; Stakiw, Julie; Radosevic, Mirjana; Burnouf, Thierry

    2014-06-01

    Unlike other blood cells, platelets are small anucleate structures derived from marrow megakaryocytes. Thought for almost a century to possess solely hemostatic potentials, platelets, however, play a much wider role in tissue regeneration and repair and interact intimately with tumor cells. On one hand, tumor cells induce platelet aggregation (TCIPA), known to act as the trigger of cancer-associated thrombosis. On the other hand, platelets recruited to the tumor microenvironment interact, directly, with tumor cells, favoring their proliferation, and, indirectly, through the release of a wide palette of growth factors, including angiogenic and mitogenic proteins. In addition, the role of platelets is not solely confined to the primary tumor site. Indeed, they escort tumor cells, helping their intravasation, vascular migration, arrest, and extravasation to the tissues to form distant metastasis. As expected, nonspecific or specific inhibition of platelets and their content represents an attractive novel approach in the fight against cancer. This review illustrates the role played by platelets at primary tumor sites and in the various stages of the metastatic process.

  9. A new ODE tumor growth modeling based on tumor population dynamics

    SciTech Connect

    Oroji, Amin; Omar, Mohd bin; Yarahmadian, Shantia

    2015-10-22

    In this paper a new mathematical model for the population of tumor growth treated by radiation is proposed. The cells dynamics population in each state and the dynamics of whole tumor population are studied. Furthermore, a new definition of tumor lifespan is presented. Finally, the effects of two main parameters, treatment parameter (q), and repair mechanism parameter (r) on tumor lifespan are probed, and it is showed that the change in treatment parameter (q) highly affects the tumor lifespan.

  10. A new ODE tumor growth modeling based on tumor population dynamics

    NASA Astrophysics Data System (ADS)

    Oroji, Amin; Omar, Mohd bin; Yarahmadian, Shantia

    2015-10-01

    In this paper a new mathematical model for the population of tumor growth treated by radiation is proposed. The cells dynamics population in each state and the dynamics of whole tumor population are studied. Furthermore, a new definition of tumor lifespan is presented. Finally, the effects of two main parameters, treatment parameter (q), and repair mechanism parameter (r) on tumor lifespan are probed, and it is showed that the change in treatment parameter (q) highly affects the tumor lifespan.

  11. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    PubMed Central

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  12. Image based modeling of tumor growth.

    PubMed

    Meghdadi, N; Soltani, M; Niroomand-Oscuii, H; Ghalichi, F

    2016-09-01

    Tumors are a main cause of morbidity and mortality worldwide. Despite the efforts of the clinical and research communities, little has been achieved in the past decades in terms of improving the treatment of aggressive tumors. Understanding the underlying mechanism of tumor growth and evaluating the effects of different therapies are valuable steps in predicting the survival time and improving the patients' quality of life. Several studies have been devoted to tumor growth modeling at different levels to improve the clinical outcome by predicting the results of specific treatments. Recent studies have proposed patient-specific models using clinical data usually obtained from clinical images and evaluating the effects of various therapies. The aim of this review is to highlight the imaging role in tumor growth modeling and provide a worthwhile reference for biomedical and mathematical researchers with respect to tumor modeling using the clinical data to develop personalized models of tumor growth and evaluating the effect of different therapies.

  13. Biochemomechanical poroelastic theory of avascular tumor growth

    NASA Astrophysics Data System (ADS)

    Xue, Shi-Lei; Li, Bo; Feng, Xi-Qiao; Gao, Huajian

    2016-09-01

    Tumor growth is a complex process involving genetic mutations, biochemical regulations, and mechanical deformations. In this paper, a thermodynamics-based nonlinear poroelastic theory is established to model the coupling among the mechanical, chemical, and biological mechanisms governing avascular tumor growth. A volumetric growth law accounting for mechano-chemo-biological coupled effects is proposed to describe the development of solid tumors. The regulating roles of stresses and nutrient transport in the tumor growth are revealed under different environmental constraints. We show that the mechano-chemo-biological coupling triggers anisotropic and heterogeneous growth, leading to the formation of layered structures in a growing tumor. There exists a steady state in which tumor growth is balanced by resorption. The influence of external confinements on tumor growth is also examined. A phase diagram is constructed to illustrate how the elastic modulus and thickness of the confinements jointly dictate the steady state of tumor volume. Qualitative and quantitative agreements with experimental observations indicate the developed model is capable of capturing the essential features of avascular tumor growth in various environments.

  14. The role of fibroblast growth factors in tumor growth.

    PubMed

    Korc, M; Friesel, R E

    2009-08-01

    Biological processes that drive cell growth are exciting targets for cancer therapy. The fibroblast growth factor (FGF) signaling network plays a ubiquitous role in normal cell growth, survival, differentiation, and angiogenesis, but has also been implicated in tumor development. Elucidation of the roles and relationships within the diverse FGF family and of their links to tumor growth and progression will be critical in designing new drug therapies to target FGF receptor (FGFR) pathways. Recent studies have shown that FGF can act synergistically with vascular endothelial growth factor (VEGF) to amplify tumor angiogenesis, highlighting that targeting of both the FGF and VEGF pathways may be more efficient in suppressing tumor growth and angiogenesis than targeting either factor alone. In addition, through inducing tumor cell survival, FGF has the potential to overcome chemotherapy resistance highlighting that chemotherapy may be more effective when used in combination with FGF inhibitor therapy. Furthermore, FGFRs have variable activity in promoting angiogenesis, with the FGFR-1 subgroup being associated with tumor progression and the FGFR-2 subgroup being associated with either early tumor development or decreased tumor progression. This review highlights the growing knowledge of FGFs in tumor cell growth and survival, including an overview of FGF intracellular signaling pathways, the role of FGFs in angiogenesis, patterns of FGF and FGFR expression in various tumor types, and the role of FGFs in tumor progression.

  15. Tumor-Induced Hyperlipidemia Contributes to Tumor Growth

    PubMed Central

    Huang, Jianfeng; Li, Lena; Lian, Jihong; Schauer, Silvia; Vesely, Paul W.; Kratky, Dagmar; Hoefler, Gerald; Lehner, Richard

    2016-01-01

    Summary The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover. To assess whether tumor progression was dependent on tumor-induced hyperlipidemia, we utilized the VLDL production-deficient mouse model, carboxylesterase3/triacylglycerol hydrolase (Ces3/TGH) knockout mice. In Ces3/Tgh–/– tumor-bearing mice, plasma triglyceride and cholesterol levels were attenuated. Importantly tumor weight was reduced in Ces3/Tgh–/– mice. Mechanistically, reduced tumor growth in Ces3/Tgh–/– mice was attributed to reversal of tumor-induced PCSK9-mediated degradation of hepatic LDLR and decrease of LDL turnover. Our data demonstrate that tumor-induced hyperlipidemia encompasses a feed-forward loop that reprograms hepatic lipoprotein homeostasis in part by providing LDL cholesterol to support tumor growth. PMID:27050512

  16. The Universal Dynamics of Tumor Growth

    PubMed Central

    Brú, Antonio; Albertos, Sonia; Luis Subiza, José; García-Asenjo, José López; Brú, Isabel

    2003-01-01

    Scaling techniques were used to analyze the fractal nature of colonies of 15 cell lines growing in vitro as well as of 16 types of tumor developing in vivo. All cell colonies were found to exhibit exactly the same growth dynamics—which correspond to the molecular beam epitaxy (MBE) universality class. MBE dynamics are characterized by 1), a linear growth rate, 2), the constraint of cell proliferation to the colony/tumor border, and 3), surface diffusion of cells at the growing edge. These characteristics were experimentally verified in the studied colonies. That these should show MBE dynamics is in strong contrast with the currently established concept of tumor growth: the kinetics of this type of proliferation rules out exponential or Gompertzian growth. Rather, a clear linear growth regime is followed. The importance of new cell movements—cell diffusion at the tumor border—lies in the fact that tumor growth must be conceived as a competition for space between the tumor and the host, and not for nutrients or other factors. Strong experimental evidence is presented for 16 types of tumor, the growth of which cell surface diffusion may be the main mechanism responsible in vivo. These results explain most of the clinical and biological features of colonies and tumors, offer new theoretical frameworks, and challenge the wisdom of some current clinical strategies. PMID:14581197

  17. Extracellular purines, purinergic receptors and tumor growth

    PubMed Central

    Di Virgilio, F; Adinolfi, E

    2017-01-01

    Virtually, all tumor cells as well as all immune cells express plasma membrane receptors for extracellular nucleosides (adenosine) and nucleotides (ATP, ADP, UTP, UDP and sugar UDP). The tumor microenvironment is characterized by an unusually high concentration of ATP and adenosine. Adenosine is a major determinant of the immunosuppressive tumor milieu. Sequential hydrolysis of extracellular ATP catalyzed by CD39 and CD73 is the main pathway for the generation of adenosine in the tumor interstitium. Extracellular ATP and adenosine mold both host and tumor responses. Depending on the specific receptor activated, extracellular purines mediate immunosuppression or immunostimulation on the host side, and growth stimulation or cytotoxicity on the tumor side. Recent progress in this field is providing the key to decode this complex scenario and to lay the basis to harness the potential benefits for therapy. Preclinical data show that targeting the adenosine-generating pathway (that is, CD73) or adenosinergic receptors (that is, A2A) relieves immunosuppresion and potently inhibits tumor growth. On the other hand, growth of experimental tumors is strongly inhibited by targeting the P2X7 ATP-selective receptor of cancer and immune cells. This review summarizes the recent data on the role played by extracellular purines (purinergic signaling) in host–tumor interaction and highlights novel therapeutic options stemming from recent advances in this field. PMID:27321181

  18. Autocrine growth factors and solid tumor malignancy.

    PubMed Central

    Walsh, J. H.; Karnes, W. E.; Cuttitta, F.; Walker, A.

    1991-01-01

    The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy. Images PMID:1926844

  19. Effects of anatomical constraints on tumor growth

    NASA Astrophysics Data System (ADS)

    Capogrosso Sansone, B.; Delsanto, P. P.; Magnano, M.; Scalerandi, M.

    2001-08-01

    Competition for available nutrients and the presence of anatomical barriers are major determinants of tumor growth in vivo. We extend a model recently proposed to simulate the growth of neoplasms in real tissues to include geometrical constraints mimicking pressure effects on the tumor surface induced by the presence of rigid or semirigid structures. Different tissues have different diffusivities for nutrients and cells. Despite the simplicity of the approach, based on a few inherently local mechanisms, the numerical results agree qualitatively with clinical data (computed tomography scans of neoplasms) for the larynx and the oral cavity.

  20. Contour Instabilities in Early Tumor Growth Models

    NASA Astrophysics Data System (ADS)

    Ben Amar, M.; Chatelain, C.; Ciarletta, P.

    2011-04-01

    Recent tumor growth models are often based on the multiphase mixture framework. Using bifurcation theory techniques, we show that such models can give contour instabilities. Restricting to a simplified but realistic version of such models, with an elastic cell-to-cell interaction and a growth rate dependent on diffusing nutrients, we prove that the tumor cell concentration at the border acts as a control parameter inducing a bifurcation with loss of the circular symmetry. We show that the finite wavelength at threshold has the size of the proliferating peritumoral zone. We apply our predictions to melanoma growth since contour instabilities are crucial for early diagnosis. Given the generality of the equations, other relevant applications can be envisaged for solving problems of tissue growth and remodeling.

  1. A tumor growth model with deformable ECM.

    PubMed

    Sciumè, G; Santagiuliana, R; Ferrari, M; Decuzzi, P; Schrefler, B A

    2014-11-26

    Existing tumor growth models based on fluid analogy for the cells do not generally include the extracellular matrix (ECM), or if present, take it as rigid. The three-fluid model originally proposed by the authors and comprising tumor cells (TC), host cells (HC), interstitial fluid (IF) and an ECM, considered up to now only a rigid ECM in the applications. This limitation is here relaxed and the deformability of the ECM is investigated in detail. The ECM is modeled as a porous solid matrix with Green-elastic and elasto-visco-plastic material behavior within a large strain approach. Jauman and Truesdell objective stress measures are adopted together with the deformation rate tensor. Numerical results are first compared with those of a reference experiment of a multicellular tumor spheroid (MTS) growing in vitro, then three different tumor cases are studied: growth of an MTS in a decellularized ECM, growth of a spheroid in the presence of host cells and growth of a melanoma. The influence of the stiffness of the ECM is evidenced and comparison with the case of a rigid ECM is made. The processes in a deformable ECM are more rapid than in a rigid ECM and the obtained growth pattern differs. The reasons for this are due to the changes in porosity induced by the tumor growth. These changes are inhibited in a rigid ECM. This enhanced computational model emphasizes the importance of properly characterizing the biomechanical behavior of the malignant mass in all its components to correctly predict its temporal and spatial pattern evolution.

  2. A tumor growth model with deformable ECM

    PubMed Central

    Sciumè, G; Santagiuliana, R; Ferrari, M; Decuzzi, P; Schrefler, B A

    2015-01-01

    Existing tumor growth models based on fluid analogy for the cells do not generally include the extracellular matrix (ECM), or if present, take it as rigid. The three-fluid model originally proposed by the authors and comprising tumor cells (TC), host cells (HC), interstitial fluid (IF) and an ECM, considered up to now only a rigid ECM in the applications. This limitation is here relaxed and the deformability of the ECM is investigated in detail. The ECM is modeled as a porous solid matrix with Green-elastic and elasto-visco-plastic material behavior within a large strain approach. Jauman and Truesdell objective stress measures are adopted together with the deformation rate tensor. Numerical results are first compared with those of a reference experiment of a multicellular tumor spheroid (MTS) growing in vitro, then three different tumor cases are studied: growth of an MTS in a decellularized ECM, growth of a spheroid in the presence of host cells and growth of a melanoma. The influence of the stiffness of the ECM is evidenced and comparison with the case of a rigid ECM is made. The processes in a deformable ECM are more rapid than in a rigid ECM and the obtained growth pattern differs. The reasons for this are due to the changes in porosity induced by the tumor growth. These changes are inhibited in a rigid ECM. This enhanced computational model emphasizes the importance of properly characterizing the biomechanical behavior of the malignant mass in all its components to correctly predict its temporal and spatial pattern evolution. PMID:25427284

  3. Stochastic Modelling of Gompertzian Tumor Growth

    NASA Astrophysics Data System (ADS)

    O'Rourke, S. F. C.; Behera, A.

    2009-08-01

    We study the effect of correlated noise in the Gompertzian tumor growth model for non-zero correlation time. The steady state probability distributions and average population of tumor cells are analyzed within the Fokker-Planck formalism to investigate the importance of additive and multiplicative noise. We find that the correlation strength and correlation time have opposite effects on the steady state probability distributions. It is observed that the non-bistable Gompertzian model, driven by correlated noise exhibits a stochastic resonance and phase transition. This behaviour of the Gompertz model is unaffected with the change of correlation time and occurs as a result of multiplicative noise.

  4. The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress

    PubMed Central

    2010-01-01

    Introduction Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF) is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo. Methods For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis. Results Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this effect. Moreover, antalarmin

  5. Devazepide, a nonpeptide antagonist of CCK receptors, induces apoptosis and inhibits Ewing tumor growth.

    PubMed

    Carrillo, Jaime; Agra, Noelia; Fernández, Noemí; Pestaña, Angel; Alonso, Javier

    2009-08-01

    The Ewing family of tumors is a group of highly malignant tumors that mainly arise in bone and most often affect children and young adults in the first two decades of life. Despite the use of multimodal therapy, the long-term disease-free survival rate of patients with Ewing tumors is still disappointingly low, making the discovery of innovative therapeutic strategies all the more necessary. We have recently shown that cholecystokinin (CCK), a neuroendocrine peptide, involved in many biological functions, including cell growth and proliferation, is a relevant target of the EWS/FLI1 oncoprotein characteristic of Ewing tumors. CCK silencing inhibits cell proliferation and tumor growth in vivo, suggesting that CCK acts as an autocrine growth factor for Ewing cells. Here, we analyzed the impact of two CCK receptor antagonists, devazepide (a CCK1-R antagonist) and L365 260 (a CCK2-R antagonist), on the growth of Ewing tumor cells. Devazepide (10 micromol/l) inhibited cell growth of four different Ewing tumor cells in vitro (range 85-88%), whereas the effect of the CCK2-R antagonist on cell growth was negligible. In a mouse tumor xenograft model, devazepide reduced tumor growth by 40%. Flow cytometry experiments showed that devazepide, but not L365 260, induced apoptosis of Ewing tumor cells. In summary, devazepide induces cell death of Ewing tumor cells, suggesting that it could represent a new therapeutic approach in the management of Ewing's tumor patients.

  6. The role of the microenvironment in tumor growth and invasion

    PubMed Central

    Kim, Yangjin; Stolarska, Magdalena A.; Othmer, Hans G.

    2011-01-01

    Mathematical modeling and computational analysis are essential for understanding the dynamics of the complex gene networks that control normal development and homeostasis, and can help to understand how circumvention of that control leads to abnormal outcomes such as cancer. Our objectives here are to discuss the different mechanisms by which the local biochemical and mechanical microenvironment, which is comprised of various signaling molecules, cell types and the extracellular matrix (ECM), affects the progression of potentially-cancerous cells, and to present new results on two aspects of these effects. We first deal with the major processes involved in the progression from a normal cell to a cancerous cell at a level accessible to a general scientific readership, and we then outline a number of mathematical and computational issues that arise in cancer modeling. In Section 2 we present results from a model that deals with the effects of the mechanical properties of the environment on tumor growth, and in Section 3 we report results from a model of the signaling pathways and the tumor microenvironment (TME), and how their interactions affect the development of breast cancer. The results emphasize anew the complexities of the interactions within the TME and their effect on tumor growth, and show that tumor progression is not solely determined by the presence of a clone of mutated immortal cells, but rather that it can be ‘community-controlled’. It Takes a Village – Hilary Clinton PMID:21736894

  7. Growth patterns of microscopic brain tumors

    NASA Astrophysics Data System (ADS)

    Sander, Leonard M.; Deisboeck, Thomas S.

    2002-11-01

    Highly malignant brain tumors such as glioblastoma multiforme form complex growth patterns in vitro in which invasive cells organize in tenuous branches. Here, we formulate a chemotaxis model for this sort of growth. A key element controlling the pattern is homotype attraction, i.e., the tendency for invasive cells to follow pathways previously explored. We investigate this in two ways: we show that there is an intrinsic instability in the model, which leads to branch formation. We also give a discrete description for the expansion of the invasive zone, and a continuum model for the nutrient supply. The results indicate that both strong heterotype chemotaxis and strong homotype chemoattraction are required for branch formation within the invasive zone. Our model thus can give a way to assess the importance of the various processes, and a way to explore and analyze transitions between different growth regimes.

  8. Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors.

    PubMed

    Voutouri, Chrysovalantis; Mpekris, Fotios; Papageorgis, Panagiotis; Odysseos, Andreani D; Stylianopoulos, Triantafyllos

    2014-01-01

    Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion.

  9. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo(-/-) mice.

    PubMed

    Campbell, Elizabeth J; Vissers, Margreet Cm; Dachs, Gabi U

    2016-01-01

    In solid tumors, HIF1 upregulates the expression of hundreds of genes involved in cell survival, tumor growth, and adaptation to the hypoxic microenvironment. HIF1 stabilization and activity are suppressed by prolyl and asparagine hydroxylases, which require oxygen as a substrate and ascorbate as a cofactor. This has led us to hypothesize that intracellular ascorbate availability could modify the hypoxic HIF1 response and influence tumor growth. In this study, we investigated the effect of variable intracellular ascorbate levels on HIF1 induction in cancer cells in vitro, and on tumor-take rate and growth in the Gulo(-/-) mouse. These mice depend on dietary ascorbate, and were supplemented with 3,300 mg/L, 330 mg/L, or 33 mg/L ascorbate in their drinking water, resulting in saturating, medium, or low plasma and tissue ascorbate levels, respectively. In Lewis lung carcinoma cells (LL/2) in culture, optimal ascorbate supplementation reduced HIF1 accumulation under physiological but not pathological hypoxia. LL/2, B16-F10 melanoma, or CMT-93 colorectal cancer cells were implanted subcutaneously into Gulo(-/-) mice at a range of cell inocula. Establishment of B16-F10 tumors in mice supplemented with 3,300 mg/L ascorbate required an increased number of cancer cells to initiate tumor growth compared with the number of cells required in mice on suboptimal ascorbate intake. Elevated ascorbate intake was also associated with decreased tumor ascorbate levels and a reduction in HIF1α expression and transcriptional activity. Following initial growth, all CMT-93 tumors regressed spontaneously, but mice supplemented with 33 mg/L ascorbate had lower plasma ascorbate levels and grew larger tumors than optimally supplemented mice. The data from this study indicate that improved ascorbate intake is consistent with increased intracellular ascorbate levels, reduced HIF1 activity and reduced tumor initiation and growth, and this may be advantageous in the management of cancer.

  10. Serial circulating immune complex levels and mitogen responses during progressive tumor growth in WF rats.

    PubMed

    Rodrick, M L; Steele, G; Ross, D S; Lahey, S J; Deasy, J M; Rayner, A A; Harte, P J; Wilson, R E; Munroe, A E; King, V P

    1983-06-01

    Inbred male WF rats were given im injections of one of two antigenically and histologically distinct syngeneic tumor isografts, adenocarcinoma DMH-W 163 or spontaneous renal cell carcinoma SPK. Serum and peripheral blood lymphocytes were harvested from tumor-bearing and normal age-matched controls before and after isograft challenge at weekly intervals. Serial circulating immune complex (CIC) levels were quantitated by polyethylene glycol (PEG) insolubilization. T-cell mitogen responses to phytohemagglutinin (PHA) and concanavalin A (Con A) were followed serially. Tumor growth was measured at least weekly. PEG-CIC values rose early after tumor injection, increased with tumor growth, and declined in some animals just before death. Mitogen response to PHA was significantly decreased in isografted tumor-bearing rats, particularly at later stages of tumor development, compared to normal uninoculated controls. Responses to Con A were variable, and suppression was not always seen in tumor bearers. In animals that did not have progressive tumor growth after isograft injection, PEG-CIC levels did not change and responses to PHA were not suppressed. Patterns of CIC change and responses to PHA were not affected by differences in tumor histology or growth rates. Thus serial CIC levels measured by the PEG assay correlate with tumor growth and precede nonspecific suppression of T-cell mitogenic response in these animal tumor models.

  11. Tumor suppressor ARF regulates tissue microenvironment and tumor growth through modulation of macrophage polarization

    PubMed Central

    Jiménez-García, Lidia; Herranz, Sandra; Higueras, María Angeles

    2016-01-01

    Tumor microenvironment has been described to play a key role in tumor growth, progression, and metastasis. Macrophages are a major cellular constituent of the tumor stroma, and particularly tumor associated macrophages (TAMs or M2-like macrophages) exert important immunosuppressive activity and a pro-tumoral role within the tumor microenvironment. Alternative-reading frame (ARF) gene is widely inactivated in human cancer. We have previously demonstrated that ARF deficiency severely impairs inflammatory response establishing a new role for ARF in the regulation of innate immunity. On the basis of these observations, we hypothesized that ARF may also regulates tumor growth through recruitment and modulation of the macrophage phenotype in the tumor microenvironment. Xenograft assays of B16F10 melanoma cells into ARF-deficient mice resulted in increased tumor growth compared to those implanted in WT control mice. Tumors from ARF-deficient mice exhibited significantly increased number of TAMs as well as microvascular density. Transwell assays showed crosstalk between tumor cells and macrophages. On the one hand, ARF-deficient macrophages modulate migratory ability of the tumor cells. And on the other, tumor cells promote the skewing of ARF−/− macrophages toward a M2-type polarization. In conclusion, these results demonstrate that ARF deficiency facilitates the infiltration of macrophages into the tumor mass and favors their polarization towards a M2 phenotype, thus promoting tumor angiogenesis and tumor growth. This work provides novel information about the critical role of ARF in the modulation of tumor microenvironment. PMID:27572316

  12. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  13. Factors affecting intellectual outcome in pediatric brain tumor patients

    SciTech Connect

    Ellenberg, L.; McComb, J.G.; Siegel, S.E.; Stowe, S.

    1987-11-01

    A prospective study utilizing repeated intellectual testing was undertaken in 73 children with brain tumors consecutively admitted to Childrens Hospital of Los Angeles over a 3-year period to determine the effect of tumor location, extent of surgical resection, hydrocephalus, age of the child, radiation therapy, and chemotherapy on cognitive outcome. Forty-three patients were followed for at least two sequential intellectual assessments and provide the data for this study. Children with hemispheric tumors had the most general cognitive impairment. The degree of tumor resection, adequately treated hydrocephalus, and chemotherapy had no bearing on intellectual outcome. Age of the child affected outcome mainly as it related to radiation. Whole brain radiation therapy was associated with cognitive decline. This was especially true in children below 7 years of age, who experienced a very significant loss of function after whole brain radiation therapy.

  14. Adiponectin deficiency promotes tumor growth in mice by reducing macrophage infiltration.

    PubMed

    Sun, Yutong; Lodish, Harvey F

    2010-08-05

    Adiponectin is an adipocyte-derived plasma protein that has been implicated in regulating angiogenesis, but the role of adiponectin in regulating this process is still controversial. In this study, in order to determine whether adiponectin affects tumor growth and tumor induced vascularization, we implanted B16F10 melanoma and Lewis Lung Carcinoma cells subcutaneously into adiponectin knockout and wild-type control mice, and found that adiponectin deficiency markedly promoted the growth of both tumors. Immunohistochemical analyses indicated that adiponectin deficiency reduced macrophage recruitment to the tumor, but did not affect cancer cell mitosis, apoptosis, or tumor-associated angiogenesis. In addition, treatment with recombinant adiponectin did not affect the proliferation of cultured B16F10 tumor cells. Importantly, the restoration of microphage infiltration at an early stage of tumorigenesis by means of co-injection of B16F10 cells and macrophages reversed the increased tumor growth in adiponectin knockout mice. Thus, we conclude that the enhanced tumor growth observed in adiponectin deficient mice is likely due to the reduction of macrophage infiltration rather than enhanced angiogenesis.

  15. Novel glycosaminoglycan biosynthetic inhibitors affect tumor-associated angiogenesis

    PubMed Central

    Raman, Karthik; Ninomiya, Masayuki; Nguyen, Thao Kim Nu; Tsuzuki, Yasuhiro; Koketsu, Mamoru; Kuberan, Balagurunathan

    2011-01-01

    Heparan sulfate proteoglycans (HSPGs) are essential players in several steps of tumor-associated angiogenesis. As co-receptors for several pro-angiogenic factors such as VEGF and FGF, HSPGs regulate receptor-ligand interactions and play a vital role in signal transduction. Previously, we have employed an enzymatic strategy to show the importance of cell surface HSPGs in endothelial tube formation in vitro. We have recently found several fluoro-xylosides that can selectively inhibit proteoglycan synthesis in endothelial cells. The current study demonstrates that these fluoro-xylosides are effective inhibitors of endothelial tube formation in vitro using a matrigel based assay to simulate tumor-associated angiogenesis. These first generation scaffolds offer a promising stepping-stone to the discovery of more potent fluoro-xylosides that can effectively neutralize tumor growth. PMID:21094131

  16. The model muddle: in search of tumor growth laws.

    PubMed

    Gerlee, Philip

    2013-04-15

    In this article, we will trace the historical development of tumor growth laws, which in a quantitative fashion describe the increase in tumor mass/volume over time. These models are usually formulated in terms of differential equations that relate the growth rate of the tumor to its current state and range from the simple one-parameter exponential growth model to more advanced models that contain a large number of parameters. Understanding the assumptions and consequences of such models is important, as they often underpin more complex models of tumor growth. The conclusion of this brief survey is that although much improvement has occurred over the last century, more effort and new models are required if we are to understand the intricacies of tumor growth.

  17. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  18. A multiphase model for three-dimensional tumor growth

    PubMed Central

    Sciumè, G; Shelton, S; Gray, WG; Miller, CT; Hussain, F; Ferrari, M; Decuzzi, P; Schrefler, BA

    2014-01-01

    Several mathematical formulations have analyzed the time-dependent behaviour of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) for the transport of nutrients. The equations are solved by a Finite Element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTS) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behaviour: initially, the rapidly growing tumor cells tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable tumor cells whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case – mostly due to the relative adhesion of the tumor and healthy cells to the ECM, and the less favourable transport of nutrients. In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced

  19. The phase-field model in tumor growth

    NASA Astrophysics Data System (ADS)

    Travasso, Rui D. M.; Castro, Mario; Oliveira, Joana C. R. E.

    2011-01-01

    Tumor growth is becoming a central problem in biophysics both from its social and medical interest and, more fundamentally, because it is a remarkable example of an emergent complex system. Focusing on the description of the spatial and dynamical features of tumor growth, in this paper we review recent tumor modeling approaches using a technique borrowed from materials science: the phase-field models. These models allow us, with a large degree of generality, to identify the paramount mechanisms causing the uncontrolled growth of tumor cells as well as to propose new guidelines for experimentation both in simulation and in the laboratory. We finish by discussing open directions of research in phase-field modeling of tumor growth to catalyze the interest of physicists and mathematicians in this emergent field.

  20. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    SciTech Connect

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-03-28

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  1. Brain tumor modeling: glioma growth and interaction with chemotherapy

    NASA Astrophysics Data System (ADS)

    Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

    2011-10-01

    In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

  2. Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

    PubMed Central

    Asting, Annika Gustafsson; Iresjö, Britt-Marie; Nilsberth, Camilla; Smedh, Ulrika; Lundholm, Kent

    2017-01-01

    Prostaglandin E2 (PGE2) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE2 receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE2-producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including stemness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE2 signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth. PMID:28123585

  3. Factors affecting the cerebral network in brain tumor patients.

    PubMed

    Heimans, Jan J; Reijneveld, Jaap C

    2012-06-01

    Brain functions, including cognitive functions, are frequently disturbed in brain tumor patients. These disturbances may result from the tumor itself, but also from the treatment directed against the tumor. Surgery, radiotherapy and chemotherapy all may affect cerebral functioning, both in a positive as well as in a negative way. Apart from the anti-tumor treatment, glioma patients often receive glucocorticoids and anti-epileptic drugs, which both also have influence on brain functioning. The effect of a brain tumor on cerebral functioning is often more global than should be expected on the basis of the local character of the disease, and this is thought to be a consequence of disturbance of the cerebral network as a whole. Any network, whether it be a neural, a social or an electronic network, can be described in parameters assessing the topological characteristics of that particular network. Repeated assessment of neural network characteristics in brain tumor patients during their disease course enables study of the dynamics of neural networks and provides more insight into the plasticity of the diseased brain. Functional MRI, electroencephalography and especially magnetoencephalography are used to measure brain function and the signals that are being registered with these techniques can be analyzed with respect to network characteristics such as "synchronization" and "clustering". Evidence accumulates that loss of optimal neural network architecture negatively impacts complex cerebral functioning and also decreases the threshold to develop epileptic seizures. Future research should be focused on both plasticity of neural networks and the factors that have impact on that plasticity as well as the possible role of assessment of neural network characteristics in the determination of cerebral function during the disease course.

  4. Nutrient diffusion and interspecies competition in tumor growth

    NASA Astrophysics Data System (ADS)

    Menchon, Silvia; Condat, Carlos A.

    2002-03-01

    A nutrient competition model of cancer growth is used to study tumor evolution when two cancer cell subpopulations are present. The emergence of a new species in the active area of a tumor can drastically change its morphology and growth rate. By using reproductive advantages, the new species may generate instabilities that transform a latent tumor into a fast-growing one. Alternatively, the increased feeding requirements of the new species can starve it, making the mutation not viable. The geometry and dynamics of competitive growth are analyzed in detail.

  5. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions.

    PubMed

    Pedrosa, Ana-Rita; Trindade, Alexandre; Carvalho, Catarina; Graça, José; Carvalho, Sandra; Peleteiro, Maria C; Adams, Ralf H; Duarte, António

    2015-09-15

    Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development, which direct contribution to the regulation of tumor angiogenesis remains to be fully characterized. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). By modulating levels of endothelial Jag1, we observed that this ligand regulates tumor vessel density, branching, and perivascular maturation, thus affecting tumor vascular perfusion. The pro-angiogenic function is exerted by its ability to positively regulate levels of Vegfr-2 while negatively regulating Vegfr-1. Additionally, endothelial Jagged1 appears to exert an angiocrine function possibly by activating Notch3/Hey1 in tumor cells, promoting proliferation, survival and epithelial-to-mesenchymal transition (EMT), potentiating tumor development. These findings provide valuable mechanistic insights into the role of endothelial Jagged1 in promoting solid tumor development and support the notion that it may constitute a promising target for cancer therapy.

  6. Pu-erh Tea Inhibits Tumor Cell Growth by Down-Regulating Mutant p53

    PubMed Central

    Zhao, Lanjun; Jia, Shuting; Tang, Wenru; Sheng, Jun; Luo, Ying

    2011-01-01

    Pu-erh tea is a kind of fermented tea with the incorporation of microorganisms’ metabolites. Unlike green tea, the chemical characteristics and bioactivities of Pu-erh tea are still not well understood. Using water extracts of Pu-erh tea, we analyzed the tumor cell growth inhibition activities on several genetically engineered mouse tumor cell lines. We found that at the concentration that did not affect wild type mouse embryo fibroblasts (MEFs) growth, Pu-erh tea extracts could inhibit tumor cell growth by down-regulated S phase and cause G1 or G2 arrest. Further study showed that Pu-erh tea extracts down-regulated the expression of mutant p53 in tumor cells at the protein level as well as mRNA level. The same concentration of Pu-erh tea solution did not cause p53 stabilization or activation of its downstream pathways in wild type cells. We also found that Pu-erh tea treatment could slightly down-regulate both HSP70 and HSP90 protein levels in tumor cells. These data revealed the action of Pu-erh tea on tumor cells and provided the possible mechanism for Pu-erh tea action, which explained its selectivity in inhibiting tumor cells without affecting wild type cells. Our data sheds light on the application of Pu-erh tea as an anti-tumor agent with low side effects. PMID:22174618

  7. Pu-erh tea inhibits tumor cell growth by down-regulating mutant p53.

    PubMed

    Zhao, Lanjun; Jia, Shuting; Tang, Wenru; Sheng, Jun; Luo, Ying

    2011-01-01

    Pu-erh tea is a kind of fermented tea with the incorporation of microorganisms' metabolites. Unlike green tea, the chemical characteristics and bioactivities of Pu-erh tea are still not well understood. Using water extracts of Pu-erh tea, we analyzed the tumor cell growth inhibition activities on several genetically engineered mouse tumor cell lines. We found that at the concentration that did not affect wild type mouse embryo fibroblasts (MEFs) growth, Pu-erh tea extracts could inhibit tumor cell growth by down-regulated S phase and cause G1 or G2 arrest. Further study showed that Pu-erh tea extracts down-regulated the expression of mutant p53 in tumor cells at the protein level as well as mRNA level. The same concentration of Pu-erh tea solution did not cause p53 stabilization or activation of its downstream pathways in wild type cells. We also found that Pu-erh tea treatment could slightly down-regulate both HSP70 and HSP90 protein levels in tumor cells. These data revealed the action of Pu-erh tea on tumor cells and provided the possible mechanism for Pu-erh tea action, which explained its selectivity in inhibiting tumor cells without affecting wild type cells. Our data sheds light on the application of Pu-erh tea as an anti-tumor agent with low side effects.

  8. Expression of nerve growth factor receptor in paraffin-embedded soft tissue tumors.

    PubMed Central

    Perosio, P. M.; Brooks, J. J.

    1988-01-01

    Identification of growth factors and receptors in mesenchymal tumors may be crucial to understanding of growth regulation in sarcomas. During an immunohistochemical study of the expression of growth factors and receptors in human soft tissue tumors (STT), only 1 antisera capable of working in paraffin-embedded tissue was noted. A detailed study of 141 STT was undertaken to determine the frequency of expression of nerve growth factor receptor (NGF-R), its specificity and sensitivity for neural tumors, and the effect of fixation on detection. In normal mesenchymal tissue, only nerve sheath and perivascular staining was seen. No immunoreactivity was seen in many tumors including rhabdomyosarcoma, angiosarcoma, liposarcoma, Ewing's sarcoma, and alveolar soft part sarcoma. Less than 15% of tumors of smooth muscle, fibrous, or fibrohistiocytic origin showed immunoreactivity, usually focal. In contrast, a high frequency of immunoreactivity was noted in tumors of neural origin (74%). This included granular cell tumors (100%), Schwannoma/neurofibroma (91%), malignant Schwannoma (78%), neuroblastoma/neuroepithelioma (60%), and paraganglioma (57%). A high rate of reactivity was also seen in synovial sarcomas (80%), undifferentiated sarcomas (60%), and hemangiopericytomas (43%), suggesting a potential relationship to the neural phenotype. Among the neural tumors, Bouin's fixation was superior to formalin, suggesting that immunoreactivity for NGF-R is affected by fixation. This antibody may be a useful adjunct marker diagnostically. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 Figure 7 Figure 9 Figure 10 PMID:2456020

  9. Compensatory renal growth and function in postnephrectomized patients with Wilms tumor

    SciTech Connect

    Walker, R.D.; Reid, C.F.; Richard, G.A.; Talbert, J.L.; Rogers, B.M.

    1982-02-01

    The objective of this study was to determine whether or not renal growth and function were adversely affected in the remaining kidneys of patients who had undergone nephrectomy for Wilms tumor. These patients received chemotherapy and some radiotherapy (tumoricidal agents which might affect the remaining kidney). Renal growth was compared between the treatment groups and normal renal growth. Hypertrophy did occur and did not appear to be affected by subsequent treatment. Renal function was minimally altered in all treatment groups irrespective of the type of treatment.

  10. Motif mimetic of epsin perturbs tumor growth and metastasis

    PubMed Central

    Dong, Yunzhou; Wu, Hao; Rahman, H.N. Ashiqur; Liu, Yanjun; Pasula, Satish; Tessneer, Kandice L.; Cai, Xiaofeng; Liu, Xiaolei; Chang, Baojun; McManus, John; Hahn, Scott; Dong, Jiali; Brophy, Megan L.; Yu, Lili; Song, Kai; Silasi-Mansat, Robert; Saunders, Debra; Njoku, Charity; Song, Hoogeun; Mehta-D’Souza, Padmaja; Towner, Rheal; Lupu, Florea; McEver, Rodger P.; Xia, Lijun; Boerboom, Derek; Srinivasan, R. Sathish; Chen, Hong

    2015-01-01

    Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID:26571402

  11. Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

    PubMed Central

    Ranjan, Alok; Srivastava, Sanjay K.

    2016-01-01

    Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6–7 μM after 24 h of treatment. Significant autophagy was induced by penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with penfluridol and chloroquine as compared to penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since penfluridol is already in clinic, positive findings from our study will accelerate its clinical development. PMID:27189859

  12. Phase transition in tumor growth: I avascular development

    NASA Astrophysics Data System (ADS)

    Izquierdo-Kulich, E.; Rebelo, I.; Tejera, E.; Nieto-Villar, J. M.

    2013-12-01

    We propose a mechanism for avascular tumor growth based on a simple chemical network. This model presents a logistic behavior and shows a “second order” phase transition. We prove the fractal origin of the empirical logistics and Gompertz constant and its relation to mitosis and apoptosis rate. Finally, the thermodynamics framework developed demonstrates the entropy production rate as a Lyapunov function during avascular tumor growth.

  13. A Mathematical Model Coupling Tumor Growth and Angiogenesis

    PubMed Central

    Gomez, Hector

    2016-01-01

    We present a mathematical model for vascular tumor growth. We use phase fields to model cellular growth and reaction-diffusion equations for the dynamics of angiogenic factors and nutrients. The model naturally predicts the shift from avascular to vascular growth at realistic scales. Our computations indicate that the negative regulation of the Delta-like ligand 4 signaling pathway slows down tumor growth by producing a larger density of non-functional capillaries. Our results show good quantitative agreement with experiments. PMID:26891163

  14. Statistical inference for tumor growth inhibition T/C ratio.

    PubMed

    Wu, Jianrong

    2010-09-01

    The tumor growth inhibition T/C ratio is commonly used to quantify treatment effects in drug screening tumor xenograft experiments. The T/C ratio is converted to an antitumor activity rating using an arbitrary cutoff point and often without any formal statistical inference. Here, we applied a nonparametric bootstrap method and a small sample likelihood ratio statistic to make a statistical inference of the T/C ratio, including both hypothesis testing and a confidence interval estimate. Furthermore, sample size and power are also discussed for statistical design of tumor xenograft experiments. Tumor xenograft data from an actual experiment were analyzed to illustrate the application.

  15. Bee venom inhibits growth of human cervical tumors in mice

    PubMed Central

    Kim, Tae Myoung; Jung, Yu Yeon; Park, Mi Hee; Oh, Sang Hyun; Yun, Hye Seok; Jun, Hyung Ok; Yoo, Hwan Soo; Han, Sang-Bae; Lee, Ung Soo; Yoon, Joo Hee; Song, Min Jong; Hong, Jin Tae

    2015-01-01

    We studied whether bee venom (BV) inhibits cervical tumor growth through enhancement of death receptor (DR) expressions and inactivation of nuclear factor kappa B (NF-κB) in mice. In vivo study showed that BV (1 mg/kg) inhibited tumor growth. Similar inhibitory effects of BV on cancer growth in primary human cervical cancer cells were also found. BV (1–5 μg/ml) also inhibited the growth of cancer cells, Ca Ski and C33Aby the induction of apoptotic cell death in a dose dependent manner. Agreed with cancer cell growth inhibition, expression of death receptors; FAS, DR3 and DR6, and DR downstream pro-apoptotic proteins including caspase-3 and Bax was concomitantly increased, but the NF-κB activity and the expression of Bcl-2 were inhibited by treatment with BV in tumor mice, human cancer cell and human tumor samples as well as cultured cancer cells. In addition, deletion of FAS, DR3 and DR6 by small interfering RNA significantly reversed BV-induced cell growth inhibitory effects as well as NF-κB inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-κB pathway. PMID:25730901

  16. A Big Bang model of human colorectal tumor growth.

    PubMed

    Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

    2015-03-01

    What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

  17. Near-criticality underlies the behavior of early tumor growth

    NASA Astrophysics Data System (ADS)

    Remy, Guillaume; Cluzel, Philippe

    2016-04-01

    The controlling factors that underlie the growth of tumors have often been hard to identify because of the presence in this system of a large number of intracellular biochemical parameters. Here, we propose a simplifying framework to identify the key physical parameters that govern the early growth of tumors. We model growth by means of branching processes where cells of different types can divide and differentiate. First, using this process that has only one controlling parameter, we study a one cell type model and compute the probability for tumor survival and the time of tumor extinction. Second, we show that when cell death and cell division are perfectly balanced, stochastic effects dominate the growth dynamics and the system exhibits a near-critical behavior that resembles a second-order phase transition. We show, in this near-critical regime, that the time interval before tumor extinction is power-law distributed. Finally, we apply this branching formalism to infer, from experimental growth data, the number of different cell types present in the observed tumor.

  18. Mathematical Modeling of Branching Morphogenesis and Vascular Tumor Growth

    NASA Astrophysics Data System (ADS)

    Yan, Huaming

    Feedback regulation of cell lineages is known to play an important role in tissue size control, but the effect in tissue morphogenesis has yet to be explored. We first use a non-spatial model to show that a combination of positive and negative feedback on stem and/or progenitor cell self-renewal leads to bistable or bi-modal growth behaviors and ultrasensitivity to external growth cues. Next, a spatiotemporal model is used to demonstrate spatial patterns such as local budding and branching arise in this setting, and are not consequences of Turing-type instabilities. We next extend the model to a three-dimensional hybrid discrete-continuum model of tumor growth to study the effects of angiogenesis, tumor progression and cancer therapies. We account for the crosstalk between the vasculature and cancer stem cells (CSCs), and CSC transdifferentiation into vascular endothelial cells (gECs), as observed experimentally. The vasculature stabilizes tumor invasiveness but considerably enhances growth. A gEC network structure forms spontaneously within the hypoxic core, consistent with experimental findings. The model is then used to study cancer therapeutics. We demonstrate that traditional anti-angiogenic therapies decelerate tumor growth, but make the tumor highly invasive. Chemotherapies help to reduce tumor sizes, but cannot control the invasion. Anti-CSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness. However, gECs inherit mutations present in CSCs and are resistant to traditional therapies. We show that anti-gEC treatments block the support on CSCs by gECs, and reduce both tumor size and invasiveness. Our study suggests that therapies targeting the vasculature, CSCs and gECs, when combined, are highly synergistic and are capable of controlling both tumor size and shape.

  19. A multiphase model for three-dimensional tumor growth

    NASA Astrophysics Data System (ADS)

    Sciumè, G.; Shelton, S.; Gray, W. G.; Miller, C. T.; Hussain, F.; Ferrari, M.; Decuzzi, P.; Schrefler, B. A.

    2013-01-01

    Several mathematical formulations have analyzed the time-dependent behavior of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the thermodynamically constrained averaging theory. A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TCs), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HCs); and an interstitial fluid for the transport of nutrients. The equations are solved by a finite element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTSs) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behavior: initially, the rapidly growing TCs tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable TCs whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case—mostly due to the relative adhesion of the TCs and HCs to the ECM, and the less favorable transport of nutrients. In particular, for HCs adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas TC

  20. Physical Activity Counteracts Tumor Cell Growth in Colon Carcinoma C26-Injected Muscles: An Interim Report

    PubMed Central

    Hiroux, Charlotte; Vandoorne, Tijs; Koppo, Katrien; De Smet, Stefan; Hespel, Peter; Berardi, Emanuele

    2016-01-01

    Skeletal muscle tissue is a rare site of tumor metastasis but is the main target of the degenerative processes occurring in cancer-associated cachexia syndrome. Beneficial effects of physical activity in counteracting cancer-related muscle wasting have been described in the last decades. Recently it has been shown that, in tumor xeno-transplanted mouse models, physical activity is able to directly affect tumor growth by modulating inflammatory responses in the tumor mass microenvironment. Here, we investigated the effect of physical activity on tumor cell growth in colon carcinoma C26 cells injected tibialis anterior muscles of BALB/c mice. Histological analyses revealed that 4 days of voluntary wheel running significantly counteracts tumor cell growth in C26-injected muscles compared to the non-injected sedentary controls. Since striated skeletal muscle tissue is the site of voluntary contraction, our results confirm that physical activity can also directly counteract tumor cell growth in a metabolically active tissue that is usually not a target for metastasis. PMID:27478560

  1. MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

    PubMed Central

    Cook, Rebecca S.; Jacobsen, Kristen M.; Wofford, Anne M.; DeRyckere, Deborah; Stanford, Jamie; Prieto, Anne L.; Redente, Elizabeth; Sandahl, Melissa; Hunter, Debra M.; Strunk, Karen E.; Graham, Douglas K.; Earp, H. Shelton

    2013-01-01

    MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK–/– mice. Transplantation of MerTK–/– bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK–/– leukocytes exhibited lower tumor cell–induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK–/– mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK–/– mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies. PMID:23867499

  2. MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis.

    PubMed

    Cook, Rebecca S; Jacobsen, Kristen M; Wofford, Anne M; DeRyckere, Deborah; Stanford, Jamie; Prieto, Anne L; Redente, Elizabeth; Sandahl, Melissa; Hunter, Debra M; Strunk, Karen E; Graham, Douglas K; Earp, H Shelton

    2013-08-01

    MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK-/- mice. Transplantation of MerTK-/- bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK-/- leukocytes exhibited lower tumor cell-induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK-/- mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK-/- mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.

  3. Phase transitions in tumor growth: III vascular and metastasis behavior

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, J. A.; Cocho, G.; Mansilla, R.; Nieto-Villar, José Manuel

    2016-11-01

    We propose a mechanism for avascular, vascular and metastasis tumor growth based on a chemical network model. Vascular growth and metastasis, appear as a hard phase transition type, as "first order", through a supercritical Andronov-Hopf bifurcation, emergence of limit cycle and then through a cascade of bifurcations type saddle-foci Shilnikov's bifurcation. Finally, the thermodynamics framework developed shows that the entropy production rate, as a Lyapunov function, indicates the directional character and stability of the dynamical behavior of tumor growth according to this model.

  4. Genes affected by mouse mammary tumor virus (MMTV) proviral insertions in mouse mammary tumors are deregulated or mutated in primary human mammary tumors

    PubMed Central

    Callahan, Robert; Mudunuri, Uma; Bargo, Sharon; Raafat, Ahmed; McCurdy, David; Boulanger, Corinne; Lowther, William; Stephens, Robert; Luke, Brian T.; Stewart, Claudia; Wu, Xiaolin; Munroe, David; Smith, Gilbert H.

    2012-01-01

    The accumulation of mutations is a contributing factor in the initiation of premalignant mammary lesions and their progression to malignancy and metastasis. We have used a mouse model in which the carcinogen is the mouse mammary tumor virus (MMTV) which induces clonal premalignant mammary lesions and malignant mammary tumors by insertional mutagenesis. Identification of the genes and signaling pathways affected in MMTV-induced mouse mammary lesions provides a rationale for determining whether genetic alteration of the human orthologues of these genes/pathways may contribute to human breast carcinogenesis. A high-throughput platform for inverse PCR to identify MMTV-host junction fragments and their nucleotide sequences in a large panel of MMTV-induced lesions was developed. Validation of the genes affected by MMTV-insertion was carried out by microarray analysis. Common integration site (CIS) means that the gene was altered by an MMTV proviral insertion in at least two independent lesions arising in different hosts. Three of the new genes identified as CIS for MMTV were assayed for their capability to confer on HC11 mouse mammary epithelial cells the ability for invasion, anchorage independent growth and tumor development in nude mice. Analysis of MMTV induced mammary premalignant hyperplastic outgrowth (HOG) lines and mammary tumors led to the identification of CIS restricted to 35 loci. Within these loci members of the Wnt, Fgf and Rspo gene families plus two linked genes (Npm3 and Ddn) were frequently activated in tumors induced by MMTV. A second group of 15 CIS occur at a low frequency (2-5 observations) in mammary HOGs or tumors. In this latter group the expression of either Phf19 or Sdc2 was shown to increase HC11 cells invasion capability. Foxl1 expression conferred on HC11 cells the capability for anchorage-independent colony formation in soft agar and tumor development in nude mice. The published transcriptome and nucleotide sequence analysis of gene

  5. Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Minyoung; Lee, Chang Geun; Jo, Wol Soon; Kim, Sung Dae; Yang, Kwangmo

    2015-07-01

    Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

  6. TNFα antagonization alters NOS2 dependent nasopharyngeal carcinoma tumor growth.

    PubMed

    Bourouba, Mehdi; Zergoun, Ahmed-Amine; Maffei, Joseph S; Chila, Dalia; Djennaoui, Djamel; Asselah, Fatima; Amir-Tidadini, Zine-Charef; Touil-Boukoffa, Chafia; Zaman, Muhammad H

    2015-07-01

    Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine which mediates via nitric oxide (NO) several carcinogenic processes. Increasing evidences suggest that NO promotes inflammation induced growth of nasopharyngeal carcinoma (NPC). In patients, TNFα synthesis associates with poor survival. To explore the effect of the cytokine on NO production and NOS2 dependent NPC growth, NO2(-) (nitrite) producing cells in patients were analyzed in vitro. We observed that patients' monocytes/macrophages (Mo/Ma) and primary tumor biopsies synthesized significant amounts of NO2(-). Interestingly, tumor explants derived NO2(-) levels were more important in elderly patients in comparison with juveniles. Endogenous TNFα neutralization with an anti-TNFα monoclonal antibody (mAb) successfully inhibited NO2(-) synthesis by blood mononuclear cells and tumor explants. Recombinant TNFα (rTNFα) enhanced NO2(-) synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNFα antagonization with an anti-TNFα mAb potently inhibited rTNFα induced C666-1 proliferation and NO2(-) production. Importantly, primary tumors treated with the anti-TNFα mAb also displayed reduced proliferation index (Ki67). Altogether, our results define monocytes/macrophages and the primary tumor as major sources of circulating NO2(-) in NPC patients and support the idea that antibody dependent inhibition of the TNFα/NOS2 pathway may alter NPC tumor growth.

  7. Role of Fetuin-A in Breast Tumor Cell Growth

    DTIC Science & Technology

    2009-03-01

    Growth PRINCIPAL INVESTIGATOR: Josiah Ochieng, Ph.D. CONTRACTING ORGANIZATION: Meharry Medical College Nashville, TN 37208...COVERED (From - To) 4. TITLE AND SUBTITLE Role of fetuin-A in Breast Tumor Cell Growth 5a. CONTRACT NUMBER W81XWH-07-1-0254 5b. GRANT NUMBER...hypothesis of this grant is that fetuin-A is a major serum derived growth factor for breast carcinoma cells and creates a favorable environment for the

  8. Model of avascular tumor growth and response to low dose exposure

    NASA Astrophysics Data System (ADS)

    Rodriguez Aguirre, J. M.; Custidiano, E. R.

    2011-12-01

    A single level cellular automata model is described and used to simulate early tumor growth, and the response of the tumor cells under low dose radiation affects. In this model the cell cycle of the population of normal and cancer cells is followed. The invasion mechanism of the tumor is simulated by a local factor that takes into account the microenvironment hardness to cell development, in a picture similar to the AMTIH model. The response of normal and cancer cells to direct effects of radiation is tested for various models and a model of bystander response is implemented.

  9. The Role of Oxygen in Avascular Tumor Growth

    PubMed Central

    Grimes, David Robert; Kannan, Pavitra; McIntyre, Alan; Kavanagh, Anthony; Siddiky, Abul; Wigfield, Simon; Harris, Adrian; Partridge, Mike

    2016-01-01

    The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model. PMID:27088720

  10. Mathematical modeling of tumor growth and metastatic spreading: validation in tumor-bearing mice.

    PubMed

    Hartung, Niklas; Mollard, Séverine; Barbolosi, Dominique; Benabdallah, Assia; Chapuisat, Guillemette; Henry, Gerard; Giacometti, Sarah; Iliadis, Athanassios; Ciccolini, Joseph; Faivre, Christian; Hubert, Florence

    2014-11-15

    Defining tumor stage at diagnosis is a pivotal point for clinical decisions about patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by a transport equation describing metastatic growth and endowed with a boundary condition for metastatic emission. Model predictions were compared with experimental results from orthotopic breast tumor xenograft experiments conducted in Nod/Scidγ mice. Primary tumor growth, metastatic spread and growth were monitored by 3D bioluminescence tomography. A tailored computational approach allowed the use of Monolix software for mixed-effects modeling with a partial differential equation model. Primary tumor growth was described best by Bertalanffy, West, and Gompertz models, which involve an initial exponential growth phase. All other tested models were rejected. The best metastatic model involved two parameters describing metastatic spreading and growth, respectively. Visual predictive check, analysis of residuals, and a bootstrap study validated the model. Coefficients of determination were [Formula: see text] for primary tumor growth and [Formula: see text] for metastatic growth. The data-based model development revealed several biologically significant findings. First, information on both growth and spreading can be obtained from measures of total metastatic burden. Second, the postulated link between primary tumor size and emission rate is validated. Finally, fast growing peritoneal metastases can only be described by such a complex partial differential equation model and not by ordinary differential equation models. This work advances efforts to predict metastatic spreading

  11. Reaction-diffusion model for the growth of avascular tumor

    NASA Astrophysics Data System (ADS)

    Ferreira, S. C.; Martins, M. L.; Vilela, M. J.

    2002-02-01

    A nutrient-limited model for avascular cancer growth including cell proliferation, motility, and death is presented. The model qualitatively reproduces commonly observed morphologies for primary tumors, and the simulated patterns are characterized by its gyration radius, total number of cancer cells, and number of cells on tumor periphery. These very distinct morphological patterns follow Gompertz growth curves, but exhibit different scaling laws for their surfaces. Also, the simulated tumors incorporate a spatial structure composed of a central necrotic core, an inner rim of quiescent cells and a narrow outer shell of proliferating cells in agreement with biological data. Finally, our results indicate that the competition for nutrients among normal and cancer cells may be a determining factor in generating papillary tumor morphology.

  12. The Importance of Neighborhood Scheme Selection in Agent-based Tumor Growth Modeling.

    PubMed

    Tzedakis, Georgios; Tzamali, Eleftheria; Marias, Kostas; Sakkalis, Vangelis

    2015-01-01

    Modeling tumor growth has proven a very challenging problem, mainly due to the fact that tumors are highly complex systems that involve dynamic interactions spanning multiple scales both in time and space. The desire to describe interactions in various scales has given rise to modeling approaches that use both continuous and discrete variables, known as hybrid approaches. This work refers to a hybrid model on a 2D square lattice focusing on cell movement dynamics as they play an important role in tumor morphology, invasion and metastasis and are considered as indicators for the stage of malignancy used for early prognosis and effective treatment. Considering various distributions of the microenvironment, we explore how Neumann vs. Moore neighborhood schemes affects tumor growth and morphology. The results indicate that the importance of neighborhood selection is critical under specific conditions that include i) increased hapto/chemo-tactic coefficient, ii) a rugged microenvironment and iii) ECM degradation.

  13. Semiautomatic growth analysis of multicellular tumor spheroids.

    PubMed

    Rodday, Bjoern; Hirschhaeuser, Franziska; Walenta, Stefan; Mueller-Klieser, Wolfgang

    2011-10-01

    Multicellular tumor spheroids (MCTS) are routinely employed as three-dimensional in vitro models to study tumor biology. Cultivation of MCTS in spinner flasks provides better growing conditions, especially with regard to the availability of nutrients and oxygen, when compared with microtiter plates. The main endpoint of drug response experiments is spheroid size. It is common practice to analyze spheroid size manually with a microscope and an ocular micrometer. This requires removal of some spheroids from the flask, which entails major limitations such as loss of MCTS and the risk of contamination. With this new approach, the authors present an efficient and highly reproducible method to analyze the size of complete MCTS populations in culture containers with transparent, flat bottoms. MCTS sediments are digitally scanned and spheroid volumes are calculated by computerized image analysis. The equipment includes regular office hardware (personal computer, flatbed scanner) and software (Adobe Photoshop, Microsoft Excel, ImageJ). The accuracy and precision of the method were tested using industrial precision steel beads with known diameter. In summary, in comparison with other methods, this approach provides benefits in terms of semiautomation, noninvasiveness, and low costs.

  14. SKI knockdown inhibits human melanoma tumor growth in vivo.

    PubMed

    Chen, Dahu; Lin, Qiushi; Box, Neil; Roop, Dennis; Ishii, Shunsuke; Matsuzaki, Koichi; Fan, Tao; Hornyak, Thomas J; Reed, Jon A; Stavnezer, Ed; Timchenko, Nikolai A; Medrano, Estela E

    2009-12-01

    The SKI protein represses the TGF-beta tumor suppressor pathway by associating with the Smad transcription factors. SKI is upregulated in human malignant melanoma tumors in a disease-progression manner and its overexpression promotes proliferation and migration of melanoma cells in vitro. The mechanisms by which SKI antagonizes TGF-beta signaling in vivo have not been fully elucidated. Here we show that human melanoma cells in which endogenous SKI expression was knocked down by RNAi produced minimal orthotopic tumor xenograft nodules that displayed low mitotic rate and prominent apoptosis. These minute tumors exhibited critical signatures of active TGF-beta signaling including high levels of nuclear Smad3 and p21(Waf-1), which are not found in the parental melanomas. To understand how SKI promotes tumor growth we used gain- and loss-of-function approaches and found that simultaneously to blocking the TGF-beta-growth inhibitory pathway, SKI promotes the switch of Smad3 from tumor suppression to oncogenesis by favoring phosphorylations of the Smad3 linker region in melanoma cells but not in normal human melanocytes. In this context, SKI is required for preventing TGF-beta-mediated downregulation of the oncogenic protein c-MYC, and for inducing the plasminogen activator inhibitor-1, a mediator of tumor growth and angiogenesis. Together, the results indicate that SKI exploits multiple regulatory levels of the TGF-beta pathway and its deficiency restores TGF-beta tumor suppressor and apoptotic activities in spite of the likely presence of oncogenic mutations in melanoma tumors.

  15. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  16. Pinning of Tumoral Growth by Enhancement of the Immune Response

    NASA Astrophysics Data System (ADS)

    Brú, A.; Albertos, S.; García-Asenjo, J. A.; Brú, I.

    2004-06-01

    Tumor growth is a surface phenomenon of the molecular beam epitaxy universality class in which diffusion at the surface is the determining factor. This Letter reports experiments performed in mice showing that these dynamics can, however, be changed. By stimulating the immune response, we induced strong neutrophilia around the tumor. The neutrophils hindered cell surface diffusion so much that they induced new dynamics compatible with the slower quenched-disorder Edwards-Wilkinson universality class. Important clinical effects were also seen, including remarkably high tumor necrosis (around 80% 90% of the tumor), a general increase in survival time [the death ratio in the control group is 15.76 times higher than in the treated group (equivalent to a Cox's model hazard ratio of 0.85; 95% confidence interval 0.76 0.95, p=0.004)], and even the total elimination of some tumors.

  17. Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth.

    PubMed

    Ganti, Sheila N; Albershardt, Tina C; Iritani, Brian M; Ruddell, Alanna

    2015-07-20

    Our previous studies found that B16-F10 melanoma growth in the rear footpad of immunocompetent mice induces marked B cell accumulation within tumor-draining popliteal lymph nodes (TDLN). This B cell accumulation drives TDLN remodeling that precedes and promotes metastasis, indicating a tumor-promoting role for TDLN B cells. Here we show that phenotypic characterization of lymphocytes in mice bearing B16-F10 melanomas identifies preferential accumulation of T2-MZP B cells in the TDLN. Comparison of non-draining LNs and spleens of tumor-bearing mice with LNs and spleens from naïve mice determined that this pattern of B cell accumulation was restricted to the TDLN. B cell-deficient and immunocompetent mice reconstituted with T2-MZP B cells but not with other B cell subsets displayed accelerated tumor growth, demonstrating that T2-MZP B cells possess regulatory activity in tumor-bearing mice. Unlike splenic regulatory B cells, however, these TDLN B cells did not exhibit increased IL-10 production, nor did they promote Treg generation in the TDLN. These findings demonstrate that tumors initially signal via the lymphatic drainage to stimulate the preferential accumulation of T2-MZP regulatory B cells. This local response may be an early and critical step in generating an immunosuppressive environment to permit tumor growth and metastasis.

  18. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment

    PubMed Central

    Yaqoob, Usman; Cao, Sheng; Shergill, Uday; Jagavelu, Kumaravelu; Geng, Zhimin; Yin, Meng; de Assuncao, Thiago M; Cao, Ying; Szabolcs, Anna; Thorgeirsson, Snorri; Schwartz, Martin; Yang, Ju Dong; Ehman, Richard; Roberts, Lewis; Mukhopadhyay, Debabrata; Shah, Vijay H.

    2012-01-01

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin (FN) that promote α5β1 integrin-dependent FN fibril assembly, matrix stiffness, and tumor growth. Tumor growth and FN fibril assembly was reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in FN fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl, that augmented α5β1 FN fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of FN fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. PMID:22738912

  19. [Effect of fenugreek on the growth of different genesis tumors].

    PubMed

    Zhilenko, V V; Zalietok, S P; Klenov, O O

    2012-01-01

    This paper deals with antitumor properties of a fenugreek (Trigonella Foenum Graecum L.) as to the different genesis tumors--the Ca755 mouse mammary carcinoma and the Guerin's carcinoma in rats. Fenugreek powder was shown to inhibit (25-40 %) growth of certain tumors, decrease (27-63%) level of malone dialdehyde in liver, heart and kidney. Consumption of fenugreek was accompanied with decreased polyamines (spermine, spermidine, putrescine) content in tumor tissue. Inclusion of fenugreek to allowance was shown to improve certain blood value.

  20. Alpha1-antitrypsin inhibits angiogenesis and tumor growth.

    PubMed

    Huang, Hanhua; Campbell, Steven C; Nelius, Thomas; Bedford, Dhugal F; Veliceasa, Dorina; Bouck, Noel P; Volpert, Olga V

    2004-12-20

    Disturbances of the ratio between angiogenic inducers and inhibitors in tumor microenvironment are the driving force behind angiogenic switch critical for tumor progression. Angiogenic inhibitors may vary depending on organismal age and the tissue of origin. We showed that alpha(1)-antitrypsin (AAT), a serine protease inhibitor (serpin) is an inhibitor of angiogenesis, which induced apoptosis and inhibited chemotaxis of endothelial cells. S- and Z-type mutations that cause abnormal folding and defective serpin activity abrogated AAT antiangiogenic activity. Removal of the C-terminal reactive site loop had no effect on its angiostatic activity. Both native AAT and AAT truncated on C-terminus (AATDelta) inhibited neovascularization in the rat cornea and delayed the growth of subcutaneous tumors in mice. Treatment with native AAT and truncated AATDelta, but not control vehicle reduced tumor microvessel density, while increasing apoptosis within tumor endothelium. Comparative analysis of the human tumors and normal tissues of origin showed correlation between reduced local alpha(1)-antitrypsin expression and more aggressive tumor growth.

  1. Effect of tumor microenvironmental factors on tumor growth dynamics modeled by correlated colored noises with colored cross-correlation

    NASA Astrophysics Data System (ADS)

    Idris, Ibrahim Mu'awiyya; Abu Bakar, Mohd Rizam

    2016-07-01

    The effect of non-immunogenic tumor microenvironmental factors on tumor growth dynamics modeled by correlated additive and multiplicative colored noises is investigated. Using the Novikov theorem, Fox approach and Ansatz of Hanggi, an approximate Fokker-Planck equation for the system is obtained and analytic expression for the steady state distribution Pst(x) is derived. Based on the numerical results, we find that fluctuations of microenvironmental factors within the tumor site with parameter θ have a diffusive effect on the tumor growth dynamics, and the tumor response to the microenvironmental factors with parameter α inhibits growth at weak correlation time τ. Moreover, at increasing correlation time τ the inhibitive effect of tumor response α is suppressed and instead a systematic growth promotion is noticed. The result also reveals that the strength of the correlation time τ has a strong influence on the growth effects exerted by the non-immunogenic component of tumor microenvironment on tumor growth.

  2. Embelin suppresses pancreatic cancer growth by modulating tumor immune microenvironment.

    PubMed

    Marsh, Justine L; Jackman, Chris P; Tang, Su-Ni; Shankar, Sharmila; Srivastava, Rakesh K

    2014-01-01

    Since pancreatic carcinoma is largely refractory to conventional therapies, development of novel agents is required for the effective treatment of pancreatic cancer. The objective of this paper was to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer growth in mice by modulating tumor immune microenvironment. Embelin inhibited PANC-1 tumor growth, angiogenesis, and metastasis which were associated with suppression of Akt and Sonic Hedgehog (Shh) pathways. Embelin inhibited the expression of Bcl-2, cyclin D1, CDK2 and CDK6, IL-6 and IL-8, and induced the expression of Bax in tumor tissues. Embelin also reversed epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, Slug and Zeb1. Embelin inhibited pancreatic cancer growth in Kras(G12D) mice by modulating tumor immune microenvironment where CTL, NKT, γδT, NK, and IFNγ (Th1 type) cells were up-regulated, and Th17, PMN-MDSC, IL-6 and IL-8 (Th2 type) immune cells were inhibited. These data suggest that embelin can inhibit pancreatic cancer growth by modulating tumor immune microenvironment and Akt and Shh pathways, and inhibiting inflammation. Embelin may offer therapeutic benefits for the treatment and/or prevention of pancreatic cancer.

  3. The transcription factor Ets21C drives tumor growth by cooperating with AP-1

    PubMed Central

    Toggweiler, Janine; Willecke, Maria; Basler, Konrad

    2016-01-01

    Tumorigenesis is driven by genetic alterations that perturb the signaling networks regulating proliferation or cell death. In order to block tumor growth, one has to precisely know how these signaling pathways function and interplay. Here, we identified the transcription factor Ets21C as a pivotal regulator of tumor growth and propose a new model of how Ets21C could affect this process. We demonstrate that a depletion of Ets21C strongly suppressed tumor growth while ectopic expression of Ets21C further increased tumor size. We confirm that Ets21C expression is regulated by the JNK pathway and show that Ets21C acts via a positive feed-forward mechanism to induce a specific set of target genes that is critical for tumor growth. These genes are known downstream targets of the JNK pathway and we demonstrate that their expression not only depends on the transcription factor AP-1, but also on Ets21C suggesting a cooperative transcriptional activation mechanism. Taken together we show that Ets21C is a crucial player in regulating the transcriptional program of the JNK pathway and enhances our understanding of the mechanisms that govern neoplastic growth. PMID:27713480

  4. Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth

    PubMed Central

    Daquinag, Alexes C; Tseng, Chieh; Zhang, Yan; Amaya-Manzanares, Felipe; Florez, Fernando; Dadbin, Ali; Zhang, Tao; Kolonin, Mikhail G

    2016-01-01

    Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK2. Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK2 that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments. PMID:26316391

  5. Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model.

    PubMed

    Zhang, Chenran; Gao, Liquan; Cai, Yuehong; Liu, Hao; Gao, Duo; Lai, Jianhao; Jia, Bing; Wang, Fan; Liu, Zhaofei

    2016-04-01

    Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-αCD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-αCD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-αCD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral microdistribution analysis indicated TAM-specific localization of the IRD-αCD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-αCD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-αCD206 PIT. These results demonstrate the utility of the IRD-αCD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics.

  6. Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate.

    PubMed

    Ram, Z; Samid, D; Walbridge, S; Oshiro, E M; Viola, J J; Tao-Cheng, J H; Shack, S; Thibault, A; Myers, C E; Oldfield, E H

    1994-06-01

    Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

  7. A Cahn-Hilliard model of vascularized tumor growth in a complex evolving confinement using a diffuse domain approach

    NASA Astrophysics Data System (ADS)

    Chuang, Yao-Li; Cristini, Vittorio; Chen, Ying; Li, Xiangrong; Frieboes, Hermann; Lowengrub, John

    2012-02-01

    Understanding the spatiotemporal evolution of tumor growth is essential for developing effective strategies to treat cancers. Various studies have suggested that spatial heterogeneity during tumors growth is a key factor associated with subsequent tumor invasion and the effectiveness of chemotherapy. Spatial heterogeneity may arise due to morphological instability of the tumors and the complex tissue structure surrounding the tumors. In previous works, we have used a Cahn-Hilliard tumor growth model to study the morphological instability for tumors in non-resisting tissues. However, most tumors are surrounded by complex tissue structures and confined in the capsules of some organs or between certain basement membranes. The capsules and basement membranes may be distorted by interacting with the evolving tumors, affecting the morphological instability. Here we adopt a novel diffuse domain approach to adapt our previous Cahn-Hilliard model for tumor growth in such complex evolving environments. As an example, we apply the model to simulate the evolution of lymphoma in a lymph node, incorporating also the tumor-induced angiogenesis.

  8. Phase transitions in tumor growth: II prostate cancer cell lines

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, A.; De Miguel, M. P.; Izquierdo-Kulich, E.; Royuela-García, M.; Tejera, E.; Nieto-Villar, J. M.

    2015-05-01

    We propose a mechanism for prostate cancer cell lines growth, LNCaP and PC3 based on a Gompertz dynamics. This growth exhibits a multifractal behavior and a "second order" phase transition. Finally, it was found that the cellular line PC3 exhibits a higher value of entropy production rate compared to LNCaP, which is indicative of the robustness of PC3, over to LNCaP and may be a quantitative index of metastatic potential tumors.

  9. Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape

    PubMed Central

    Chouaib, Salem; Messai, Yosra; Couve, Sophie; Escudier, Bernard; Hasmim, Meriem; Noman, Muhammad Zaeem

    2012-01-01

    Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection. Tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival, and metastasis. Hypoxia-inducible factor (HIF-1) and vascular endothelial growth factor (VEGF) play a determinant role in promoting tumor cell growth and survival. Hypoxia contributes to immune suppression by activating HIF-1 and VEGF pathways. Accumulating evidence suggests a link between hypoxia and tumor tolerance to immune surveillance through the recruitment of regulatory cells (regulatory T cells and myeloid derived suppressor cells). In this regard, hypoxia (HIF-1α and VEGF) is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed. PMID:22566905

  10. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo−/− mice

    PubMed Central

    Campbell, Elizabeth J; Vissers, Margreet CM; Dachs, Gabi U

    2016-01-01

    In solid tumors, HIF1 upregulates the expression of hundreds of genes involved in cell survival, tumor growth, and adaptation to the hypoxic microenvironment. HIF1 stabilization and activity are suppressed by prolyl and asparagine hydroxylases, which require oxygen as a substrate and ascorbate as a cofactor. This has led us to hypothesize that intracellular ascorbate availability could modify the hypoxic HIF1 response and influence tumor growth. In this study, we investigated the effect of variable intracellular ascorbate levels on HIF1 induction in cancer cells in vitro, and on tumor-take rate and growth in the Gulo−/− mouse. These mice depend on dietary ascorbate, and were supplemented with 3,300 mg/L, 330 mg/L, or 33 mg/L ascorbate in their drinking water, resulting in saturating, medium, or low plasma and tissue ascorbate levels, respectively. In Lewis lung carcinoma cells (LL/2) in culture, optimal ascorbate supplementation reduced HIF1 accumulation under physiological but not pathological hypoxia. LL/2, B16-F10 melanoma, or CMT-93 colorectal cancer cells were implanted subcutaneously into Gulo−/− mice at a range of cell inocula. Establishment of B16-F10 tumors in mice supplemented with 3,300 mg/L ascorbate required an increased number of cancer cells to initiate tumor growth compared with the number of cells required in mice on suboptimal ascorbate intake. Elevated ascorbate intake was also associated with decreased tumor ascorbate levels and a reduction in HIF1α expression and transcriptional activity. Following initial growth, all CMT-93 tumors regressed spontaneously, but mice supplemented with 33 mg/L ascorbate had lower plasma ascorbate levels and grew larger tumors than optimally supplemented mice. The data from this study indicate that improved ascorbate intake is consistent with increased intracellular ascorbate levels, reduced HIF1 activity and reduced tumor initiation and growth, and this may be advantageous in the management of cancer

  11. Ecto-5’-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model

    PubMed Central

    Cappellari, Angélica R.; Pillat, Micheli M.; Souza, Hellio D. N.; Dietrich, Fabrícia; Oliveira, Francine H.; Figueiró, Fabrício; Abujamra, Ana L.; Roesler, Rafael; Lecka, Joanna; Sévigny, Jean; Battastini, Ana Maria O.; Ulrich, Henning

    2015-01-01

    Background Ecto-5’-nucleotidase/CD73 (ecto-5’-NT) participates in extracellular ATP catabolism by converting adenosine monophosphate (AMP) into adenosine. This enzyme affects the progression and invasiveness of different tumors. Furthermore, the expression of ecto-5’-NT has also been suggested as a favorable prognostic marker, attributing to this enzyme contradictory functions in cancer. Medulloblastoma (MB) is the most common brain tumor of the cerebellum and affects mainly children. Materials and Methods The effects of ecto-5’-NT overexpression on human MB tumor growth were studied in an in vivo model. Balb/c immunodeficient (nude) 6 to 14-week-old mice were used for dorsal subcutaneous xenograph tumor implant. Tumor development was evaluated by pathophysiological analysis. In addition, the expression patterns of adenosine receptors were verified. Results The human MB cell line D283, transfected with ecto-5’-NT (D283hCD73), revealed reduced tumor growth compared to the original cell line transfected with an empty vector. D283hCD73 generated tumors with a reduced proliferative index, lower vascularization, the presence of differentiated cells and increased active caspase-3 expression. Prominent A1 adenosine receptor expression rates were detected in MB cells overexpressing ecto-5’-NT. Conclusion This work suggests that ecto-5’-NT promotes reduced tumor growth to reduce cell proliferation and vascularization, promote higher differentiation rates and initiate apoptosis, supposedly by accumulating adenosine, which then acts through A1 adenosine receptors. Therefore, ecto-5’-NT might be considered an important prognostic marker, being associated with good prognosis and used as a potential target for therapy. PMID:26491983

  12. Joint fitting reveals hidden interactions in tumor growth.

    PubMed

    Barberis, L; Pasquale, M A; Condat, C A

    2015-01-21

    Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Crucial to the system evolution are the interactions between these populations. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses alone, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination.

  13. Development, Selection, and Validation of Tumor Growth Models

    NASA Astrophysics Data System (ADS)

    Shahmoradi, Amir; Lima, Ernesto; Oden, J. Tinsley

    In recent years, a multitude of different mathematical approaches have been taken to develop multiscale models of solid tumor growth. Prime successful examples include the lattice-based, agent-based (off-lattice), and phase-field approaches, or a hybrid of these models applied to multiple scales of tumor, from subcellular to tissue level. Of overriding importance is the predictive power of these models, particularly in the presence of uncertainties. This presentation describes our attempt at developing lattice-based, agent-based and phase-field models of tumor growth and assessing their predictive power through new adaptive algorithms for model selection and model validation embodied in the Occam Plausibility Algorithm (OPAL), that brings together model calibration, determination of sensitivities of outputs to parameter variances, and calculation of model plausibilities for model selection. Institute for Computational Engineering and Sciences.

  14. Vascular CD39/ENTPD1 Directly Promotes Tumor Cell Growth by Scavenging Extracellular Adenosine Triphosphate12

    PubMed Central

    Feng, Lili; Sun, Xiaofeng; Csizmadia, Eva; Han, Lihui; Bian, Shu; Murakami, Takashi; Wang, Xin; Robson, Simon C; Wu, Yan

    2011-01-01

    Extracellular adenosine triphosphate (ATP) is known to boost immune responses in the tumor microenvironment but might also contribute directly to cancer cell death. CD39/ENTPD1 is the dominant ectonucleotidase expressed by endothelial cells and regulatory T cells and catalyzes the sequential hydrolysis of ATP to AMP that is further degraded to adenosine by CD73/ecto-5′-nucleotidase. We have previously shown that deletion of Cd39 results in decreased growth of transplanted tumors in mice, as a result of both defective angiogenesis and heightened innate immune responses (secondary to loss of adenosinergic immune suppression). Whether alterations in local extracellular ATP and adenosine levels as a result of CD39 bioactivity directly affect tumor growth and cytotoxicity has not been investigated to date. We show here that extracellular ATP exerts antitumor activity by directly inhibiting cell proliferation and promoting cancer cell death. ATP-induced antiproliferative effects and cell death are, in large part, mediated through P2X7 receptor signaling. Tumors in Cd39 null mice exhibit increased necrosis in association with P2X7 expression. We further demonstrate that exogenous soluble NTPDase, or CD39 expression by cocultured liver sinusoidal endothelial cells, stimulates tumor cell proliferation and limits cell death triggered by extracellular ATP. Collectively, our findings indicate that local expression of CD39 directly promotes tumor cell growth by scavenging extracellular ATP. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy in cancer management. PMID:21390184

  15. Building Context with Tumor Growth Modeling Projects in Differential Equations

    ERIC Educational Resources Information Center

    Beier, Julie C.; Gevertz, Jana L.; Howard, Keith E.

    2015-01-01

    The use of modeling projects serves to integrate, reinforce, and extend student knowledge. Here we present two projects related to tumor growth appropriate for a first course in differential equations. They illustrate the use of problem-based learning to reinforce and extend course content via a writing or research experience. Here we discuss…

  16. Altered tumor cell growth and tumorigenicity in models of microgravity

    NASA Astrophysics Data System (ADS)

    Yamauchi, K.; Taga, M.; Furian, L.; Odle, J.; Sundaresan, A.; Pellis, N.; Andrassy, R.; Kulkarni, A.

    Spaceflight environment and microgravity (MG) causes immune dysfunction and is a major health risk to humans, especially during long-term space missions. The effects of microgravity environment on tumor growth and carcinogenesis are yet unknown. Hence, we investigated the effects of simulated MG (SMG) on tumor growth and tumorigenicity using in vivo and in vitro models. B16 melanoma cells were cultured in static flask (FL) and rotating wall vessel bioreactors (BIO) to measure growth and properties, melanin production and apoptosis. BIO cultures had 50% decreased growth (p<0.01), increased doubling time and a 150% increase in melanin production (p<0.05). Flow cytometric analysis showed increased apoptosis in BIO. When BIO cultured melanoma cells were inoculated sc in mice there was a significant increase in tumorigenicity as compared to FL cells. Thus SMG may have supported &selected highly tumorigenic cells and it is pos sible that in addition to decreased immune function MG may alter tumor cell characteristics and invasiveness. Thus it is important to study effects of microgravity environment and its stressors using experimental tumors and SMG to understand and evaluate carcinogenic responses to true microgravity. Further studies on carcinogenic events and their mechanisms will allow us develop and formulate countermeasures and protect space travelers. Additional results will be presented. (Supported by NASA NCC8-168 grant, ADK)

  17. Supplementation by vitamin D compounds does not affect colonic tumor development in vitamin D sufficient murine models

    PubMed Central

    Irving, Amy A.; Halberg, Richard B.; Albrecht, Dawn M.; Plum, Lori A.; Krentz, Kathleen J.; Clipson, Linda; Drinkwater, Norman; Amos-Landgraf, James M.; Dove, William F.; DeLuca, Hector F.

    2012-01-01

    Epidemiological studies indicate that sunlight exposure and vitamin D are each associated with a lower risk of colon cancer. The few controlled supplementation trials testing vitamin D in humans reported to date show conflicting results. We have used two genetic models of familial colon cancer, the ApcPirc/+ (Pirc) rat and the ApcMin/+ (Min) mouse, to investigate the effect of 25-hydroxyvitamin D3 [25(OH)D3] and two analogs of vitamin D hormone on colonic tumors. Longitudinal endoscopic monitoring allowed us to test the efficacy of these compounds in preventing newly arising colonic tumors and in affecting established colonic tumors. 25(OH)D3 and two analogs of vitamin D hormone each failed to reduce tumor multiplicities or alter the growth patterns of colonic tumors in the Pirc rat or the Min mouse. PMID:21907701

  18. Dietary branched-chain amino acid (BCAA) and tumor growth

    SciTech Connect

    Chan, W.; Baron, L.; Baron, P.; White, F.; Banks, W.L. Jr.

    1986-03-05

    The effects of high dietary BCAA on tumor growth was examined in adult male Fischer 344 rats inoculated with 10/sup 6/ viable MCA fibrosarcoma cells. Ten days after tumor inoculation, when tumors were of palpable size, rats were divided into two groups at random. The experimental(E) group was fed the AIN-76 diet supplemented with 4X the BCAA content of diet casein and the control(C) group was fed the AIN-76 made isonitrogenous with the E diet by glutamic acid supplementation. Five rats from each group were killed at days 0,3,6, and 9. Rats were injected with /sup 14/C-Tyrosine and /sup 3/H-Thymidine i.p. (2 and 4 uCi/100g BW, respectively) an hour before they were killed. The incorporation of /sup 14/C and /sup 3/H into the acid insoluble fraction of the tumor tissues samples were measured. Single cell suspension of tumor were prepared for cell cycle kinetics analysis using a Coulter EPICS IV flow microflorometer. The percentage of normal and hyperdiploid cells were analyzed. Results showed that both tumor size and weight were doubled at each time point the rats were killed. At day 0, the /sup 3/H and /sup 14/C incorporation were 32 +/- 10dpm and 27 +/- 4dpm/mg tumor, respectively. The /sup 3/H incorporation dropped in both diet groups at days 6 and 9 but the /sup 14/C incorporation showed a decrease only at day 9. These changes were statistically significant, P>0.05. No difference in the tumor growth parameters used in this study can be attributed to the high dietary BCAA.

  19. Loss of endothelial programmed cell death 10 activates glioblastoma cells and promotes tumor growth

    PubMed Central

    Zhu, Yuan; Zhao, Kai; Prinz, Anja; Keyvani, Kathy; Lambertz, Nicole; Kreitschmann-Andermahr, Ilonka; Lei, Ting; Sure, Ulrich

    2016-01-01

    Background Neo-angiogenesis is a hallmark of glioblastoma (GBM) and is sustained by autocrine and paracrine interactions between neoplastic and nonneoplastic cells. Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. We recently discovered the absence of PDCD10 expression in the tumor vessels of GBM patients. This raised the hypothesis that loss of endothelial PDCD10 affected GBM cell phenotyping and tumor progression. Methods Endothelial PDCD10 was silenced by siRNA and lentiviral shRNA. The tumor cell phenotype was studied in direct and indirect co-culture of endothelial cells (ECs) with U87 or LN229. Angiogenic protein array was performed in the media of PDCD10-silenced ECs. Tumor angiogenesis and tumor growth were investigated in a human GBM xenograft mouse model. Results Endothelial silence of PDCD10 significantly stimulated tumor cell proliferation, migration, adhesion, and invasion and inhibited apoptosis in co-cultures. Stable knockdown of endothelial PDCD10 increased microvessel density and the formation of a functional vascular network, leading to a 4-fold larger tumor mass in mice. Intriguingly, endothelial deletion of PDCD10 increased (≥2-fold) the release of 20 of 55 tested proangiogenic factors including VEGF, which in turn activated Erk1/2 and Akt in GBM cells. Conclusions For the first time, we provide evidence that loss of endothelial PDCD10 activates GBM cells and promotes tumor growth, most likely via a paracrine mechanism. PDCD10 shows a tumor-suppressor-like function in the cross talk between ECs and tumor cells and is potentially implicated in GBM progression. PMID:26254477

  20. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition.

    PubMed

    Prada, Carlos E; Jousma, Edwin; Rizvi, Tilat A; Wu, Jianqiang; Dunn, R Scott; Mayes, Debra A; Cancelas, Jose A; Dombi, Eva; Kim, Mi-Ok; West, Brian L; Bollag, Gideon; Ratner, Nancy

    2013-01-01

    Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30-50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1(flox/flox) mouse model of GEM grade I neurofibroma. In mice aged 1-4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7-9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy.

  1. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition

    PubMed Central

    Prada, Carlos E.; Jousma, Edwin; Rizvi, Tilat A.; Wu, Jianqiang; Dunn, R. Scott; Mayes, Debra A.; Cancelas, Jose A.; Dombi, Eva; Kim, Mi-Ok; West, Brian L.; Bollag, Gideon

    2012-01-01

    Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30–50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1flox/flox mouse model of GEM grade I neurofibroma. In mice aged 1–4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7–9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy. PMID:23099891

  2. Human STEAP3 maintains tumor growth under hypoferric condition

    SciTech Connect

    Isobe, Taichi; Baba, Eishi; Arita, Shuji; Komoda, Masato; Tamura, Shingo; Shirakawa, Tsuyoshi; Ariyama, Hiroshi; Takaishi, Shigeo; Kusaba, Hitoshi; and others

    2011-11-01

    Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced STEAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more STEAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition. -- Highlights: {yields} STEAP3 expression results in increment of stored intracellular iron. {yields} Iron deprivation induces expression of STEAP3. {yields} Colorectal cancer expresses STEAP3 highly and stores iron much. {yields} STEAP3 expressing tumors preserves growth even in mice being hypoferremia.

  3. Dietary rice component, Oryzanol, inhibits tumor growth in tumor-bearing Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scope: We investigated the effects of rice bran and components on tumor growth in mice. Methods and results: Mice fed standard diets supplemented with rice bran, '-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet fo...

  4. Noscapine inhibits tumor growth in TMZ-resistant gliomas.

    PubMed

    Jhaveri, Niyati; Cho, Heeyeon; Torres, Shering; Wang, Weijun; Schönthal, Axel H; Petasis, Nicos A; Louie, Stan G; Hofman, Florence M; Chen, Thomas C

    2011-12-22

    Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas.

  5. Chemical agents and peptides affect hair growth.

    PubMed

    Uno, H; Kurata, S

    1993-07-01

    During the past decade we have examined both the therapeutic and the prophylactic effects of several agents on the macaque model of androgenetic alopecia. Minoxidil and diazoxide, potent hypotensive agents acting as peripheral vasodilators, are known to have a hypertrichotic side effect. Topical use of both agents induced significant hair regrowth in the bald scalps of macaques. The application of a steroid 5 alpha-reductase inhibitor (4MA) in non-bald preadolescent macaques has prevented baldness, whereas controls developed it during 2 years of treatment. The effects of hair growth were determined by 1) phototrichogram, 2) folliculogram (micro-morphometric analysis), and 3) the rate of DNA synthesis in the follicular cells. These effects were essentially a stimulation of the follicular cell proliferation, resulting in an enlargement of the anagen follicles from vellus to terminal type (therapy) or a maintenance of the prebald terminal follicles (prevention). A copper binding peptide (PC1031) had the effect of follicular enlargement on the back skin of fuzzy rats, covering the vellus follicles; the effect was similar to that of topical minoxidil. Analyzing the quantitative sequences of follicular size and cyclic phases, we speculate on the effect of agents on follicular growth. We also discuss the triggering mechanism of androgen in the follicular epithelial-mesenchymal (dermal papilla) interaction.

  6. Netrin-4 regulates angiogenic responses and tumor cell growth

    SciTech Connect

    Nacht, Mariana; St Martin, Thia B.; Byrne, Ann; Klinger, Katherine W.; Teicher, Beverly A.; Madden, Stephen L. Jiang, Yide

    2009-03-10

    Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.

  7. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells.

    PubMed

    Zheng, Yisheng; Xu, Meng; Li, Xiao; Jia, Jinpeng; Fan, Kexing; Lai, Guoxiang

    2013-05-01

    Cimetidine, a histamine type-2 receptor antagonist, is known to inhibit the growth of several tumors in human and animals, however the mechanism of action underlying this effect remains largely unknown. Here, in the mice model of 3LL lung tumor, cimetidine showed significant inhibition of tumor growth. However, an in vitro study demonstrated that cimetidine showed no effect on proliferation, survival, migration and invasion of 3LL cells. We found that cimetidine reduced CD11b(+)Gr-1(+) myeloid derived-suppressive cell (MDSC) accumulation in spleen, blood and tumor tissue of tumor-bearing mice. In vitro coculture assay showed that cimetidine reversed MDSC-mediated T-cell suppression, and improved IFN-γ production. Further investigation demonstrated that the NO production and arginase I expression of MDSCs were reduced, and MDSCs prone to apoptosis by cimetidine treatment. However, MDSC differentiation was not affect by cimetidine. Importantly, although histamine H2 receptor was expressed in MDSC surface, histamine could not reverse the proapoptosis of cimetidine. Moreover, famotidine also did not have this capacity. We found that cimetidine could induce Fas and FasL expression in MDSC surface, and sequentially regulate caspase-dependent apoptosis pathway. Thus, these findings revealed a novel mechanism for cimetidine to inhibit tumor via modulation of MDSC apoptosis.

  8. The role of mechanical forces in tumor growth and therapy

    PubMed Central

    Jain, Rakesh K.; Martin, John D.; Stylianopoulos, Triantafyllos

    2014-01-01

    Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase their invasive and metastatic potential. Tumor vessels - while nourishing the tumor - are usually leaky and tortuous, which further decreases perfusion. Hypo-perfusion and hypoxia contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression cause a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nano-therapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers. PMID:25014786

  9. Integrative models of vascular remodeling during tumor growth

    PubMed Central

    Rieger, Heiko; Welter, Michael

    2015-01-01

    Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551

  10. Genetic background affects susceptibility to tumoral stem cell reprogramming

    PubMed Central

    García-Ramírez, Idoia; Ruiz-Roca, Lucía; Martín-Lorenzo, Alberto; Blanco, Óscar; García-Cenador, María Begoña; García-Criado, Francisco Javier; Vicente-Dueñas, Carolina; Sánchez-García, Isidro

    2013-01-01

    The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRABLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRABLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRABLp210 FVB mice developed thymomas that were not seen in the Sca1-BCRABLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control. PMID:23839033

  11. Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

    PubMed

    McIntyre, Alan; Hulikova, Alzbeta; Ledaki, Ioanna; Snell, Cameron; Singleton, Dean; Steers, Graham; Seden, Peter; Jones, Dylan; Bridges, Esther; Wigfield, Simon; Li, Ji-Liang; Russell, Angela; Swietach, Pawel; Harris, Adrian L

    2016-07-01

    Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR.

  12. Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth

    NASA Astrophysics Data System (ADS)

    Sano, Michael B.; Arena, Christopher B.; Bittleman, Katelyn R.; Dewitt, Matthew R.; Cho, Hyung J.; Szot, Christopher S.; Saur, Dieter; Cissell, James M.; Robertson, John; Lee, Yong W.; Davalos, Rafael V.

    2015-10-01

    Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models.

  13. Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth.

    PubMed

    Sano, Michael B; Arena, Christopher B; Bittleman, Katelyn R; DeWitt, Matthew R; Cho, Hyung J; Szot, Christopher S; Saur, Dieter; Cissell, James M; Robertson, John; Lee, Yong W; Davalos, Rafael V

    2015-10-13

    Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models.

  14. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

    PubMed Central

    Zelenay, Santiago; van der Veen, Annemarthe G.; Böttcher, Jan P.; Snelgrove, Kathryn J.; Rogers, Neil; Acton, Sophie E.; Chakravarty, Probir; Girotti, Maria Romina; Marais, Richard; Quezada, Sergio A.; Sahai, Erik; Reis e Sousa, Caetano

    2015-01-01

    Summary The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant BrafV600E mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in BrafV600E mouse melanoma cells, as well as in NrasG12D melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways. This mouse COX-dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing for COX activity as a driver of immune suppression across species. Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients. PMID:26343581

  15. Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth

    PubMed Central

    Sano, Michael B.; Arena, Christopher B.; Bittleman, Katelyn R.; DeWitt, Matthew R.; Cho, Hyung J.; Szot, Christopher S.; Saur, Dieter; Cissell, James M.; Robertson, John; Lee, Yong W.; Davalos, Rafael V.

    2015-01-01

    Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models. PMID:26459930

  16. In-vivo visualization of melanoma tumor microvessels and blood flow velocity changes accompanying tumor growth

    NASA Astrophysics Data System (ADS)

    Ishida, Hiroki; Hachiga, Tadashi; Andoh, Tsugunobu; Akiguchi, Shunsuke

    2012-11-01

    We demonstrate that using micro multipoint laser Doppler velocimetry (μ-MLDV) for noninvasive in-vivo imaging of blood vessels is useful for diagnosing malignant melanomas by comparison with visual diagnosis by dermoscopy. The blood flow velocity in microvessels varied during growth of melanomas transplanted in mouse ears. Mouse ears were observed by μ-MLDV up to 16 days after transplantation. The blood flow velocity in the tumor increased with increasing time and reached maximum of 4.5 mm/s at 9 days, which is more than twice that prior to transplantation. After 12 days, when the lesion had grown to an area of 6.6 mm2, we observed the formation of new blood vessels in the tumor. Finally, when the lesion had an area of 18 mm2 after 16 days, the flow velocity in the tumor decreased to approximately 3.2 mm/s.

  17. Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.

    PubMed

    Zhao, Helong; Ahirwar, Dinesh K; Oghumu, Steve; Wilkie, Tasha; Powell, Catherine A; Nasser, Mohd W; Satoskar, Abhay R; Li, Dean Y; Ganju, Ramesh K

    2016-02-01

    Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein-1 (ZO-1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.

  18. Senescence from glioma stem cell differentiation promotes tumor growth

    PubMed Central

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs’ role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. PMID:26775840

  19. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.

    PubMed

    Campbell, Elizabeth J; Vissers, Margreet C M; Bozonet, Stephanie; Dyer, Arron; Robinson, Bridget A; Dachs, Gabi U

    2015-02-01

    Hypoxia-inducible factor-1 (HIF-1) governs cellular adaption to the hypoxic microenvironment and is associated with a proliferative, metastatic, and treatment-resistant tumor phenotype. HIF-1 levels and transcriptional activity are regulated by proline and asparagine hydroxylases, which require ascorbate as cofactor. Ascorbate supplementation reduced HIF-1 activation in vitro, but only limited data are available in relevant animal models. There is no information of the effect of physiological levels of ascorbate on HIF activity and tumor growth, which was measured in this study. C57BL/6 Gulo(-/-) mice (a model of the human ascorbate dependency condition) were supplemented with 3300 mg/L, 330 mg/L, or 33 mg/L of ascorbate in their drinking water before and during subcutaneous tumor growth of B16-F10 melanoma or Lewis lung carcinoma (LL/2). Ascorbate levels in tumors increased significantly with elevated ascorbate intake and restoration of wild-type ascorbate levels led to a reduction in growth of B16-F10 (log phase P < 0.001) and LL/2 tumors (lag growth P < 0.001, log phase P < 0.05). Levels of HIF-1α protein in tumors decreased as dietary ascorbate supplementation increased for both tumor models (P < 0.001). Similarly, tumor ascorbate was inversely correlated with levels of the HIF-1 target proteins CA-IX, GLUT-1, and VEGF in both B16-F10 and LL/2 tumors (P < 0.05). The extent of necrosis was similar between ascorbate groups but varied between models (30% for B16-F10 and 21% for LL/2), indicating that ascorbate did not affect tumor hypoxia. Our data support the hypothesis that restoration of optimal intracellular ascorbate levels reduces tumor growth via moderation of HIF-1 pathway activity.

  20. Location of tumor affects local and distant immune cell type and number

    PubMed Central

    Hensel, Jonathan A.; Khattar, Vinayak; Ashton, Reading; Lee, Carnellia; Siegal, Gene P.

    2017-01-01

    Abstract Introduction Tumors comprise heterogeneous populations of cells, including immune infiltrates that polarize during growth and metastasis. Our preclinical studies on breast cancer (BCa) identified functional differences in myeloid‐derived suppressor cells based on tumor microenvironment (TME), prompting variations in host immune response to tumor growth, and dissemination based on tissue type. Methods In order to understand if such variations existed among other immune cells, and if such alteration occurs in response to tumor growth at the primary site or due to bone dissemination, we characterized immune cells, examining localized growth and in the tibia. In addition, immune cells from the spleen were examined from animals of both tumor locations by flow cytometry. Results The study demonstrates that location of tumor, and not simply the tumor itself, has a definitive role in regulating immune effectors. Among all immune cells characterized, macrophages were decreased and myeloid dendritic cell were increased in both tumor locations. This difference was more evident in subcutaneous tumors. Additionally, spleens from mice with subcutaneous tumors contained greater increases in both macrophages and myeloid dendritic cells than in mice with bone tumors. Furthermore, in subcutaneous tumors there was an increase in CD4+ and CD8+ T‐cell numbers, which was also observed in their spleens. Conclusions These data indicate that alterations in tumor‐reactive immune cells are more pronounced at the primary site, and exert a similar change at the major secondary lymphoid organ than in the bone TME. These findings could provide translational insight into designing therapeutic strategies that account for location of metastatic foci. PMID:28250928

  1. Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas.

    PubMed

    Griffith, Obi L; Chan, Szeman Ruby; Griffith, Malachi; Krysiak, Kilannin; Skidmore, Zachary L; Hundal, Jasreet; Allen, Julie A; Arthur, Cora D; Runci, Daniele; Bugatti, Mattia; Miceli, Alexander P; Schmidt, Heather; Trani, Lee; Kanchi, Krishna-Latha; Miller, Christopher A; Larson, David E; Fulton, Robert S; Vermi, William; Wilson, Richard K; Schreiber, Robert D; Mardis, Elaine R

    2016-09-27

    Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1(-/-) mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation.

  2. Mediastinal Desmoid Tumor With Remarkably Rapid Growth: A Case Report.

    PubMed

    Lee, Joon Hyung; Jeong, Jae Seok; Kim, So Ri; Jin, Gong Yong; Chung, Myoung Ja; Kuh, Ja Hong; Lee, Yong Chul

    2015-12-01

    Desmoid tumors (DTs) are a group of rare and benign soft tissue tumors that result from monoclonal proliferation of well-differentiated fibroblasts. Since DTs tend to infiltrate and compress adjacent structures, the location of DTs is one of the most crucial factors for determining the severity of the disease. Furthermore, DTs can further complicate the clinical course of patients when the growth is remarkably rapid, especially for DTs occurring in anatomically critical compartments, including the thoracic cavity.The authors report a case of a 71-year-old man with a known mediastinal mass incidentally detected 4 months ago, presenting dyspnea with right-sided atelectasis and massive pleural effusion. Imaging studies revealed a 16.4 × 9.4-cm fibrous mass with high glucose metabolism in the anterior mediastinum. The mass infiltrated into the chest wall and also displaced the mediastinum contralaterally. Interestingly, the tumor had an extremely rapid doubling time of 31.3 days.En bloc resection of the tumor was performed as a curative as well as a diagnostic measure. Histopathologic examination showed spindle cells with low cellularity and high collagen deposition in the stroma. Immunohistochemical staining was positive for nuclear β-catenin. Based on these pathologic findings, the mass was diagnosed as DT. After surgery, there has been no evidence of recurrence of disease in the patient.This patient presents a mediastinal DT with extremely rapid growth. Notably, the doubling time of DT in our case was the shortest among reported cases of DT. Our experience also highlights the benefits of early interventional strategy, especially for rapidly growing DTs in the thoracic cavity.

  3. Triparanol suppresses human tumor growth in vitro and in vivo

    SciTech Connect

    Bi, Xinyu; Han, Xingpeng; Zhang, Fang; He, Miao; Zhang, Yi; Zhi, Xiu-Yi; Zhao, Hong

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  4. STC1 expression is associated with tumor growth and metastasis in breast cancer.

    PubMed

    Chang, Andy C-M; Doherty, Judy; Huschtscha, Lily I; Redvers, Richard; Restall, Christina; Reddel, Roger R; Anderson, Robin L

    2015-01-01

    Stanniocalcin-1 (STC1) is a secreted glycoprotein implicated in several pathologies including retinal degeneration, cerebral ischemia, angiogenesis and inflammation. Aberrant STC1 expression has been reported in breast cancer but the significance of this is not clear. High levels of STC1 expression were found in the aggressive 4T1 murine mammary tumor cells and in the MDA-MB-231 human breast cancer line. To investigate its significance, stable clones with STC1 down-regulation using shRNA were generated in both tumor models. The consequences of STC1 down-regulation on cell proliferation, chemotactic invasion, tumor growth and metastasis were assessed. Down-regulation of STC1 in the 4T1 murine mammary tumor cells had a major impact on mammary tumor growth. This observation was replicated in a second tumor model with the MDA-MB-231 human breast cancer line, with a significant reduction in primary tumor formation and a major inhibition of metastasis as well. Interestingly, in both models, proliferation in vitro was not affected. Subsequent microarray gene expression profiling identified 30 genes to be significantly altered by STC1 down-regulation, the majority of which are associated with known hallmarks of carcinogenesis. Furthermore, bioinformatic analysis of breast cancer datasets revealed that high expression of STC1 is associated with poor survival. This is the first study to show definitively that STC1 plays an oncogenic role in breast cancer, and indicates that STC1 could be a potential therapeutic target for treatment of breast cancer patients.

  5. AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells

    PubMed Central

    Maenhout, Sarah K.; Four, Stephanie Du; Corthals, Jurgen; Neyns, Bart; Thielemans, Kris; Aerts, Joeri L.

    2014-01-01

    AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses. PMID:25149535

  6. Analysis of a diffuse interface model of multispecies tumor growth

    NASA Astrophysics Data System (ADS)

    Dai, Mimi; Feireisl, Eduard; Rocca, Elisabetta; Schimperna, Giulio; Schonbek, Maria E.

    2017-04-01

    We consider a diffuse interface model for tumor growth recently proposed in Chen et al (2014 Int. J. Numer. Methods Biomed. Eng. 30 726–54). In this new approach sharp interfaces are replaced by narrow transition layers arising due to adhesive forces among the cell species. Hence, a continuum thermodynamically consistent model is introduced. The resulting PDE system couples four different types of equations: a Cahn–Hilliard type equation for the tumor cells (which include proliferating and dead cells), a Darcy law for the tissue velocity field, whose divergence may be different from 0 and depend on the other variables, a transport equation for the proliferating (viable) tumor cells, and a quasi-static reaction diffusion equation for the nutrient concentration. We establish existence of weak solutions for the PDE system coupled with suitable initial and boundary conditions. In particular, the proliferation function at the boundary is supposed to be nonnegative on the set where the velocity \\mathbf{u} satisfies \\mathbf{u}\\centerdot ν >0 , where ν is the outer normal to the boundary of the domain.

  7. Resveratrol Is Rapidly Metabolized in Athymic (Nu/Nu) Mice and Does Not Inhibit Human Melanoma Xenograft Tumor Growth1

    PubMed Central

    Niles, Richard M.; Cook, Carla P.; Meadows, Gary G.; Fu, Ya-Min; McLaughlin, Jerry L.; Rankin, Gary O.

    2006-01-01

    Resveratrol has been shown to have anticarcinogenic activity. We previously found that resveratrol inhibited growth and induced apoptosis in 2 human melanoma cell lines. In this study we determined whether resveratrol would inhibit human melanoma xenograft growth. Athymic mice received control diets or diets containing 110 μmol/L or 263 μmol/L resveratrol, 2 wk prior to subcutaneous injection of the tumor cells. Tumor growth was measured during a 3-wk period. Metabolism of resveratrol was assayed by bolus gavage of 75 mg/kg resveratrol in tumor-bearing and nontumor-bearing mice. Pellets containing 10–100 mg resveratrol were implanted into the mice, next to newly palpated tumors, and tumor growth determined. We also determined the effect of a major resveratrol metabolite, piceatannol, on experimental lung metastasis. Resveratrol, at any concentration tested, did not have a statistically significant effect on tumor growth. The higher levels of resveratrol tested (0.006% in food or 100 mg in slow-release pellets) tended to stimulate tumor growth (P = 0.08–0.09). Resveratrol and its major metabolites, resveratrol glucuronide and piceatannol, were found in serum, liver, skin, and tumor tissue. Piceatannol did not affect the in vitro growth of a murine melanoma cell line, but significantly stimulated the number of lung metastases when these melanoma cells were directly injected into the tail vein of the mouse. These results suggest that resveratrol is not likely to be useful in the treatment of melanoma and that the effects of phytochemicals on cell cultures may not translate to the whole animal system. PMID:16988123

  8. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    SciTech Connect

    Yu, Wei; Chai, Hongyan; Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue; Yang, Guifang; Cai, Xiaojun; Falck, John R.; Yang, Jing

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  9. Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

    PubMed Central

    Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar

    2011-01-01

    Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer. PMID:21541211

  10. Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice.

    PubMed

    Shinya, Tomohiro; Yokota, Tsubasa; Nakayama, Shiori; Oki, Sayuri; Mutoh, Junpei; Takahashi, Satoru; Sato, Keizo

    2015-09-01

    Angiogenesis, the formation of new blood vessels from pre-existing vessels, is essential for the growth and metastasis of tumors. In this study, we found that l-carbocisteine, a widely used expectorant, potently inhibits angiogenesis in vitro and in vivo. An in vivo Matrigel plug assay revealed that l-carbocisteine (2.5 mg/kg i.p. twice daily) significantly inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. l-Carbocisteine also suppressed VEGF-stimulated proliferation, migration, and formation of capillary-like structures of human umbilical vein endothelial cells (HUVECs). We examined the signaling pathways affected in VEGF-stimulated HUVECs, and found that l-carbocisteine significantly inhibited VEGF-induced phosphorylation of phospholipase C (PLC) γ, protein kinase C (PKC) μ, and extracellular signal-related kinases (ERK) 1/2, which have been shown to be essential for angiogenesis. However, these inhibitory effects of l-carbocisteine were not observed in the HeLa human cervical cancer cell line. An in vivo study of Colon-26 tumor-bearing mice found that tumor volumes were significantly smaller in mice treated with l-carbocisteine (150 mg/kg administered orally twice daily) in comparison with vehicle-treated mice. However, l-carbocisteine had no direct effect on Colon-26 cell proliferation or ERK activation. Collectively, our results suggest that l-carbocisteine inhibits tumor angiogenesis by suppressing PLCγ/PKC/ERK signaling.

  11. VCC-1, a novel chemokine, promotes tumor growth

    SciTech Connect

    Weinstein, Edward J.; Head, Richard; Griggs, David W.; Sun Duo; Evans, Robert J.; Swearingen, Michelle L.; Westlin, Marisa M.; Mazzarella, Richard . E-mail: richard.a.mazzarella@pfizer.com

    2006-11-10

    We have identified a novel human gene by transcriptional microarray analysis, which is co-regulated in tumors and angiogenesis model systems with VEGF expression. Isolation of cDNA clones containing the full-length VCC-1 transcript from both human and mouse shows a 119 amino acid protein with a 22 amino acid cleavable signal sequence in both species. Comparison of the protein product of this gene with hidden Markov models of all known proteins shows weak but significant homology with two known chemokines, SCYA17 and SCYA16. Northern analysis of human tissues detects a 1 kb band in lung and skeletal muscle. Murine VCC-1 expression can also be detected in lung as well as thyroid, submaxillary gland, epididymis, and uterus tissues by slot blot analysis. By quantitative real time RT-PCR 71% of breast tumors showed 3- to 24-fold up-regulation of VCC-1. In situ hybridization of breast carcinomas showed strong expression of the gene in both normal and transformed mammary gland ductal epithelial cells. In vitro, human microvascular endothelial cells grown on fibronectin increase VCC-1 expression by almost 100-fold. In addition, in the mouse angioma endothelial cell line PY4.1 the gene was over-expressed by 28-fold 6 h after induction of tube formation while quiescent and proliferating cells showed no change. VCC-1 expression is also increased by VEGF and FGF treatment, about 6- and 5-fold, respectively. Finally, 100% of mice injected with NIH3T3 cells over-expressing VCC-1 develop rapidly progressing tumors within 21 days while no growth is seen in any control mice injected with NIH3T3 cells containing the vector alone. These results strongly suggest that VCC-1 plays a role in angiogenesis and possibly in the development of tumors in some tissue types.

  12. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    PubMed Central

    Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

    2016-01-01

    Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials. PMID:27485515

  13. Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels

    NASA Astrophysics Data System (ADS)

    Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.

    2016-08-01

    Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials.

  14. Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity.

    PubMed

    Novosyadlyy, Ruslan; Leroith, Derek

    2012-06-01

    Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity.

  15. Use of a smooth press-fit stem preserves physeal growth after tumor resection.

    PubMed

    Neel, Michael D; Heck, Robert; Britton, Lunetha; Daw, Najat; Rao, Bhaskar N

    2004-09-01

    We conducted this study to determine whether the small-diameter, press-fit stem of a novel, noninvasive expandable endoprosthetic device implanted in the limbs of 6 pediatric patients with Stage IIB osteosarcoma affected the growth of the physis through which the stem was inserted. Local control of the tumor necessitated resection of the involved growth plate, and implantation of the device required penetration of the adjacent uninvolved bone, through the growth plate, by the stem of the device. We measured longitudinal growth and the rate of growth of the adjacent uninvolved bone in the salvaged limb and of the equivalent bone in the unoperated contralateral limb. In all cases but one (in which the patient's growth in the contralateral limb appeared complete), longitudinal growth continued in the limb into which the device was implanted: the adjacent uninvolved bone in the salvaged limb grew by an average of 2.4 cm, and the equivalent bone in the unoperated contralateral limb grew by an average of 2.3 cm. We conclude that implantation of a smooth, press-fit stem through the central portion of the uninvolved adjacent physis does not result in growth retardation or arrest.

  16. Tumor inoculation site affects the development of cancer cachexia and muscle wasting.

    PubMed

    Matsuyama, Tatsuzo; Ishikawa, Takeshi; Okayama, Tetsuya; Oka, Kaname; Adachi, Satoko; Mizushima, Katsura; Kimura, Reiko; Okajima, Manabu; Sakai, Hiromi; Sakamoto, Naoyuki; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Kokura, Satoshi; Naito, Yuji; Itoh, Yoshito

    2015-12-01

    The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF-β family, and found that levels of IL-6, TNF-α and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment.

  17. T Model of Growth and its Application in Systems of Tumor-Immune Dynamics

    PubMed Central

    Tabatabai, Mohammad A.; Eby, Wayne M.; Singh, Karan P.; Bae, Sejong

    2015-01-01

    In this paper we introduce a new growth model called T growth model. This model is capable of representing sigmoidal growth as well as biphasic growth. This dual capability is achieved without introducing additional parameters. The T model is useful in modeling cellular proliferation or regression of cancer cells, stem cells, bacterial growth and drug dose-response relationships. We recommend usage of the T growth model for the growth of tumors as part of any system of differential equations. Use of this model within a system will allow more flexibility in representing the natural rate of tumor growth. For illustration, we examine some systems of tumor-immune interaction in which the T growth rate is applied. We also apply the model to a set of tumor growth data. PMID:23906156

  18. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    SciTech Connect

    Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  19. Oxygen microenvironment affects the uptake of nanoparticles in head and neck tumor cells

    NASA Astrophysics Data System (ADS)

    Chen, Eunice Y.; Hodge, Sasson; Tai, Katherine; Hou, Huagang; Khan, Nadeem; Hoopes, P. Jack; Samkoe, Kimberley S.

    2013-02-01

    Survival of head and neck cancer patients has not improved in several decades despite advances in diagnostic and therapeutic techniques. Tumor hypoxia in head and neck cancers is a critical factor that leads to poor prognosis, resistance to radiation and chemotherapies, and increased metastatic potential. Magnetic nanoparticle hyperthermia (mNPHT) is a promising therapy for hypoxic tumors because nanoparticles (NP) can be directly injected into, or targeted to, hypoxic tumor cells and exposed to alternating magnetic fields (AMF) to induce hyperthermia. Magnetic NPHT can improve therapeutic effectiveness by two modes of action: 1) direct killing of hypoxic tumor cells; and 2) increase in tumor oxygenation, which has the potential to make the tumor more susceptible to adjuvant therapies such as radiation and chemotherapy. Prior studies in breast cancer cells demonstrated that a hypoxic microenvironment diminished NP uptake in vitro; however, mNPHT with intratumoral NP injection in hypoxic tumors increased tumor oxygenation and delayed tumor growth. In this study, head and neck squamous cell carcinoma (HNSCC) cell lines were incubated in normoxic, hypoxic, and hyperoxic conditions with iron oxide NP for 4-72 hours. After incubation, the cells were analyzed for iron uptake by mass spectrometry, Prussian blue staining, and electron microscopy. In contrast to breast cancer cells, uptake of NPs was increased in hypoxic microenvironments as compared to normoxic conditions in HNSCC cells. In future studies, we will confirm the effect of the oxygen microenvironment on NP uptake and efficacy of mNPHT both in vitro and in vivo.

  20. Analysis of a ``phase transition'' from tumor growth to latency

    NASA Astrophysics Data System (ADS)

    Delsanto, P. P.; Romano, A.; Scalerandi, M.; Pescarmona, G. P.

    2000-08-01

    A mathematical model, based on the local interaction simulation approach, is developed in order to allow simulations of the spatiotemporal evolution of neoplasies. The model consists of a set of rules, which govern the interaction of cancerous cells among themselves and in competition with other cell populations for the acquisition of essential nutrients. As a result of small variations in the basic parameters, it leads to four different outcomes: indefinite growth, metastasis, latency, and complete regression. In the present contribution a detailed analysis of the dormant phase is carried on and the critical parameters for the transition to other phases are computed. Interesting chaotic behaviors can also be observed, with different attractors in the parameters space. Interest in the latency phase has been aroused by therapeutical strategies aiming to reduce a growing tumor to dormancy. The effect of such strategies may be simulated with our approach.

  1. Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth.

    PubMed

    Wegiel, Barbara; Gallo, David; Csizmadia, Eva; Harris, Clair; Belcher, John; Vercellotti, Gregory M; Penacho, Nuno; Seth, Pankaj; Sukhatme, Vikas; Ahmed, Asif; Pandolfi, Pier Paolo; Helczynski, Leszek; Bjartell, Anders; Persson, Jenny Liao; Otterbein, Leo E

    2013-12-01

    One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion.

  2. Targeting Gli Transcription Activation by Small Molecule Suppresses Tumor Growth

    PubMed Central

    Bosco-Clément, Geneviève; Zhang, Fang; Chen, Zhao; Zhou, Hai-Meng; Li, Hui; Mikami, Iwao; Hirata, Tomomi; Yagui-Beltran, Adam; Lui, Natalie; Do, Hanh T.; Cheng, Tiffany; Tseng, Hsin-Hui; Choi, Helen; Fang, Li-Tai; Kim, Il-Jin; Yue, Dongsheng; Wang, Changli; Zheng, Qingfeng; Fujii, Naoaki; Mann, Michael; Jablons, David M.; He, Biao

    2014-01-01

    Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anti-cancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study we identified an interaction between Gli proteins and a transcription co-activator TAF9, and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and down-regulate Gli/TAF9 dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, a key control point of multiple oncogenic pathways, may be an effective anti-cancer strategy. PMID:23686308

  3. The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis

    NASA Astrophysics Data System (ADS)

    Ding, Yihong

    Targeting cytotoxic agents to tumor angiogenesis, instead of the tumor itself, is an attractive new approach in Radiation Oncology. Unlike tumor cells, endothelial cells are less likely to develop radio-resistance. Investigations have shown that radiation can cause a definite increase in cell permeability. Permeability changes in the tumor capillary endothelium can contribute to circulatory failure and serve as a site for clot formation. Therefore, radiation could initiate platelet aggregation and blood coagulation locally within the tumor vasculature, leading to tumor cell killing through depletion of oxygen and nutrients. In order to analyze the efficacy of a potential 90Y-labeled compound for vascular targeting radiotherapy and to evaluate the factors that may affect targets' absorbed dose, a tumor vasculature model including its angiogenesis process as a function of time and tumor growth are adopted and improved from the Liotta model. Its output is used to estimate targets' absorbed doses by Monte Carlo simulation. The results show that the effectiveness of vascular targeting therapy depends on the existence of available tumor endothelial cells and target expression. The alphavbeta3 antagonist model compound is less effective in the early stage tumors, which have very few vessels. Although a high administered dose, such as injecting of 2.1 mCi/kg to saturate all available binding sites, can destroy tumor endothelium network, the toxicity to bone marrow makes it impossible to inject such a dose. To a vascularized tumor, after giving one maximum allowable administered activity, 0.83 mCi/kg for the 90Y-labeled model compound, an average of 9.8%, 27.3%, 34.7% and 37.8% of endothelial cells would be killed when treatment starts at day 4, 7, 9 and 12 after tumor development, respectively. Therefore, recurrent treatment by vascular targeting therapy to well-vascularized tumor has the potential to slow down tumor growth or may even cause tumor regression at the primary

  4. Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation.

    PubMed

    Rodriguez-Puebla, Marcelo L; Miliani de Marval, Paula L; LaCava, Margaret; Moons, David S; Kiyokawa, Hiroaki; Conti, Claudio J

    2002-08-01

    Most human tumors have mutations that result in deregulation of the cdk4/cyclin-Ink4-Rb pathway. Overexpression of D-type cyclins or cdk4 and inactivation of Ink4 inhibitors are common in human tumors. Conversely, lack of cyclin D1 expression results in significant reduction in mouse skin and mammary tumor development. However, complete elimination of tumor development was not observed in these models, suggesting that other cyclin/cdk complexes play an important role in tumorigenesis. Here we described the effects of cdk4 deficiency on mouse skin proliferation and tumor development. Cdk4 deficiency resulted in a 98% reduction in the number of tumors generated through the two-stage carcinogenesis model. The absence of cdk4 did not affect normal keratinocyte proliferation and both wild-type and cdk4 knockout epidermis are equally affected after topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in epidermal hyperplasia. In similar fashion, cdk4 knockout keratinocytes proliferated well in an in vivo model of wound-induced proliferation. Biochemical studies in mouse epidermis showed that cdk6 activity increased twofold in cdk4-deficient mice compared to wild-type siblings. These results suggest that therapeutic approaches to inhibit cdk4 activity could provide a target to inhibit tumor development with minimal or no effect in normal tissue.

  5. ARNT2 Regulates Tumoral Growth in Oral Squamous Cell Carcinoma

    PubMed Central

    Kimura, Yasushi; Kasamatsu, Atsushi; Nakashima, Dai; Yamatoji, Masanobu; Minakawa, Yasuyuki; Koike, Kazuyuki; Fushimi, Kazuaki; Higo, Morihiro; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2016-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) 2 is a transcriptional factor related to adaptive responses against cellular stress from a xenobiotic substance. Recent evidence indicates ARNT is involved in carcinogenesis and cancer progression; however, little is known about the relevance of ARNT2 in the behavior of oral squamous cell carcinoma (OSCC). In the current study, we evaluated the ARNT2 mRNA and protein expression levels in OSCC in vitro and in vivo and the clinical relationship between ARNT2 expression levels in primary OSCCs and their clinicopathologic status by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry. Using ARNT2 overexpression models, we performed functional analyses to investigate the critical roles of ARNT2 in OSCC. ARNT2 mRNA and protein were down-regulated significantly (P < 0.05 for both comparisons) in nine OSCC-derived cells and primary OSCC (n=100 patients) compared with normal counterparts. In addition to the data from exogenous experiments that ARNT2-overexpressed cells showed decreased cellular proliferation, ARNT2-positive OSCC cases were correlated significantly (P < 0.05) with tumoral size. Since von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase, a negative regulator of hypoxia-inducible factor (HIF1)-α, is a downstream molecule of ARNT2, we speculated that HIF1-α and its downstream molecules would have key functions in cellular growth. Consistent with our hypothesis, overexpressed ARNT2 cells showed down-regulation of HIF1-α, which causes hypofunctioning of glucose transporter 1, leading to decreased cellular growth. Our results proposed for the first time that the ARNT2 level is an indicator of cellular proliferation in OSCCs. Therefore, ARNT2 may be a potential therapeutic target against progression of OSCCs. PMID:27076852

  6. Growth inhibition of MCF-7 tumor cell line by phenylacetate linked to functionalized dextran.

    PubMed

    Frank, L; Avramoglou, T; Sainte-Catherine, O; Jozefonvicz, J; Kraemer, M

    2004-01-01

    We investigated the antiproliferative effect of phenylacetate covalently linked to dextran derivatives (DMCBPA conjugates) on human breast cancer MCF-7 cells. We show that free sodium phenylacetate (NaPA) inhibits the cell growth (IC50 = 14 mM), while an important inhibitory effect is observed for DMCBPA conjugates. The IC50 dose of these conjugates is as low as 1.0 mg/ml, corresponding to 1.3 mM of phenylacetate. The precursors, dextran substituted with methylcarboxylate and benzylamide groups, did not affect the growth of MCF-7 tumor cells. We have observed that MCF-7 cell growth inhibition depends on amount of phenylacetate linked to the conjugate. The data indicated that an optimum antiproliferative effect is more significant when the amount of phenylacetate groups present on the dextran backbone is high. Analysis of doubling time by growth kinetics study shows that conjugates have more time-sustained effect than free NaPA. It is noteworthy that the inhibitory effect is observed at non-toxic concentration. Theses conjugates could be considered as acceptable derivatives to prevent tumor progression.

  7. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.

    PubMed

    Pedersen, Line; Idorn, Manja; Olofsson, Gitte H; Lauenborg, Britt; Nookaew, Intawat; Hansen, Rasmus Hvass; Johannesen, Helle Hjorth; Becker, Jürgen C; Pedersen, Katrine S; Dethlefsen, Christine; Nielsen, Jens; Gehl, Julie; Pedersen, Bente K; Thor Straten, Per; Hojman, Pernille

    2016-03-08

    Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth.

  8. Photoacoustic endoscopic imaging study of melanoma tumor growth in a rat colorectum in vivo

    NASA Astrophysics Data System (ADS)

    Li, Chiye; Yang, Joon-Mo; Chen, Ruimin; Zhang, Yu; Xia, Younan; Zhou, Qifa; Shung, K. Kirk; Wang, Lihong V.

    2013-03-01

    We performed a photoacoustic endoscopic imaging study of melanoma tumor growth in a nude rat in vivo. After inducing the tumor at the colorectal wall of the animal, we monitored the tumor development in situ by using a photoacoustic endoscopic system. This paper introduces our experimental method for tumor inoculation and presents imaging results showing the morphological changes of the blood vasculature near the tumor region according to the tumor progress. Our study could provide insights for future studies on tumor development in small animals.

  9. Dietary phosphorus affects the growth of larval Manduca sexta.

    PubMed

    Perkins, Marc C; Woods, H Arthur; Harrison, Jon F; Elser, James J

    2004-03-01

    Although phosphorus has long been considered an important factor in the growth of diverse biota such as bacteria, algae, and zooplankton, insect nutrition has classically focused on dietary protein and energy content. However, research in elemental stoichiometry has suggested that primary producer biomass has similar N:P ratios in aquatic and terrestrial systems, and phosphorus-rich herbivores in freshwater systems frequently face phosphorus-limited nutritional conditions. Therefore, herbivorous insects should also be prone to phosphorus limitation. We tested this prediction by rearing Manduca sexta larvae on artificial and natural (Datura wrightii leaves) diets containing varying levels of phosphorus (approximately 0.20, 0.55, or 1.2% phosphorus by dry weight). For both artificial and natural diets, increased dietary phosphorus significantly increased growth rates and body phosphorus contents, and shortened the time to the final instar molt. Caterpillars did not consistently exhibit compensatory feeding for phosphorus on either type of diet. The growth and body phosphorus responses were not explicable by changes in amounts of potassium or calcium, which co-varied with phosphorus in the diets. Concentrations of phosphorus in D. wrightii leaves collected in the field varied over a range in which leaf phosphorus is predicted to affect M. sexta's growth rates. These results suggest that natural variation in dietary phosphorus is likely to affect the growth rate and population dynamics of M. sexta, and perhaps larval insects more generally.

  10. Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth.

    PubMed

    Carito, Valentina; Bonuccelli, Gloria; Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Caroleo, Maria Cristina; Cione, Erika; Howell, Anthony; Pestell, Richard G; Lisanti, Michael P; Sotgia, Federica

    2012-09-15

    Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate production) in the tumor microenvironment. Consistent with the idea that glycolytic fibroblasts fuel tumor growth (via L-lactate, a high-energy mitochondrial fuel), MSF fibroblasts significantly increased tumor growth, by up to 4-fold. Mechanistic dissection of the MSF signaling pathway indicated that Cdc42 lies downstream of MSF and fibroblast activation. In accordance with this notion, Cdc42 overexpression in immortalized fibroblasts was sufficient to drive myofibroblast differentiation, to provoke a shift towards glycolytic metabolism and to promote tumor growth by up to 2-fold. In conclusion, the MSF/Cdc42/NFκB signaling cascade may be a critical druggable target in preventing "Warburg-like" cancer metabolism in tumor-associated fibroblasts. Thus, MSF functions in the metabolic remodeling of the tumor microenvironment by metabolically reprogramming cancer-associated fibroblasts toward glycolytic metabolism.

  11. Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells

    PubMed Central

    2010-01-01

    Background In spite of recent advances in diagnostic and therapeutic measures, the prognosis of hepatocellular carcinoma (HCC) patients remains poor. Therefore, it is crucial to understand what factors are involved in promoting development of HCC. Evidence is accumulating that members of the chemokine receptor family are viewed as promising therapeutic targets in the fight against cancer. More recent studies have revealed that chemokine receptor CXCR7 plays an important role in cancer development. However, little is known about the effect of CXCR7 on the process of HCC cell invasion and angiogenesis. The aim of this study is to investigate the expression of CXCR7 in hepatocellular carcinoma tissues and cell lines and to evaluate the role of CXCR7 in tumor growth, angiogenesis and invasion of HCC cells. Methods We constructed CXCR7 expressing shRNA, and CXCR7shRNA was subsequently stably transfected into human HCC cells. We evaluated the effect of CXCR7 inhibition on cell invasion, adhesion, VEGF secretion, tube formation and tumor growth. Immunohistochemistry was done to assess the expression of CXCR7 in human hepatocellular carcinoma tissues and CD31 in tumor of mice. We also evaluated the effect of VEGF stimulation on expression of CXCR7. Results CXCR7 was overexpressed in hepatocellular carcinoma tissues. We showed that high invasive potential HCC cell lines express high levels of CXCR7. In vitro, CXCL12 was found to induce invasion, adhesion, tube formation, and VEGF secretion in SMMC-7721 cells. These biological effects were inhibited by silencing of CXCR7 in SMMC-7721 cells. In addition, we also found that VEGF stimulation can up-regulate CXCR7 expression in SMMC-7721 cells and HUVECs. More importantly, enhanced expression of CXCR7 by VEGF was founctional. In vivo, tumor growth and angiogenesis were suppressed by knockdown of CXCR7 in SMMC-7721 cells. However, silencing of CXCR7 did not affect metastasis of tumor in vivo. Conclusions Increased CXCR7

  12. The Contributions of HIF-Target Genes to Tumor Growth in RCC

    PubMed Central

    Zhang, Ting; Niu, Xiaohua; Liao, Lili; Cho, Eun-Ah; Yang, Haifeng

    2013-01-01

    Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it’s causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth. PMID:24260413

  13. Tumor Growth Model with PK Input for Neuroblastoma Drug Development

    DTIC Science & Technology

    2015-09-01

    toward this goal by developing a whole-body PBPK model with an individualized tumor compartment for topotecan in mice bearing NB5 neuroblastoma tumors...utilized contrast-enhanced ultrasound (CEUS) derived individual tumor blood flow and blood volume measurements from NB5 tumor bearing mice. We were... bearing mice for each of the four TPT dosages. The second priority time points have been completed for three of the four dosages in tumor bearing

  14. Silencing of Foxp3 delays the growth of murine melanomas and modifies the tumor immunosuppressive environment

    PubMed Central

    Franco-Molina, Moisés A; Miranda-Hernández, Diana F; Mendoza-Gamboa, Edgar; Zapata-Benavides, Pablo; Coronado-Cerda, Erika E; Sierra-Rivera, Crystel A; Saavedra-Alonso, Santiago; Taméz-Guerra, Reyes S; Rodríguez-Padilla, Cristina

    2016-01-01

    Forkhead box p3 (Foxp3) expression was believed to be specific for T-regulatory cells but has recently been described in non-hematopoietic cells from different tissue origins and in tumor cells from both epithelial and non-epithelial tissues. The aim of this study was to elucidate the role of Foxp3 in murine melanoma. The B16F10 cell line Foxp3 silenced with small interference Foxp3 plasmid transfection was established and named B16F10.1. These cells had lower levels of Foxp3 mRNA (quantitative real-time reverse transcription-polymerase chain reaction [0.235-fold]), protein (flow cytometry [0.02%]), CD25+ expression (0.06%), cellular proliferation (trypan blue staining), and interleukin (IL)-2 production (enzyme-linked immunosorbent assay [72.35 pg/mL]) than those in B16F10 wild-type (WT) cells (P<0.05). Subcutaneous inoculation of the B16F10.1 cell line into C57BL/6 mice delayed the time of visible tumor appearance, increased the time of survival, and affected the weight of tumors, and also decreased the production of IL-10, IL-2, and transforming growth factor beta compared with mice inoculated with the B16F10 WT cell line. The B16F10.1 cells derived from tumors and free of T-cells (isolated by Dynabeads and plastic attachment) expressed relatively lower levels of Foxp3 and CD25+ than B16F10 WT cells (P<0.05) in a time-dependent manner. The population of tumor-infiltrating lymphocytes of T CD4+ cells (CD4+, CD4+CD25+, and CD4+CD25+Foxp3+) increased in a time-dependent manner (P<0.05) in tumors derived from B16F10 WT cells and decreased in tumors derived from B16F10.1 cells. Similar data were obtained from spleen cells. These results suggest that, in melanomas, Foxp3 partly induces tumor growth by modifying the immune system at the local and peripheral level, shifting the environment toward an immunosuppressive profile. Therapies incorporating this transcription factor could be strategies for cancer treatment. PMID:26834483

  15. Patient-derived xenograft (PDX) tumors increase growth rate with time.

    PubMed

    Pearson, Alexander T; Finkel, Kelsey A; Warner, Kristy A; Nör, Felipe; Tice, David; Martins, Manoela D; Jackson, Trachette L; Nör, Jacques E

    2016-02-16

    Patient-derived xenograft (PDX) models are frequently used for translational cancer research, and are assumed to behave consistently as the tumor ages. However, growth rate constancy as a function of time is unclear. Notably, variable PDX growth rates over time might have implications for the interpretation of translational studies. We characterized four PDX models through several in vivo passages from primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma. We developed a mathematical approach to merge growth data from different passages into a single measure of relative tumor volume normalized to study initiation size. We analyzed log-relative tumor volume increase with linear mixed effect models. Two oral pathologists analyzed the PDX tissues to determine if histopathological feature changes occurred over in vivo passages. Tumor growth rate increased over time. This was determined by repeated measures linear regression statistical analysis in four different PDX models. A quadratic statistical model for the temporal effect predicted the log-relative tumor volume significantly better than a linear time effect model. We found a significant correlation between passage number and histopathological features of higher tumor grade. Our mathematical treatment of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple passages. Non-linear tumor growth in our regression models revealed the exponential growth rate increased over time. The dynamic tumor growth rates correlated with quantifiable histopathological changes that related to passage number in multiple types of cancer.

  16. Patient-derived xenograft (PDX) tumors increase growth rate with time

    PubMed Central

    Pearson, Alexander T.; Finkel, Kelsey A.; Warner, Kristy A.; Nör, Felipe; Tice, David; Martins, Manoela D.; Jackson, Trachette L.; Nör, Jacques E.

    2016-01-01

    Patient-derived xenograft (PDX) models are frequently used for translational cancer research, and are assumed to behave consistently as the tumor ages. However, growth rate constancy as a function of time is unclear. Notably, variable PDX growth rates over time might have implications for the interpretation of translational studies. We characterized four PDX models through several in vivo passages from primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma. We developed a mathematical approach to merge growth data from different passages into a single measure of relative tumor volume normalized to study initiation size. We analyzed log-relative tumor volume increase with linear mixed effect models. Two oral pathologists analyzed the PDX tissues to determine if histopathological feature changes occurred over in vivo passages. Tumor growth rate increased over time. This was determined by repeated measures linear regression statistical analysis in four different PDX models. A quadratic statistical model for the temporal effect predicted the log-relative tumor volume significantly better than a linear time effect model. We found a significant correlation between passage number and histopathological features of higher tumor grade. Our mathematical treatment of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple passages. Non-linear tumor growth in our regression models revealed the exponential growth rate increased over time. The dynamic tumor growth rates correlated with quantifiable histopathological changes that related to passage number in multiple types of cancer. PMID:26783960

  17. An Off-Lattice Hybrid Discrete-Continuum Model of Tumor Growth and Invasion

    PubMed Central

    Jeon, Junhwan; Quaranta, Vito; Cummings, Peter T.

    2010-01-01

    Abstract We have developed an off-lattice hybrid discrete-continuum (OLHDC) model of tumor growth and invasion. The continuum part of the OLHDC model describes microenvironmental components such as matrix-degrading enzymes, nutrients or oxygen, and extracellular matrix (ECM) concentrations, whereas the discrete portion represents individual cell behavior such as cell cycle, cell-cell, and cell-ECM interactions and cell motility by the often-used persistent random walk, which can be depicted by the Langevin equation. Using this framework of the OLHDC model, we develop a phenomenologically realistic and bio/physically relevant model that encompasses the experimentally observed superdiffusive behavior (at short times) of mammalian cells. When systemic simulations based on the OLHDC model are performed, tumor growth and its morphology are found to be strongly affected by cell-cell adhesion and haptotaxis. There is a combination of the strength of cell-cell adhesion and haptotaxis in which fingerlike shapes, characteristic of invasive tumor, are observed. PMID:20074513

  18. Spaceflight and age affect tibial epiphyseal growth plate histomorphometry

    NASA Technical Reports Server (NTRS)

    Montufar-Solis, Dina; Duke, Pauline J.; Durnova, G.

    1992-01-01

    Growth plate histomorphometry of rats flown aboard the Soviet biosatellite Cosmos 2044, a 14-day spaceflight, was compared with that of control groups. In growth plates of flight animals, there was a significant increase in cell number per column and height of the proliferative zone and a reduction in height and cell number in the hypertrophy/calcification zone. No significant differences were found in matrix organization at the ultrastructural level of flight animals, indicating that although spacefligfht continues to affect bone growth of 15-wk-old rats, extracellular matrix is not altered in the same manner as seen previously in younger animals. All groups showed growth plate characteristics attributed to aging: lack of calcification zone, reduced hypertrophy zone, and unraveling of collagen fibrils. Tail-suspended controls did not differ from other controls in any of the parameters measured. The results suggest that growth plates of older rats are less responsive to unloading by spaceflight or suspension than those of younger rats and provide new evidence about the modifying effect of spaceflight on the growth plate.

  19. RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

    PubMed Central

    Alkasalias, Twana; Alexeyenko, Andrey; Hennig, Katharina; Danielsson, Frida; Lebbink, Robert Jan; Fielden, Matthew; Turunen, S. Pauliina; Lehti, Kaisa; Kashuba, Vladimir; Madapura, Harsha S.; Bozoky, Benedek; Lundberg, Emma; Balland, Martial; Guvén, Hayrettin; Klein, George; Gad, Annica K. B.; Pavlova, Tatiana

    2017-01-01

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth. PMID:28174275

  20. RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo.

    PubMed

    Alkasalias, Twana; Alexeyenko, Andrey; Hennig, Katharina; Danielsson, Frida; Lebbink, Robert Jan; Fielden, Matthew; Turunen, S Pauliina; Lehti, Kaisa; Kashuba, Vladimir; Madapura, Harsha S; Bozoky, Benedek; Lundberg, Emma; Balland, Martial; Guvén, Hayrettin; Klein, George; Gad, Annica K B; Pavlova, Tatiana

    2017-02-21

    Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

  1. Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth.

    PubMed

    Tan, Zongqing; Wortman, Matthew; Dillehay, Kelsey L; Seibel, William L; Evelyn, Chris R; Smith, Shanna J; Malkas, Linda H; Zheng, Yi; Lu, Shan; Dong, Zhongyun

    2012-06-01

    Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (K(d)) of ~0.2 to 0.4 μM. PCNA-Is promoted the formation of SDS-refractory PCNA trimers. PCNA-I1 dose- and time-dependently reduced the chromatin-associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC(50) of ~0.2 μM, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC(50), ~1.6 μM). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G(2)/M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.

  2. Inhibition of polyamine oxidase activity affects tumor development during the maize-Ustilago maydis interaction.

    PubMed

    Jasso-Robles, Francisco Ignacio; Jiménez-Bremont, Juan Francisco; Becerra-Flora, Alicia; Juárez-Montiel, Margarita; Gonzalez, María Elisa; Pieckenstain, Fernando Luis; García de la Cruz, Ramón Fernando; Rodríguez-Kessler, Margarita

    2016-05-01

    Ustilago maydis is a biotrophic plant pathogenic fungus that leads to tumor development in the aerial tissues of its host, Zea mays. These tumors are the result of cell hypertrophy and hyperplasia, and are accompanied by the reprograming of primary and secondary metabolism of infected plants. Up to now, little is known regarding key plant actors and their role in tumor development during the interaction with U. maydis. Polyamines are small aliphatic amines that regulate plant growth, development and stress responses. In a previous study, we found substantial increases of polyamine levels in tumors. In the present work, we describe the maize polyamine oxidase (PAO) gene family, its contribution to hydrogen peroxide (H2O2) production and its possible role in tumor development induced by U. maydis. Histochemical analysis revealed that chlorotic lesions and maize tumors induced by U. maydis accumulate H2O2 to significant levels. Maize plants inoculated with U. maydis and treated with the PAO inhibitor 1,8-diaminooctane exhibit a notable reduction of H2O2 accumulation in infected tissues and a significant drop in PAO activity. This treatment also reduced disease symptoms in infected plants. Finally, among six maize PAO genes only the ZmPAO1, which encodes an extracellular enzyme, is up-regulated in tumors. Our data suggest that H2O2 produced through PA catabolism by ZmPAO1 plays an important role in tumor development during the maize-U. maydis interaction.

  3. Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis.

    PubMed

    Liśkiewicz, Arkadiusz D; Kasprowska, Daniela; Wojakowska, Anna; Polański, Krzysztof; Lewin-Kowalik, Joanna; Kotulska, Katarzyna; Jędrzejowska-Szypułka, Halina

    2016-02-19

    Nutritional imbalance underlies many disease processes but can be very beneficial in certain cases; for instance, the antiepileptic action of a high fat and low carbohydrate ketogenic diet. Besides this therapeutic feature it is not clear how this abundant fat supply may affect homeostasis, leading to side effects. A ketogenic diet is used as anti-seizure therapy i.a. in tuberous sclerosis patients, but its impact on concomitant tumor growth is not known. To examine this we have evaluated the growth of renal lesions in Eker rats (Tsc2+/-) subjected to a ketogenic diet for 4, 6 and 8 months. In spite of existing opinions about the anticancer actions of a ketogenic diet, we have shown that this anti-seizure therapy, especially in its long term usage, leads to excessive tumor growth. Prolonged feeding of a ketogenic diet promotes the growth of renal tumors by recruiting ERK1/2 and mTOR which are associated with the accumulation of oleic acid and the overproduction of growth hormone. Simultaneously, we observed that Nrf2, p53 and 8-oxoguanine glycosylase α dependent antitumor mechanisms were launched by the ketogenic diet. However, the pro-cancerous mechanisms finally took the ascendency by boosting tumor growth.

  4. Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis

    PubMed Central

    Liśkiewicz, Arkadiusz D.; Kasprowska, Daniela; Wojakowska, Anna; Polański, Krzysztof; Lewin–Kowalik, Joanna; Kotulska, Katarzyna; Jędrzejowska–Szypułka, Halina

    2016-01-01

    Nutritional imbalance underlies many disease processes but can be very beneficial in certain cases; for instance, the antiepileptic action of a high fat and low carbohydrate ketogenic diet. Besides this therapeutic feature it is not clear how this abundant fat supply may affect homeostasis, leading to side effects. A ketogenic diet is used as anti-seizure therapy i.a. in tuberous sclerosis patients, but its impact on concomitant tumor growth is not known. To examine this we have evaluated the growth of renal lesions in Eker rats (Tsc2+/−) subjected to a ketogenic diet for 4, 6 and 8 months. In spite of existing opinions about the anticancer actions of a ketogenic diet, we have shown that this anti-seizure therapy, especially in its long term usage, leads to excessive tumor growth. Prolonged feeding of a ketogenic diet promotes the growth of renal tumors by recruiting ERK1/2 and mTOR which are associated with the accumulation of oleic acid and the overproduction of growth hormone. Simultaneously, we observed that Nrf2, p53 and 8-oxoguanine glycosylase α dependent antitumor mechanisms were launched by the ketogenic diet. However, the pro-cancerous mechanisms finally took the ascendency by boosting tumor growth. PMID:26892894

  5. Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth

    PubMed Central

    Guido, Carmela; Whitaker-Menezes, Diana; Capparelli, Claudia; Balliet, Renee; Lin, Zhao; Pestell, Richard G.; Howell, Anthony; Aquila, Saveria; Andò, Sebastiano; Martinez-Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P.

    2012-01-01

    We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive TGF-β signaling. However, it remains unknown whether hyperactivation of the TGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. To address these issues, we overexpressed TGF-β ligands and the TGF-β receptor I (TGFβ-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of TGF-β in tumorigenesis is compartment-specific, and that TGF-β promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumor-promoting effects of TGF-β are independent of the cell type generating TGF-β. Thus, stromal-derived TGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that TGF-β-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the TGF-β pathway in cancer cells does not influence tumor growth, but cancer cell-derived-TGF-β ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cell-autonomous activation of the TGF-β pathway in stromal cells induces their metabolic

  6. Preliminary terrestrial based experiments on gravity-affected crystal growth

    NASA Technical Reports Server (NTRS)

    Johnston, M. H.

    1970-01-01

    Tin was melted in a heating assembly secured to the arm of a centrifuge. The furnace was allowed to pivot and reach its equilibrium angle of swing for the gravity force being experienced. The crucible was cooled during rotation to allow the growth of single crystals. The crystals were etched for the purpose of observing the growth striations. Slices were removed from some of the crystals to permit observation of the striations in the interior. Visual analyses were made with a scanning electron microscope. Preliminary conclusions relating the appearance of the striations to gravity forces and the affected growth mechanisms are presented. Further experiments that will verify these conclusions and determine other gravity effects are proposed.

  7. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    SciTech Connect

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  8. Tumor STAT1 transcription factor activity enhances breast tumor growth and immune suppression mediated by myeloid-derived suppressor cells.

    PubMed

    Hix, Laura M; Karavitis, John; Khan, Mohammad W; Shi, Yihui H; Khazaie, Khashayarsha; Zhang, Ming

    2013-04-26

    Previous studies had implicated the IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33(+) myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.

  9. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    SciTech Connect

    Maneckjee, R.; Minna, J.D. Uniformed Services Univ. of the Health Sciences, Bethesda, MD )

    1990-05-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for {mu}, {delta}, and {kappa} opioid agonists and for nicotine and {alpha}-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas {mu}, {delta}, and {kappa} opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides ({beta}-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer.

  10. Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

    PubMed

    Fendrich, V; Lopez, C L; Manoharan, J; Maschuw, K; Wichmann, S; Baier, A; Holler, J P; Ramaswamy, A; Bartsch, D K; Waldmann, J

    2014-10-01

    Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

  11. Enhancing chemotherapeutic drug inhibition on tumor growth by ultrasound: an in vivo experiment.

    PubMed

    Zhao, Ying-Zheng; Lu, Cui-Tao; Zhou, Zhi-Cai; Jin, Zhuo; Zhang, Lu; Sun, Chang-Zheng; Xu, Yan-Yan; Gao, Hui-Sheng; Tian, Ji-Lai; Gao, Feng-Hou; Tang, Qin-Qin; Li, Wei; Xiang, Qi; Li, Xiao-Kun; Li, Wen-Feng

    2011-02-01

    An in vivo study on enhancing epirubicin hydrochloride (EPI) inhibition on tumor growth by ultrasound (US) was reported. Five-week-old male nude mice were used and HL-60 cells were s.c. (subcutaneous injection) inoculated in axilla of these mice. Six groups were designed and five consecutive treatments were applied to investigate the inhibition on tumor growth and body weight growth. US applied locally to the tumor resulted in a substantially increased drug uptake in tumor cells. The inhibition on tumor growth depended on the position of drug injection and phospholipid-based microbubble (PMB) application. Tumor growth rate under group 1 (PMB+US) was similar to that of blank control. The order of the inhibition on tumor volume growth was: group 4 (s.c. EPI+PMB+US) > group 5 intraperitoneal (i.p. EPI+PMB+US) > group 2 (i.p. EPI) > group 3 (s.c. EPI+US) > group 1 (PMB+US). Similar conclusion was obtained from experimental measurements of tumor weight change. The order of animal survival status for EPI administration groups was: group 4 > group 5 > group 2 > group 3. Chemotherapeutic drug inhibition on tumor growth could be enhanced by local US combined with PMB, which might provide a potential application for US-mediated chemotherapy.

  12. Factors affecting growth of foodborne pathogens on minimally processed apples.

    PubMed

    Alegre, Isabel; Abadias, Maribel; Anguera, Marina; Oliveira, Marcia; Viñas, Inmaculada

    2010-02-01

    Escherichia coli O157:H7, Salmonella and Listeria innocua increased by more than 2 log(10) units over a 24 h period on fresh-cut 'Golden Delicious' apple plugs stored at 25 and 20 degrees C. L. innocua reached the same final population level at 10 degrees C meanwhile E. coli and Salmonella only increased 1.3 log(10) units after 6 days. Only L. innocua was able to grow at 5 degrees C. No significant differences were observed between the growth of foodborne pathogens on fresh-cut 'Golden Delicious', 'Granny Smith' and 'Shampion' apples stored at 25 and 5 degrees C. The treatment of 'Golden Delicious' and 'Granny Smith' apple plugs with the antioxidants, ascorbic acid (2%) and NatureSeal (6%), did not affect pathogen growth. The effect of passive modified atmosphere packaging (MAP) on the growth of E. coli, Salmonella and L. innocua on 'Golden Delicious' apple slices was also tested. There were no significant differences in growth of pathogens in MAP conditions compared with air packaging of 'Golden Delicious' apple plugs, but the growth of mesophilic and psychrotrophic microorganisms was inhibited. These results highlight the importance of avoiding contamination of fresh-cut fruit with foodborne pathogens and the maintenance of the cold chain during storage until consumption.

  13. Assessment of antitumor activity for tumor xenograft studies using exponential growth models.

    PubMed

    Wu, Jianrong

    2011-05-01

    In preclinical tumor xenograft experiments, the antitumor activity of the tested agents is often assessed by endpoints such as tumor doubling time, tumor growth delay (TGD), and log10 cell kill (LCK). In tumor xenograft literature, the values of these endpoints are presented without any statistical inference, which ignores the noise in the experimental data. However, using exponential growth models, these endpoints can be quantified by their growth curve parameters, thus allowing parametric inference, such as an interval estimate, to be used to assess the antitumor activity of the treatment.

  14. Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

    PubMed

    Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

    2016-08-01

    Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

  15. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.

    PubMed

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D; Shetake, Neena; Balla, Murali M S; Kumar, Amit; Ray, Pritha; Ghosh, Anu; Pandey, B N

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  16. Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model

    PubMed Central

    Desai, Sejal; Srambikkal, Nishad; Yadav, Hansa D.; Shetake, Neena; Balla, Murali M. S.; Kumar, Amit; Ray, Pritha; Ghosh, Anu

    2016-01-01

    Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about

  17. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

    PubMed Central

    Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L.; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.

    2016-01-01

    Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

  18. 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.

  19. Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis.

    PubMed

    Nokin, Marie-Julie; Durieux, Florence; Peixoto, Paul; Chiavarina, Barbara; Peulen, Olivier; Blomme, Arnaud; Turtoi, Andrei; Costanza, Brunella; Smargiasso, Nicolas; Baiwir, Dominique; Scheijen, Jean L; Schalkwijk, Casper G; Leenders, Justine; De Tullio, Pascal; Bianchi, Elettra; Thiry, Marc; Uchida, Koji; Spiegel, David A; Cochrane, James R; Hutton, Craig A; De Pauw, Edwin; Delvenne, Philippe; Belpomme, Dominique; Castronovo, Vincent; Bellahcène, Akeila

    2016-10-19

    Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.

  20. A discrimination index for selecting markers of tumor growth dynamic across multiple cancer studies with a cure fraction.

    PubMed

    Rouam, Sigrid; Broët, Philippe

    2013-08-01

    To identify genomic markers with consistent effect on tumor dynamics across multiple cancer series, discrimination indices based on proportional hazards models can be used since they do not depend heavily on the sample size. However, the underlying assumption of proportionality of the hazards does not always hold, especially when the studied population is a mixture of cured and uncured patients, like in early-stage cancers. We propose a novel index that quantifies the capability of a genomic marker to separate uncured patients, according to their time-to-event outcomes. It allows to identify genomic markers characterizing tumor growth dynamic across multiple studies. Simulation results show that our index performs better than classical indices based on the Cox model. It is neither affected by the sample size nor the cure rate fraction. In a cross-study of early-stage breast cancers, the index allows to select genomic markers with a potential consistent effect on tumor growth dynamics.

  1. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis.

    PubMed

    Roy, Debasmita; Sin, Sang-Hoon; Lucas, Amy; Venkataramanan, Raman; Wang, Ling; Eason, Anthony; Chavakula, Veenadhari; Hilton, Isaac B; Tamburro, Kristen M; Damania, Blossom; Dittmer, Dirk P

    2013-04-01

    Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.

  2. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

    PubMed Central

    2013-01-01

    Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage

  3. IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma.

    PubMed

    Ma, Shoubao; Cheng, Qiao; Cai, Yifeng; Gong, Huanle; Wu, Yan; Yu, Xiao; Shi, Liyun; Wu, Depei; Dong, Chen; Liu, Haiyan

    2014-04-01

    Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8(+) T-cell responses. Furthermore, we found that IL-17A was produced mainly by Vγ4 γδ T cells, insofar as depleting Vγ4 γδ T cells reduced tumor growth, whereas adoptive transfer of Vγ4 γδ T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing γδ T cells via production of IL-1β and IL-23. Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among γδ T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy.

  4. Pituitary Tumors

    MedlinePlus

    ... pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body. Pituitary tumors are common, but often they don't cause health ... tumor produces hormones and disrupts the balance of hormones in your ...

  5. How managed care growth affects where physicians locate their practices.

    PubMed

    Polsky, D; Escarce, J J

    2000-11-01

    Managed care has had a profound effect on physician practice. It has altered patterns in the use of physician services, and consequently, the practice and employment options available to physicians. But managed care growth has not been uniform across the United States, and has spawned wide geographic disparities in earning opportunities for generalists and specialists. This Issue Brief summarizes new information on how managed care has affected physicians' labor market decisions and the impact of managed care on the number and distribution of physicians across the country.

  6. miR-21 coordinates tumor growth and modulates KRIT1 levels.

    PubMed

    Orso, Francesca; Balzac, Fiorella; Marino, Marco; Lembo, Antonio; Retta, Saverio Francesco; Taverna, Daniela

    2013-08-16

    miR-21 is overexpressed in tumors and it displays oncogenic activity. Here, we show that expression of miR-21 in primary tumors anticorrelates with KRIT1/CCM1, an interacting partner of the Ras-like GTPase Rap1, involved in Cerebral Cavernous Malformations (CCM). We present evidences that miR-21 silences KRIT1 by targeting its mRNA 3'UTR and that this interaction is involved in tumor growth control. In fact, miR-21 over-expression or KRIT1 knock-down promote anchorage independent tumor cell growth compared to controls, whereas the opposite is observed when anti-miR-21 or KRIT1 overexpression are employed. Our findings suggest that miR-21 promotes tumor cell growth, at least in part, by down-modulating the potential tumor suppressor KRIT1.

  7. miR-21 coordinates tumor growth and modulates KRIT1 levels

    PubMed Central

    Orso, Francesca; Balzac, Fiorella; Marino, Marco; Lembo, Antonio; Retta, Saverio Francesco; Taverna, Daniela

    2013-01-01

    miR-21 is overexpressed in tumors and it displays oncogenic activity. Here, we show that expression of miR-21 in primary tumors anticorrelates with KRIT1/CCM1, an interacting partner of the Ras-like GTPase Rap1, involved in Cerebral Cavernous Malformations (CCM). We present evidences that miR-21 silences KRIT1 by targeting its mRNA 3′UTR and that this interaction is involved in tumor growth control. In fact, miR-21 over-expression or KRIT1 knock-down promote anchorage independent tumor cell growth compared to controls, whereas the opposite is observed when anti-miR-21 or KRIT1 overexpression are employed. Our findings suggest that miR-21 promotes tumor cell growth, at least in part, by down-modulating the potential tumor suppressor KRIT1. PMID:23872064

  8. Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors

    PubMed Central

    Jiménez-Triana, Clímaco Andres; Castelán-Martínez, Osvaldo D.; Rivas-Ruiz, Rodolfo; Jiménez-Méndez, Ricardo; Medina, Aurora; Clark, Patricia; Rassekh, Rod; Castañeda-Hernández, Gilberto; Carleton, Bruce; Medeiros, Mara

    2015-01-01

    Abstract Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight. We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4). Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07–24.3, P = 0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r = −0.527, P = <0.001). PMID:26313789

  9. [Autowaves in a model of growth of an invasive tumor].

    PubMed

    Kolobov, A V; Gubernov, V V; Polezhaev, A A

    2009-01-01

    A mathematical model for the invasive tumour growth has been constructed, which takes cell division, death, and motility into account. The model includes local cell density and the distribution of nutrient (oxygen) concentration. Cancer cells die in the absence of nutrients; therefore, the distribution of oxygen in tissue substantially affects both the tumour proliferation rate and structure. The model adequately describes the experimentally measured rate of tumour proliferation. The existence of autowave solutions has been demonstrated, and their properties have been investigated. The results are compared with the properties of the Kolmogorov-Petrovskii-Piskunov and Fisher equations. It is shown that the nutrient distribution influences the speed selection and the convergence of the initial conditions to the automodel solution.

  10. Zoledronic acid reduces bone loss and tumor growth in an orthotopic xenograft model of osteolytic oral squamous cell carcinoma

    PubMed Central

    Martin, Chelsea K; Werbeck, Jillian L.; Thudi, Nanda K.; Lanigan, Lisa G.; Wolfe, Tobie D.; Toribio, Ramiro E.; Rosol, Thomas J.

    2010-01-01

    Squamous cell carcinoma is the most common form of oral cancer. Destruction and invasion of mandibular and maxillary bone frequently occurs and contributes to morbidity and mortalilty. We hypothesized that the bisphosphonate drug zoledronic acid (ZOL) would inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a murine xenograft model of bone-invasive oral squamous cell carcinoma (OSCC) derived from an osteolytic feline OSCC. Luciferase-expressing OSCC cells (SCCF2Luc) were injected into the perimaxillary subgingiva of nude mice which were then treated with 100 μg/kg ZOL or vehicle. ZOL treatment reduced tumor growth and prevented loss of bone volume and surface area, but had no effect on tumor invasion. Effects on bone were associated with reduced osteolysis and increased periosteal new bone formation. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by reduced numbers of tartrate-resistant acid phosphatase-positive osteoclasts at the tumor-bone interface, where it was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not affected by treatment, arguing that ZOL-mediated inhibition of osteolysis was independent of effects on osteoclast activation or initiation of bone resorption. In summary, our results establish that ZOL can reduce OSCC-induced osteolysis and my be valuable as an adjuvant therapy in OSCC to preserve mandibular and maxillary bone volume and function. PMID:20959474

  11. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Casey, Trimmer; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G; Sotgia, Federica; Lisanti, Michael P

    2010-11-01

    The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an

  12. Growth, nitrogen uptake and flow in maize plants affected by root growth restriction.

    PubMed

    Xu, Liangzheng; Niu, Junfang; Li, Chunjian; Zhang, Fusuo

    2009-07-01

    The objective of the present study was to investigate the influence of a reduced maize root-system size on root growth and nitrogen (N) uptake and flow within plants. Restriction of shoot-borne root growth caused a strong decrease in the absorption of root: shoot dry weight ratio and a reduction in shoot growth. On the other hand, compensatory growth and an increased N uptake rate in the remaining roots were observed. Despite the limited long-distance transport pathway in the mesocotyl with restriction of shoot-borne root growth, N cycling within these plants was higher than those in control plants, implying that xylem and phloem flow velocities via the mesocotyl were considerably higher than in plants with an intact root system. The removal of the seminal roots in addition to restricting shoot-borne root development did not affect whole plant growth and N uptake, except for the stronger compensatory growth of the primary roots. Our results suggest that an adequate N supply to maize plant is maintained by compensatory growth of the remaining roots, increased N uptake rate and flow velocities within the xylem and phloem via the mesocotyl, and reduction in the shoot growth rate.

  13. Expectant management of vestibular schwannoma: a retrospective multivariate analysis of tumor growth and outcome.

    PubMed

    Hughes, Mark; Skilbeck, Christopher; Saeed, Shakeel; Bradford, Robert

    2011-09-01

    We conducted a retrospective observational study to assess the consequences of conservative management of vestibular schwannoma (VS). Data were collected from tertiary neuro-otological referral units in United Kingdom. The study included 59 patients who were managed conservatively with radiological diagnosis of VS. The main outcome measures were growth rate and rate of failure of conservative management. Multivariate analysis sought correlation between tumor growth and (i) demographic features, (ii) tumor characteristics. The mean tumor growth was 0.66 mm/y. 11 patients (19%) required intervention. Mean time to intervention was 37 months with two notable late "failures" occurring at 75 and 84 months. Tumors extending into the cerebellopontine angle (CPA) grew significantly faster than intracanalicular tumors (p = 0.0045). No association was found between growth rate and age, sex, tumor laterality, facial nerve function, and grade of hearing loss. Conservative management is acceptable for a subset of patients. Tumors extending into the CPA at diagnosis grow significantly faster than intracanalicular tumors. No growth within 5 years of surveillance does not guarantee a continued indolent growth pattern; surveillance must therefore continue.

  14. Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment.

    PubMed

    Zhang, M; Yan, L; Kim, J A

    2015-10-01

    Macrophage migration inhibitory factor (MIF) has been identified as a major gene product upregulated in breast cancer cells-tissues upon the accumulation of macrophages. However, regulatory role of MIF in tumor microenvironment is not well understood. Previously, we have developed small interfering RNA (siRNA)-loaded nanoparticle system to effectively reduce MIF expression in both breast cancer cells and macrophages. Using this nanoparticle system, in this study we demonstrated that the siRNA-induced MIF reduction in murine mammary cancer line 4T1 and human breast cancer line MDA-MB-231 resulted in significant reduction of cell proliferation and increase of apoptosis; the siRNA-induced MIF reduction in tumor-associated macrophages resulted in a significant reduction of surface expression of CD74 and CD206 and a significant increase of surface expression of major histocompatibility complex II, as well as intracellular expression of tumor necrosis factor-α and interleukin-2. A direct injection of the MIF-siRNA-loaded nanoparticles into 4T1 tumor in mice resulted in effective reduction of intratumoral MIF. This led to a reduction of tumor growth and metastasis. This also resulted in a reduction of circulating myeloid-derived suppressive cells both in number and in suppressive function. CD4 T-cell infiltration to tumor was increased. More importantly, this not only slowed the growth of treated 4T1 tumor, but also delayed the growth and metastasis of a contralateral untreated 4T1-luc tumor, suggesting the development of systemic antitumor responses. This study demonstrates for the first time that the siRNA-mediated intratumoral MIF reduction can induce antitumoral immune response via reducing systemic immune suppression.

  15. Halofuginone inhibits angiogenesis and growth in implanted metastatic rat brain tumor model--an MRI study.

    PubMed

    Abramovitch, Rinat; Itzik, Anna; Harel, Hila; Nagler, Arnon; Vlodavsky, Israel; Siegal, Tali

    2004-01-01

    Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF) is a potent inhibitor of collagen type alpha1(I). In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI), we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001). Treatment with HF significantly prolonged survival of treated animals (142%; P = .001). In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05). Additionally, HF treatment inhibited vessel maturation (P = .03). Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

  16. Lichen secondary metabolites affect growth of Physcomitrella patens by allelopathy.

    PubMed

    Goga, Michal; Antreich, Sebastian J; Bačkor, Martin; Weckwerth, Wolfram; Lang, Ingeborg

    2016-09-19

    Lichen secondary metabolites can function as allelochemicals and affect the development and growth of neighboring bryophytes, fungi, vascular plants, microorganisms, and even other lichens. Lichen overgrowth on bryophytes is frequently observed in nature even though mosses grow faster than lichens, but there is still little information on the interactions between lichens and bryophytes.In the present study, we used extracts from six lichen thalli containing secondary metabolites like usnic acid, protocetraric acid, atranorin, lecanoric acid, nortistic acid, and thamnolic acid. To observe the influence of these metabolites on bryophytes, the moss Physcomitrella patens was cultivated for 5 weeks under laboratory conditions and treated with lichen extracts. Toxicity of natural mixtures of secondary metabolites was tested at three selected doses (0.001, 0.01, and 0.1 %). When the mixture contained substantial amounts of usnic acid, we observed growth inhibition of protonemata and reduced development of gametophores. Significant differences in cell lengths and widths were also noticed. Furthermore, usnic acid had a strong effect on cell division in protonemata suggesting a strong impact on the early stages of bryophyte development by allelochemicals contained in the lichen secondary metabolites.Biological activities of lichen secondary metabolites were confirmed in several studies such as antiviral, antibacterial, antitumor, antiherbivore, antioxidant, antipyretic, and analgetic action or photoprotection. This work aimed to expand the knowledge on allelopathic effects on bryophyte growth.

  17. Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model

    PubMed Central

    2014-01-01

    Background Osteosarcomas are the most common primary malignant tumors of bone, showing complex chromosomal rearrangements with multiple gains and losses. A frequent deletion within the chromosomal region 3q13.31 has been identified by us and others, and is mainly reported to be present in osteosarcomas. The purpose of the study was to further characterize the frequency and the extent of the deletion in an extended panel of osteosarcoma samples, and the expression level of the affected genes within the region. We have identified LSAMP as the target gene for the deletion, and have studied the functional implications of LSAMP-reexpression. Methods LSAMP copy number, expression level and protein level were investigated by quantitative PCR and western blotting in an osteosarcoma panel. The expression of LSAMP was restored in an osteosarcoma cell line, and differences in proliferation rate, tumor formation, gene expression, migration rate, differentiation capabilities, cell cycle distribution and apoptosis were investigated by metabolic dyes, tumor formation in vivo, gene expression profiling, time-lapse photography, differentiation techniques and flow cytometry, respectively. Results We found reduced copy number of LSAMP in 45/76 osteosarcoma samples, reduced expression level in 25/42 samples and protein expression in 9/42 samples. By restoring the expression of LSAMP in a cell line with a homozygous deletion of the gene, the proliferation rate in vitro was significantly reduced and tumor growth in vivo was significantly delayed. In response to reexpression of LSAMP, mRNA expression profiling revealed consistent upregulation of the genes hairy and enhancer of split 1 (HES1), cancer/testis antigen 2 (CTAG2) and kruppel-like factor 10 (KLF10). Conclusions The high frequency and the specificity of the deletion indicate that it is important for the development of osteosarcomas. The deletion targets the tumor suppressor LSAMP, and based on the functional evidence, the tumor

  18. Pericyte–fibroblast transition promotes tumor growth and metastasis

    PubMed Central

    Hosaka, Kayoko; Yang, Yunlong; Seki, Takahiro; Fischer, Carina; Dubey, Olivier; Fredlund, Erik; Hartman, Johan; Religa, Piotr; Ishii, Yoko; Sasahara, Masakiyo; Larsson, Ola; Cossu, Giulio; Cao, Renhai; Lim, Sharon; Cao, Yihai

    2016-01-01

    Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte–fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB–activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB–induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB–promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis. PMID:27608497

  19. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis

    PubMed Central

    Lim, Sharon; Hosaka, Kayoko; Nakamura, Masaki; Cao, Yihai

    2016-01-01

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth. PMID:27203675

  20. A tumor cell growth inhibitor from Saposhnikovae divaricata.

    PubMed

    Kuo, Yuh-Chi; Lin, Yun-Lian; Huang, Cheng-Po; Shu, Jia-Wei; Tsai, Wei-Jern

    2002-01-01

    In the present study, we tested ethanolic extracts from 10 Chinese herbs for their effects on K562, Raji, Wish, HeLa, Calu-1, and Vero tumor cells proliferation. On a percentage basis, panaxynol purified from Saposhnikovae divaricata had the highest inhibitory activity on various tumor cells proliferation. Cell-cycle analysis indicated that panaxynol arrested the cell cycle progression of tumor cells from the G1 transition to the S phase. In an attempt to further localize the point in the cell cycle where arrest occurred, gene expression of cyclin E, a key regulatory event leading to the G1/S boundary was examined. Results indicated that the levels of cyclin E mRNA in various tumor cells were decreased by panaxynol. Thus, the suppressant effects of panaxynol on proliferation of various tumor cells appeared to be mediated, at least in part, through impairments of cyclin E mRNA levels and arresting cell cycle progression in the cells.

  1. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy12

    PubMed Central

    Baker, Gregory J.; Yadav, Viveka Nand; Motsch, Sebastien; Koschmann, Carl; Calinescu, Anda-Alexandra; Mineharu, Yohei; Camelo-Piragua, Sandra Ines; Orringer, Daniel; Bannykh, Serguei; Nichols, Wesley S.; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2014-01-01

    As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. PMID:25117977

  2. Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

    PubMed Central

    Zhao, Zhizheng; Fan, Huiting; Higgins, Tim; Qi, Jia; Haines, Diana; Trivett, Anna; Oppenheim, Joost J.; Wei, Hou; Li, Jie; Lin, Hongsheng; Howard, O.M. Zack

    2014-01-01

    Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and antiinflammatory drugs provide first line treatment for cancer pain, but both are limited by side effects. Fufang Kushen injection (FKI) is GMP produced, traditional Chinese medicine used alone or with chemotherapy to reduce cancer-associated pain. FKI limited mouse sarcoma growth both in vivo and in vitro, in part, by reducing the phosphorylation of ERK and AKT kinases and BAD. FKI inhibited TRPV1 mediated capsaicin-induced ERK phosphorylation and reduced tumor-induced proinflammatory cytokine production. Thus, FKI limited cancer pain both directly by blocking TRPV1 signaling and indirectly by reducing tumor growth. PMID:25242356

  3. Inhibition of melanocortin 1 receptor slows melanoma growth, reduces tumor heterogeneity and increases survival

    PubMed Central

    Kansal, Rita G.; McCravy, Matthew S.; Basham, Jacob H.; Earl, Joshua A.; McMurray, Stacy L.; Starner, Chelsey J.

    2016-01-01

    Melanoma risk is increased in patients with mutations of melanocortin 1 receptor (MC1R) yet the basis for the increased risk remains unknown. Here we report in vivo evidence supporting a critical role for MC1R in regulating melanoma tumor growth and determining overall survival time. Inhibition of MC1R by its physiologically relevant competitive inhibitor, agouti signaling protein (ASIP), reduced melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. In the lungs of syngeneic C57BL/6 mice, mCherry-marked, ASIP-secreting lung tumors inhibited MC1R on neighboring tumors lacking ASIP in a dose dependent manner as evidenced by a proportional loss of pigment in tumors from mice injected with 1:1, 3:1 and 4:1 mixtures of parental B16-F10 to ASIP-expressing tumor cells. ASIP-expressing B16-F10 cells formed poorly pigmented tumors in vivo that correlated with a 20% longer median survival than those bearing parental B16-F10 tumors (p=0.0005). Mice injected with 1:1 mixtures also showed survival benefit (p=0.0054), whereas injection of a 4:1 mixture showed no significant difference in survival. The longer survival time of mice bearing ASIP-expressing tumors correlated with a significantly slower growth rate than parental B16-F10 tumors as judged by quantification of numbers of tumors and total tumor load (p=0.0325), as well as a more homogeneous size and morphology of ASIP-expressing lung tumors. We conclude that MC1R plays an important role in regulating melanoma growth and morphology. Persistent inhibition of MC1R provided a significant survival advantage resulting in part from slower tumor growth, establishing MC1R as a compelling new molecular target for metastatic melanoma. PMID:27028866

  4. Effects of tumor growth on interleukins and circulating immune complexes. Mechanisms of immune unresponsiveness.

    PubMed

    Ravikumar, T; Steele, G; Rodrick, M; Ross, D; Wilson, R; Lahey, S; Wright, D; Munroe, A; King, V

    1984-03-15

    This study delineates the temporal relationship between immune complex formation and tumor growth, and provides one possible explanation for host immunosuppression during tumor growth. The authors have studied serial circulating immune complex (CIC) levels and interleukin (IL) elaboration by peripheral blood cells (IL-1 production by adherent mononuclear cells [AMC]; and IL-2 generation by peripheral blood mononuclear cells [PBMC]) during the growth of syngeneic tumor isografts in an inbred rat model. Male Wistar/Furth (W/Fu) rats were injected, subcutaneously (SC) with 2 X 10(6) W163 ( a dimethylhydrazine [DMH]-induced colon adenocarcinoma) cells into their hind limbs. Serial CIC levels, (measured by the antigen nonspecific polyethylene glycol turbidity assay) and IL-1 and IL-2 production were measured before isografting and weekly thereafter. Progressive local tumor growth occurred for 3 weeks followed by regional lymph node metastases during the fourth week. During local tumor growth, there was a progressive rise in CIC levels (123% rise compared with baseline value; P less than 0.05) which correlated with a fall in both IL-1 and IL-2 generation (r = -0.768). At the time of regional metastasis, the mean CIC levels declined, and there was a further significant decrease in IL production (IL-1 = 0.9% and IL-2 = 10% of controls in tumor bearers). These results show that progressive tumor growth results in decreased IL production by host PBC, and suggest that CIC may be involved in regulating IL generation.

  5. Endothelial cell tumor growth is Ape/ref-1 dependent

    PubMed Central

    Biswas, Ayan; Khanna, Savita; Roy, Sashwati; Pan, Xueliang; Sen, Chandan K.

    2015-01-01

    Tumor-forming endothelial cells have highly elevated levels of Nox-4 that release H2O2 into the nucleus, which is generally not compatible with cell survival. We sought to identify compensatory mechanisms that enable tumor-forming endothelial cells to survive and proliferate under these conditions. Ape-1/ref-1 (Apex-1) is a multifunctional protein that promotes DNA binding of redox-sensitive transcription factors, such as AP-1, and repairs oxidative DNA damage. A validated mouse endothelial cell (EOMA) tumor model was used to demonstrate that Nox-4-derived H2O2 causes DNA oxidation that induces Apex-1 expression. Apex-1 functions as a chaperone to keep transcription factors in a reduced state. In EOMA cells Apex-1 enables AP-1 binding to the monocyte chemoattractant protein-1 (mcp-1) promoter and expression of that protein is required for endothelial cell tumor formation. Intraperitoneal injection of the small molecule inhibitor E3330, which specifically targets Apex-1 redox-sensitive functions, resulted in a 50% decrease in tumor volume compared with mice injected with vehicle control (n = 6 per group), indicating that endothelial cell tumor proliferation is dependent on Apex-1 expression. These are the first reported results to establish Nox-4 induction of Apex-1 as a mechanism promoting endothelial cell tumor formation. PMID:26108661

  6. Downregulation of ZEB2-AS1 decreased tumor growth and metastasis in hepatocellular carcinoma

    PubMed Central

    Lan, Tian; Chang, Lei; Wu, Long; Yuan, Yufeng

    2016-01-01

    Hepatocellular carcinoma (HCC) remains one of the most common types of cancer worldwide and prognosis remains poor. Previous studies have suggested that long non-coding RNAs (lncRNAs) may be key regulators of tumor development and progression in HCC. It has been determined that 61–72% of transcribed regions contain lncRNAs in the antisense orientation (aslncRNAs). However, the function of aslncRNAs in HCC remains to be elucidated. The present study investigated the function of the aslncRNA zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1) in 40 HCC tissues and 5 different human HCC cell lines using reverse transcription-quantitative polymerase chain reaction. Additionally, the expression levels of ZEB2-AS1 were downregulated by transfection of small interfering RNAs (siRNAs) to determine whether ZEB2-AS1 is capable of affecting cell proliferation, invasion and metastasis by regulating ZEB2, vimentin, fibronectin, E-cadherin and N-cadherin expression levels. The results of the present study demonstrated that the expression levels of ZEB2-AS1 were greater in HCC tissues when compared with the adjacent normal tissues. Furthermore, ZEB2-AS1 expression was significantly associated with the size of the primary tumor, intrahepatic metastasis and tumor-node-metastasis stage. The Kaplan-Meier survival curves suggested that patients with high ZEB2-AS1 expression levels experienced the lowest overall and recurrence-free survival rates compared with those that had low expression levels. In addition, the current study demonstrated that the downregulation of ZEB2-AS1 was associated with decreased tumor growth and metastasis in HCC by the regulation of the expression levels of epithelial mesenchymal transition-induced markers. In conclusion, lncRNA ZEB2-AS1 may be used as a valuable biomarker in patients with HCC. PMID:27748842

  7. Tumor growth model for atlas based registration of pathological brain MR images

    NASA Astrophysics Data System (ADS)

    Moualhi, Wafa; Ezzeddine, Zagrouba

    2015-02-01

    The motivation of this work is to register a tumor brain magnetic resonance (MR) image with a normal brain atlas. A normal brain atlas is deformed in order to take account of the presence of a large space occupying tumor. The method use a priori model of tumor growth assuming that the tumor grows in a radial way from a starting point. First, an affine transformation is used in order to bring the patient image and the brain atlas in a global correspondence. Second, the seeding of a synthetic tumor into the brain atlas provides a template for the lesion. Finally, the seeded atlas is deformed combining a method derived from optical flow principles and a model for tumor growth (MTG). Results show that an automatic segmentation method of brain structures in the presence of large deformation can be provided.

  8. Rescued expression of WIF-1 in gallbladder cancer inhibits tumor growth and induces tumor cell apoptosis with altered expression of proteins

    PubMed Central

    Huang, Yan; Du, Qiang; Wu, Weibao; She, Feifei; Chen, Yanling

    2016-01-01

    As a highly conserved metabolic pathway, the Wnt signaling pathway is involved in cell differentiation, proliferation and several other processes. In normal cells, this pathway is suppressed, and abnormal activation is often associated with tumor occurrence and development. In certain types of tumor, Wnt inhibitory factor 1 (WIF-1), an inhibitor of the Wnt pathway, inhibits tumor growth. However, the effect of the expression of WIF-1 on gallbladder cancer remains to be fully elucidated. In the current study, reverse transcription-quantitative polymerase chain reaction and western blotting were conducted. The present study demonstrated that, in gallbladder cancer, WIF-1 generally exhibited low levels of expression as a result of gene promoter methylation. Treatment with the drug, 5-aza-2-deoxycytidine, increased the expression of WIF-1 in the GBC-SD gallbladder cell line. In addition, a WIF-1-expression plasmid was transfected into GBC-SD cells, and it was found that cell proliferation, invasion and metastasis declined significantly, whereas the apoptotic rate increased. A nude mouse tumor transplantation experiment showed that the oncogenicity of the GBC-SD cells expressing WIF-1 was substantially lower, compared with that of the untransfected GBC-SD cells and of GBD-SD cells expressing the control plasmid. A fluorescent protein chip experiment showed that the restored expression of WIF-1 affected the expression of several cellular proteins. These alterations may explain the different biological behavior of the tumor cells expressing WIF-1. As an effective inhibitory factor of the Wnt signaling pathway, WIF-1 modulated the expression of proteins controlling the proliferation, apoptosis and metastasis of gallbladder tumor cells, thus suppressing the tumor. Therefore, WIF-1 may be an effective treatment target for gallbladder cancer. PMID:27430608

  9. Modification of an apparatus for tumor-suppressor protein crystal growth in the International Space Station

    NASA Astrophysics Data System (ADS)

    de Morais Mendonca Teles, Antonio

    Some human diseases as tumors are being studied continuously for the development of vaccines against them. And a way of doing that is by means of proteins research. There are some kinds of proteins, like the p53 and p73 proteins, which are tumor suppressors. There are other diseases such as A.I.D.S., hansenosis, the Parkinson's and Chagas' diseases which are protein-related. The determination of how proteins geometrically order themselves, during its biological functions is very necessary to understand how a protein's structure affects its function, to design vaccines that intercede in tumor-protein activities and in other proteins related to those other diseases. The protein crystal growth in microgravity environment produces purer crystallization than on the ground, and it is a powerful tool to produce better vaccines. Several data have already been acquired using ground-based research and in spaceflight experiments aboard the Spacelab and Space Shuttle missions, and in the MIR and in the International Space Station (ISS). Here in this paper, I propose to be performed in the ISS Biological Research Facility (which is being developed), multiple crystal growth of proteins related to cancer (as tumors suppressors and oncoproteins), A.I.D.S., hansenosis, the Parkinson's and Chagas' diseases, for the future obtaining of possible vaccines against them. I also propose a simple and practical equipment, a modification of the crystallization plates (which use a vapor diffusion technique) inside each cylinder of the Protein Crystallization Apparatus in Microgravity (PCAM), with multiple chambers with different sizes. Instead of using some chambers with the same size it is better to use several chambers with different sizes. Why is that? The answer is: the energy associated with the surface tension of the liquid in the chamber is directly related to the circle area of it. So, to minimize the total energy of the surface tension of a proteins liquid -making it more stable

  10. Modeling tumor growth in the presence of a therapy with an effect on rate growth and variability by means of a modified Gompertz diffusion process.

    PubMed

    Román-Román, Patricia; Román-Román, Sergio; Serrano-Pérez, Juan José; Torres-Ruiz, Francisco

    2016-10-21

    In experimental studies on tumor growth, whenever the time evolution of the relative volume of a tumor in an untreated (control) group can be fitted by a Gompertz diffusion process there is a possibility that an antiproliferative therapy, which modifies the growth rate of the process that fits the treated group, may also affect its variability. The present paper proposes several procedures for the estimation of the time function included in the infinitesimal variance of the new process, as well as the time function affecting the growth rate (which is included in the infinitesimal mean). Also, a hypothesis testing is designed to confirm or refute the need for including such a time-dependent function in the infinitesimal variance. In order to validate and compare the proposed procedures a simulation study has been carried out. In addition, a proposal is made for a strategy aimed at finding the optimal combination of procedures for each case. A real data application concerning the effects of cisplatin on a patient-derived xenograft (PDX) tumor model showcases the advantages of this model over others that have been used in the past.

  11. Do plastic particles affect microalgal photosynthesis and growth?

    PubMed

    Sjollema, Sascha B; Redondo-Hasselerharm, Paula; Leslie, Heather A; Kraak, Michiel H S; Vethaak, A Dick

    2016-01-01

    The unbridled increase in plastic pollution of the world's oceans raises concerns about potential effects these materials may have on microalgae, which are primary producers at the basis of the food chain and a major global source of oxygen. Our current understanding about the potential modes and mechanisms of toxic action that plastic particles exert on microalgae is extremely limited. How effects might vary with particle size and the physico-chemical properties of the specific plastic material in question are equally unelucidated, but may hold clues to how toxicity, if observed, is exerted. In this study we selected polystyrene particles, both negatively charged and uncharged, and three different sizes (0.05, 0.5 and 6μm) for testing the effects of size and material properties. Microalgae were exposed to different polystyrene particle sizes and surface charges for 72h. Effects on microalgal photosynthesis and growth were determined by pulse amplitude modulation fluorometry and flow cytometry, respectively. None of the treatments tested in these experiments had an effect on microalgal photosynthesis. Microalgal growth was negatively affected (up to 45%) by uncharged polystyrene particles, but only at high concentrations (250mg/L). Additionally, these adverse effects were demonstrated to increase with decreasing particle size.

  12. Effects of Acanthus ebracteatus Vahl on tumor angiogenesis and on tumor growth in nude mice implanted with cervical cancer

    PubMed Central

    Mahasiripanth, Taksanee; Hokputsa, Sanya; Niruthisard, Somchai; Bhattarakosol, Parvapan; Patumraj, Suthiluk

    2012-01-01

    Purpose The aim of this study was to examine the effects of the crude extract of Acanthus ebracteatus Vahl (AE) on tumor growth and angiogenesis by utilizing a tumor model in which nude mice were implanted with cervical cancer cells containing human papillomavirus 16 DNA (HPV-16 DNA). Materials and methods The growth-inhibitory effect of AE was investigated in four different cell types: CaSki (HPV-16 positive), HeLa (HPV-18 positive), hepatocellular carcinoma cells (HepG2), and human dermal fibroblast cells (HDFs). The cell viabilities and IC50 values of AE were determined in cells incubated with AE for different lengths of time. To conduct studies in vivo, female BALB/c nude mice (aged 6–7 weeks, weighing 20–25 g) were used. A cervical cancer-derived cell line (CaSki) with integrated HPV-16 DNA was injected subcutaneously (1 × 107 cells/200 μL) in the middle dorsum of each animal (HPV group). One week after injection, mice were fed orally with AE crude extract at either 300 or 3000 mg/kg body weight/day for 14 or 28 days (HPV-AE groups). Tumor microvasculature and capillary vascularity were determined using laser scanning confocal microscopy. Tumor tissue was collected from each mouse to evaluate tumor histology and vascular endothelial growth factor (VEGF) immunostaining. Results The time-response curves of AE and the dose-dependent effect of AE on growth inhibition were determined. After a 48-hour incubation period, the IC50 of AE in CaSki was discovered to be significantly different from that of HDFs (P < 0.05). A microvascular network was observed around the tumor area in the HPV group on days 21 and 35. Tumor capillary vascularity in the HPV group was significantly increased compared with the control group (P < 0.001). High-dose treatment of AE extract (HPV-3000AE group) significantly attenuated the increase in VEGF expression and tumor angiogenesis in mice that received either the 14- or 28-day treatment period (P < 0.001). Conclusion Our novel

  13. Family poverty affects the rate of human infant brain growth.

    PubMed

    Hanson, Jamie L; Hair, Nicole; Shen, Dinggang G; Shi, Feng; Gilmore, John H; Wolfe, Barbara L; Pollak, Seth D

    2013-01-01

    Living in poverty places children at very high risk for problems across a variety of domains, including schooling, behavioral regulation, and health. Aspects of cognitive functioning, such as information processing, may underlie these kinds of problems. How might poverty affect the brain functions underlying these cognitive processes? Here, we address this question by observing and analyzing repeated measures of brain development of young children between five months and four years of age from economically diverse backgrounds (n = 77). In doing so, we have the opportunity to observe changes in brain growth as children begin to experience the effects of poverty. These children underwent MRI scanning, with subjects completing between 1 and 7 scans longitudinally. Two hundred and three MRI scans were divided into different tissue types using a novel image processing algorithm specifically designed to analyze brain data from young infants. Total gray, white, and cerebral (summation of total gray and white matter) volumes were examined along with volumes of the frontal, parietal, temporal, and occipital lobes. Infants from low-income families had lower volumes of gray matter, tissue critical for processing of information and execution of actions. These differences were found for both the frontal and parietal lobes. No differences were detected in white matter, temporal lobe volumes, or occipital lobe volumes. In addition, differences in brain growth were found to vary with socioeconomic status (SES), with children from lower-income households having slower trajectories of growth during infancy and early childhood. Volumetric differences were associated with the emergence of disruptive behavioral problems.

  14. Family Poverty Affects the Rate of Human Infant Brain Growth

    PubMed Central

    Hanson, Jamie L.; Hair, Nicole; Shen, Dinggang G.; Shi, Feng; Gilmore, John H.; Wolfe, Barbara L.; Pollak, Seth D.

    2013-01-01

    Living in poverty places children at very high risk for problems across a variety of domains, including schooling, behavioral regulation, and health. Aspects of cognitive functioning, such as information processing, may underlie these kinds of problems. How might poverty affect the brain functions underlying these cognitive processes? Here, we address this question by observing and analyzing repeated measures of brain development of young children between five months and four years of age from economically diverse backgrounds (n = 77). In doing so, we have the opportunity to observe changes in brain growth as children begin to experience the effects of poverty. These children underwent MRI scanning, with subjects completing between 1 and 7 scans longitudinally. Two hundred and three MRI scans were divided into different tissue types using a novel image processing algorithm specifically designed to analyze brain data from young infants. Total gray, white, and cerebral (summation of total gray and white matter) volumes were examined along with volumes of the frontal, parietal, temporal, and occipital lobes. Infants from low-income families had lower volumes of gray matter, tissue critical for processing of information and execution of actions. These differences were found for both the frontal and parietal lobes. No differences were detected in white matter, temporal lobe volumes, or occipital lobe volumes. In addition, differences in brain growth were found to vary with socioeconomic status (SES), with children from lower-income households having slower trajectories of growth during infancy and early childhood. Volumetric differences were associated with the emergence of disruptive behavioral problems. PMID:24349025

  15. Notch1 and notch2 have opposite effects on embryonal brain tumor growth.

    PubMed

    Fan, Xing; Mikolaenko, Irina; Elhassan, Ihab; Ni, Xingzhi; Wang, Yunyue; Ball, Douglas; Brat, Daniel J; Perry, Arie; Eberhart, Charles G

    2004-11-01

    The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.

  16. Comparing immune-tumor growth models with drug therapy using optimal control

    NASA Astrophysics Data System (ADS)

    Martins, Marisa C.; Rocha, Ana Maria A. C.; Costa, M. Fernanda P.; Fernandes, Edite M. G. P.

    2016-06-01

    In this paper we compare the dynamics of three tumor growth models that include an immune system and a drug administration therapy using optimal control. The objective is to minimize a combined function of the total of tumor cells over time and a chemotherapeutic drug administration.

  17. Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors.

    PubMed Central

    Hatva, E.; Kaipainen, A.; Mentula, P.; Jääskeläinen, J.; Paetau, A.; Haltia, M.; Alitalo, K.

    1995-01-01

    Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7856749

  18. Platelets Promote Tumor Growth and Metastasis via Direct Interaction between Aggrus/Podoplanin and CLEC-2

    PubMed Central

    Takagi, Satoshi; Sato, Shigeo; Oh-hara, Tomoko; Takami, Miho; Koike, Sumie; Mishima, Yuji; Hatake, Kiyohiko; Fujita, Naoya

    2013-01-01

    The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus–CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus–CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet–tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma. PMID:23991201

  19. Growth factors from tumor microenvironment possibly promote the proliferation of glioblastoma-derived stem-like cells in vitro.

    PubMed

    Guo, JingJing; Niu, Rui; Huang, Wenhui; Zhou, Mengliang; Shi, Jixing; Zhang, Luyong; Liao, Hong

    2012-10-01

    Glioblastoma multiform is a lethal brain glial tumor characterized by low survival and high recurrence, partially attributed to the glioblastoma stem cells according to recent researches. Microenvironment or niche in tumor tissue is believed to provide essential support for the aberrant growth of tumor stem cells. In order to explore the effect of growth factors in tumor microenvironment on glioblastoma stem cells behavior, glioblastoma-derived stem-like cells (GDSCs) were isolated from adult human glioblastoma specimen with antibody against surface marker CD133 and were co-cultured with various tumor cells including U87MG cells, unsorted glioblastoma tumor cells, CD133(-) cells and normal rat primary astrocytes. Results suggested that tumor cells could promote GDSCs proliferation while non-tumor cells could not, and several growth factors were exclusively detected in the co-culture system with tumor cells. It was concluded that growth factors derived from tumor microenvironment possibly contributed to the uncontrolled proliferation of GDSCs.

  20. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.

    PubMed

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-02-09

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.

  1. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer

    PubMed Central

    2012-01-01

    Introduction Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer. Methods Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis. Results Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells

  2. Oral pathogens change proliferation properties of oral tumor cells by affecting gene expression of human defensins.

    PubMed

    Hoppe, T; Kraus, D; Novak, N; Probstmeier, R; Frentzen, M; Wenghoefer, M; Jepsen, S; Winter, J

    2016-10-01

    The impact of oral pathogens onto the generation and variability of oral tumors has only recently been investigated. To get further insights, oral cancer cells were treated with pathogens and additionally, as a result of this bacterial cellular infection, with human defensins, which are as anti-microbial peptide members of the innate immune system. After cell stimulation, proliferation behavior, expression analysis of oncogenic relevant defensin genes, and effects on EGFR signaling were investigated. The expression of oncogenic relevant anti-microbial peptides was analyzed with real-time PCR and immunohistochemistry. Cell culture experiments were performed to examine cellular impacts caused by stimulation, i.e., altered gene expression, proliferation rate, and EGF receptor-dependent signaling. Incubation of oral tumor cells with an oral pathogen (Porphyromonas gingivalis) and human α-defensins led to an increase in cell proliferation. In contrast, another oral bacterium used, Aggregatibacter actinomycetemcomitans, enhanced cell death. The bacteria and anti-microbial peptides exhibited diverse effects on the transcript levels of oncogenic relevant defensin genes and epidermal growth factor receptor signaling. These two oral pathogens exhibited opposite primary effects on the proliferation behavior of oral tumor cells. Nevertheless, both microbe species led to similar secondary impacts on the proliferation rate by modifying expression levels of oncogenic relevant α-defensin genes. In this respect, oral pathogens exerted multiplying effects on tumor cell proliferation. Additionally, human defensins were shown to differently influence epidermal growth factor receptor signaling, supporting the hypothesis that these anti-microbial peptides serve as ligands of EGFR, thus modifying the proliferation behavior of oral tumor cells.

  3. Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways

    SciTech Connect

    Tong, Qingyi; Qing, Yong; Wu, Yang; Hu, Xiaojuan; Jiang, Lei; Wu, Xiaohua

    2014-12-01

    Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways. - Highlights: • Dioscin inhibits tumor growth in vivo and does not exhibit any toxicity. • Dioscin inhibits angiogenesis within solid tumors. • Dioscin inhibits the proliferation, migration, invasion, and tube formation of HUVECs. • Dioscin inhibits VEGF–induced blood vessel formation in vivo. • Dioscin inhibits VEGFR2 signaling pathway as well as AKT/MAPK pathway.

  4. Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering.

    PubMed

    Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

    2016-04-29

    Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

  5. Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

    NASA Astrophysics Data System (ADS)

    Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

    2016-06-01

    Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

  6. Modified Gompertz equation for electrotherapy murine tumor growth kinetics: predictions and new hypotheses

    PubMed Central

    2010-01-01

    Background Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed and perturbed tumors through use of the modified Gompertz equation in order to generate useful insight into the mechanisms that underpin this devastating disease. Methods The complete tumor growth kinetics for control and treated groups are obtained by interpolation and extrapolation methods with different time steps, using experimental data of fibrosarcoma Sa-37. In the modified Gompertz equation, a delay time is introduced to describe the tumor's natural history before treatment. Different graphical strategies are used in order to reveal new information in the complete kinetics of this tumor type. Results The first stage of complete tumor growth kinetics is highly non linear. The model, at this stage, shows different aspects that agree with those reported theoretically and experimentally. Tumor reversibility and the proportionality between regions before and after electrotherapy are demonstrated. In tumors that reach partial remission, two antagonistic post-treatment processes are induced, whereas in complete remission, two unknown antitumor mechanisms are induced. Conclusion The modified Gompertz equation is likely to lead to insights within cancer research. Such insights hold promise for increasing our understanding of tumors as self-organizing systems and, the possible existence of phase transitions in tumor growth kinetics, which, in turn, may have significant impacts both on cancer research and on clinical practice. PMID:21029411

  7. Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants.

    PubMed

    Heidenreich, Regina; Machein, Marcia; Nicolaus, Anke; Hilbig, Andreas; Wild, Carola; Clauss, Matthias; Plate, Karl H; Breier, Georg

    2004-09-01

    Vascular endothelial growth factor (VEGF) and the high-affinity VEGF receptor Flk-1/KDR (VEGFR-2) are key regulators of tumor angiogenesis. Strategies to block VEGF/VEGFR-2 signaling were successfully used to inhibit experimental tumor growth and indicated that VEGFR-2 is the main signaling VEGF receptor in proliferating tumor endothelium. Here, we investigated the role of the VEGF receptor-1 (VEGFR-1/Flt-1) in the vascularization of 2 different experimental tumors in vivo. VEGFR-1 mutants were generated that lack the intracellular tyrosine kinase domain. Retrovirus-mediated gene transfer of the VEGFR-1 mutants led to a strong reduction of tumor growth and angiogenesis in xenografted C6 glioma and in syngeneic BFS-1 fibrosarcoma. Histological analysis of the inhibited fibrosarcoma revealed reduced vascular density, decreased tumor cell proliferation as well as increased tumor cell apoptosis and the formation of necrosis. The retroviral gene transfer of the full length VEGFR-1 also caused a significant reduction of tumor growth in both models. The inhibitory effects of the VEGFR-1 mutants and the full length VEGFR-1 in BFS-1 fibrosarcoma were mediated through host tumor endothelial cells because the BFS-1 fibrosarcoma cells were not infected by the retrovirus. The formation of heterodimers between VEGFR-2 and full length or truncated VEGFR-1 was observed in vitro and might contribute to the growth inhibitory effect by modulating distinct signal transduction pathways. The results of our study underline the central role of the VEGF/VEGFR-1 signaling system in tumor angiogenesis and demonstrate that VEGFR-1 can serve as a target for anti-angiogenic gene therapy.

  8. Recruitment of myeloid but not endothelial precursor cells facilitates tumor re-growth after local irradiation

    PubMed Central

    Kozin, Sergey V.; Kamoun, Walid S.; Huang, Yuhui; Dawson, Michelle R.; Jain, Rakesh K.; Duda, Dan G.

    2010-01-01

    Tumor neovascularization and growth may be promoted by recruitment of bone marrow-derived cells (BMDCs), which include endothelial precursor cells (EPCs) and “vascular modulatory” myelomonocytic (CD11b+) cells. BMDCs may also drive tumor re-growth after certain chemotherapeutic and vascular disruption treatments. In this study, we evaluated the role of BMDC recruitment in breast and lung carcinoma xenograft models after local irradiation (LI). We depleted the bone marrow by including whole body irradiation (WBI) of 6Gy as part of a total tumor dose of 21Gy, and compared the growth delay with the one achieved after LI of 21Gy. In both models, including WBI induced longer tumor growth delays. Moreover, including WBI increased lung tumor control probability by LI. Exogenous delivery of BMDCs from radiation-naïve donors partially abrogated the WBI effect. Myeloid BMDCs, primarily macrophages, rapidly accumulated in tumors after LI. Intratumoral expression of SDF-1α, a chemokine that promotes tissue retention of BMDCs, was noted 2 days after LI. Conversely, treatment with an inhibitor of SDF-1α receptor CXCR4 (AMD3100) with LI significantly delayed tumor re-growth. However, when administered starting from 5 days post-LI, AMD3100 treatment was ineffective. Lastly, with restorative bone marrow transplantation of Tie2-GFP-labeled BMDC population we observed an increased number of monocytes but not EPCs in tumors that recurred following LI. Our results suggest that an increase in intratumoral SDF-1α triggered by local irradiation recruits myelomonocyte/macrophage which promote tumor re-growth. PMID:20631066

  9. Tumor growth in complex, evolving microenvironmental geometries: A diffuse domain approach

    PubMed Central

    Chen, Ying; Lowengrub, John S.

    2014-01-01

    We develop a mathematical model of tumor growth in complex, dynamic microenvironments with active, deformable membranes. Using a diffuse domain approach, the complex domain is captured implicitly using an auxiliary function and the governing equations are appropriately modified, extended and solved in a larger, regular domain. The diffuse domain method enables us to develop an efficient numerical implementation that does not depend on the space dimension or the microenvironmental geometry. We model homotypic cell-cell adhesion and heterotypic cell-basement membrane (BM) adhesion with the latter being implemented via a membrane energy that models cell-BM interactions. We incorporate simple models of elastic forces and the degradation of the BM and ECM by tumor-secreted matrix degrading enzymes. We investigate tumor progression and BM response as a function of cell-BM adhesion and the stiffness of the BM. We find tumor sizes tend to be positively correlated with cell-BM adhesion since increasing cell-BM adhesion results in thinner, more elongated tumors. Prior to invasion of the tumor into the stroma, we find a negative correlation between tumor size and BM stiffness as the elastic restoring forces tend to inhibit tumor growth. In order to model tumor invasion of the stroma, we find it necessary to downregulate cell-BM adhesiveness, which is consistent with experimental observations. A stiff BM promotes invasiveness because at early stages the opening in the BM created by MDE degradation from tumor cells tends to be narrower when the BM is stiffer. This requires invading cells to squeeze through the narrow opening and thus promotes fragmentation that then leads to enhanced growth and invasion. In three dimensions, the opening in the BM was found to increase in size even when the BM is stiff because of pressure induced by growing tumor clusters. A larger opening in the BM can increase the potential for further invasiveness by increasing the possibility that additional

  10. Early treatment with metformin induces resistance against tumor growth in adult rats.

    PubMed

    Trombini, Amanda B; Franco, Claudinéia Cs; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane As; Fabricio, Gabriel S; de Sant'Anna, Juliane R; Castro-Prado, Marialba Aa; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo Cf

    2015-01-01

    It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

  11. Simulation of 3D tumor cell growth using nonlinear finite element method.

    PubMed

    Dong, Shoubing; Yan, Yannan; Tang, Liqun; Meng, Junping; Jiang, Yi

    2016-01-01

    We propose a novel parallel computing framework for a nonlinear finite element method (FEM)-based cell model and apply it to simulate avascular tumor growth. We derive computation formulas to simplify the simulation and design the basic algorithms. With the increment of the proliferation generations of tumor cells, the FEM elements may become larger and more distorted. Then, we describe a remesh and refinement processing of the distorted or over large finite elements and the parallel implementation based on Message Passing Interface to improve the accuracy and efficiency of the simulation. We demonstrate the feasibility and effectiveness of the FEM model and the parallelization methods in simulations of early tumor growth.

  12. PHOSPHOLIPASE D (PLD) DRIVES CELL INVASION, TUMOR GROWTH AND METASTASIS IN A HUMAN BREAST CANCER XENOGRAPH MODEL

    PubMed Central

    Henkels, Karen M.; Boivin, Gregory P.; Dudley, Emily S.; Berberich, Steven J.; Gomez-Cambronero, Julian

    2014-01-01

    Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based shRNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, p<0.05) and their onset delayed when compared to control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (FIPI and NOPT). These inhibitors led to significant (>70%, p<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid (PA), WASp, Grb2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows that PLD has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target. PMID:23752189

  13. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

    PubMed Central

    Li, Nan; Zhang, Yajie; Han, Xin; Liang, Ke; Wang, Jiadong; Feng, Lin; Wang, Wenqi; Songyang, Zhou; Lin, Chunru; Yang, Liuqing; Yu, Yonghao

    2015-01-01

    PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN–AKT pathway that can be explored further for cancer treatment. PMID:25547115

  14. Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK

    PubMed Central

    Neufert, Clemens; Becker, Christoph; Türeci, Özlem; Waldner, Maximilian J.; Backert, Ingo; Floh, Katharina; Atreya, Imke; Leppkes, Moritz; Jefremow, Andre; Vieth, Michael; Schneider-Stock, Regine; Klinger, Patricia; Greten, Florian R.; Threadgill, David W.; Sahin, Ugur; Neurath, Markus F.

    2013-01-01

    Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms. PMID:23549083

  15. Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK.

    PubMed

    Neufert, Clemens; Becker, Christoph; Türeci, Özlem; Waldner, Maximilian J; Backert, Ingo; Floh, Katharina; Atreya, Imke; Leppkes, Moritz; Jefremow, Andre; Vieth, Michael; Schneider-Stock, Regine; Klinger, Patricia; Greten, Florian R; Threadgill, David W; Sahin, Ugur; Neurath, Markus F

    2013-04-01

    Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.

  16. The effect of housing temperature on the growth of CT26 tumor expressing fluorescent protein EGFP

    NASA Astrophysics Data System (ADS)

    Yuzhakova, Diana V.; Shirmanova, Marina V.; Lapkina, Irina V.; Serebrovskaya, Ekaterina O.; Lukyanov, Sergey A.; Zagaynova, Elena V.

    2016-04-01

    To date, the effect of housing temperature on tumor development in the immunocompetent mice has been studied on poorly immunogenic cancer models. Standard housing temperature 20-26°C was shown to cause chronic metabolic cold stress and promote tumor progression via suppression of the antitumor immune response, whereas a thermoneutral temperature 30-31°C was more preferable for normal metabolism of mice and inhibited tumor growth. Our work represents the first attempt to discover the potential effect of housing temperature on the development of highly immunogenic tumor. EGFP-expressing murine colon carcinoma CT26 generated in Balb/c mice was used as a tumor model. No statistically significant differences were shown in tumor incidences and growth rates at 20°C, 25°C and 30°C for non-modified CT26. Maintaining mice challenged with CT26-EGFP cells at 30°C led to complete inhibition of tumor development. In summary, we demonstrated that the housing temperature is important for the regulation of growth of highly immunogenic tumors in mice through antitumor immunity.

  17. A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport.

    PubMed

    Kazmi, Nabila; Hossain, M A; Phillips, Roger M

    2012-01-01

    Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \\mu {\\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.

  18. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Roles in Tumor Growth, Progression, and Drug Resistance

    PubMed Central

    Tu, Huaijun; Yang, Yazhi; Wu, Qiong

    2017-01-01

    Mesenchymal stem cells (MSCs) are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs) could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy. PMID:28377788

  19. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors.

    PubMed

    Rubin, Joshua B; Kung, Andrew L; Klein, Robyn S; Chan, Jennifer A; Sun, YanPing; Schmidt, Karl; Kieran, Mark W; Luster, Andrew D; Segal, Rosalind A

    2003-11-11

    The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

  20. Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

    PubMed Central

    Martín-Rodríguez, Juan F.; Muñoz-Bravo, Jose L.; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A.

    2015-01-01

    Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. PMID:26549306

  1. Extravascular red blood cells and hemoglobin promote tumor growth and therapeutic resistance as endogenous danger signals.

    PubMed

    Yin, Tao; He, Sisi; Liu, Xiaoling; Jiang, Wei; Ye, Tinghong; Lin, Ziqiang; Sang, Yaxiong; Su, Chao; Wan, Yang; Shen, Guobo; Ma, Xuelei; Yu, Min; Guo, Fuchun; Liu, Yanyang; Li, Ling; Hu, Qiancheng; Wang, Yongsheng; Wei, Yuquan

    2015-01-01

    Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1β release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance.

  2. Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

    PubMed

    Martín-Rodríguez, Juan F; Muñoz-Bravo, Jose L; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M; Castaño, Justo P; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A

    2015-11-09

    Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

  3. Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance.

    PubMed

    Salem, Ahmed F; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1β and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial "power" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1α, PGC-1β, mitoNEET and POLRMT should all be considered as tumor promoters or "metabolic oncogenes." Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial "poison") prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.

  4. Blocking tumor growth by targeting autophagy and SQSTM1 in vivo.

    PubMed

    Wei, Huijun; Guan, Jun-Lin

    2015-01-01

    Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials in response to starvation and maintenance of cellular homeostasis. Dysfunction of autophagy is implicated in a variety of diseases including cancer. In a recent study, we devised a system for inducible deletion of an essential autophagy gene Rb1cc1/Fip200 in established tumor cells in vivo and showed that Rb1cc1 is required for maintaining tumor growth. We further investigated the role of the accumulated SQSTM1 in Rb1cc1-null autophagy-deficient tumor cells. To our surprise, the increased SQSTM1 was not responsible for the inhibition of tumor growth, but rather supported the residual growth of tumors (i.e., partially compensated for the defective growth caused by Rb1cc1 deletion). Further analysis indicated that SQSTM1 promoted tumor growth in autophagy-deficient cells at least partially through its activation of the NFKB signaling pathway. A working model is proposed to account for our findings, which suggest that targeting both autophagy and the consequently increased SQSTM1 may be exploited for developing more effective cancer therapies.

  5. Multicenter study on adult growth hormone level in postoperative pituitary tumor patients.

    PubMed

    Cheng, Jing-min; Gu, Jian-wen; Kuang, Yong-qin; Ma, Yuan; Xia, Xun; Yang, Tao; Lu, Min; He, Wei-qi; Sun, Zhi-yong; Zhang, Yan-chao

    2015-03-01

    The objective of this study is to observe the adult growth hormone level in postoperative pituitary tumor patients of multi-centers, and explore the change of hypophyseal hormones in postoperative pituitary tumor patients. Sixty patients with pituitary tumor admitted during March, 2011-March, 2012 were selected. Postoperative hypophyseal hormone deficiency and the change of preoperative, intraoperative, and postoperative growth hormone levels were recorded. Growth hormone hypofunction was the most common hormonal hypofunction, which took up to 85.0 %. Adrenocortical hormone hypofunction was next to it and accounted for 58.33 %. GH + ACTH + TSH + Gn deficiency was the most common in postoperative hormone deficiency, which took up to 40.00 %, and GH + ACTH + TSH + Gn + AVP and GH deficiencies were next to it and accounted for 23.33 and 16.67 %, respectively. The hormone levels in patients after total pituitary tumor resection were significantly lower than those after partial pituitary tumor resection, and the difference was statistically significant; growth hormone and serum prolactin levels after surgery in two groups were decreased, and the difference was statistically significant. The incidence rate of growth hormone deficiency in postoperative pituitary tumor patients is high, which is usually complicated with deficiency of various hypophyseal hormones. In clinical, we should pay attention to the levels of the hypopnyseal hormones, and take timely measures to avoid postoperative complications.

  6. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    PubMed

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  7. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models

    PubMed Central

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-01-01

    Fisetin (3,7,3′,4′-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers. PMID:28105204

  8. Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

    NASA Astrophysics Data System (ADS)

    Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

    2014-02-01

    Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

  9. Targeted endostatin-cytosine deaminase fusion gene therapy plus 5-fluorocytosine suppresses ovarian tumor growth.

    PubMed

    Sher, Y-P; Chang, C-M; Juo, C-G; Chen, C-T; Hsu, J L; Lin, C-Y; Han, Z; Shiah, S-G; Hung, M-C

    2013-02-28

    There are currently no effective therapies for cancer patients with advanced ovarian cancer, therefore developing an efficient and safe strategy is urgent. To ensure cancer-specific targeting, efficient delivery, and efficacy, we developed an ovarian cancer-specific construct (Survivin-VISA-hEndoyCD) composed of the cancer specific promoter survivin in a transgene amplification vector (VISA; VP16-GAL4-WPRE integrated systemic amplifier) to express a secreted human endostatin-yeast cytosine deaminase fusion protein (hEndoyCD) for advanced ovarian cancer treatment. hEndoyCD contains an endostatin domain that has tumor-targeting ability for anti-angiogenesis and a cytosine deaminase domain that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic drug, 5-fluorouracil. Survivin-VISA-hEndoyCD was found to be highly specific, selectively express secreted hEndoyCD from ovarian cancer cells, and induce cancer-cell killing in vitro and in vivo in the presence of 5-FC without affecting normal cells. In addition, Survivin-VISA-hEndoyCD plus 5-FC showed strong synergistic effects in combination with cisplatin in ovarian cancer cell lines. Intraperitoneal (i.p.) treatment with Survivin-VISA-hEndoyCD coupled with liposome attenuated tumor growth and prolonged survival in mice bearing advanced ovarian tumors. Importantly, there was virtually no severe toxicity when hEndoyCD is expressed by Survivin-VISA plus 5-FC compared with CMV plus 5-FC. Thus, the current study demonstrates an effective cancer-targeted gene therapy that is worthy of development in clinical trials for treating advanced ovarian cancer.

  10. Loss of glycogen debranching enzyme AGL drives bladder tumor growth via induction of hyaluronic acid synthesis

    PubMed Central

    Guin, Sunny; Ru, Yuanbin; Agarwal, Neeraj; Lew, Carolyn R.; Owens, Charles; Comi, Giacomo P.; Theodorescu, Dan

    2015-01-01

    Purpose We demonstrated that Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) is a tumor growth suppressor and prognostic marker in human bladder cancer. Here we determine how AGL loss enhances tumor growth, hoping to find therapeutically tractable targets/pathways that could be used in patients with low AGL expressing tumors. Experimental Design We transcriptionally profiled bladder cell lines with different AGL expression. By focusing on transcripts overexpressed as a function of low AGL and associated with adverse clinicopathologic variables in human bladder tumors, we sought to increase the chances of discovering novel therapeutic opportunities. Results One such transcript was hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis. HAS2 expression was inversely proportional to that of AGL in bladder cancer cells and immortalized and normal urothelium. HAS2 driven HA synthesis was enhanced in bladder cancer cells with low AGL and this drove anchorage dependent and independent growth. siRNA mediated depletion of HAS2 or inhibition of HA synthesis by 4-Methylumbelliferone (4MU) abrogated in vitro and xenograft growth of bladder cancer cells with low AGL. AGL and HAS2 mRNA expression in human tumors was inversely correlated in patient datasets. Patients with high HAS2 and low AGL tumor mRNA expression had poor survival lending clinical support to xenograft findings that HAS2 drives growth of tumors with low AGL. Conclusion Our study establishes HAS2 mediated HA synthesis as a driver of growth of bladder cancer with low AGL and provides preclinical rationale for personalized targeting of HAS2/HA signaling in patients with low AGL expressing tumors. PMID:26490312

  11. Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer

    PubMed Central

    Jardim-Perassi, Bruna Victorasso; Arbab, Ali S.; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R. S.; Iskander, A. S. M.; Shankar, Adarsh; Ali, Meser M.; de Campos Zuccari, Debora Aparecida Pires

    2014-01-01

    As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell

  12. Prevalent expression of fibroblast growth factor (FGF) receptors and FGF2 in human tumor cell lines.

    PubMed

    Chandler, L A; Sosnowski, B A; Greenlees, L; Aukerman, S L; Baird, A; Pierce, G F

    1999-05-05

    Basic fibroblast growth factor (FGF2) has potent mitogenic and angiogenic activities that have been implicated in tumor development and malignant progression. The biological effects of FGF2 and other members of the FGF ligand family are mediated by 4 transmembrane tyrosine kinase receptors (FGFRs). To better understand the roles of FGFRs in cancer, the expression of FGF2 and each of the 4 FGFRs was assessed by RNase protection analysis of 60 human tumor cell lines, representing 9 tumor types. Expression of at least one FGFR isoform was detected in 90% and FGF2 mRNA in 35% of the cell lines. Our comprehensive analysis of FGF2 and FGFR expression in human tumor cell lines provides evidence that FGF signaling pathways are active in a majority of human tumor cell lines, and lends support to the development of anti-tumor strategies that target FGFRs.

  13. L-carnosine affects the growth of Saccharomyces cerevisiae in a metabolism-dependent manner.

    PubMed

    Cartwright, Stephanie P; Bill, Roslyn M; Hipkiss, Alan R

    2012-01-01

    The dipeptide L-carnosine (β-alanyl-L-histidine) has been described as enigmatic: it inhibits growth of cancer cells but delays senescence in cultured human fibroblasts and extends the lifespan of male fruit flies. In an attempt to understand these observations, the effects of L-carnosine on the model eukaryote, Saccharomyces cerevisiae, were examined on account of its unique metabolic properties; S. cerevisiae can respire aerobically, but like some tumor cells, it can also exhibit a metabolism in which aerobic respiration is down regulated. L-Carnosine exhibited both inhibitory and stimulatory effects on yeast cells, dependent upon the carbon source in the growth medium. When yeast cells were not reliant on oxidative phosphorylation for energy generation (e.g. when grown on a fermentable carbon source such as 2% glucose), 10-30 mM L-carnosine slowed growth rates in a dose-dependent manner and increased cell death by up to 17%. In contrast, in media containing a non-fermentable carbon source in which yeast are dependent on aerobic respiration (e.g. 2% glycerol), L-carnosine did not provoke cell death. This latter observation was confirmed in the respiratory yeast, Pichia pastoris. Moreover, when deletion strains in the yeast nutrient-sensing pathway were treated with L-carnosine, the cells showed resistance to its inhibitory effects. These findings suggest that L-carnosine affects cells in a metabolism-dependent manner and provide a rationale for its effects on different cell types.

  14. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma

    SciTech Connect

    Zhao, Xiaohai; Li, Jinfeng; Zhuo, Jianxin; Cai, Liuxin

    2010-12-17

    Research highlights: {yields} Reconstitution of ARHI suppresses the growth of HCC xenografts. {yields} ARHI reexpression impairs tumor angiogenesis in vivo. {yields} Inhibition of the mTOR/VEGF signaling by forced expression of ARHI. {yields} Manipulating ARHI may be of therapeutic benefit in treatment of ARHI-negative HCCs. -- Abstract: The Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI) is frequently downregulated in many types of cancer, including hepatocellular carcinoma (HCC). In this study, we sought to explore the therapeutic implications of ARHI reconstitution in the treatment of HCC. We generated stable cell lines overexpressing ARHI in Hep3B and SK-Hep1 cells, both of which lack endogenous ARHI. The effects of ARHI reexpression on tumor growth and angiogenesis were assessed. Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway. Forced expression of ARHI resulted in a significant inhibition of the proliferation of both Hep3B and SK-Hep1 cells compared to control cells (P < 0.01). Cell cycle analysis revealed a G0-G1 arrest induced by ARHI reexpression. Moreover, ARHI reexpression significantly retarded Hep3B xenograft growth in vivo, and caused a marked reduction in tumor angiogenesis assessed by CD31-stained microvessel count. Western blot analysis of the xenografts showed that ARHI overexpression substantially reduced the phosphorylation of two mTOR substrates, S6K1 and 4E-BP1, indicative of an inactivation of the mTOR pathway. Accompanying with the mTOR inactivation, the angiogenic factors, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor, were significantly downregulated. These data highlighted an important role for ARHI in controlling HCC growth and angiogenesis, therefore offering a possible therapeutic strategy against this malignancy.

  15. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

    PubMed Central

    Saha, Nayanendu; Eissman, Moritz F.; Xu, Kai; Llerena, Carmen; Kusebauch, Ulrike; Ding, Bi-Sen; Cao, Zhongwei; Rafii, Shahin; Ernst, Matthias; Scott, Andrew M.; Nikolov, Dimitar B.; Lackmann, Martin

    2016-01-01

    The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID:27503072

  16. SPOCK1 promotes tumor growth and metastasis in human prostate cancer

    PubMed Central

    Chen, Qi; Yao, Yuan-ting; Xu, Huan; Chen, Yan-bo; Gu, Meng; Cai, Zhi-kang; Wang, Zhong

    2016-01-01

    Prostate cancer is the most diagnosed noncutaneous cancer and ranks as the second leading cause of cancer-related deaths in American males. Metastasis is the primary cause of prostate cancer mortality. Survival rate is only 28% for metastatic patients, but is nearly 100% for patients with localized prostate cancers. Molecular mechanisms that underlie this malignancy remain obscure, and this study investigated the role of SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) in prostate cancer progression. Initially, we found that SPOCK1 expression was significantly higher in prostate cancer tissues relative to noncancerous tissues. In particular, SPOCK1 expression was also markedly high in metastatic tissues compared with nonmetastatic cancerous tissues. SPOCK1 expression knockdown by specific short hairpin RNA in PC3 cells was significantly inhibited, whereas SPOCK1 overexpression in RWPE-1 cells promoted cell viability, colony formation in vitro, and tumor growth in vivo. Moreover, the SPOCK1 knockdown in PC3 cells was associated with cell cycle arrest in G0/G1 phase, while the SPOCK1 overexpression in RWPE-1 cells induced cell cycle arrest in S phase. The SPOCK1 knockdown in PC3 cells even increased cell apoptosis. SPOCK1 modulation was also observed to affect cancerous cell proliferation and apoptotic processes in the mouse model of prostate cancer. Additionally, the SPOCK1 knockdown decreased, whereas the SPOCK1 overexpression increased cell migration and invasion abilities in vitro. Injection of SPOCK1-depleted PC3 cells significantly decreased metastatic nodules in mouse lungs. These findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer. PMID:27486308

  17. SPOCK1 promotes tumor growth and metastasis in human prostate cancer.

    PubMed

    Chen, Qi; Yao, Yuan-Ting; Xu, Huan; Chen, Yan-Bo; Gu, Meng; Cai, Zhi-Kang; Wang, Zhong

    2016-01-01

    Prostate cancer is the most diagnosed noncutaneous cancer and ranks as the second leading cause of cancer-related deaths in American males. Metastasis is the primary cause of prostate cancer mortality. Survival rate is only 28% for metastatic patients, but is nearly 100% for patients with localized prostate cancers. Molecular mechanisms that underlie this malignancy remain obscure, and this study investigated the role of SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) in prostate cancer progression. Initially, we found that SPOCK1 expression was significantly higher in prostate cancer tissues relative to noncancerous tissues. In particular, SPOCK1 expression was also markedly high in metastatic tissues compared with nonmetastatic cancerous tissues. SPOCK1 expression knockdown by specific short hairpin RNA in PC3 cells was significantly inhibited, whereas SPOCK1 overexpression in RWPE-1 cells promoted cell viability, colony formation in vitro, and tumor growth in vivo. Moreover, the SPOCK1 knockdown in PC3 cells was associated with cell cycle arrest in G0/G1 phase, while the SPOCK1 overexpression in RWPE-1 cells induced cell cycle arrest in S phase. The SPOCK1 knockdown in PC3 cells even increased cell apoptosis. SPOCK1 modulation was also observed to affect cancerous cell proliferation and apoptotic processes in the mouse model of prostate cancer. Additionally, the SPOCK1 knockdown decreased, whereas the SPOCK1 overexpression increased cell migration and invasion abilities in vitro. Injection of SPOCK1-depleted PC3 cells significantly decreased metastatic nodules in mouse lungs. These findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer.

  18. Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors in Human Colon Cancer Surgical Specimens and Orthotopic Tumors

    PubMed Central

    Kuwai, Toshio; Nakamura, Toru; Kim, Sun-Jin; Sasaki, Takamitsu; Kitadai, Yasuhiko; Langley, Robert R.; Fan, Dominic; Hamilton, Stanley R.; Fidler, Isaiah J.

    2008-01-01

    The design of targeted therapy, particularly patient-specific targeted therapy, requires knowledge of the presence and intratumoral distribution of tyrosine kinase receptors. To determine whether the expression of such receptors is constant or varies between and within individual colon cancer neoplasms, we examined the pattern of expression of the ligands, epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factor-B as well as their respective receptors in human colon cancer surgical specimens and orthotopic human colon cancers growing in the cecal wall of nude mice. The expression of the epidermal growth factor receptor and the vascular endothelial growth factor receptor on tumor cells and stromal cells, including tumor-associated endothelial cells, was heterogeneous in surgical specimens and orthotopic tumors. In some tumors, the receptor was expressed on both tumor cells and stromal cells, and in other tumors the receptor was expressed only on tumor cells or only on stromal cells. In contrast, the platelet-derived growth factor receptor was expressed only on stromal cells in both surgical specimens and orthotopic tumors. Examination of receptor expression in both individual surgical specimens and orthotopic tumors revealed that the platelet-derived growth factor receptor was expressed only on stromal cells and that the patterns of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 expression differed between tumor cells. This heterogeneity in receptor expression among different tumor cells suggests that targeting a single tyrosine kinase may not yield eradication of the disease. PMID:18202197

  19. Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

    PubMed

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-03-09

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

  20. Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

    PubMed Central

    Zhang, Huimin; Ren, Yu; Tang, Xiaojiang; Wang, Ke; Liu, Yang; Zhang, Li; Li, Xiao; Liu, Peijun; Zhao, Changqi; He, Jianjun

    2015-01-01

    Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage. PMID:25749075

  1. A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T-cell epitope delays tumor growth in a murine model of prostate cancer.

    PubMed

    Klyushnenkova, Elena N; Kouiavskaia, Diana V; Parkins, Christopher J; Caposio, Patrizia; Botto, Sara; Alexander, Richard B; Jarvis, Michael A

    2012-06-01

    Cytomegalovirus (CMV) is a highly immunogenic virus that results in a persistent, life-long infection in the host typically with no ill effects. Certain unique features of CMV, including its capacity to actively replicate in the presence of strong host CMV-specific immunity, may give CMV an advantage compared with other virus-based vaccine delivery platforms. In the present study, we tested the utility of mouse CMV (mCMV)-based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in double-transgenic mice expressing PSA and HLA-DRB1*1501 (DR2bxPSA F1 mice). We assessed the capacity of 2 mCMV-based vectors to induce PSA-specific CD8 T-cell responses and affect the growth of PSA-expressing Transgenic Adenocarcinoma of the Mouse Prostate tumors (TRAMP-PSA). In the absence of tumor challenge, immunization with mCMV vectors expressing either a H2-D(b)-restricted epitope PSA(65-73) (mCMV/PSA(65-73)) or the full-length gene for PSA (mCMV/PSA(FL)) induced comparable levels of CD8 T-cell responses that increased (inflated) with time. Upon challenge with TRAMP-PSA tumor cells, animals immunized with mCMV/PSA(65-73) had delay of tumor growth and increased PSA-specific CD8 T-cell responses, whereas animals immunized with mCMV/PSA(FL) showed progressive tumor growth and no increase in number of splenic PSA(65-73)-specific T cells. The data show that a prototype CMV-based prostate cancer vaccine can induce an effective antitumor immune response in a "humanized" double-transgenic mouse model. The observation that mCMV/PSA(FL) is not effective against TRAMP-PSA is consistent with our previous findings that HLA-DRB1*1501-restricted immune responses to PSA are associated with suppression of effective CD8 T-cell responses to TRAMP-PSA tumors.

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

    PubMed

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

    2015-07-01

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

  3. Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β.

    PubMed

    Kim, Jung-Eun; Phan, Thuy Xuan; Nguyen, Vu Hong; Dinh-Vu, Hong-Van; Zheng, Jin Hai; Yun, Misun; Park, Sung-Gyoo; Hong, Yeongjin; Choy, Hyon E; Szardenings, Michael; Hwang, Won; Park, Jin-A; Park, SunHee; Im, Sin-Hyeog; Min, Jung-Joon

    2015-01-01

    Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (ΔppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ΔppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1β and TNF-α were markedly increased in tumors colonized by ΔppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1β and TNF-α returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1β and TNF-α. We found that macrophages and dendritic cells were the main producers of TNF-α and IL-1β. Inhibiting IL-1β production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1β or TNF-α in conjunction with Salmonella therapy. These findings suggested that IL-1β and TNF-α play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.

  4. Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β

    PubMed Central

    Kim, Jung-Eun; Phan, Thuy Xuan; Nguyen, Vu Hong; Dinh-Vu, Hong-Van; Zheng, Jin Hai; Yun, Misun; Park, Sung-Gyoo; Hong, Yeongjin; Choy, Hyon E.; Szardenings, Michael; Hwang, Won; Park, Jin-A; Park, SunHee; Im, Sin-Hyeog; Min, Jung-Joon

    2015-01-01

    Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (ΔppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ΔppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1β and TNF-α were markedly increased in tumors colonized by ΔppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1β and TNF-α returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1β and TNF-α. We found that macrophages and dendritic cells were the main producers of TNF-α and IL-1β. Inhibiting IL-1β production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1β or TNF-α in conjunction with Salmonella therapy. These findings suggested that IL-1β and TNF-α play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy. PMID:26516371

  5. Does Training Affect Growth? Answers to Common Questions.

    ERIC Educational Resources Information Center

    Daly, Robin M.; Bass, Shona; Caine, Dennis; Howe, Warren

    2002-01-01

    Adolescent athletes may be at risk of restricted growth and delayed maturation when combining intense training with insufficient energy intake. Because catch-up growth commonly occurs with reduced training, final adult stature is generally not compromised. However, in athletes with long-term, clinically delayed maturation, catch-up growth may be…

  6. Silencing survivin expression inhibits the tumor growth of non-small-cell lung cancer cells in vitro and in vivo.

    PubMed

    Zhang, Kejian; Li, Yang; Liu, Wei; Gao, Xinliang; Zhang, Kewei

    2015-01-01

    Survivin is a promising anticancer therapeutic target due to its important role in the inhibition of apoptosis of tumor cells. However, little is currently known about its role in non small cell lung cancer (NSCLC). The present study evaluated whether the downregulation of survivin expression would affect cell proliferation, cell cycle distribution, apoptosis and colony formation of NSCLC. A recombinant lentiviral small hairpin RNA (shRNA) expression vector, which specifically targeted survivin, was constructed and transfected into the A549 human NSCLC cell line. Quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of survivin, 48 h following the knockdown of survivin expression. Cell proliferation, apoptosis, cell cycle distribution and colony formation were determined following the downregulation of survivin by shRNA. In addition, A549 cells were injected into nude mice, and the effects of shRNA targeting the survivin gene on tumor growth were assessed. Downregulation of survivin expression, using the RNA silencing approach in A549 tumor cells, significantly suppressed the proliferation and colony formation ability of the cells, and induced tumor apoptosis in vitro. The nude mice inoculated with A549 cells developed cancer, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers, with no obvious side effects. The results of the present study suggest that suppression of survivin expression by RNA interference may induce NSCLC apoptosis, and provide a novel approach for anticancer gene therapy.

  7. Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth

    PubMed Central

    Kim, Kimberly H.; Roberts, Charles W. M.

    2014-01-01

    SMARCB1 (INI1/SNF5/BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in the large majority of rhabdoid tumors and germline heterozygous SMARCB1 mutations form the basis for rhabdoid predisposition syndrome. Mouse models validated Smarcb1 as a bona fide tumor suppressor as Smarcb1 inactivation in mice results in 100% of the animals rapidly developing cancer. SMARCB1 was the first subunit of the SWI/SNF complex found mutated in cancer. More recently, at least seven other genes encoding SWI/SNF subunits have been identified as recurrently mutated in cancer. Collectively, 20% of all human cancers contain a SWI/SNF mutation. Consequently, investigation of the mechanisms by which SMARCB1 mutation causes cancer has relevance not only for rhabdoid tumors, but also potentially for the wide variety of SWI/NSNF mutant cancers. Here we discuss normal functions of SMARCB1 and the SWI/SNF complex as well as mechanistic and potentially therapeutic insights that have emerged. PMID:24853101

  8. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    PubMed

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models.

  9. Non-invasive optical imaging of tumor growth in intact animals

    NASA Astrophysics Data System (ADS)

    Lu, Jinling; Li, Pengcheng; Luo, Qingming; Zhu, Dan

    2003-12-01

    We describe here a system for rapidly visualizing tumor growth in intact rodent mice that is simple, rapid, and eminently accessible and repeatable. We have established new rodent tumor cell line -- SP2/0-GFP cells that stably express high level of green fluorescent protein (GFP) by transfected with a plasmid that encoded GFP using electroporation and selected with G418 for 3 weeks. 1 x 104 - 1x107 SP2/0-GFP mouse melanoma cells were injected s.c. in the ears and legs of 6- to 7-week-old syngeneic male BALB/c mice, and optical images visualized real-time the engrafted tumor growth. The tumor burden was monitored over time by cryogenically cooled charge coupled device (CCD) camera focused through a stereo microscope. The results show that the fluorescence intensity of GFP-expressing tumor is comparably with the tumor growth and/or depress. This in vivo optical imaging based on GFP is sensitive, external, and noninvasive. It affords continuous visual monitoring of malignant growth within intact animals, and may comprise an ideal tool for evaluating antineoplastic therapies.

  10. Tumor Growth Prediction with Reaction-Diffusion and Hyperelastic Biomechanical Model by Physiological Data Fusion

    PubMed Central

    Wong, Ken C. L.; Summers, Ronald M.; Kebebew, Electron; Yao, Jianhua

    2015-01-01

    The goal of tumor growth prediction is to model the tumor growth process, which can be achieved by physiological modeling and model personalization from clinical measurements. Although image-driven frameworks have been proposed with promising results, several issues such as infinitesimal strain assumptions, complicated personalization procedures, and the lack of functional information, may limit their prediction accuracy. In view of these issues, we propose a framework for pancreatic neuroendocrine tumor growth prediction, which comprises a FEM-based tumor growth model with coupled reaction-diffusion equation and nonlinear biomechanics. Physiological data fusion of structural and functional images is used to improve the subject-specificity of model personalization, and a derivative-free global optimization algorithm is adopted to facilitate the complicated model and accommodate flexible choices of objective functions. With this flexibility, we propose an objective function accounting for both the tumor volume difference and the root-mean-squared error of intracellular volume fractions. Experiments were performed on synthetic and clinical data to verify the parameter estimation capability and the prediction performance. Comparisons of using different biomechanical models and objective functions were also performed. From the experimental results of eight patient data sets, the average recall, precision, Dice coefficient, and relative volume difference between predicted and measured tumor volumes were 84.5±6.9%, 85.8±8.2%, 84.6±1.7%, and 14.2±8.4%, respectively. PMID:25962846

  11. Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

    PubMed

    Yan, Ping; Gong, Hui; Zhai, Xiaoyan; Feng, Yi; Wu, Jun; He, Sheng; Guo, Jian; Wang, Xiaoxia; Guo, Rui; Xie, Jun; Li, Ren-Ke

    2016-04-01

    Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.

  12. Stochastic modeling of the tumor volume assessment and growth patterns in hepatocellular carcinoma.

    PubMed

    Sãftoiu, Adrian; Ciurea, Tudorel; Gorunescu, Florin; Rogoveanu, Ion; Georgescu, Claudia

    2004-06-01

    The growth pattern of hepatocellular carcinoma (HCC) arising from cirrhosis is variable and depends on the degree of differentiation and vascularization. Because growth is not constant in the natural history of HCC, prediction of subsequent growth rate based on tumor volume doubling time and correlation with histological and ultrasonographical characteristics at the moment of initial diagnosis are usually unreliable. The aim of our study was to assess the growth patterns of HCC with the aid of stochastic modeling. Thus, we included in our study 27 patients with histologically proven HCC, which had multiple (more than three)follow-up ultrasound studies in a six months interval. The patients did not receive any treatment during the observation period. HCC was visualized by computer aided ultrasound imaging, obtaining both the primary size quantification and the edge-detection enhancement. By a bi-cubic B-spline interpolation of points on the edges (3-D Bezier approximation) we approximated the surfaces shapes, and using the hit or miss Monte Carlo method we accurately estimate the tumor volume. Starting from the previous tumor volumes time series recorded during the first six months of evolution we applied both a linear, exponential and logarithmic smoothing to forecast the future size of the HCC tumor in the next six months. Our conclusion was that a dynamic forecasting model of HCC volumes could be very accurate for the assessment of tumor volume doubling time usually obtained by two discrete volume measurements of the tumor.

  13. A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

    PubMed Central

    Wen, Frank T.; Thisted, Ronald A.; Rowley, Donald A.; Schreiber, Hans

    2012-01-01

    We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords “immunotherapy” AND “cancer” for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5–121 mm3 in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm3 was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm3, and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm3, and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth. PMID:22720238

  14. Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis

    PubMed Central

    Zhao, Ting; Yan, Cong; Du, Hong

    2016-01-01

    Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal−/−) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest. The synthesis and secretion of cytokines and chemokines that are known to mediate MSCs' tumor-stimulating and immunosuppressive effects, i.e., IL-6, MCP-1 and IL-10, were down-regulated in lal−/− MSCs. When tumor cells were treated with the conditioned medium from lal−/− MSCs, decreased proliferation was observed, accompanied by reduced activation of oncogenic intracellular signaling molecules in tumor cells. Co-injection of lal−/− MSCs and B16 melanoma cells into wild type mice not only induced CD8+ cytotoxic T cells, but also decreased accumulation of tumor-promoting Ly6G+CD11b+ myeloid-derived suppressor cells (MDSCs), which may synergistically contribute to the impairment of tumor progression. Furthermore, lal−/− MSCs showed impaired differentiation towards tumor-associated fibroblasts. In addition, MDSCs facilitated MSC proliferation, which was mediated by MDSC-secreted cytokines and chemokines. Our results indicate that LAL plays a critical role in regulating MSCs' ability to stimulate tumor growth and metastasis, which provides a mechanistic basis for targeting LAL in MSCs to reduce the risk of cancer metastasis. PMID:27531897

  15. Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads

    PubMed Central

    2014-01-01

    Background Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. Methods The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Results Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Conclusions Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes. PMID:24886322

  16. Perfusion, oxygenation status and growth of experimental tumors upon photodynamic therapy with Pd-bacteriopheophorbide.

    PubMed

    Kelleher, Debra K; Thews, Oliver; Scherz, Avigdor; Salomon, Yoram; Vaupel, Peter

    2004-06-01

    The aim of this study was to assess the anti-tumor effect of photodynamic therapy (PDT) using a novel bacteriochlorophyll derivative, palladium-bacteriopheophorbide (TOOKAD) on tumor growth, perfusion and oxygenation. Rat DS-sarcomas were treated with either TOOKAD-PDT (2 mg/kg, i.v., immediate illumination) or one of the control treatments (sham-treatment, illumination without photosensitizer, or photosensitizer without illumination). The light source was an infrared-A irradiator fitted with appropriate filters, so that the wavelengths applied (665-800 nm) included the absorption maximum of TOOKAD at 763 nm. Tumor volume was monitored for 90 days after treatment or until a target volume (3.5 ml) was reached. TOOKAD-PDT dramatically inhibited tumor growth with 92% of tumors not reaching the target volume within the observation period. In further experiments, tumor perfusion was assessed using laser Doppler flowmetry. Upon TOOKAD-PDT treatment, a rapid, pronounced decrease in perfusion was seen, down to levels corresponding to only 3% of initial values. Tumor oxygenation monitoring revealed parallel decreases, with levels corresponding to anoxia being reached. The significant anti-tumor effects presented in this report, taken together with the chemical and pharmacokinetic properties of the novel photosensitizer TOOKAD, underline the therapeutic potential of this approach in which flow stasis and induction of anoxia are key elements.

  17. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  18. In vivo Cytokine Gene Transfer by Gene Gun Reduces Tumor Growth in Mice

    NASA Astrophysics Data System (ADS)

    Sun, Wenn H.; Burkholder, Joseph K.; Sun, Jian; Culp, Jerilyn; Turner, Joel; Lu, Xing G.; Pugh, Thomas D.; Ershler, William B.; Yang, Ning-Sun

    1995-03-01

    Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investigators to result in potent in vivo antitumor activities in mice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumorbearing animals by particle-mediated gene transfer. In vivo transfection of the human interleukin 6 gene into the tumor site reduced methylcholanthrene-induced fibrosarcoma growth, and a combination of murine tumor necrosis factor α and interferon γ genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin 2 and interferon γ genes prolonged the survival of Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was demonstrated in treated tissues by ELISA and immunohistochemical analysis. Significant serum levels of interleukin 6 and interferon γ were detected, demonstrating effective secretion of transgenic proteins from treated skin into the bloodstream. This in vivo cytokine gene therapy approach provides a system for evaluating the antitumor properties of various cytokines in different tumor models and has potential utility for human cancer gene therapy.

  19. Monoclonal Antibodies Targeting Tumor Growth | NCI Technology Transfer Center | TTC

    Cancer.gov

    The NCI Nanobiology Program, Protein Interaction Group is seeking parties to license or co-develop, evaluate, or commercialize monoclonal antibodies against the insulin-like growth factor for the treatment of cancer.

  20. The growth of cultured human foreskin keratinocytes is not stimulated by a tumor promoter.

    PubMed

    Fischer, S M; Viaje, A; Mills, G D; Wong, E W; Weeks, C E; Slaga, T J

    1984-01-01

    The tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) does not stimulate the growth of human epidermal cells in foreskin explant cultures; a dose-dependent inhibition is seen at doses higher than 10(-5) micrograms/ml. TPA also inhibits epidermal growth factor-stimulated growth and does not induce ornithine decarboxylase activity or increase polyamine levels. This is not due to the rapid breakdown of TPA, since TPA is not metabolized to any appreciable extent.

  1. The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

    DTIC Science & Technology

    2012-09-01

    Sica . Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23: 549-555...2002 3. Alberto Mantovani, Paola Allavena1, Antonio Sica and Frances Balkwill. Cancer-related inflammation. Nature. 454: 436-444, 2008 4. Karin E. de

  2. Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers.

    PubMed

    Perez, Roberto; Schally, Andrew V; Vidaurre, Irving; Rincon, Ricardo; Block, Norman L; Rick, Ferenc G

    2012-09-01

    This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFγ, IL-1α, IL-4, IL-6, IL-8, IL-10, and TNFα, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers.

  3. a Discrete Simulation of Tumor Growth Concerning Nutrient Influence

    NASA Astrophysics Data System (ADS)

    Sun, L.; Chang, Y. F.; Cai, X.

    We develop a 2-D discrete model to simulate malignant cells growing in healthy tissues using a thermodynamic method on the basis of Potts model. After introducing a malignant seed in a healthy tissue, we use a set of adjustment factors, including the interaction between cells and nutrient, to simulate the growth of malignant cells under different environments. This allows us to investigate the effects of environment on malignant cell growth and the formation of cancer.

  4. The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase.

    PubMed

    Chang, Da-Young; Yoo, Seung-Wan; Hong, Youngtae; Kim, Sujeong; Kim, Se Joong; Yoon, Sung-Hwa; Cho, Kyung-Gi; Paek, Sun Ha; Lee, Young-Don; Kim, Sung-Soo; Suh-Kim, Haeyoung

    2010-10-15

    Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential ex vivo therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene, cytosine deaminase (CD) to brain tumors. MSCs were engineered to produce CD enzymes at various levels using different promoters. When co-cultured, CD-expressing MSCs had a bystander, anti-cancer effect on neighboring C6 glioma cells in proportion to the levels of CD enzymes that could convert a nontoxic prodrug, 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) in vitro. Consistent with the in vitro results, for early stage brain tumors induced by intracranial inoculation of C6 cells, transplantation of CD-expressing MSCs reduced tumor mass in proportion to 5-FC dosages. However, for later stage, established tumors, a single treatment was insufficient, but only multiple transplantations were able to successfully repress tumor growth. Our findings indicate that the level of total CD enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent glioblastomas through repetitive treatments.

  5. Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice.

    PubMed

    Holmstrom, Alexandra; Wu, Ryan T Y; Zeng, Huawei; Lei, K Y; Cheng, Wen-Hsing

    2012-09-01

    The inhibitory effect of oral methylseleninic acid or methylselenocysteine administration on cancer cell xenograft development in nude mice is well characterized; however, less is known about the efficacy of selenate and age on selenium chemoprevention. In this study, we tested whether selenate and duration on diets would regulate prostate cancer xenograft in nude mice. Thirty-nine homozygous NU/J nude mice were fed a selenium-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se) or 1.0 (Se+) mg selenium/kg (as Na₂SeO₄) for 6 months in Experiment 1 and for 4 weeks in Experiment 2, followed by a 47-day PC-3 prostate cancer cell xenograft on the designated diet. In Experiment 1, the Se- diet enhanced the initial tumor development on days 11-17, whereas the Se+ diet suppressed tumor growth on days 35-47 in adult nude mice. Tumors grown in Se- mice were loosely packed and showed increased necrosis and inflammation as compared to those in Se and Se+ mice. In Experiment 2, dietary selenium did not affect tumor development or histopathology throughout the time course. In both experiments, postmortem plasma selenium concentrations in Se and Se+ mice were comparable and were twofold greater than those in Se- mice. Taken together, dietary selenate at nutritional and supranutritional levels differentially inhibit tumor development in adult, but not young, nude mice engrafted with PC-3 prostate cancer cells.

  6. Chicken HSP70 DNA vaccine inhibits tumor growth in a canine cancer model.

    PubMed

    Yu, Wen-Ying; Chuang, Tien-Fu; Guichard, Cécile; El-Garch, Hanane; Tierny, Dominique; Laio, Albert Taiching; Lin, Ching-Si; Chiou, Kuo-Hao; Tsai, Cheng-Long; Liu, Chen-Hsuan; Li, Wen-Chiuan; Fischer, Laurent; Chu, Rea-Min

    2011-04-18

    Immunization with xenogeneic DNA is a promising cancer treatment to overcome tolerance to self-antigens. Heat shock protein 70 (HSP70) is over-expressed in various kinds of tumors and is believed to be involved in tumor progression. This study tested a xenogeneic chicken HSP70 (chHSP70) DNA vaccine in an experimental canine transmissible venereal tumor (CTVT) model. Three vaccination strategies were compared: the first (PE) was designed to evaluate the prophylactic efficacy of chHSP70 DNA vaccination by delivering the vaccine before tumor inoculation in a prime boost setting, the second (T) was designed to evaluate the therapeutic efficacy of the same prime boost vaccine by vaccinating the dogs after tumor inoculation; the third (PT) was similar to the first strategy (PE), with the exception that the electroporation booster injection was replaced with a transdermal needle-free injection. Tumor growth was notably inhibited only in the PE dogs, in which the vaccination program triggered tumor regression significantly sooner than in control dogs (NT). The CD4(+) subpopulation of tumor-infiltrating lymphocytes and canine HSP70 (caHSP70)-specific IFN-γ-secreting lymphocytes were significantly increased during tumor regression in the PE dogs as compared to control dogs, demonstrating that specific tolerance to caHSP70 has been overcome. In contrast, no benefit of the therapeutic strategy (T) could be noticed and the (PT) strategy only led to partial control of tumor growth. In summary, antitumor prophylactic activity was demonstrated using the chHSP70 DNA vaccine including a boost via electroporation. Our data stressed the importance of DNA electroporation as a booster to get the full benefit of DNA vaccination but also of cancer immunotherapy initiation as early as possible. Xenogeneic chHSP70 DNA vaccination including an electroporation boost is a potential vaccine to HSP70-expressing tumors, although further research is still required to better understand true

  7. Diffuse optical spectroscopy monitoring of oxygen state and hemoglobin concentration during SKBR-3 tumor model growth

    NASA Astrophysics Data System (ADS)

    Orlova, A. G.; Kirillin, M. Yu; Volovetsky, A. B.; Shilyagina, N. Yu; Sergeeva, E. A.; Golubiatnikov, G. Yu; Turchin, I. V.

    2017-01-01

    Tumor oxygenation and hemoglobin content are the key indicators of the tumor status which can be efficiently employed for prognosis of tumor development and choice of treatment strategy. We report on monitoring of these parameters in SKBR-3 (human breast adenocarcinoma) tumors established as subcutaneous tumor xenografts in athymic nude mice by diffuse optical spectroscopy (DOS). A simple continuous wave fiber probe DOS system is employed. Optical properties extraction approach is based on diffusion approximation. Statistically significant difference between measured values of normal tissue and tumor are demonstrated. Hemoglobin content in tumor increases from 7.0  ±  4.2 μM to 30.1  ±  16.1 μM with tumor growth from 150  ±  80 mm3 to 1300  ±  650 mm3 which is determined by gradual increase of deoxyhemoglobin content while measured oxyhemoglobin content does not demonstrate any statistically significant variations. Oxygenation in tumor falls quickly from 52.8  ±  24.7% to 20.2  ±  4.8% preceding acceleration of tumor growth. Statistical analysis indicated dependence of oxy-, deoxy- and total hemoglobin on tumor volume (p  <  0.01). DOS measurements of oxygen saturation are in agreement with independent measurements of oxygen partial pressure by polarography (Pearson’s correlation coefficient equals 0.8).

  8. CD200-expressing human basal cell carcinoma cells initiate tumor growth.

    PubMed

    Colmont, Chantal S; Benketah, Antisar; Reed, Simon H; Hawk, Nga V; Telford, William G; Ohyama, Manabu; Udey, Mark C; Yee, Carole L; Vogel, Jonathan C; Patel, Girish K

    2013-01-22

    Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200(+) CD45(-) BCC subpopulation that represents 1.63 ± 1.11% of all BCC cells resides in small clusters at the tumor periphery. By using reproducible in vivo xenograft growth assays, we determined that tumor initiating cell frequencies approximate one per 1.5 million unsorted BCC cells. The CD200(+) CD45(-) BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200(+) CD45(-) cells, representing ~1,500-fold enrichment. CD200(-) CD45(-) BCC cells were unable to form tumors. These findings establish a platform to study the effects of Smoothened antagonists on BCC tumor initiating cell and also suggest that currently available anti-CD200 therapy be considered, either as monotherapy or an adjunct to Smoothened antagonists, in the treatment of inoperable BCC.

  9. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect.

    PubMed

    Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Tanaka, Hiroaki; Ohta, Hiroshi; Itoi, Takao; Tsuchida, Akihiko

    2011-11-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected.

  10. Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect

    PubMed Central

    KASUYA, KAZUHIKO; NAGAKAWA, YUICHI; SUZUKI, MINAKO; TANAKA, HIROAKI; OHTA, HIROSHI; ITOI, TAKAO; TSUCHIDA, AKIHIKO

    2011-01-01

    At present, no effective chemotherapy for pancreatic neuroendocrine carcinoma (PNEC) exists. However, anti-angiogenic therapy is expected to be effective for PNEC, a hypervascular tumor. We treated PNEC and hypovascular pancreatic ductal cell carcinoma (DCC) cell lines with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab, and compared the antitumor effect between the two different types of cell lines. The PNEC cell line QGP-1 and the DCC cell lines BxPC-3 and AsPC-1 were used. We evaluated the ability of the cell lines to proliferate and secrete VEGF in vitro, the antitumor effect of bevacizumab administration in vivo and the side effects of bevacizumab on the pancreas in a caerulein-induced pancreatitis model. Comparison of the QGP-1 and DCC cell lines showed that QGP-1 secreted a higher level of VEGF under a hypoxic environment than the DCC cell line, and bevacizumab exerted the most marked growth-inhibitory effect on QGP-1; the number of intratumoral blood vessels decreased and the percentage of proliferating cells was approximately the same. In the pancreatitis model, bevacizumab administration did not adversely affect the pancreatitis or the associated hypoxic environment. Bevacizumab does not affect the pancreas itself; therefore, its potent inhibitory effect on the growth of pancreatic neuroendocrine tumors alone can be expected. PMID:22977618

  11. Relationship Between Organization of Mammary Tumors and the Ability of Tumor Cells to Replicate Mammary Tumor Virus and to Recognize Growth-Inhibitory Contact Signals In Vitro

    PubMed Central

    McGrath, Charles M.; Nandi, S.; Young, Lawrence

    1972-01-01

    Mammary tumor virus (MTV) replication was confined primarily to cells organized as acini in intact mouse mammary glands. Primary mammary tumors maintained a high degree of acinar organization and cells therein continued to replicate MTV vegetatively. Nonacinar mammary cells, derived by serial transplantation of acinar tumor cells, no longer actively replicated MTV. This suggests that phenotypic differences exist among mammary epithelial cells in their ability to support virus replication, that a fundamental relationship exists between the organization of epithelium for secretion and active virus replication, and that this relationship is not altered as a primary consequence of neoplastic transformation. Mammary epithelial cells from pregnant, non-tumor-bearing, MTV-infected BALB/cfC3H mice or from acinar mammary tumors from a number of mouse strains were grown in primary monolayer cultures. Such cell cultures under the influence of insulin and cortisol exhibited the ability to organize into discrete three-dimensional structures called “domes.” MTV replication in such cultures took place primarily in cells within the organized domes. Cells cultured from nonacinar tumors did not exhibit any propensity to organize into domes, nor did they replicate MTV in primary culture. This suggests that the cell organizational requirement for MTV replication observed in vivo is conserved in primary culture. Dome formation is not an effect of virus replication, as cells from uninfected BALB/c animals organized into domes in culture without concomitant MTV replication. Growth-regulating signals, exerted between contiguous cells in cultures of non-MTV-infected mammary epithelium, were not modified by the occurrence of active virus replication nor as a direct consequence of neoplastic transformation. Cells derived from nontumor BALB/cfC3H glands and from spontaneous tumors exhibited cell growth kinetics, saturation densities, and deoxyribonucleic acid synthesis kinetics nearly

  12. Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro.

    PubMed

    Kelter, Gerhard; Schierholz, Jörg M; Fischer, Imma U; Fiebig, Heinz-Herbert

    2007-01-01

    Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity [T/C (Test/Control) < 30%]: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts.

  13. Growth status significantly affects the response of human lung cancer cells to antitumor polyamine-analogue exposure.

    PubMed

    Carlisle, Diane L; Devereux, Wendy L; Hacker, Amy; Woster, Patrick M; Casero, Robert A

    2002-08-01

    Human solid tumors frequently have a relatively small growth fraction,which interferes with the action of many chemotherapeutic agents that target actively cycling cells. Several polyamine analogues are currently being developed for clinical application against human solid tumors including N1,N11-bis(ethyl)norspermine. Therefore, an effort was made to examine the effects of growth rate on polyamine-analogue efficacy. Low growth fraction (LGF) cell cultures of the human non-small cell lung cancer cell line NCI-H157 were generated to partially mimic solid tumors with low mitotic indices. Log-phase cells were compared with LGF cells with respect to cell survival and biochemical effects after exposure to polyamine analogues. The results demonstrate generally that LGF NCI-H157 cells were sensitive to analogue treatment. However, the dose necessary to elicit a response in LGF cells was an order of magnitude higher than the dose needed in log-phase cells. Additionally, the biochemical effects of analogues were similar between log phase and LGF cells with regard to a down-regulation of polyamine biosynthesis as measured by ornithine decarboxylase activity and an increase in polyamine catabolism as indicated by an increase in spermidine/spermine N1-acetyltransferase activity. However, biochemical effects were less dramatic in the LGF cells than those observed in the log-phase cells. The overall results of these studies suggest that the growth status of solid tumors can significantly affect the response to antitumor polyamine analogues, and growth fraction must be considered in the continued development and use of the polyamine analogues.

  14. A Rigorous Sharp Interface Limit of a Diffuse Interface Model Related to Tumor Growth

    NASA Astrophysics Data System (ADS)

    Rocca, Elisabetta; Scala, Riccardo

    2016-11-01

    In this paper, we study the rigorous sharp interface limit of a diffuse interface model related to the dynamics of tumor growth, when a parameter ɛ, representing the interface thickness between the tumorous and non-tumorous cells, tends to zero. More in particular, we analyze here a gradient-flow-type model arising from a modification of the recently introduced model for tumor growth dynamics in Hawkins-Daruud et al. (Int J Numer Math Biomed Eng 28:3-24, 2011) (cf. also Hilhorst et al. Math Models Methods Appl Sci 25:1011-1043, 2015). Exploiting the techniques related to both gradient flows and gamma convergence, we recover a condition on the interface Γ relating the chemical and double-well potentials, the mean curvature, and the normal velocity.

  15. Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth

    PubMed Central

    Mobergslien, Anne; Peng, Qian; Vasovic, Vlada; Sioud, Mouldy

    2016-01-01

    Therapeutic strategies aiming at mobilizing immune effector cells to kill tumor cells independent of tumor mutational load and MHC expression status are expected to benefit cancer patients. Recently, we engineered various peptide-Fc fusion proteins for directing Fcg receptor-bearing immune cells toward tumor cells. Here, we investigated the immunostimulatory and anti-tumor effects of one of the engineered Fc fusion proteins (WN-Fc). In contrast to the Fc control, soluble WN-Fc-1 fusion protein activated innate immune cells (e.g. monocytes, macrophages, dendritic cells, NK cells), resulting in cytokine production and surface display of the lytic granule marker CD107a on NK cells. An engineered Fc-fusion variant carrying two peptide sequences (WN-Fc-2) also activated immune cells and bound to various cancer cell types with high affinity, including the murine 4T1 breast carcinoma cells. When injected into 4T1 tumor-bearing BALB/c mice, both peptide-Fc fusions accumulated in tumor tissues as compared to other organs such as the lungs. Moreover, treatment of 4T1 tumor-bearing BALB/c mice by means of two intravenous injections of the WN-Fc fusion proteins inhibited tumor growth with WN-Fc-2 being more effective than WN-Fc-1. Treatment resulted in tumor infiltration by T cells and NK cells. These new engineered WN-Fc fusion proteins may be a promising alternative to existing immunotherapies for cancer. PMID:27713158

  16. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

    PubMed

    Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

    2014-07-01

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

  17. Role of CD44 in Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis

    DTIC Science & Technology

    2002-09-01

    Malignant peripheral nerve sheath tumors ( MPNSTs ) are aggressive malignancies that arise within peripheral nerves. These tumors occur with increased...and abnormal expression of the epidermal growth factor receptor (EGFR). We previously found that MPNSTs express increased levels of the CD44 family...kinase activity (and not increased Ras-GTP) contributes to MPNST cell invasion. We further find that EGFR contributes at least part of the elevated Src

  18. Glomus tumors of the fingers: Expression of vascular endothelial growth factor

    PubMed Central

    Honsawek, Sittisak; Kitidumrongsook, Pravit; Luangjarmekorn, Pobe; Pataradool, Kawee; Thanakit, Voranuch; Patradul, Adisorn

    2016-01-01

    Glomus tumors are uncommon, benign, small neurovascular neoplasms derived from glomus bodies in the reticular dermis. Glomus bodies are found throughout the body to regulate body temperature and skin circulation; however, they are concentrated in the fingers and the sole of the foot. The typical presentation is a solitary nodule in the subungual or periungual area of the distal phalanx. The primary treatment of choice is surgical removal. We investigated expression of vascular endothelial growth factor (VEGF) using immunohistochemistry in glomus tumors of the fingers. All five glomus tumor samples were positive for VEGF expression. VEGF immunoreactivity was largely localized to the cytoplasm of tumor cells, suggesting a contribution of VEGF to the vascularization of glomus tumors. PMID:28032039

  19. Immunohistochemical detection of growth hormone (GH) in canine hepatoid gland tumors.

    PubMed

    Petterino, Claudio; Martini, Marco; Castagnaro, Massimo

    2004-05-01

    The aim of this study was to detect immunohistochemically means growth hormone (GH) in 24 hepatoid gland adenomas and 5 hepatoid gland carcinomas and to compare the difference of immunoreactivity between types of tumors. The tumors were classified according to the WHO standards. Tissue sections which were prepared from formalin-fixed, paraffin wax-embedded tissues from 25 male and 4 female dogs were carried out immunostaining using polyclonal primary anti-hGH and EnVision method. Of 24 hepatoid gland adenomas (perianal gland adenomas) 23 (95.8%) were positive. All 5 hepatoid gland carcinomas (perianal gland carcinomas) were positive. No statistically significant differences in percentage of labelled cells between malignant and benign tumors were seen. The present demonstration of GH in hepatoid gland tumors adds new data on GH in extra-pituitary tissues and hormon-dependent tumors.

  20. PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis

    PubMed Central

    Panigrahy, Dipak; Singer, Samuel; Shen, Lucy Q.; Butterfield, Catherine E.; Freedman, Deborah A.; Chen, Emy J.; Moses, Marsha A.; Kilroy, Susan; Duensing, Stefan; Fletcher, Christopher; Fletcher, Jonathan A.; Hlatky, Lynn; Hahnfeldt, Philip; Folkman, Judah; Kaipainen, Arja

    2002-01-01

    Several drugs approved for a variety of indications have been shown to exhibit antiangiogenic effects. Our study focuses on the PPARγ ligand rosiglitazone, a compound widely used in the treatment of type 2 diabetes. We demonstrate, for the first time to our knowledge, that PPARγ is highly expressed in tumor endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, we show that rosiglitazone suppresses primary tumor growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumor cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In our in vivo studies, rosiglitazone suppresses angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumors. These results suggest that PPARγ ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis. PMID:12370270

  1. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.

    PubMed

    Benjamin, L E; Golijanin, D; Itin, A; Pode, D; Keshet, E

    1999-01-01

    Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

  2. Inhibition of hyperglycemia-induced angiogenesis and breast cancer tumor growth by systemic injection of microRNA-467 antagonist.

    PubMed

    Krukovets, Irene; Legerski, Matthew; Sul, Pavel; Stenina-Adognravi, Olga

    2015-09-01

    Abnormal angiogenesis in multiple tissues is a key characteristic of the vascular complications of diabetes. However, angiogenesis may be increased in one tissue but decreased in another in the same patient at the same time point in the disease. The mechanisms of aberrant angiogenesis in diabetes are not understood. There are no selective therapeutic approaches to target increased neovascularization without affecting physiologic angiogenesis and angiogenesis in ischemic tissues. We recently reported a novel miRNA-dependent pathway that up-regulates angiogenesis in response to hyperglycemia in a cell- and tissue-specific manner. The goal of the work described herein was to test whether systemic administration of an antagonist of miR-467 would prevent hyperglycemia-induced local angiogenesis in a tissue-specific manner. We examined the effect of the antagonist on hyperglycemia-induced tumor growth and angiogenesis and on skin wound healing in mouse models of diabetes. Our data demonstrated that the systemic injection of the antagonist prevented hyperglycemia-induced angiogenesis and growth of mouse and human breast cancer tumors, where the miR-467 pathway was active in hyperglycemia. In tissues where the miR-467-dependent mechanism was not activated by hyperglycemia, there was no effect of the antagonist: the systemic injection did not affect skin wound healing or the growth of prostate tumors. The data show that systemic administration of the miR-467 antagonist could be a breakthrough approach in the treatment and prevention of diabetes-associated breast cancer in a tissue-specific manner without affecting physiologic angiogenesis and angiogenesis in ischemic tissues.

  3. Transplantation of human renal cell carcinoma into NMRI nu/nu mice. III. Effect of irradiation on tumor acceptance and tumor growth

    SciTech Connect

    Otto, U.; Huland, H.; Baisch, H.; Kloeppel, G.

    1985-07-01

    Irradiation of human renal cell carcinoma before radical tumor nephrectomy resulted in a significantly lower acceptance rate (1 of 7) in nude mice than for nonirradiated tumors (all of 13). The tumor tissue was transplanted into NMRI nu/nu mice immediately after nephrectomy. In this experimental system the authors demonstrated the reduced vitality of human tumor cells after irradiation. In a second series of experiments, 3 morphologically different human renal cell carcinomas were irradiated at various doses after establishment in nude mice. The irradiated tumor tissue was transplanted to the next passage. The morphology, proliferation rate and growth of these tumors were compared with those of nonirradiated controls. Radiation effect was dose dependent in the responding tumor types. The characteristics correlated with radiosensitivity were high proliferation rate (measured by flow cytometry), low cytologic grading and fast growth rate in the nude mice.

  4. Food intake, tumor growth, and weight loss in EP2 receptor subtype knockout mice bearing PGE2-producing tumors

    PubMed Central

    Iresjö, Britt-Marie; Wang, Wenhua; Nilsberth, Camilla; Andersson, Marianne; Lönnroth, Christina; Smedh, Ulrika

    2015-01-01

    Previous studies in our laboratory have demonstrated that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. In the present study, we investigate the role of PGE receptor subtype EP2 in the development of anorexia after MCG 101 implantation in wild-type (EP2+/+) or EP2-receptor knockout (EP2−/−) mice. Our results showed that host absence of EP2 receptors attenuated tumor growth and development of anorexia in tumor-bearing EP2 knockout mice compared to tumor-bearing wild-type animals. Microarray profiling of the hypothalamus revealed a relative twofold change in expression of around 35 genes including mRNA transcripts coding for Phospholipase A2 and Prostaglandin D2 synthase (Ptgds) in EP2 receptor knockout mice compared to wild-type mice. Prostaglandin D2 synthase levels were increased significantly in EP2 receptor knockouts, suggesting that improved food intake may depend on altered balance of prostaglandin production in hypothalamus since PGE2 and PGD2 display opposing effects in feeding control. PMID:26197930

  5. Fish oil supplementation reduces cachexia and tumor growth while improving renal function in tumor-bearing rats.

    PubMed

    Coelho, Isabela; Casare, Fernando; Pequito, Danielle C T; Borghetti, Gina; Yamazaki, Ricardo K; Brito, Gleisson A P; Kryczyk, Marcelo; Fernandes, Luiz Claudio; Coimbra, Terezila M; Fernandez, Ricardo

    2012-11-01

    The objective of the present work was to study the renal function of healthy and tumor-bearing rats chronically supplemented with fish oil (FO), a source of n-3 polyunsaturated fatty acids. Weanling male rats were divided in two groups, one control (C) and another orally supplemented for 70 days with FO (1 g/kg body weight). After this time, half the animals of each group were injected in the right flank with a suspension of Walker 256 tumor cells (W and WFO). The W group had less proteinemia reflecting cachectic proteolysis, FO reversed this fact. Tumor weight gain was also reduced in WFO. Glomerular filtration rate (GFR) was not different in FO or W compared to C, but was higher in WFO. Renal plasma flow (RPF) was higher in the FO supplemented groups. The W group had lower plasma osmolality than the C group, but FO supplementation resulted in normalization of this parameter. Fractional sodium excretion (FE(Na+)) of FO rats was similar to C. Proximal Na(+) reabsorption, evaluated by lithium clearance, was similar among the groups. Urinary thromboxane B(2) (TXB(2)) excretion was lower in the supplemented groups. The number of macrophages in renal tissue was higher in W compared to C rats, but was lower in WFO rats compared to W rats. In conclusion, FO supplementation resulted in less tumor growth and cachexia, and appeared to be renoprotective, as suggested by higher RPF and GFR.

  6. Organizational Career Growth, Affective Occupational Commitment and Turnover Intentions

    ERIC Educational Resources Information Center

    Weng, Qingxiong; McElroy, James C.

    2012-01-01

    Survey data, collected from the People's Republic of China, were used to test Weng's (2010) four facet model of career growth and to examine its effect on occupational commitment and turnover intentions. Weng conceptualized career growth as consisting of four factors: career goal progress, professional ability development, promotion speed, and…

  7. Placental growth factor is a survival factor for tumor endothelial cells and macrophages.

    PubMed

    Adini, Avner; Kornaga, Tad; Firoozbakht, Farshid; Benjamin, Laura E

    2002-05-15

    The vascular endothelial growth factor (VEGF)-related factor, placental growth factor (PlGF),has been shown recently to play an important role in pathological VEGF-driven angiogenesis. In this study, we examine the effects of mPlGF/PlGF-2 overexpression in tumors grown from glioma cells containing a tetracycline-regulated mPlGF cDNA. Overexpression of mPlGF leads to increased tumor growth and vascular survival. When tetracycline is used to abruptly withdraw mPlGF overexpression, we see increased apoptosis in both vascular cells and macrophages. In addition, PlGF-2 induces survival gene expression and inhibits apoptosis in vitro. Thus, we propose that PlGF-2 contributes to tumor angiogenesis by providing increased survival function to endothelial cells and macrophages.

  8. Time until first significant difference in in vivo tumor growth experiments.

    PubMed

    Heitjan, D F; Kunselman, S

    1995-01-01

    In in vivo tumor growth experiments it is common to report the tumor measurement time at which the volume distributions of the treatment groups become significantly different. This method of analysis, as commonly practiced, is deficient in that its type I error rate exceeds the usual nominal rate of 5%, unless one specifically corrects for multiple comparisons. A second problem is that many investigators evidently interpret the time of first significance as a statistical parameter--i.e., a fixed but unknown property of the model that one can estimate by experimentation. In fact the time until first significance, like the power of the test, depends both on true model parameters (such as mean growth curves and experimental variability) and on features of the experimental design, such as the sample size and the spacing of the measurement times. We argue that investigators would do better to compare treatment groups by modeling tumor growth curves or estimating volume doubling times.

  9. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis.

  10. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

    PubMed Central

    Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

    2013-01-01

    Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

  11. Influence of selenium on the growth of N-nitrosomethylurea-induced mammary tumor cells in culture

    SciTech Connect

    Lewko, W.M.; McConnell, K.P.

    1985-10-01

    Selenium is an essential dietary trace element which has anticancer properties. Among its effects in rats, selenium has been shown to inhibit the development of carcinogen-induced mammary tumors by interfering with the post-initiation, promotion phase of carcinogenesis. We studied the effects of selenium on the growth of rat mammary tumor cells in primary culture. The objective was to determine whether selenium had any direct influence on cell growth which might explain its influence on tumor development. Rat mammary tumors were induced by N-nitrosomethylurea. The addition of low concentrations of sodium selenite, less than 1.0 ..mu..g/ml, stimulated tumor cell proliferation. Protein synthesis and the production of type IV collagen increased within the first hour of exposure, prior to any measurable increase in DNA synthesis. Concentrations of selenite greater than 1.0 ..mu..g/ml inhibited cell proliferation, the synthesis of protein, and the replication of DNA in a dose-related manner. These studies demonstrated that selenium has the potential to influence the post-initiation phase of rat mammary tumorigenesis by directly altering the growth of tumor cells, possibly through the regulation of protein synthesis.

  12. A Time-Delayed Mathematical Model for Tumor Growth with the Effect of a Periodic Therapy.

    PubMed

    Xu, Shihe; Wei, Xiangqing; Zhang, Fangwei

    2016-01-01

    A time-delayed mathematical model for tumor growth with the effect of periodic therapy is studied. The establishment of the model is based on the reaction-diffusion dynamics and mass conservation law and is considered with a time delay in cell proliferation process. Sufficient conditions for the global stability of tumor free equilibrium are given. We also prove that if external concentration of nutrients is large the tumor will not disappear and the conditions under which there exist periodic solutions to the model are also determined. Results are illustrated by computer simulations.

  13. On the growth rates of human malignant tumors: implications for medical decision making.

    PubMed

    Friberg, S; Mattson, S

    1997-08-01

    Testicular carcinomas, pediatric tumors, and some mesenchymal tumors are examples of rapidly proliferating cell populations, for which the tumor volume doubling time (TVDT) can be counted in days. Cancers from the breast, prostate, and colon are frequently slow-growing, displaying a TVDT of months or years. Irrespective of their growth rates, most human tumors have been found: to start from one single cell, to have a long subclinical period, to grow at constant rates for long periods of time, to start to metastasize often even before the primary is detected, and to have metastases that often grow at approximately the same rate as the primary tumor. The recognition of basic facts in tumor cell kinetics is essential in the evaluation of important present-day strategies in oncology. Among the facts emphasized in this review are: (1) Screening programs. Most tumors are several years old when detectable by present-day diagnostic methods. This makes the term "early detection" questionable. (2) Legal trials. The importance of so-called doctor's delay is often discussed, but the prognostic value of "early" detection is overestimated. (3) Analyses of clinical trials. Such analysis may be differentiated depending on the growth rates of the type of tumor studied. Furthermore, uncritical analysis of survival data may be misleading if the TVDT is not taken into consideration. (4) Analyses of epidemiological data. If causes of malignant tumors in humans are searched for, the time of exposure must be extended far back in the subject's history. (5) Risk estimations by insurance companies. For the majority of human cancers, the 5-year survival rate is not a valid measurement for cure. Thus, basic knowledge of tumor kinetics may have important implications for political health programs, legal trials, medical science, and insurance policies.

  14. The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

    PubMed

    Dang, Mai T; Wehrli, Suzanne; Dang, Chi V; Curran, Tom

    2015-01-01

    The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

  15. Tumor growth reduction in Walker 256 tumor-bearing rats performing anaerobic exercise: participation of Bcl-2, Bax, apoptosis, and peroxidation.

    PubMed

    de Lima, Carina; Alves, Luciana; Iagher, Fabíola; Machado, Andressa Franzoi; Kryczyk, Marcelo; Yamazaki, Ricardo Key; Brito, Gleisson Alisson Pereira; Nunes, Everson Araújo; Naliwaiko, Katya; Fernandes, Luiz Cláudio

    2011-08-01

    Physical activity has been used in cancer prevention and treatment. In this study, we investigated some of the mechanisms by which anaerobic exercise reduces tumor growth. To do so, rats were trained for 8 weeks. Training consisted of jumping in a swimming pool for ten 30-s sets, with a load that was 50% of body weight attached to the back, 4 times per week. At the sixth week, anaerobic exercise trained rats (EX group) were inoculated with a suspension of Walker 256 tumor cells. Tumor weight, apoptotic tumor cells, tumor Bax and Bcl-2 protein expression, tumor lipid peroxidation, and tumor cell proliferation ex vivo were evaluated. Tumor weight was significantly lower in the EX group (∼30%) than in rats that did not undergo training (sedentary group) (p < 0.05). Apoptosis in the tumor cells of EX rats was 2-fold higher than in the tumor cells of sedentary rats; in addition, Bax expression increased by 10% and Bcl-2 decreased by 13% in EX rats. Lipid peroxidation was 4-fold higher in the tumor cells of EX rats than in those of sedentary rats (p < 0.05). Tumor cell proliferation ex vivo was 29% lower in the EX group than in the sedentary group (p < 0.05). In conclusion, Walker 256 tumor-bearing exercised rats presented more tumor cell apoptosis, a higher tumor content of lipid peroxides, pro-apoptotic protein expression balance, and reduced tumor weight and cell proliferation ex vivo, compared with sedentary rats. These events, together, account for the lower tumor growth we observed in the EX rats.

  16. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

    PubMed

    Young, Christian D; Pfefferle, Adam D; Owens, Philip; Kuba, María G; Rexer, Brent N; Balko, Justin M; Sánchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

  17. Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model.

    PubMed

    Yoshida, Fumiyo; Yamamoto, Tetsuya; Nakai, Kei; Kumada, Hiroaki; Shibata, Yasushi; Tsuruta, Wataro; Endo, Kiyoshi; Tsurubuchi, Takao; Matsumura, Akira

    2008-05-18

    We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.

  18. Agent-Based Modeling of Cancer Stem Cell Driven Solid Tumor Growth.

    PubMed

    Poleszczuk, Jan; Macklin, Paul; Enderling, Heiko

    2016-01-01

    Computational modeling of tumor growth has become an invaluable tool to simulate complex cell-cell interactions and emerging population-level dynamics. Agent-based models are commonly used to describe the behavior and interaction of individual cells in different environments. Behavioral rules can be informed and calibrated by in vitro assays, and emerging population-level dynamics may be validated with both in vitro and in vivo experiments. Here, we describe the design and implementation of a lattice-based agent-based model of cancer stem cell driven tumor growth.

  19. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion.

    PubMed

    Sebban, Shulamit; Farago, Marganit; Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-10-15

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways.

  20. Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion

    PubMed Central

    Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

    2014-01-01

    Vav1 is a signal transducer that functions as a scaffold protein and a regulator of cytoskeleton organization in the hematopoietic system, where it is exclusively expressed. Recently, Vav1 was shown to be involved in diverse human cancers, including lung cancer. We demonstrate that lung cancer cells that abnormally express Vav1 secrete growth factors in a Vav1-dependent manner. Transcriptome analysis demonstrated that Vav1 depletion results in a marked reduction in the expression of colony-stimulating-factor-1 (CSF1), a hematopoietic growth factor. The association between Vav1 expression and CSF1 was further supported by signal transduction experiments, supporting involvement of Vav1 in regulating lung cancer secretome. Blocking of ERK phosphorylation, led to a decrease in CSF1 transcription, thus suggesting a role for ERK, a downstream effector of Vav1, in CSF1 expression. CSF1-silenced cells exhibited reduced focus formation, proliferation abilities, and growth in NOD/SCID mice. CSF1-silenced H358 cells resulted in significantly smaller tumors, showing increased fibrosis and a decrease in tumor infiltrating macrophages. Finally, immunohistochemical analysis of primary human lung tumors revealed a positive correlation between Vav1 and CSF1 expression, which was associated with tumor grade. Additional results presented herein suggest a potential cross-talk between cancer cells and the microenvironment controlled by CSF1/Vav1 signaling pathways. PMID:25313137

  1. Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

    PubMed Central

    Laukkanen, Mikko O.

    2016-01-01

    Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2−) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction. PMID:27293512

  2. Biomarker- versus drug-driven tumor growth inhibition models: an equivalence analysis.

    PubMed

    Sardu, Maria Luisa; Poggesi, Italo; De Nicolao, Giuseppe

    2015-12-01

    The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic-pharmacodynamic (PK-PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor growth inhibition (TGI) models, drug-to-biomarker, e.g. indirect response models, and biomarker-to-tumor, e.g. the more recent biomarker-driven TGI models. In particular, this paper derives a mathematical relationship that guarantees the steady-state equivalence of the cascade of drug-to-biomarker and biomarker-to-tumor models with a drug-to-tumor TGI model. Using the Simeoni TGI model as a reference, conditions for steady-state equivalence are worked out and used to derive a new biomarker-driven model. Simulated and real data are used to show that in realistic cases the steady-state equivalence extends also to transient responses. The possibility of predicting the drug-to-tumor potency of a new candidate drug based only on biomarker response is discussed.

  3. The Host Defense Peptide Cathelicidin Is Required for NK Cell-Mediated Suppression of Tumor Growth

    PubMed Central

    Büchau, Amanda S.; Morizane, Shin; Trowbridge, Janet; Schauber, Jürgen; Kotol, Paul; Bui, Jack D.; Gallo, Richard L.

    2010-01-01

    Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide, although it is now clear that it fulfills a variety of immune functions beyond microbial killing. Recent data have suggested contrasting roles for cathelicidin in tumor development. Because its role in tumor surveillance is not well understood, we investigated the requirement of cathelicidin in controlling transplantable tumors in mice. Cathelicidin was observed to be abundant in tumor-infiltrating NK1.1+ cells in mice. The importance of this finding was demonstrated by the fact that cathelicidin knockout mice (Camp−/−) permitted faster tumor growth than wild type controls in two different xenograft tumor mouse models (B16.F10 and RMA-S). Functional in vitro analyses found that NK cells derived from Camp−/− versus wild type mice showed impaired cytotoxic activity toward tumor targets. These findings could not be solely attributed to an observed perforin deficiency in freshly isolated Camp−/− NK cells, because this deficiency could be partially restored by IL-2 treatment, whereas cytotoxic activity was still defective in IL-2-activated Camp−/− NK cells. Thus, we demonstrate a previously unrecognized role of cathelicidin in NK cell antitumor function. PMID:19949065

  4. The Rac Inhibitor EHop-016 Inhibits Mammary Tumor Growth and Metastasis in a Nude Mouse Model

    PubMed Central

    Castillo-Pichardo, Linette; Humphries-Bickley, Tessa; De La Parra, Columba; Forestier-Roman, Ingrid; Martinez-Ferrer, Magaly; Hernandez, Eliud; Vlaar, Cornelis; Ferrer-Acosta, Yancy; Washington, Anthony V.; Cubano, Luis A.; Rodriguez-Orengo, Jose; Dharmawardhane, Suranganie

    2014-01-01

    Metastatic disease still lacks effective treatments, and remains the primary cause of cancer mortality. Therefore, there is a critical need to develop better strategies to inhibit metastatic cancer. The Rho family GTPase Rac is an ideal target for anti-metastatic cancer therapy, because Rac is a key molecular switch that is activated by a myriad of cell surface receptors to promote cancer cell migration/invasion and survival. Previously, we reported the design and development of EHop-016, a small molecule compound, which inhibits Rac activity of metastatic cancer cells with an IC50 of 1 μM. EHop-016 also inhibits the activity of the Rac downstream effector p21-activated kinase (PAK), lamellipodia extension, and cell migration in metastatic cancer cells. Herein, we tested the efficacy of EHop-016 in a nude mouse model of experimental metastasis, where EHop-016 administration at 25 mg/kg body weight (BW) significantly reduced mammary fat pad tumor growth, metastasis, and angiogenesis. As quantified by UPLC MS/MS, EHop-016 was detectable in the plasma of nude mice at 17 to 23 ng/ml levels at 12 h following intraperitoneal (i.p.) administration of 10 to 25 mg/kg BW EHop-016. The EHop-016 mediated inhibition of angiogenesis In Vivo was confirmed by immunohistochemistry of excised tumors and by In Vitro tube formation assays of endothelial cells. Moreover, EHop-016 affected cell viability by down-regulating Akt and Jun kinase activities and c-Myc and Cyclin D expression, as well as increasing caspase 3/7 activities in metastatic cancer cells. In conclusion, EHop-016 has potential as an anticancer compound to block cancer progression via multiple Rac-directed mechanisms. PMID:25389450

  5. Thyroid hormone suppresses expression of stathmin and associated tumor growth in hepatocellular carcinoma

    PubMed Central

    Tseng, Yi-Hsin; Huang, Ya-Hui; Lin, Tzu-Kang; Wu, Sheng-Ming; Chi, Hsiang-Cheng; Tsai, Chung-Ying; Tsai, Ming-Ming; Lin, Yang-Hsiang; Chang, Wei-Chun; Chang, Ya-Ting; Chen, Wei-Jan; Lin, Kwang-Huei

    2016-01-01

    Stathmin (STMN1), a recognized oncoprotein upregulated in various solid tumors, promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms underlying the genetic regulation of STMN1 have yet to be elucidated. In the current study, we report that thyroid hormone receptor (THR) expression is negatively correlated with STMN1 expression in a subset of clinical hepatocellular carcinoma (HCC) specimens. We further identified the STMN1 gene as a target of thyroid hormone (T3) in the HepG2 hepatoma cell line. An analysis of STMN1 expression profile and mechanism of transcriptional regulation revealed that T3 significantly suppressed STMN1 mRNA and protein expression, and further showed that THR directly targeted the STMN1 upstream element to regulate STMN1 transcriptional activity. Specific knockdown of STMN1 suppressed cell proliferation and xenograft tumor growth in mice. In addition, T3 regulation of cell growth arrest and cell cycle distribution were attenuated by overexpression of STMN1. Our results suggest that the oncogene STMN1 is transcriptionally downregulated by T3 in the liver. This T3-mediated suppression of STMN1 supports the theory that T3 plays an inhibitory role in HCC tumor growth, and suggests that the lack of normal THR function leads to elevated STMN1 expression and malignant growth. PMID:27934948

  6. Ovarian high-grade serous carcinoma with a noninvasive growth pattern simulating a serous borderline tumor.

    PubMed

    Imamura, Hiroko; Ohishi, Yoshihiro; Aman, Murasaki; Shida, Kaai; Shinozaki, Tomoko; Yasutake, Nobuko; Sonoda, Kenzo; Kato, Kiyoko; Oda, Yoshinao

    2015-10-01

    Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT.

  7. Regulation of tumor growth by circulating full-length chromogranin A

    PubMed Central

    Gasparri, Anna; Sacchi, Angelina; Colombo, Barbara; Fiocchi, Martina; Perani, Laura; Venturini, Massimo; Tacchetti, Carlo; Sen, Suvajit; Borges, Ricardo; Dondossola, Eleonora; Esposito, Antonio; Mahata, Sushil K.; Corti, Angelo

    2016-01-01

    Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves. Tumor growth inhibition was associated with reduction of microvessel density and blood flow in neoplastic tissues. Neutralization of endogenous CgA with antibodies against its C-terminal region (residues 410-439) promoted tumor growth. Structure-function studies showed that the C-terminal region of CgA contains a bioactive site and that cleavage of this region causes a marked loss of anti-angiogenic and anti-tumor potency. Mechanistic studies showed that full-length CgA could induce, with a U-shaped dose-response curve, the production of protease nexin-1 in endothelial cells, a serine protease inhibitor endowed of anti-angiogenic activity. Gene silencing or neutralization of protease nexin-1 with specific antibodies abolished both anti-angiogenic and anti-tumor effects of CgA. These results suggest that circulating full-length CgA is an important inhibitor of angiogenesis and tumor growth, and that cleavage of its C-terminal region markedly reduces its activity. Pathophysiological changes in CgA blood levels and/or its fragmentation might regulate disease progression in cancer patients. PMID:27683038

  8. 2-(ω-Carboxyethyl)pyrrole Antibody as a New Inhibitor of Tumor Angiogenesis and Growth.

    PubMed

    Wu, Chunying; Wang, Xizhen; Tomko, Nicholas; Zhu, Junqing; Wang, William R; Zhu, Jinle; Wang, Yanming; Salomon, Robert G

    2016-09-22

    Angiogenesis is a fundamental process in the progression, invasion, and metastasis of tumors. Therapeutic drugs such as bevacizumab and ranibuzumab have thus been developed to inhibit vascular endothelial growth factor (VEFG)-promoted angiogenesis. While these anti-angiogenic drugs have been commonly used in the treatment of cancer, patients often develop significant resistance that limits the efficacy of anti-VEGF therapies to a short period of time. This is in part due to the fact that an independent pathway of angiogenesis exists, which is mediated by 2-(ω-carboxyethyl)pyrrole (CEP) in a TLR2 receptor-dependent manner that can compensate for inhibition of the VEGF-mediated pathway. In this work, we evaluated a CEP antibody as a new tumor growth inhibitor that blocks CEP-induced angiogenesis. We first evaluated the effectiveness of a CEP antibody as a monotherapy to impede tumor growth in two human tumor xenograft models. We then determined the synergistic effects of bevacizumab and CEP antibody in a combination therapy, which demonstrated that blocking of the CEP-mediated pathway significantly enhanced the anti-angiogenic efficacy of bevacizumab in tumor growth inhibition indicating that CEP antibody is a promising chemotherapeutic drug. To facilitate potential translational studies of CEP-antibody, we also conducted longitudinal imaging studies and identified that FMISO-PET is a non-invasive imaging tool that can be used to quantitatively monitor the anti-angiogenic effects of CEP-antibody in the clinical setting. That treatment with CEP antibody induces hypoxia in tumor tissue was indicated by 43% higher uptake of [18F]FMISO in CEP antibody-treated tumor xenografs than in the control PBS-treated littermates.

  9. Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies

    PubMed Central

    Kwon, Youngjoo

    2014-01-01

    Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors. PMID:25493176

  10. Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data

    SciTech Connect

    Schwachoefer, J.H.C.; Crooijmans, R.P.; van Gasteren, J.J.; Hoogenhout, J.; Jerusalem, C.R.; Kal, H.B.; Theeuwes, A.G. )

    1989-11-01

    Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity.

  11. Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose redistribution.

    PubMed

    Unkelbach, Jan; Menze, Bjoern H; Konukoglu, Ender; Dittmann, Florian; Ayache, Nicholas; Shih, Helen A

    2014-02-07

    Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose-the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm(-1). It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm(-1). The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a

  12. Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose redistribution

    NASA Astrophysics Data System (ADS)

    Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Ayache, Nicholas; Shih, Helen A.

    2014-02-01

    Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose—the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm-1. It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm-1. The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a continuous

  13. Activation of trkA induces differentiation and inhibits the growth of JK-GMS Askin tumor cells.

    PubMed

    Kim, Gi-Jin; Kim, Chong Jai; Cho, So Young; Chung, In Pyung; Park, Sun-Hwa; Lee, Min Jung; Chi, Je G

    2002-02-01

    Peripheral primitive neuroectodermal tumor (PNET) and Ewing's sarcoma (ES) constitute a unique group of small round cell tumors in childhood and young adults that are characterized by the same chromosomal translocation t(11;22)(q24;q12). Recently, the expression of neurotrophin receptors has been found in various human tumors including PNET/ES, but the functional significance of these receptor expressions has not been documented in PNET/ES. In the present study, we investigated the biologic effects of trkA neurotrophin receptor activation by nerve growth factor (NGF) in a newly established Askin tumor cell line, JK-GMS, which constitutively expresses a high level of trkA. The activation of trkA induced differentiation and inhibited the growth of JK-GMS cells, which was characteristically associated with down-regulation of c-myc and N-myc mRNA expression. NGF did not exert significant changes in two different PNET/ES cell lines, CADO-ES1 and RD-ES, which did not express detectable levels of trkA. The biologic effects mediated by NGF were abrogated by treatment of the cells with K-252a, and the treatment with brain-derived neurotrophic factor did not affect the biologic behavior of JK-GMS cells, indicating that the effects are trkA specific. The results observed were quite similar to those of neuroblastoma cells, another childhood tumor of neural crest origin. Overall findings strongly suggest that the trkA-mediated signaling pathway plays a crucial role in controlling the basic biologic properties of JK-GMS cells.

  14. Cellular and Tumor Radiosensitivity is Correlated to Epidermal Growth Factor Receptor Protein Expression Level in Tumors Without EGFR Amplification;Epidermal growth factor receptor; Radiotherapy; Squamous cell carcinoma; Biomarker; Local tumor control

    SciTech Connect

    Kasten-Pisula, Ulla; Saker, Jarob; Eicheler, Wolfgang; Krause, Mechthild; Yaromina, Ala; Meyer-Staeckling, Soenke; Scherkl, Benjamin; Kriegs, Malte; Brandt, Burkhard; Grenman, Reidar; Petersen, Cordula; Baumann, Michael; Dikomey, Ekkehard

    2011-07-15

    Purpose: There is conflicting evidence for whether the expression of epidermal growth factor receptor in human tumors can be used as a marker of radioresponse. Therefore, this association was studied in a systematic manner using squamous cell carcinoma (SCC) cell lines grown as cell cultures and xenografts. Methods and Materials: The study was performed with 24 tumor cell lines of different tumor types, including 10 SCC lines, which were also investigated as xenografts on nude mice. Egfr gene dose and the length of CA-repeats in intron 1 were determined by polymerase chain reaction, protein expression in vitro by Western blot and in vivo by enzyme-linked immunosorbent assay, and radiosensitivity in vitro by colony formation. Data were correlated with previously published tumor control dose 50% data after fractionated irradiation of xenografts of the 10 SCC. Results: EGFR protein expression varies considerably, with most tumor cell lines showing moderate and only few showing pronounced upregulation. EGFR upregulation could only be attributed to massive gene amplification in the latter. In the case of little or no amplification, in vitro EGFR expression correlated with both cellular and tumor radioresponse. In vivo EGFR expression did not show this correlation. Conclusions: Local tumor control after the fractionated irradiation of tumors with little or no gene amplification seems to be dependent on in vitro EGFR via its effect on cellular radiosensitivity.

  15. Critical Role of Shp2 in Tumor Growth Involving Regulation of c-Myc

    PubMed Central

    Ren, Yuan; Chen, Zhengming; Chen, Liwei; Fang, Bin; Win-Piazza, Hla; Haura, Eric; Koomen, John M.; Wu, Jie

    2010-01-01

    Activating mutants of Shp2 protein tyrosine phosphatase, encoded by the PTPN11 gene, are linked to leukemia. In solid tumors, however, PTPN11 mutations occur at low frequencies, while the wild-type Shp2 is activated by protein tyrosine kinases (PTKs) in cancer cells and mediates PTK signaling. Therefore, it is important to address whether the wild-type Shp2 plays a functional role critical for tumor growth. Using shRNAs and a PTP-inactive mutant to inhibit Shp2, we find here that tumor growth of DU145 prostate cancer and H292 lung cancer cells depends on Shp2. Suppression of Shp2 inhibited cell proliferation, decreased c-Myc, and increased p27 expression in cell cultures. In H292 tumor tissues, c-Myc–positive cells coincided with Ki67-positive cells, and smaller tumors from Shp2 knockdown cells had less c-Myc–positive cells and more nuclear p27. Shp2-regulated c-Myc expression was mediated by Src and Erk1/2. Down-regulation of c-Myc reduced cell proliferation, while up-regulation of c-Myc in Shp2 knockdown H292 cells partially rescued the inhibitory effect of Shp2 suppression on cell proliferation. Tyrosine phosphoproteomic analysis of H292 tumor tissues showed that Shp2 could both up-regulate and down-regulate tyrosine phosphorylation on cellular proteins. Among other changes, Shp2 inhibition increased phosphorylation of Src Tyr-530 and Cdk1 Thr-14/Tyr-15 and decreased phosphorylation of Erk1- and Erk2-activating sites in the tumors. Significantly, we found that Shp2 positively regulated Gab1 Tyr-627/Tyr-659 phosphorylation. This finding reveals that Shp2 can autoregulate its own activating signal. Shp2 Tyr-62/Tyr-63 phosphorylation was observed in tumor tissues, indicating that Shp2 is activated in the tumors. PMID:21442024

  16. β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation

    PubMed Central

    Sayeed, Aejaz; Lu, Huimin; Liu, Qin; II, David Deming; Duffy, Alexander; McCue, Peter; Dicker, Adam P.; Davis, Roger J.; Gabrilovich, Dmitry; Rodeck, Ulrich; Altieri, Dario C.; Languino, Lucia R.

    2016-01-01

    Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (β1wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1pc-/- /TRAMP). Since JNK is known to be suppressed by β1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in β1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the β1/IGF-IR crosstalk and report that β1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that β1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation. PMID:27438371

  17. Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

    PubMed Central

    Nokin, Marie-Julie; Durieux, Florence; Peixoto, Paul; Chiavarina, Barbara; Peulen, Olivier; Blomme, Arnaud; Turtoi, Andrei; Costanza, Brunella; Smargiasso, Nicolas; Baiwir, Dominique; Scheijen, Jean L; Schalkwijk, Casper G; Leenders, Justine; De Tullio, Pascal; Bianchi, Elettra; Thiry, Marc; Uchida, Koji; Spiegel, David A; Cochrane, James R; Hutton, Craig A; De Pauw, Edwin; Delvenne, Philippe; Belpomme, Dominique; Castronovo, Vincent; Bellahcène, Akeila

    2016-01-01

    Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment. DOI: http://dx.doi.org/10.7554/eLife.19375.001 PMID:27759563

  18. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    SciTech Connect

    Hua Chiaho; Wu Shengjie; Chemaitilly, Wassim; Lukose, Renin C.; Merchant, Thomas E.

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  19. Phytochemical potential of Eruca sativa for inhibition of melanoma tumor growth.

    PubMed

    Khoobchandani, M; Ganesh, N; Gabbanini, S; Valgimigli, L; Srivastava, M M

    2011-06-01

    Solvent extracts from the aerial and root parts and seed oil from E. sativa (rocket salad) were assayed for anticancer activity against melanoma cells. The seed oil (isothiocyanates rich) significantly (p<0.01) reduced the tumor growth comparable to the control. Remarkably, the seed oil inhibited melanoma growth and angiogenesis in mice without any major toxicity. The findings qualify seed oil for further investigations in the real of cancer prevention and treatment.

  20. Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

    PubMed Central

    Al-Jamal, Khuloud T.; Al-Jamal, Wafa’ T.; Akerman, Simon; Podesta, Jennifer E.; Yilmazer, Açelya; Turton, John A.; Bianco, Alberto; Vargesson, Neil; Kanthou, Chryso; Florence, Alexander T.; Tozer, Gillian M.; Kostarelos, Kostas

    2010-01-01

    This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G6) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems. PMID:20150514

  1. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress

    PubMed Central

    Zaugg, Kathrin; Yao, Yi; Reilly, Patrick T.; Kannan, Karuppiah; Kiarash, Reza; Mason, Jacqueline; Huang, Ping; Sawyer, Suzanne K.; Fuerth, Benjamin; Faubert, Brandon; Kalliomäki, Tuula; Elia, Andrew; Luo, Xunyi; Nadeem, Vincent; Bungard, David; Yalavarthi, Sireesha; Growney, Joseph D.; Wakeham, Andrew; Moolani, Yasmin; Silvester, Jennifer; Ten, Annick You; Bakker, Walbert; Tsuchihara, Katsuya; Berger, Shelley L.; Hill, Richard P.; Jones, Russell G.; Tsao, Ming; Robinson, Murray O.; Thompson, Craig B.; Pan, Guohua; Mak, Tak W.

    2011-01-01

    Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors. PMID:21576264

  2. An Adaptive Multigrid Algorithm for Simulating Solid Tumor Growth Using Mixture Models

    PubMed Central

    Wise, S.M.; Lowengrub, J.S.; Cristini, V.

    2010-01-01

    In this paper we give the details of the numerical solution of a three-dimensional multispecies diffuse interface model of tumor growth, which was derived in (Wise et al., J. Theor. Biol. 253 (2008)) and used to study the development of glioma in (Frieboes et al., NeuroImage 37 (2007) and tumor invasion in (Bearer et al., Cancer Research, 69 (2009)) and (Frieboes et al., J. Theor. Biol. 264 (2010)). The model has a thermodynamic basis, is related to recently developed mixture models, and is capable of providing a detailed description of tumor progression. It utilizes a diffuse interface approach, whereby sharp tumor boundaries are replaced by narrow transition layers that arise due to differential adhesive forces among the cell-species. The model consists of fourth-order nonlinear advection-reaction-diffusion equations (of Cahn-Hilliard-type) for the cell-species coupled with reaction-diffusion equations for the substrate components. Numerical solution of the model is challenging because the equations are coupled, highly nonlinear, and numerically stiff. In this paper we describe a fully adaptive, nonlinear multigrid/finite difference method for efficiently solving the equations. We demonstrate the convergence of the algorithm and we present simulations of tumor growth in 2D and 3D that demonstrate the capabilities of the algorithm in accurately and efficiently simulating the progression of tumors with complex morphologies. PMID:21076663

  3. Possible mechanisms by which pro- and prebiotics influence colon carcinogenesis and tumor growth.

    PubMed

    Reddy, B S

    1999-07-01

    Oligofructose and inulin, selective fermentable chicory fructans, have been shown to stimulate the growth of bifidobacteria, which are regarded as beneficial strains in the colon. Studies were designed to evaluate inulin (Raftiline) and oligofructose (Raftilose) for their potential inhibitory properties against the development of colonic aberrant crypt foci (ACF) in rats. ACF are putative preneoplastic lesions from which adenomas and carcinomas may develop in the colon. The results of this study indicate that dietary administration of oligofructose and inulin inhibits the development of ACF in the colon, suggesting the potential colon tumor inhibitory properties of chicory fructans. The degree of ACF inhibition was more pronounced in animals given inulin than in those fed oligofructose. Because these prebiotics selectively stimulate the growth of bifidobacteria, ornithine decarboxylase (ODC) activities, ras-p21 ontoprotein expressions and tumor inhibitory activity of lyophilized cultures of Bifidobacterium longum against chemically induced colon and mammary carcinogenesis and against colonic tumor cell proliferation were examined. Dietary administration of lyophilized cultures of B. longum strongly suppressed colon and mammary tumor development and tumor burden. Inhibition of colon carcinogenesis was associated with a decrease in colonic mucosal cell proliferation and activities of colonic mucosal and tumor ornithine decarboxylase and ras-p21. Human clinical trials are likely to broaden our insight into the importance of the pre- and probiotics in health and disease.

  4. Fluence rate-dependent photobleaching of intratumorally administered Pc 4 does not predict tumor growth delay.

    PubMed

    Baran, Timothy M; Foster, Thomas H

    2012-01-01

    We examined effects of fluence rate on the photobleaching of the photosensitizer Pc 4 during photodynamic therapy (PDT) and the relationship between photobleaching and tumor response to PDT. BALB/c mice with intradermal EMT6 tumors were given 0.03 mg kg(-1) Pc 4 by intratumor injection and irradiated at 667 nm with an irradiance of 50 or 150 mW cm(-2) to a fluence of 100 J cm(-2). While no cures were attained, significant tumor growth delay was demonstrated at both irradiances compared with drug-only controls. There was no significant difference in tumor responses to these two irradiances (P = 0.857). Fluorescence spectroscopy was used to monitor the bleaching of Pc 4 during irradiation, with more rapid bleaching with respect to fluence shown at the higher irradiance. No significant correlation was found between fluorescence photobleaching and tumor regrowth for the data interpreted as a whole. Within each treatment group, weak associations between photobleaching and outcome were observed. In the 50 mW cm(-2) group, enhanced photobleaching was associated with prolonged growth delay (P = 0.188), while at 150 mW cm(-2) this trend was reversed (P = 0.308). Thus, it appears that Pc 4 photobleaching is not a strong predictor of individual tumor response to Pc 4-PDT under these treatment conditions.

  5. A cellular automata model for avascular solid tumor growth under the effect of therapy

    NASA Astrophysics Data System (ADS)

    Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

    2009-04-01

    Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

  6. Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.

    PubMed

    Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

    2010-07-09

    Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.

  7. An uncleavable form of pro–scatter factor suppresses tumor growth and dissemination in mice

    PubMed Central

    Mazzone, Massimiliano; Basilico, Cristina; Cavassa, Silvia; Pennacchietti, Selma; Risio, Mauro; Naldini, Luigi; Comoglio, Paolo M.; Michieli, Paolo

    2004-01-01

    Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF–induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions. PMID:15545993

  8. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice.

    PubMed

    Mazzone, Massimiliano; Basilico, Cristina; Cavassa, Silvia; Pennacchietti, Selma; Risio, Mauro; Naldini, Luigi; Comoglio, Paolo M; Michieli, Paolo

    2004-11-01

    Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions.

  9. Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

    PubMed

    Lal-Nag, Madhu; McGee, Lauren; Titus, Steven A; Brimacombe, Kyle; Michael, Sam; Sittampalam, Gurusingham; Ferrer, Marc

    2017-03-01

    Two-dimensional monolayer cell proliferation assays for cancer drug discovery have made the implementation of large-scale screens feasible but only seem to reflect a simplified view that oncogenes or tumor suppressor genes are the genetic drivers of cancer cell proliferation. However, there is now increased evidence that the cellular and physiological context in which these oncogenic events occur play a key role in how they drive tumor growth in vivo and, therefore, in how tumors respond to drug treatments. In vitro 3D spheroid tumor models are being developed to better mimic the physiology of tumors in vivo, in an attempt to improve the predictability and efficiency of drug discovery for the treatment of cancer. Here we describe the establishment of a real-time 3D spheroid growth, 384-well screening assay. The cells used in this study constitutively expressed green fluorescent protein (GFP), which enabled the real-time monitoring of spheroid formation and the effect of chemotherapeutic agents on spheroid size at different time points of sphere growth and drug treatment. This real-time 3D spheroid assay platform represents a first step toward the replication in vitro of drug dosing regimens being investigated in vivo. We hope that further development of this assay platform will allow the investigation of drug dosing regimens, efficacy, and resistance before preclinical and clinical studies.

  10. Tumor growth delay by adjuvant alternating electric fields which appears non-thermally mediated.

    PubMed

    Castellví, Quim; Ginestà, Mireia M; Capellà, Gabriel; Ivorra, Antoni

    2015-10-01

    Delivery of the so-called Tumor Treatment Fields (TTFields) has been proposed as a cancer therapy. These are low magnitude alternating electric fields at frequencies from 100 to 300 kHz which are applied continuously in a non-invasive manner. Electric field delivery may produce an increase in temperature which cannot be neglected. We hypothesized that the reported results obtained by applying TTFields in vivo could be due to heat rather than to electrical forces as previously suggested. Here, an in vivo study is presented in which pancreatic tumors subcutaneously implanted in nude mice were treated for a week either with mild hyperthermia (41 °C) or with TTFields (6 V/cm, 150 kHz) and tumor growth was assessed. Although the TTFields applied singly did not produce any significant effect, the combination with chemotherapy did show a delay in tumor growth in comparison to animals treated only with chemotherapy (median relative reduction=47%). We conclude that concomitant chemotherapy and TTFields delivery show a beneficial impact on pancreatic tumor growth. Contrary to our hypothesis, this impact is non-related with the induced temperature increase.

  11. Minesoil grading and ripping affect black walnut growth and survival

    SciTech Connect

    Josiah, S.J.

    1986-07-01

    In 1980 and 1981, the Botany Department of Southern Illinois University and Sahara Coal Company, Inc. of Harrisburg, Illinois established a series of experimental tree plantings, including black walnut, on a variety of minesoils to explore the effects of different intensities of grading on tree growth. Subsequent walnut stem and root growth were examined during 1985 on five different mine sites: unmined former agricultural land, graded minespoil, replaced (with pan scrapers) topsoil over graded spoil, ripped-graded spoil, and ungraded spoil. Soil bulk density, resistance to penetration, and spoil/soil fertility levels were also measured. The most vigorous trees were found on sites having the lowest soil bulk density and soil strength and lacking horizontal barriers to root growth - the ungraded and ripped sites. Topsoiled sites had the poorest growth and survival, and the greatest stem dieback of any site measured, probably attributable to the confinement of root growth to the upper 15 cm of friable soil above the severely compacted zone. The overall results indicate that most of the minesoil construction techniques examined in this study, which are representative of techniques commonly used in the midwestern US, cause severe minesoil compaction and do not create the proper soil conditions necessary for the survival and vigorous growth of black walnut. Ripping compacted spoil in this and other studies proved to be very effective in alleviating the negative impacts of minesoil compaction. When planning surface mine reclamation activities, ripping should be considered as a possible ameliorative technique when compaction of mined lands is unavoidable and trees are the desired vegetative cover. 4 figures.

  12. Factors affecting plant growth in membrane nutrient delivery

    NASA Technical Reports Server (NTRS)

    Dreschel, T. W.; Wheeler, R. M.; Sager, J. C.; Knott, W. M.

    1990-01-01

    The development of the tubular membrane plant growth unit for the delivery of water and nutrients to roots in microgravity has recently focused on measuring the effects of changes in physical variables controlling solution availability to the plants. Significant effects of membrane pore size and the negative pressure used to contain the solution were demonstrated. Generally, wheat grew better in units with a larger pore size but equal negative pressure and in units with the same pore size but less negative pressure. Lettuce also exhibited better plant growth at less negative pressure.

  13. Fibrosarcoma of the jaws: two cases of primary tumors with intraosseous growth.

    PubMed

    Angiero, Francesca; Rizzuti, Tommaso; Crippa, Rolando; Stefani, Michele

    2007-01-01

    Fibrosarcoma (FS) is a malignant mesenchymal neoplasm of the fibroblasts that rarely affects the oral cavity. Two cases of primary FS of the jaws with intraosseous growth (2 men, aged 53 and 71 years) are described. Microscopically, in one case the tumor showed an intense proliferation of spindle-shaped cells, varying little in size and shape and arranged in parallel bands, partly crossing each other, with significant mitotic activity and nuclear pleomorphism; the second case was characterized by low cellularity comprising spindle-shaped cells, deposited in a variably fibrous and myxoid stroma. On immunohistochemistry, cells in both cases were strongly immunoreactive for MIB-1 and vimentin, focally positive for CD68, and negative for S-100 protein, pancytokeratin, HMB45, CD34, desmin, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). Based on clinical, histological and immunohistochemical findings, the final diagnosis was FS in the first case, myxofibrosarcoma in the second. Treatment was radical surgery with mandibular reconstruction. After two years, the first patient displayed multiple metastases and died during the third year after the initial diagnosis; the second patient was still alive and doing well five years after treatment. We discuss the differential diagnosis versus other forms of sarcoma, examining the morphological appearance that is frequently very similar, the immunohistochemical expression of MIB-1, vimentin, S-100, CD-34, CD68, EMA, as well as conventional clinicopathological features that may help to distinguish FS from other sarcomas.

  14. NSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo.

    PubMed

    Duncan, Kristal; Uwimpuhwe, Henriette; Czibere, Akos; Sarkar, Devanand; Libermann, Towia A; Fisher, Paul B; Zerbini, Luiz F

    2012-07-01

    Ovarian cancer (OC) is one of the most lethal gynaecological cancers, which usually has a poor prognosis due to late diagnosis. A large percentage of the OC cell population is in a nonproliferating and quiescent stage, which poses a barrier to success when using most chemotherapeutic agents. Recent studies have shown that several nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of OC. Furthermore, we have previously described the molecular mechanisms of NSAIDs' induction of cancer apoptosis. In this report, we evaluated various structurally distinct NSAIDs for their efficacies in inducing apoptosis in nonproliferating OC cells. Although several NSAIDs-induced apoptosis, Flufenamic Acid, Flurbiprofen, Finasteride, Celocoxib, and Ibuprofen were the most potent NSAIDs inducing apoptosis. A combination of these agents resulted in an enhanced effect. Furthermore, we demonstrate that the combination of Flurbiprofen, which targets nonproliferative cells, and Sulindac Sulfide, that affects proliferative cells, strongly reduced tumor growth when compared with a single agent treatment. Our data strongly support the hypothesis that drug treatment regimens that target nonproliferating and proliferating cells may have significant efficacy against OC. These results also provide a rationale for employing compounds or even chemically modified NSAIDs, which selectively and efficiently induce apoptosis in cells during different stages of the cell cycle, to design more potent anticancer drugs.

  15. Lack of growth of a pregnancy-dependent mouse mammary tumor (TPDMT-4) in the absence of pituitary hormones.

    PubMed

    Matsuzawa, A; Yamamoto, T

    1977-04-01

    Mammary tumors of line TPDMT-4, established in DDD mice, were characterized by growth during pregnancy and regression after parturition; this resulted in higher growth peaks in subsequent pregnancies in breeders and no growth in virgins. The effect of hypophysectomy on tumor growth in mice given 17beta-estradiol (E) and progesterone (P) or deoxycorticosterone acetate (DCA) was investigated. Growth of cancers occurred in E+P- and E+DCA-treated virgins, but not in cholesterol-treated virgins. Tumors did not grow to palpable sizes in cholesterol-, E+P-, and E+DCA-treated hypophysectomized virgins; this indicated that pituitary hormones were essential for tumor growth. Impalpable cholesterol-treated, 5 of 10 E+P-treated, and 3 of 6 E+DCA-treated hypophysectomized animals. The neoplasms showed ductal and tubular structures that were lined by a single layer of well-differentiated buoidal epithelium, which suggested that the tumor line might be derived from ductal cells.

  16. Melanoma Proteoglycan Modifies Gene Expression to Stimulate Tumor Cell Motility, Growth and Epithelial to Mesenchymal Transition

    PubMed Central

    Yang, Jianbo; Price, Matthew A.; Li, GuiYuan; Bar-Eli, Menashe; Salgia, Ravi; Jagedeeswaran, Ramasamy; Carlson, Jennifer H.; Ferrone, Soldano; Turley, Eva A.; McCarthy, James B.

    2009-01-01

    Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane-associated proteoglycan that facilitates the growth, motility and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk 1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results demonstrate that MCSP expression in radial growth phase (RGP), vertical growth phase (VGP) or metastatic cell lines causes sustained activation of Erk 1,2, enhanced growth and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in an RGP cell line also promotes an epithelial to mesenchymal transition (EMT) based on changes in cell morphology and the expression of several EMT markers. Finally MCSP enhances the expression of c-Met and HGF, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively demonstrate an importance for MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients. PMID:19738072

  17. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study.

    PubMed

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors.

  18. Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study

    PubMed Central

    Caz, Victor; Elvira, Marcos; Tabernero, Maria; Grande, Antonio G.; Lopez-Plaza, Bricia; de Miguel, Enrique; Largo, Carlota; Santamaria, Monica

    2015-01-01

    The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors. PMID:26670463

  19. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth.

    PubMed

    Soman, Neelesh R; Baldwin, Steven L; Hu, Grace; Marsh, Jon N; Lanza, Gregory M; Heuser, John E; Arbeit, Jeffrey M; Wickline, Samuel A; Schlesinger, Paul H

    2009-09-01

    The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

  20. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

    PubMed Central

    Soman, Neelesh R.; Baldwin, Steven L.; Hu, Grace; Marsh, Jon N.; Lanza, Gregory M.; Heuser, John E.; Arbeit, Jeffrey M.; Wickline, Samuel A.; Schlesinger, Paul H.

    2009-01-01

    The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages. PMID:19726870

  1. Mathematical model and its fast numerical method for the tumor growth.

    PubMed

    Lee, Hyun Geun; Kim, Yangjin; Kim, Junseok

    2015-12-01

    In this paper, we reformulate the diffuse interface model of the tumor growth (S.M. Wise et al., Three-dimensional multispecies nonlinear tumor growth-I: model and numerical method, J. Theor. Biol. 253 (2008) 524--543). In the new proposed model, we use the conservative second-order Allen--Cahn equation with a space--time dependent Lagrange multiplier instead of using the fourth-order Cahn--Hilliard equation in the original model. To numerically solve the new model, we apply a recently developed hybrid numerical method. We perform various numerical experiments. The computational results demonstrate that the new model is not only fast but also has a good feature such as distributing excess mass from the inside of tumor to its boundary regions.

  2. Dissolved oxygen concentration affects hybrid striped bass growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Management of dissolved oxygen (DO) concentration in ponds at night during the growing season is important because fish growth and yield are greater in ponds with higher nightly DO concentrations. Three studies were conducted to quantify performance traits and metabolic responses of hybrid striped b...

  3. Shade periodicity affects growth of container grown dogwoods

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Container-grown dogwoods rank third in the US in nursery sales of ornamental trees. However, Dogwoods are a challenging crop to produce in container culture, especially when bare root liners are used as the initial transplant into containers due unacceptable levels of mortality and poor growth. This...

  4. Fluctuations induced extinction and stochastic resonance effect in a model of tumor growth with periodic treatment

    NASA Astrophysics Data System (ADS)

    Li, Dongxi; Xu, Wei; Guo, Yongfeng; Xu, Yong

    2011-01-01

    We investigate a stochastic model of tumor growth derived from the catalytic Michaelis-Menten reaction with positional and environmental fluctuations under subthreshold periodic treatment. Firstly, the influences of environmental fluctuations on the treatable stage are analyzed numerically. Applying the standard theory of stochastic resonance derived from the two-state approach, we derive the signal-to-noise ratio (SNR) analytically, which is used to measure the stochastic resonance phenomenon. It is found that the weak environmental fluctuations could induce the extinction of tumor cells in the subthreshold periodic treatment. The positional stability is better in favor of the treatment of the tumor cells. Besides, the appropriate and feasible treatment intensity and the treatment cycle should be highlighted considered in the treatment of tumor cells.

  5. Statins improve survival by inhibiting spontaneous metastasis and tumor growth in a mouse melanoma model

    PubMed Central

    Tsubaki, Masanobu; Takeda, Tomoya; Kino, Toshiki; Obata, Naoya; Itoh, Tatsuki; Imano, Motohiro; Mashimo, Kenji; Fujiwara, Daichiro; Sakaguchi, Katsuhiko; Satou, Takao; Nishida, Shozo

    2015-01-01

    Metastatic melanoma is a life-threatening disease for which no effective treatment is currently available. In melanoma cells, Rho overexpression promotes invasion and metastasis. However, the effect of statins on spontaneous metastasis and tumor growth remains unclear. In the present study, we investigated the mechanism of statin-mediated tumor growth and metastasis inhibition in an in vivo model. We found that statins significantly inhibited spontaneous metastasis and tumor growth. Statins inhibited the mRNA expression and enzymatic activities of matrix metalloproteinases (MMPs) in vivo and also suppressed the mRNA and protein expression of very late antigens (VLAs). Moreover, statins inhibited the prenylation of Rho as well as the phosphorylation of LIM kinase, serum response factor (SRF), and c-Fos downstream of the Rho signaling pathway. In addition, statins enhanced p53, p21, and p27 expression and reduced phosphorylation of cyclin-dependent kinase and expression of cyclin D1 and E2. These results indicate that statins suppress Rho signaling pathways, thereby inhibiting tumor metastasis and growth. Furthermore, statins markedly improved the survival rate in a metastasis model, suggesting that statins have potential clinical applications for the treatment of metastatic cancers. PMID:26693069

  6. Chaotic attractors in tumor growth and decay: a differential equation model.

    PubMed

    Harney, Michael; Yim, Wen-sau

    2015-01-01

    Tumorigenesis can be modeled as a system of chaotic nonlinear differential equations. A simulation of the system is realized by converting the differential equations to difference equations. The results of the simulation show that an increase in glucose in the presence of low oxygen levels decreases tumor growth.

  7. Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4

    PubMed Central

    Brigatte, Patrícia; Faiad, Odair Jorge; Ferreira Nocelli, Roberta Cornélio; Landgraf, Richardt G.; Palma, Mario Sergio; Cury, Yara; Curi, Rui; Sampaio, Sandra Coccuzzo

    2016-01-01

    We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs. PMID:27190493

  8. The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

    PubMed Central

    Hwang, Jae Ryoung; Cho, Young-Jae; Lee, Yoonna; Park, Youngmee; Han, Hee Dong; Ahn, Hyung Jun; Lee, Je-Ho; Lee, Jeong-Won

    2016-01-01

    Insulin-like growth factor-binding protein 5 (IGFBP-5) plays a role in cell growth, differentiation, and apoptosis. In this study, we found that IGFBP5 was markedly downregulated in ovarian cancer tissue. We investigated the functional significance of IGFBP-5 as a tumor suppressor. To determine functional regions of IGFBP-5, truncation mutants were prepared and were studied the effect on tumor growth. Expression of C-terminal region of IGFBP-5 significantly decreased tumor growth in an ovarian cancer xenograft. A peptide derived from the C-terminus of IGFBP-5 (BP5-C) was synthesized to evaluate the minimal amino acid motif that retained anti-tumorigenic activity and its effect on angiogenesis was studied. BP5-C peptide decreased the expression of VEGF-A and MMP-9, phosphorylation of Akt and ERK, and NF-kB activity, and inhibited angiogenesis in in vitro and ex vivo systems. Furthermore, BP5-C peptide significantly decreased tumor weight and angiogenesis in both ovarian cancer orthotopic xenograft and patient-derived xenograft mice. These results suggest that the C-terminus of IGFBP-5 exerts anti-cancer activity by inhibiting angiogenesis via regulation of the Akt/ERK and NF-kB–VEGF/MMP-9 signaling pathway, and might be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer. PMID:28008951

  9. A Multi-Compartment Mathematical Model of Cancer Stem Cell Driven Tumor Growth Dynamics

    PubMed Central

    Weekes, Suzanne L.; Barker, Brian; Bober, Sarah; Cisneros, Karina; Cline, Justina; Thompson, Amanda; Hlatky, Lynn; Hahnfeldt, Philip; Enderling, Heiko

    2014-01-01

    Tumors are appreciated to be an intrinsically heterogeneous population of cells with varying proliferation capacities and tumorigenic potentials. As a central tenet of the so-called cancer stem cell hypothesis, most cancer cells have only a limited lifespan and thus cannot initiate or re-initiate tumors. Longevity and clonogenicity are properties unique to the subpopulation of cancer stem cells. To understand the implications of the population structure suggested by this hypothesis - a hierarchy consisting of cancer stem cells and progeny non-stem cancer cells which experience a reduction in their remaining proliferation capacity per division - we set out to develop a mathematical model for the development of the aggregate population. We show that overall tumor progression rate during the exponential growth phase is identical to the growth rate of the cancer stem cell compartment. Tumors with identical stem cell proportions, however, can have different growth rates, dependent on the proliferation kinetics of all participating cell populations. Analysis of the model revealed that the proliferation potential of non-stem cancer cells is likely to be small to reproduce biologic observations. Furthermore, a single compartment of non-stem cancer cell population may adequately represent population growth dynamics only when the compartment proliferation rate is scaled with the generational hierarchy depth. PMID:24840956

  10. Inhibition of Tumor Growth and Metastasis by a Combination of Escherichia coli–mediated Cytolytic Therapy and Radiotherapy

    PubMed Central

    Jiang, Sheng-Nan; Phan, Thuy X; Nam, Taek-Keun; Nguyen, Vu H; Kim, Hyung-Seok; Bom, Hee-Seung; Choy, Hyon E; Hong, Yeongjin; Min, Jung-Joon

    2010-01-01

    We have reported that Escherichia coli K-12 colonizes hypoxic and necrotic tumor regions after intravenous injection into tumor-bearing mice. In this study, we established a novel strategy for cancer therapy using engineered bacteria to enhance the therapeutic effects of radiation. E. coli strain K-12 was engineered to produce cytolysin A (ClyA), and its effects on tumor growth in primary and metastatic tumor models were evaluated. A single treatment with E. coli–expressing ClyA significantly decreased tumor growth rates initially (9 days after treatment); however, the tumors tended to grow thereafter. With only radiotherapy (RT; 21 Gy), the tumor growth rates were retarded, but not the tumor sizes. A combination of therapy with E. coli–expressing ClyA and radiation [a total of 5 × 107 colony-forming units (CFU) and 21 Gy] resulted in significant tumor shrinkage and even complete disappearance of tumors in mice with tumors derived from murine CT26 colon cancer. Furthermore, treatment with E. coli–expressing ClyA markedly suppressed metastatic tumor growth and prolonged the survival time in mice. The results described here indicate that therapy with engineered E. coli could significantly improve the results of RT, and could exert a striking inhibitory effect on the development of lung metastasis. PMID:20051939

  11. The stem cell mobilizer StemEnhance does not promote tumor growth in an orthotopic model of human breast cancer.

    PubMed

    Drapeau, Christian; Ma, Huaiyu; Yang, Zhijian; Tang, Li; Hoffman, Robert M; Schaeffer, David J

    2009-01-01

    Bone marrow-derived stem cells (BMDSC) have been implicated in tumor formation, though it is not clear whether they contribute to tumor growth. A novel mobilizer of BMDSC (StemEnhance; SE) was used to investigate whether its daily administration promotes tumor growth. Forty mice were surgically transplanted with human MDA-MB-435-GFP breast cancer into the mammary fat pad of nude mice, The mice were gavaged for six weeks with 300 mg/kg of SE. Tumor growth was monitored using live whole-body fluorescence imaging. At the end of the study, tumors were excised and weighed. At the start of the feeding trial, tumor areas for both control and experimental group were statistically identical. Tumor growth rate was slower in the SE group (p = 0.014) when compared to the control group. After 6 weeks, tumor areas were 40% larger in the control p < 0.01) and mean tumor weight was 35% smaller in the SE-treated group (0.44 g vs. 0.68 g; p = 0.031). Feeding of SE did not promote tumor growth but rather reduced the growth of human MDA-MB-435 breast cancer.

  12. Patrinia scabiosaefolia inhibits colorectal cancer growth through suppression of tumor angiogenesis.

    PubMed

    Chen, Liwu; Liu, Liya; Ye, Ling; Shen, Aling; Chen, Youqin; Sferra, Thomas J; Peng, Jun

    2013-09-01

    Angiogenesis is an essential process for tumor development and metastasis, therefore inhibition of tumor angiogenesis has become a promising strategy for anticancer treatments. Patrinia scabiosaefolia, a well-known Oriental folk medicine, has been shown to be effective in the clinical treatment of gastrointestinal cancers. However, the precise mechanism of its tumoricidal activity remains largely unknown. Using a colorectal cancer (CRC) mouse xenograft model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the effects of an ethanol extract of Patrinia scabiosaefolia (EEPS) on tumor angiogenesis in vivo and in vitro, and investigated the underlying molecular mechanisms. We found that EEPS treatment significantly reduced the tumor volume in CRC mice and decreased the intratumoral microvessel density in tumor tissues. In addition, EEPS inhibited several key processes of angiogenesis, including the proliferation, migration and tube formation of HUVECs. Moreover, EEPS treatment suppressed the expression of VEGF-A in CRC tumors and HT-29 cells. Collectively, our data suggest that Patrinia scabiosaefolia inhibits CRC growth likely via suppression of tumor angiogenesis.

  13. Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.

    PubMed

    Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S; Schaffner, Carl P; Zurakowski, David; Solomon, Keith R; Moses, Marsha A

    2014-07-01

    Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo.

  14. Forkhead box protein A1 is a prognostic predictor and promotes tumor growth of gastric cancer

    PubMed Central

    Ren, Hongyu; Zhang, Pei; Tang, Yong; Wu, Mengping; Zhang, Weikang

    2015-01-01

    Previous studies have demonstrated the cancer-type specific role of forkhead box protein A1 (FOXA1) in human malignancies. However, the clinical significance of FOXA1 and its biological function in gastric cancer remain unknown. In this study, the expression of FOXA1 in 80 pairs of gastric cancer tissues and corresponding non-tumor tissues was analyzed using immunohistochemistry and quantitative real-time polymerase chain reaction. We found that the levels of FOXA1 protein and mRNA in gastric cancer tissues were significantly higher than those in matched tumor-adjacent tissues. Furthermore, clinical association analysis indicated that the positive expression of FOXA1 was associated with adverse clinicopathological characteristics of gastric cancer patients including poor tumor differentiation, large tumor size, and advanced tumor-node-metastasis tumor stage. Notably, gastric cancer patients with positive expression of FOXA1 had a poorer 5-year overall survival and recurrence-free survival. In addition, FOXA1 knockdown remarkably inhibited cell proliferation and induced apoptosis in both SGC-7901 and MGC-803 cells. In vivo studies indicated that FOXA1 knockdown prominently suppressed tumor growth of gastric cancer in a nude mouse xenograft model. Mechanistically, we disclosed that the expression of Yes-associated protein was decreased accordingly after FOXA1 knockdown in both SGC-7901 and MGC-803 cells. Taken together, our data suggest that FOXA1 may serve as a promising prognostic indicator and an attractive therapeutic target of gastric cancer. PMID:26527889

  15. Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo

    NASA Astrophysics Data System (ADS)

    Som, Avik; Raliya, Ramesh; Tian, Limei; Akers, Walter; Ippolito, Joseph E.; Singamaneni, Srikanth; Biswas, Pratim; Achilefu, Samuel

    2016-06-01

    The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors. Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) in vivo increases pH asymptotically to 7.4. We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pH over time. The associated induction of tumor growth stasis is putatively interpreted as a pHe increase. This study establishes an approach to prepare nano-CaCO3 over a wide particle size range, a formulation that stabilizes the nanomaterials in aqueous solutions, and a pH-sensitive nano-platform capable of modulating the acidic environment of cancer for potential therapeutic benefits.The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors. Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) in vivo increases pH asymptotically to 7.4. We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3

  16. Tumor-specific mutations in low-frequency genes affect their functional properties.

    PubMed

    Erdem-Eraslan, Lale; Heijsman, Daphne; de Wit, Maurice; Kremer, Andreas; Sacchetti, Andrea; van der Spek, Peter J; Sillevis Smitt, Peter A E; French, Pim J

    2015-05-01

    Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole-genome sequencing identified a total of 55 coding mutations (range 8-32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type.

  17. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy.

    PubMed

    McWilliams, Geoffrey D; SantaCruz, Karen; Hart, Blaine; Clericuzio, Carol

    2016-01-01

    Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.

  18. GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS

    PubMed Central

    SALGADO, Flávio L. L.; ARTIGIANI-NETO, Ricardo; LOPES-FILHO, Gaspar de Jesus

    2016-01-01

    ABSTRACT Background: Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. Aim: To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Methods: Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Results: Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Conclusion: Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate

  19. Phasic temperature change patterns affect growth and tuberization in potatoes

    SciTech Connect

    Cao, W.; Tibbitts, T.W. . Dept. of Horticulture)

    1994-07-01

    This study determined the response of potato (Solanum tuberosum L., cv. Norland) plants to various patterns of air temperature changes over different growth periods. In each of two experiments under controlled environments, eight treatments of temperature changes were carried out in two growth rooms maintained at 17 and 22 C and a constant vapor pressure deficit of 0.60 kPa and 14-hour photoperiod. Plants were grown for 63 days after transplanting of tissue culture plantlets in 20-liter pots containing peat-vermiculite mix. Temperature changes were imposed on days 21 and 42, which were essentially at the beginning of tuber initiation and tuber enlargement, respectively, for this cultivar. Plants were moved between two temperature rooms to obtain eight temperature change patterns: 17-17-17, 17-17-22, 17-22-17, 22-17-17, 17-22-22, 22-17-22, 22-22-17, and 22-22-22C over three 21-day growth periods. At harvest on day 63, total plant dry weight was higher for the treatments beginning with 22 C than for those beginning with 17C, with highest biomass obtained at 22-22-17 and 22-17-17C. Shoot dry weight increased with temperature increased from 17-17-17 to 22-22-22C during the three growth periods. Tuber dry weight was highest with 22-17-17C, and lowest with 17-17-22 and 17-22-22C. With 22-17-17C, both dry weights of stolons and roots were lowest. Total tuber number and number of small tubers were highest with 17-17-17 and 17-17-22C, and lowest with 17-22-22 and 22-22-22C, whereas number of medium tubers was highest with 22-17-22C, and number of large tubers was highest with 22-17-17C. This study indicates that tuber development of potatoes is optimized with a phasic pattern of high temperature during early growth and low temperature during later growth.

  20. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype

    PubMed Central

    Shrestha, Sanjeeb; Noh, Jae Myoung; Kim, Shin-Yeong; Ham, Hwa-Yong; Kim, Yeon-Ja; Yun, Young-Jin; Kim, Min-Ju; Kwon, Min-Soo; Song, Dong-Keun; Hong, Chang-Won

    2016-01-01

    ABSTRACT Tumor microenvironments polarize neutrophils to protumoral phenotypes. Here, we demonstrate that the angiotensin converting enzyme inhibitors (ACEis) and angiotensin II type 1 receptor (AGTR1) antagonist attenuate tumor growth via polarization of neutrophils toward an antitumoral phenotype. The ACEis or AGTR1 antagonist enhanced hypersegmentation of human neutrophils and increased neutrophil cytotoxicity against tumor cells. This neutrophil hypersegmentation was dependent on the mTOR pathway. In a murine tumor model, ACEis and AGTR1 antagonist attenuated tumor growth and enhanced neutrophil hypersegmentation. ACEis inhibited tumor-induced polarization of neutrophils to a protumoral phenotype. Neutrophil depletion reduced the antitumor effect of ACEi. Together, these data suggest that the modulation of Ang II pathway attenuates tumor growth via polarization of neutrophils to an antitumoral phenotype. PMID:26942086

  1. Steps in Cu(111) thin films affect graphene growth kinetics

    NASA Astrophysics Data System (ADS)

    Miller, David L.; Gannett, Will; Keller, Mark W.

    2014-03-01

    The kinetics of chemical vapor deposition of graphene on Cu substrates depend on the relative rates of C diffusion on the surface, C attachment to graphene islands, and removal of C from the surface or from graphene islands by etching processes involving H atoms. Using Cu(111) thin films with centimeter-sized grains, we have grown graphene under a variety of conditions and examined the edges of graphene islands with SEM and AFM. The Cu surface shows a series of regular steps, roughly 2 nm in height, and the graphene islands are diamond-shaped with faster growth along the edges of Cu steps. In contrast, growth on polycrystalline Cu foils under the same conditions shows hexagonal graphene islands with smooth edges.

  2. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.

    PubMed

    Bono, Françoise; De Smet, Frederik; Herbert, Corentin; De Bock, Katrien; Georgiadou, Maria; Fons, Pierre; Tjwa, Marc; Alcouffe, Chantal; Ny, Annelii; Bianciotto, Marc; Jonckx, Bart; Murakami, Masahiro; Lanahan, Anthony A; Michielsen, Christof; Sibrac, David; Dol-Gleizes, Frédérique; Mazzone, Massimiliano; Zacchigna, Serena; Herault, Jean-Pascal; Fischer, Christian; Rigon, Patrice; Ruiz de Almodovar, Carmen; Claes, Filip; Blanc, Isabelle; Poesen, Koen; Zhang, Jie; Segura, Inmaculada; Gueguen, Geneviève; Bordes, Marie-Françoise; Lambrechts, Diether; Broussy, Roselyne; van de Wouwer, Marlies; Michaux, Corinne; Shimada, Toru; Jean, Isabelle; Blacher, Silvia; Noel, Agnès; Motte, Patrick; Rom, Eran; Rakic, Jean-Marie; Katsuma, Susumu; Schaeffer, Paul; Yayon, Avner; Van Schepdael, Ann; Schwalbe, Harald; Gervasio, Francesco Luigi; Carmeliet, Geert; Rozensky, Jef; Dewerchin, Mieke; Simons, Michael; Christopoulos, Arthur; Herbert, Jean-Marc; Carmeliet, Peter

    2013-04-15

    Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

  3. Organic matter loading affects lodgepole pine seedling growth.

    PubMed

    Wei, Xiaohua; Li, Qinglin; Waterhouse, M J; Armleder, H M

    2012-06-01

    Organic matter plays important roles in returning nutrients to the soil, maintaining forest productivity and creating habitats in forest ecosystems. Forest biomass is in increasing demand for energy production, and organic matter has been considered as a potential supply. Thus, an important management question is how much organic matter should be retained after forest harvesting to maintain forest productivity. To address this question, an experimental trial was established in 1996 to evaluate the responses of lodgepole pine seedling growth to organic matter loading treatments. Four organic matter loading treatments were randomly assigned to each of four homogeneous pine sites: removal of all organic matter on the forest floor, organic matter loading quantity similar to whole-tree-harvesting residuals left on site, organic matter loading quantity similar to stem-only-harvesting residuals, and organic matter loading quantity more similar to what would be found in disease- or insect-killed stands. Our 10-year data showed that height and diameter had 29 and 35 % increase, respectively, comparing the treatment with the most organic matter loading to the treatment with the least organic matter loading. The positive response of seedling growth to organic matter loading may be associated with nutrients and/or microclimate change caused by organic matter, and requires further study. The dynamic response of seedling growth to organic matter loading treatments highlights the importance of long-term studies. Implications of those results on organic matter management are discussed in the context of forest productivity sustainability.

  4. Organic Matter Loading Affects Lodgepole Pine Seedling Growth

    NASA Astrophysics Data System (ADS)

    Wei, Xiaohua; Li, Qinglin; Waterhouse, M. J.; Armleder, H. M.

    2012-06-01

    Organic matter plays important roles in returning nutrients to the soil, maintaining forest productivity and creating habitats in forest ecosystems. Forest biomass is in increasing demand for energy production, and organic matter has been considered as a potential supply. Thus, an important management question is how much organic matter should be retained after forest harvesting to maintain forest productivity. To address this question, an experimental trial was established in 1996 to evaluate the responses of lodgepole pine seedling growth to organic matter loading treatments. Four organic matter loading treatments were randomly assigned to each of four homogeneous pine sites: removal of all organic matter on the forest floor, organic matter loading quantity similar to whole-tree-harvesting residuals left on site, organic matter loading quantity similar to stem-only-harvesting residuals, and organic matter loading quantity more similar to what would be found in disease- or insect-killed stands. Our 10-year data showed that height and diameter had 29 and 35 % increase, respectively, comparing the treatment with the most organic matter loading to the treatment with the least organic matter loading. The positive response of seedling growth to organic matter loading may be associated with nutrients and/or microclimate change caused by organic matter, and requires further study. The dynamic response of seedling growth to organic matter loading treatments highlights the importance of long-term studies. Implications of those results on organic matter management are discussed in the context of forest productivity sustainability.

  5. Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion

    PubMed Central

    Lee, Yu-Hsin; Jhuang, Yu-Lin; Chen, Yu-Ling; Jeng, Yung-Ming; Yuan, Ray-Hwang

    2016-01-01

    Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis. PMID:27564110

  6. Comparative effects of CT imaging measurement on RECIST endpoints and tumor growth kinetics modeling

    PubMed Central

    Li, Claire H.; Bies, Robert R.; Wang, Yaning; Sharma, Manish R.; Karovic, Sanja; Werk, Lynn; Edelman, Martin J.; Miller, Antonius A.; Vokes, Everett E.; Oto, Aytek; Ratain, Mark J.; Schwartz, Lawrence H.; Maitland, Michael L.

    2015-01-01

    Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase 2 oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from 3 published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor-growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. RECIST-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intra-class correlation coefficient (ICC) = 1), but these routine inter-rater differences in the identification and measurement of target lesions were associated with an average 18 week delay (range −20 – 55 weeks) in TTG (ICC = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments. PMID:26790562

  7. Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors

    PubMed Central

    Niinuma, Takeshi; Yamano, Hiro-o; Nojima, Masanori; Yoshikawa, Kennjiro; Kimura, Tomoaki; Takagi, Ryo; Harada, Eiji; Harada, Taku; Maruyama, Reo; Sasaki, Yasushi; Tokino, Takashi; Shinomura, Yasuhisa; Sugai, Tamotsu; Imai, Kohzoh; Suzuki, Hiromu

    2015-01-01

    Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (≥20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC. PMID:26334593

  8. Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment.

    PubMed

    Michael, James V; Wurtzel, Jeremy G T; Goldfinger, Lawrence E

    2016-10-01

    The goal of this study was to develop combinatorial application of two drugs currently either in active use as anticancer agents (rapamycin) or in clinical trials (OTX008) as a novel strategy to inhibit Harvey RAS (HRAS)-driven tumor progression. HRAS anchored to the plasma membrane shuttles from the lipid ordered (Lo) domain to the lipid ordered/lipid disordered border upon activation, and retention of HRAS at these sites requires galectin-1. We recently showed that genetically enforced Lo sequestration of HRAS inhibited mitogen-activated protein kinase (MAPK) signaling, but not phoshatidylinositol 3-kinase (PI3K) activation. Here we show that inhibition of galectin-1 with OTX008 sequestered HRAS in the Lo domain, blocked HRAS-mediated MAPK signaling, and attenuated HRAS-driven tumor progression in mice. HRAS-driven tumor growth was also attenuated by treatment with mammalian target of rapamycin (mTOR) inhibitor rapamycin, and this effect was further enhanced in tumors driven by Lo-sequestered HRAS. These drugs also revealed bidirectional cross-talk in HRAS pathways. Moreover, dual pathway inhibition with OTX008 and rapamycin resulted in nearly complete ablation of HRAS-driven tumor growth. These findings indicate that membrane microdomain sequestration of HRAS with galectin-1 inhibition, coupled with mTOR inhibition, may support a novel therapeutic approach to treat HRAS-mutant cancer.

  9. Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis.

    PubMed

    Bracher, Andreas; Cardona, Ana Soler; Tauber, Stefanie; Fink, Astrid M; Steiner, Andreas; Pehamberger, Hubert; Niederleithner, Heide; Petzelbauer, Peter; Gröger, Marion; Loewe, Robert

    2013-01-01

    Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor-derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node-negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis.

  10. Growth hormone deficiency following radiation therapy of primary brain tumors in children.

    PubMed

    Kanev, P M; Lefebvre, J F; Mauseth, R S; Berger, M S

    1991-05-01

    The medical records of 123 patients treated for brain tumors at Children's Hospital and Medical Center, Seattle, Washington, between 1985 and 1987 were reviewed. The endocrinological complications of radiation therapy and the effectiveness of growth hormone (GH) replacement therapy were assessed. These were the first 2 years after synthetic GH became available. The disease pathology was confirmed at craniotomy or biopsy in 108 patients. Ninety-five children completed radiation therapy and 65 of these were alive at the time of review; these 65 children represent the study population. The most common tumor types were medulloblastoma, craniopharyngioma, and ependymoma. Endocrine evaluation was initiated with changes in the patients' growth velocity. Patient workup included skeletal x-ray films for determination of bone and analysis of thyroxin, thyroid-stimulating hormone, and somatomedin-C levels. Following 1-dopa and clonidine stimulation, provocative studies of GH levels were performed. Growth hormone failure and short stature were observed in 26 children, most commonly in the 2nd year after tumor treatment. Eight patients with GH failure were also hypothyroid. Hormone replacement therapy was initiated with recombinant GH, 0.05 mg/kg/day, and all children so treated showed an increase in height, with eight patients experiencing catch-up growth. There were no complications of therapy or tumor recurrence. Studies of baseline bone age and somatomedin-C levels on completion of radiation therapy are recommended. Comprehensive endocrine studies should follow changes in the patients' growth velocity. With early GH replacement, catch-up growth is possible and normal adult heights may be achieved.

  11. Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo.

    PubMed

    Schultz, Chad; Lemke, Nancy; Ge, Shugang; Golembieski, William A; Rempel, Sandra A

    2002-11-01

    Secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human astrocytomas, grades II-IV. We demonstrated previously that SPARC promotes invasion in vitro using the U87MG-derived clone U87T2 and U87T2-derived SPARC-transfected clones, A2b2, A2bi, and C2a4, in the spheroid confrontation assay. Additional in vitro studies demonstrated that SPARC delays growth, increases attachment, and modulates migration of tumor cells in extracellular matrix-specific and concentration-dependent manners. Therefore, we propose that SPARC functionally contributes to brain tumor invasion and delays tumor growth in vivo, and that the effects of SPARC are related to the level of SPARC secreted into the extracellular matrix. To test these hypotheses, we stereotactically injected these clones into nude rat brains (six animals were injected per clone). Animals were sacrificed on day 7 to assess growth and invasion for all clones at the same time in tumor development. To determine whether SPARC delayed but did not inhibit growth, rats were injected with U87T2 or clone A2b2, and the animals were sacrificed on days 9 (U87T2) and 20 (A2b2), when the animals demonstrated neurological deficit. Brains were removed, fixed, photographed, paraffin embedded, and sectioned. Sections were then serially stained with H&E for morphological assessment of invasion and to measure tumor volume, immunohistochemically stained to visualize SPARC, subjected to in situ hybridization with the human AluII DNA-binding probe to identify human cells, and immunohistochemically stained with MIB-1 to measure proliferation index. The results demonstrate that SPARC promotes invasion in vivo at day 7. Both the low (A2bi) and the high (A2b2) SPARC-secreting clones produced invasive tumors, invading with fingerlike projections and satellite masses into adjacent brain, as well as along the corpus collosum. The intermediate SPARC secreting clone (C2a4) primarily migrated as a bulk tumor along the corpus

  12. Effect of cadmium exposure on primary tumor growth and cell-mediated cytotoxicity in mice bearing MSB sarcomas.

    PubMed

    Kerkvliet, N I; Koller, L D; Baecher, L G; Brauner, J A

    1979-08-01

    In vivo MSB tumor growth and cell-mediated cytotoxicity (CMC) to MSB tumor cells in vitro were studied in male C57BL/6 mice exposed to 0, 3, 30, or 300 ppm Cd as CdCl2 in their drinking water for 21 weeks prior to and during tumor growth. CMC was assessed on days 5, 12, and 19 post injection with the use of both a 51Cr release assay and a 51Cr post-label assay. Cd exposure significantly inhibited the growth of MSB tumors in vivo and enhanced the levels of CMC in the tumor-bearing hosts. Peak levels of CMC on day 12 post tumor injection were significantly increased in Cd-exposed animals. However, whereas the inhibition of tumor growth was directly dependent on the dose of Cd, the enhancement of CMC was inversely related to dosage. These data suggested that other mechanisms in addition to increased CMC were involved in tumor growth inhibition. Possible factors such as direct inhibition of tumor growth by Cd and decreased serum blocking levels in Cd-exposed animals are discussed.

  13. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

    PubMed

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Delle Fave, Gianfranco; Jensen, Robert T

    2013-03-01

    Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

  14. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

    PubMed Central

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Fave, Gianfranco Delle; Jensen, Robert T.

    2012-01-01

    Foregut Neuroendocrine Tumors[NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor(EGFR) by growth factors, gastrointestinal(GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid, BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. PMID:23220008

  15. c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations.

    PubMed

    Otte, Anna; Rauprich, Finn; von der Ohe, Juliane; Yang, Yuanyuan; Kommoss, Friedrich; Feuerhake, Friedrich; Hillemanns, Peter; Hass, Ralf

    2015-10-13

    A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr1349 and downstream Thr202/Tyr204 phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC50 of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NODscid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth.

  16. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo

    SciTech Connect

    Chian, Song; Thapa, Ruby; Chi, Zhexu; Wang, Xiu Jun; Tang, Xiuwen

    2014-05-16

    Highlights: • Luteolin inhibits the Nrf2 pathway in mouse liver and in xenografted tumors. • Luteolin markedly inhibits the growth of xenograft tumors. • Luteolin enhances the anti-cancer effect of cisplatin in mice in vivo. • Luteolin could serve as an adjuvant in the chemotherapy of NSCLC. - Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2{sup −/−} mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.

  17. Cell-permeable iron inhibits vascular endothelial growth factor receptor-2 signaling and tumor angiogenesis

    PubMed Central

    Kir, Devika; Saluja, Manju; Modi, Shrey; Venkatachalam, Annapoorna; Schnettler, Erica; Roy, Sabita; Ramakrishnan, Sundaram

    2016-01-01

    Angiogenesis is important for tumor growth and metastasis. Hypoxia in tumors drives this angiogenic response by stabilizing Hypoxia Inducible Factors (HIF) and target genes like Vascular Endothelial Growth Factor (VEGF). HIF stability is regulated by Prolylhydroxylases (PHD)-mediated modification. Iron is an important cofactor in regulating the enzymatic activity of PHDs. Reducing intracellular iron, for instance, mimics hypoxia and induces a pro-angiogenic response. It is hypothesized that increasing the intracellular iron levels will have an opposite, anti-angiogenic effect. We tested this hypothesis by perturbing iron homeostasis in endothelial cells using a unique form of iron, Ferric Ammonium Citrate (FAC). FAC is a cell-permeable form of iron, which can passively enter into cells bypassing the transferrin receptor mediated uptake of transferrin-bound iron. Our studies show that FAC does not decrease the levels of HIF-1α and HIF-2α in endothelial cells but inhibits the autocrine stimulation of VEGF-Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) system by blocking receptor tyrosine kinase phosphorylation. FAC inhibits VEGF-induced endothelial cell proliferation, migration, tube formation and sprouting. Finally, systemic administration of FAC inhibits VEGF and tumor cell-induced angiogenesis in vivo. In conclusion, our studies show that cell-permeable iron attenuates VEGFR-2 mediated signaling and inhibits tumor angiogenesis. PMID:27589831

  18. Contour instabilities and micro-structures in early tumor growth models

    NASA Astrophysics Data System (ADS)

    Ben Amar, Martine; Ciarletta, Pasquale; Chatelain, Clément; Balois, Thibaut

    2012-02-01

    Clinical diagnosis of skin cancers is based on several morphological criteria, among which growth, color, border instabilities and microstructures (e.g. dots, nests) sparsely distributed within the tumor lesion. We use the multiphase mixture models adapted to the skin to explain various patterning occurring in the avascular phase. Restricting to a simple but realistic version of these models with an elastic cell-to-cell interaction and a growth rate dependent on diffusing nutrients, we prove analytically that the tumor cell concentration at the border acts as a control parameter inducing a bifurcation with loss of circular symmetry which explains the instabilities of the tumor border. The finite wavelength at threshold has the size of the proliferating peritumoral zone. We apply our predictions to melanoma growth since these instabilities are crucial for the early diagnosis. The same model is used to show the existence of micro-structures. Taking into account a reaction-diffusion coupling between nutrient consumption and cellular proliferation, we show that two-phase models may undergo a spinodal decomposition even when considering mass exchanges between the phases. The cell-nutrient interaction defines a typical diffusive length in the problem, which is found to control the saturation of a growing separated domain, thus stabilizing the microstructural pattern. The distribution and the evolution of such emerging cluster morphologies are successfully compared to the clinical observation of microstructural patterns in tumor lesions.

  19. The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells

    SciTech Connect

    Takahashi, Rei; Hashimoto, Tomoko; Hongji Xu; Shixu Hu; Bigo-Marshall, H.; Benedict, W.F. ); Matsui, Toshimitsu Kobe Univ. School of Medicine ); Miki, Toru; Aaronson, S.A. )

    1991-06-15

    The product of the human retinoblastoma gene (RB) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Mutations of RB frequently occur in human bladder carcinoma. To investigate the significance of the functional loss of this gene in bladder cancer, an RB expression plasmid (pBARB) under control of the human {beta}-actin promoter was transfected into the bladder carcinoma cell line HTB9, which lacks RB expression. Marker-selected transfectants that expressed RB protein were identified by immunoblotting and immunohistochemical staining. In selected clones, stable RB expression has persisted over 1 yr under standard culture conditions with 10% serum. However, RB expression caused major alterations of HTB9 growth properties both in vitro and in vivo. RB{sup +} tranfectants lacked the ability to form colonies in semi-solid medium, and their growth rate was significantly decreased in 3% serum. In addition, the tumorigenicity of these transfectants was markedly decreased. Tumors that formed in nude mice were much smaller and had a longer latency period but were indistinguishable microscopically from those produced by parental cells. Slower growing tumors were RB{sup +}, as measured by nuclear staining of their RB protein and by a normal RB protein pattern on immunoblots. These findings support the concept that the RB gene acts as both a growth and tumor suppressor in bladder cancer cells.

  20. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

    PubMed

    Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2015-02-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro. However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

  1. SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

    PubMed Central

    Lee, Namgyu; Ryu, Hye Guk; Kwon, Jung-Hee; Kim, Dae-Kyum; Kim, Sae Rom; Wang, Hee Jung; Kim, Kyong-Tai; Choi, Kwan Yong

    2016-01-01

    The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC. PMID:27824900

  2. Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.

    PubMed

    Tang, Xiaoyun; Benesch, Matthew G K; Dewald, Jay; Zhao, Yuan Y; Patwardhan, Neeraj; Santos, Webster L; Curtis, Jonathan M; McMullen, Todd P W; Brindley, David N

    2014-11-01

    Lipid phosphate phosphatase-1 (LPP1) degrades lysophosphatidate (LPA) and attenuates receptor-mediated signaling. LPP1 expression is low in many cancer cells and tumors compared with normal tissues. It was hypothesized from studies with cultured cells that increasing LPP1 activity would decrease tumor growth and metastasis. This hypothesis has never been tested in vivo. To do this, we inducibly expressed LPP1 or a catalytically inactive mutant in cancer cells. Expressing active LPP1 increased extracellular LPA degradation by 5-fold. It also decreased the stimulation of Ca(2+) transients by LPA, a nondephosphorylatable LPA1/2 receptor agonist and a protease-activated receptor-1 peptide. The latter results demonstrate that LPP1 has effects downstream of receptor activation. Decreased Ca(2+) mobilization and Rho activation contributed to the effects of LPP1 in attenuating the LPA-induced migration of MDA-MB-231 breast cancer cells and their growth in 3D culture. Increasing LPP1 expression in breast and thyroid cancer cells decreased tumor growth and the metastasis by up to 80% compared with expression of inactive LPP1 or green fluorescent protein in syngeneic and xenograft mouse models. The present work demonstrates for the first time that increasing the LPP1 activity in three lines of aggressive cancer cells decreases their abilities to produce tumors and metastases in mice.

  3. An Investigation of the Growth Inhibitory Capacity of Several Medicinal Plants From Iran on Tumor Cell Lines

    PubMed Central

    Esmaeilbeig, Maryam; Kouhpayeh, Seyed Amin; Amirghofran, Zahra

    2015-01-01

    Background: Traditional herbal medicine is a valuable resource that provides new drugs for cancer treatment. Objectives: In this study we aim to screen and investigate the in vitro anti-tumor activities of ten species of plants commonly grown in Southern Iran. Materials and Methods: We used the MTT colorimetric assay to evaluate the cytotoxic activities of the methanol extracts of these plants on various tumor cell lines. The IC50 was calculated as a scale for this evaluation. Results: Satureja bachtiarica, Satureja hortensis, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed the inhibitoriest effects on Jurkat cells with > 80% inhibition at 200 µg/mL. Satureja hortensis (IC50: 66.7 µg/mL) was the most effective. These plants also strongly inhibited K562 cell growth; Satureja bachtiarica (IC50: 28.3 µg/mL), Satureja hortensis (IC50: 52 µg/mL) and Thymus vulgaris (IC50: 87 µg/mL) were the most effective extracts. Cichorium intybus, Rheum ribes, Alhagi pseudalhagi and Glycyrrihza glabra also showed notable effects on the leukemia cell lines. The Raji cell line was mostly inhibited by Satureja bachtiarica and Thymus vulgaris with approximately 40% inhibition at 200µg/ml. The influence of these extracts on solid tumor cell lines was not strong. Fen cells were mostly affected by Glycyrrihza glabra (IC50: 182 µg/mL) and HeLa cells by Satureja hortensis (31.6% growth inhibitory effect at 200 µg/mL). Conclusions: Leukemic cell lines were more sensitive to the extracts than the solid tumor cell lines; Satureja hortensis, Satureja bachtiarica, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed remarkable inhibitory potential. PMID:26634114

  4. Diffuse growth pattern affects E-cadherin expression in invasive breast cancer.

    PubMed

    Brinck, Ulrich; Jacobs, Susanne; Neuss, Michael; Tory, Kalman; Rath, Werner; Kulle, Bettina; Füzesi, Laszlo

    2004-01-01

    We investigated the correlations between growth patterns and E-cadherin expression by immunohistochemistry and the presence of mutations of exons 6-10 of the E-cadherin gene by PCR-SSCP, in 79 cases of invasive lobular and ductal breast cancer. E-cadherin expression showed a tendency to be lower in lobular than in ductal carcinomas (p=0.064). In 60% of lobular carcinomas the diffuse growth pattern and in 72% of ductal carcinomas the compact growth pattern predominated. E-cadherin expression was significantly lower in diffuse than in compact tumor area (p<0.001) and not related to carcinoma type when it was considered in tumor areas with either diffuse (p=0.278) or compact (p=0.128) growth pattern. No mutations were detected. In conclusion, loss of E-cadherin expression is related to an increase of diffuse growth pattern in both lobular and ductal types of breast cancer, and the differential proportions of growth patterns in both tumor types cause the tendency for lower E-cadherin expression in the lobular type.

  5. Mexican propolis flavonoids affect photosynthesis and seedling growth.

    PubMed

    King-Díaz, Beatriz; Granados-Pineda, Jessica; Bah, Mustapha; Rivero-Cruz, J Fausto; Lotina-Hennsen, Blas

    2015-10-01

    As a continuous effort to find new natural products with potential herbicide activity, flavonoids acacetin (1), chrysin (2) and 4',7-dimethylnarangenin (3) were isolated from a propolis sample collected in the rural area of Mexico City and their effects on the photosynthesis light reactions and on the growth of Lolium perenne, Echinochloa crus-galli and Physalis ixocarpa seedlings were investigated. Acacetin (1) acted as an uncoupler by enhancing the electron transport under basal and phosphorylating conditions and the Mg(2+)-ATPase. Chrysin (2) at low concentrations behaved as an uncoupler and at concentrations up to 100 μM its behavior was as a Hill reaction inhibitor. Finally, 4',7-dimethylnarangenin (3) in a concentration-dependent manner behaved as a Hill reaction inhibitor. Flavonoids 2 and 3 inhibited the uncoupled photosystem II reaction measured from water to 2,5-dichloro-1,4-benzoquinone (DCBQ), and they did not inhibit the uncoupled partial reactions measured from water to sodium silicomolybdate (SiMo) and from diphenylcarbazide (DPC) to diclorophenol indophenol (DCPIP). These results indicated that chrysin and 4',7-dimethylnarangenin inhibited the acceptor side of PS II. The results were corroborated with fluorescence of chlorophyll a measurements. Flavonoids also showed activity on the growth of seedlings of Lolium perenne and Echinochloa crus-galli.

  6. Interferon gamma-induced human guanylate binding protein 1 inhibits mammary tumor growth in mice.

    PubMed

    Lipnik, Karoline; Naschberger, Elisabeth; Gonin-Laurent, Nathalie; Kodajova, Petra; Petznek, Helga; Rungaldier, Stefanie; Astigiano, Simonetta; Ferrini, Silvano; Stürzl, Michael; Hohenadl, Christine

    2010-01-01

    Interferon gamma (IFN-gamma) has recently been implicated in cancer immunosurveillance. Among the most abundant proteins induced by IFN-gamma are guanylate binding proteins (GBPs), which belong to the superfamily of large GTPases and are widely expressed in various species. Here, we investigated whether the well-known human GBP-1 (hGBP-1), which has been shown to exert antiangiogenic activities and was described as a prognostic marker in colorectal carcinomas, may contribute to an IFN-gamma-mediated tumor defense. To this end, an IFN-independent, inducible hGBP-1 expression system was established in murine mammary carcinoma (TS/A) cells, which were then transplanted into syngeneic immune-competent Balb/c mice. Animals carrying TS/A cells that had been given doxycycline for induction of hGBP-1 expression revealed a significantly reduced tumor growth compared with mock-treated mice. Immunohistochemical analysis of the respective tumors demonstrated a tightly regulated, high-level expression of hGBP-1. No signs of an enhanced immunosurveillance were observed by investigating the number of infiltrating B and T cells. However, hemoglobin levels as well as the number of proliferating tumor cells were shown to be significantly reduced in hGBP-1-expressing tumors. This finding corresponded to reduced amounts of vascular endothelial growth factor A (VEGF-A) released by hGBP-1-expressing TS/A cells in vitro and reduced VEGF-A protein levels in the corresponding mammary tumors in vivo. The results suggest that hGBP-1 may contribute to IFN-gamma-mediated antitumorigenic activities by inhibiting paracrine effects of tumor cells on angiogenesis. Consequently, owing to these activities GBPs might be considered as potent members in an innate, IFN-gamma-induced antitumoral defense system.

  7. In vivo tumor growth of high-grade serous ovarian cancer cell lines

    PubMed Central

    Mitra, Anirban; Davis, David A.; Tomar, Sunil; Roy, Lynn; Gurler, Hilal; Xie, Jia; Lantvit, Daniel D.; Cardenas, Horacio; Fang, Fang; Liu, Yueying; Loughran, Elizabeth; Yang, Jing; Stack, M. Sharon; Emerson, Robert E; Cowden Dahl, Karen D.; Barbolina, Maria; Nephew, Kenneth P.; Matei, Daniela; Burdette, Joanna E.

    2015-01-01

    Objective Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. Methods To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH-OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119, UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. Results Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. Conclusions Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community. PMID:26050922

  8. 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.

  9. Classical Mathematical Models for Description and Prediction of Experimental Tumor Growth

    PubMed Central

    Benzekry, Sébastien; Lamont, Clare; Beheshti, Afshin; Tracz, Amanda; Ebos, John M. L.; Hlatky, Lynn; Hahnfeldt, Philip

    2014-01-01

    Despite internal complexity, tumor growth kinetics follow relatively simple laws that can be expressed as mathematical models. To explore this further, quantitative analysis of the most classical of these were performed. The models were assessed against data from two in vivo experimental systems: an ectopic syngeneic tumor (Lewis lung carcinoma) and an orthotopically xenografted human breast carcinoma. The goals were threefold: 1) to determine a statistical model for description of the measurement error, 2) to establish the descriptive power of each model, using several goodness-of-fit metrics and a study of parametric identifiability, and 3) to assess the models' ability to forecast future tumor growth. The models included in the study comprised the exponential, exponential-linear, power law, Gompertz, logistic, generalized logistic, von Bertalanffy and a model with dynamic carrying capacity. For the breast data, the dynamics were best captured by the Gompertz and exponential-linear models. The latter also exhibited the highest predictive power, with excellent prediction scores (≥80%) extending out as far as 12 days in the future. For the lung data, the Gompertz and power law models provided the most parsimonious and parametrically identifiable description. However, not one of the models was able to achieve a substantial prediction rate (≥70%) beyond the next day data point. In this context, adjunction of a priori information on the parameter distribution led to considerable improvement. For instance, forecast success rates went from 14.9% to 62.7% when using the power law model to predict the full future tumor growth curves, using just three data points. These results not only have important implications for biological theories of tumor growth and the use of mathematical modeling in preclinical anti-cancer drug investigations, but also may assist in defining how mathematical models could serve as potential prognostic tools in the clinic. PMID:25167199

  10. Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion.

    PubMed

    Cossu, Irene; Bottoni, Gianluca; Loi, Monica; Emionite, Laura; Bartolini, Alice; Di Paolo, Daniela; Brignole, Chiara; Piaggio, Francesca; Perri, Patrizia; Sacchi, Angelina; Curnis, Flavio; Gagliani, Maria Cristina; Bruno, Silvia; Marini, Cecilia; Gori, Alessandro; Longhi, Renato; Murgia, Daniele; Sementa, Angela Rita; Cilli, Michele; Tacchetti, Carlo; Corti, Angelo; Sambuceti, Gianmario; Marchiò, Serena; Ponzoni, Mirco; Pastorino, Fabio

    2015-11-01

    Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.

  11. Cimetidine induces apoptosis in gastric cancer cells in vitro and inhibits tumor growth in vivo.

    PubMed

    Jiang, Cheng-Gang; Liu, Fu-Rong; Yu, Miao; Li, Jia-Bin; Xu, Hui-Mian

    2010-03-01

    Cimetidine, a histamine-2 (H2) receptor antagonist, has been demonstrated to have anticancer effects on various types of malignancies. However, the mechanisms of its action on gastric cancer are not completely understood. This study was designed to investigate its antitumor effect and underlying mechanisms in human gastric cancer SGC-7901 and MGC-803 cells. The MTT assay was used to evaluate cell viability, and flow cytometry, acridine orange staining and transmission electron microscopy were used to detect apoptosis, for cultured cells. The protein expression in cells was evaluated by Western blot analysis and colorimetric assay. Gastric tumors were established by subcutaneous injection of SGC-7901 cells in nude BALB/c mice, and cimetidine was administered to the mice. The size of tumors was monitored and the weight of tumors was examined. The exposure of gastric cancer cells to cimetidine resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. Activation of the caspase cascade for both the extrinsic and intrinsic pathways were demonstrated in vitro, including caspase-8, -9 and -3. We also found that the expression of Bcl-2 protein decreased and the expression of Bax protein increased which lead to an increase of the Bax/Bcl-2 ratio. In mice bearing SGC-7901 xenograft tumors, administration of cimetidine showed a significant decrease of tumor volumes and tumor weight compared with the control. Our results showed that cimetidine exhibited antitumor effects in gastric cancer cells with an induction of apoptosis.

  12. Oral ingestion of Streptococcus thermophilus does not affect mucositis severity or tumor progression in the tumor-bearing rat.

    PubMed

    Tooley, Katie L; Howarth, Gordon S; Lymn, Kerry A; Lawrence, Andrew; Butler, Ross N

    2011-07-15

    Preventative or adjunctive agents for the amelioration of small intestinal chemotherapy-induced mucositis are not currently available for clinical use. We have previously demonstrated that oral ingestion of Streptococcus thermophilus (TH-4) partially attenuated chemotherapy-induced mucositis in the rat. Here we assess the effects of TH-4 on small intestinal damage and tumor progression in tumor-bearing rats with experimentally-induced mucositis. Female Dark Agouti tumor-bearing (mammary adenocarcinoma) rats (n = 36; 139 ± 1 g) had small intestinal damage induced via the administration of methotrexate (MTX). Rats were administered MTX; (1.5 mg/kg intramuscular) or saline at 0 and 24 h; with daily gavage administration of TH-4 (109 cfu/mL) or skim milk from -48 to +96 h post-MTX. Rats were allocated to groups (n=9): saline control, TH-4 control, MTX control or TH-4+MTX. The non-invasive ( 13) C-sucrose breath test (SBT) was conducted prior to tumor inoculation, pre-MTX (-24 h) and prior to sacrifice (96 h) to monitor gut function. At sacrifice small intestinal segments were excised and assessed for sucrase and myeloperoxidase activity as well as histological damage. Irrespective of TH-4 treatment, MTX-treated rats had a significant decrease in bodyweight, SBT levels, sucrase and myeloperoxidase activity, and histological damage score (p < 0.05) compared to saline and TH-4 control rats. TH-4 treatment did not result in tumor progression (p > 0.05) but failed to alleviate mucositis indices. Although TH-4, at a dose of 109 cfu/mL, yielded neither protection nor amelioration of chemotherapy-induced mucositis, progression of mammary adenocarcinoma was unaffected.

  13. The functional interaction between Acyl-CoA synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth: a novel therapeutic target.

    PubMed

    Orlando, Ulises D; Garona, Juan; Ripoll, Giselle V; Maloberti, Paula M; Solano, Ángela R; Avagnina, Alejandra; Gomez, Daniel E; Alonso, Daniel F; Podestá, Ernesto J

    2012-01-01

    The acyl-CoA synthetase 4 (ACSL4), which esterify mainly arachidonic acid (AA) into acyl-CoA, is increased in breast, colon and hepatocellular carcinoma. The transfection of MCF-7 cells with ACSL4 cDNA transforms the cells into a highly aggressive phenotype and controls both lipooxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) metabolism of AA, suggesting a causal role of ACSL4 in tumorigenesis. We hypothesized that ACSL4, LOX-5 and COX-2 may constitute potential therapeutic targets for the control of tumor growth. Therefore, the aim of this study was to use a tetracycline Tet-Off system of MCF-7 xenograft model of breast cancer to confirm the effect of ACSL4 overexpression on tumor growth in vivo. We also aim to determine whether a combinatorial inhibition of the ACSL4-LOX-COX-2 pathway affects tumor growth in vivo using a xenograft model based on MDA-MB-231 cells, a highly aggressive breast cancer cell line naturally overexpressing ACSL4. The first novel finding is that stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system of MCF-7 cells resulted in development of growing tumors when injected into nude mice. Tumor xenograft development measured in animals that received doxycycline resulted in tumor growth inhibition. The tumors presented marked nuclear polymorphism, high mitotic index and low expression of estrogen and progesterone receptor. These results demonstrate the transformational capacity of ACSL4 overexpression. We examined the effect of a combination of inhibitors of ACSL4, LOX-5 and COX-2 on MDA-MB-231 tumor xenografts. This treatment markedly reduced tumor growth in doses of these inhibitors that were otherwise ineffective when used alone, indicating a synergistic effect of the compounds. Our results suggest that these enzymes interact functionally and form an integrated system that operates in a concerted manner to regulate tumor growth and consequently may be potential therapeutic targets for the control of

  14. Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma.

    PubMed

    Meerang, Mayura; Bérard, Karima; Felley-Bosco, Emanuela; Lauk, Olivia; Vrugt, Bart; Boss, Andreas; Kenkel, David; Broggini-Tenzer, Angela; Stahel, Rolf A; Arni, Stephan; Weder, Walter; Opitz, Isabelle

    2016-05-01

    An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa Primary cells isolated from the rat model cultured in 3% O2 continued to express Dhh but did not respond to vismodegib in vitro However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095-105. ©2016 AACR.

  15. Formaldehyde exposure affects growth and metabolism of common bean

    SciTech Connect

    Mutters, R.G.; Madore, M. ); Bytnerowicz, A. )

    1993-01-01

    Recent state and federal directives have slated a substantial increase in the use of methanol as an alternative to gasoline in both fleet and private vehicles in the coming decade. The incomplete combustion of methanol produces formaldehyde vapor, and catalytic converter technology that completely oxidizes formaldehyde has yet to be developed. The approach of this study was to use a range of methanol concentrations encompassing levels currently found or that may occur in the future in the ambient air of some heavily polluted areas to test the potential phytotoxicity of formaldehyde. The study had the following objectives: (1) design and build a formaldehyde vapor generator with sufficient capacity for long-term plant fumigations; (2) determine growth response of common bean to formaldehyde; (3) evaluate physiological and biochemical changes of bean plants associated with formaldehyde exposures. 20 refs., 2 figs., 2 tabs.

  16. Autocrine Transforming Growth Factor-β Growth Pathway in Murine Osteosarcoma Cell Lines Associated with Inability to Affect Phosphorylation of Retinoblastoma Protein

    PubMed Central

    Letterio, John J.; Yeung, Choh L.; Pegtel, Michiel; Helman, Lee J.

    2000-01-01

    Purpose. Production of active transforming growth factor-β (TGF-β ) by human osteosarcoma may contribute to malignant progression through mechanisms that include induction of angiogenesis, immune suppression and autocrine growth stimulation of tumor cell growth.To study events associated with induction of cell proliferation by TGF-β , we have evaluated the TGF-β pathway in two murine osteosarcoma cell lines, K7 and K12. Results. Northern and immunohistochemical analyses show that each cell line expressesTGF-β1 and TGF-β3 mRNA and protein. Both cell lines secrete activeTGF-β 1 and display a 30–50% reduction in growth when cultured in the presence of a TGF-β blocking antibody. Expression of TGF-β receptors TβRI, TβRII and TβRIII is demonstrated by affinity labeling with 125 -TGF-β 1, and the intermediates, Smads 2, 3 and 4, are uniformly expressed. Smads 2 and 3 are phosphorylated in response toTGF-β , while pRb phosphorylation in each osteosarcoma cell line is not affected by either exogenousTGF-β or TGF-β antibody. Conclusions. The data implicate events downstream of Smad activation, including impaired regulation of pRb, in the lack of a growth inhibitory response toTGF-β , and indicate that this murine model of osteosarcoma is valid for investigating the roles of autocrineTGF-β in vivo. PMID:18521287

  17. INHIBITION OF RHABDOMYOSARCOMA CELL AND TUMOR GROWTH BY TARGETING SPECIFICITY PROTEIN (Sp) TRANSCRIPTION FACTORS

    PubMed Central

    Chadalapaka, Gayathri; Jutooru, Indira; Sreevalsan, Sandeep; Pathi, Satya; Kim, Kyounghyun; Chen, Candy; Crose, Lisa; Linardic, Corinne; Safe, Stephen

    2012-01-01

    Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in rhabdomyosarcoma (RMS) cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes in RMS cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c-MET, insulin-like growth factor receptor (IGFR), PDGFRα and CXCR4, are also Sp-regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients. PMID:22815231

  18. Digital holographic microscopy for imaging growth and treatment response in 3D tumor models

    NASA Astrophysics Data System (ADS)

    Li, Yuyu; Petrovic, Ljubica; Celli, Jonathan P.; Yelleswarapu, Chandra S.

    2014-03-01

    While three-dimensional tumor models have emerged as valuable tools in cancer research, the ability to longitudinally visualize the 3D tumor architecture restored by these systems is limited with microscopy techniques that provide only qualitative insight into sample depth, or which require terminal fixation for depth-resolved 3D imaging. Here we report the use of digital holographic microscopy (DHM) as a viable microscopy approach for quantitative, non-destructive longitudinal imaging of in vitro 3D tumor models. Following established methods we prepared 3D cultures of pancreatic cancer cells in overlay geometry on extracellular matrix beds and obtained digital holograms at multiple timepoints throughout the duration of growth. The holograms were digitally processed and the unwrapped phase images were obtained to quantify nodule thickness over time under normal growth, and in cultures subject to chemotherapy treatment. In this manner total nodule volumes are rapidly estimated and demonstrated here to show contrasting time dependent changes during growth and in response to treatment. This work suggests the utility of DHM to quantify changes in 3D structure over time and suggests the further development of this approach for time-lapse monitoring of 3D morphological changes during growth and in response to treatment that would otherwise be impractical to visualize.

  19. Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

    PubMed Central

    Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

    2015-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

  20. Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients.

    PubMed

    Yang, I; Park, S; Ryu, M; Woo, J; Kim, S; Kim, J; Kim, Y; Choi, Y

    1996-06-01

    A subset of human growth hormone (GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the alpha-subunit of the stimulatory GTP-binding protein (G(S) alpha). This study was undertaken to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical characteristics of these patients to endocrine testing. Direct polymerase chain reaction sequencing revealed the gsp oncogene mutation in 9 out of 21 tumors (43%) at amino acid 201 of the G(S) alpha protein. A single nucleotide mutation in the tumors carrying the gsp oncogene was observed, which replaced an arginine (CGT) in the normal protein with cysteine (TGT) in eight tumors and serine (AGT) in one tumor. The patients with the gsp oncogene mutation (group 1) were older (54 +/- 10 vs 41 +/- 11 years, p = 0.0085) than those without the mutation (group 2). Sex, tumor size and grade, basal GH and prolactin levels, the GH response to oral glucose loading, the GH fluctuation and the paradoxical response to thyrotropin-releasing hormone or gonadotropin-releasing hormone did not differ between the groups. The gsp oncogene was found mostly in somatotroph adenomas. The octreotide-induced GH suppression was significantly higher in group 1 than in group 2 (95 +/- 5% vs 81 +/- 17%, p = 0.0335). The GH response to bromocriptine did not differ between the groups. These results suggest that the G(S) alpha mutations of GH-secreting tumor are observed in Korean acromegalic patients with similar frequency to those of western countries. The patients with gsp oncogene are likely to be older than those without the oncogene, and show excellent response of GH suppression to octreotide.

  1. Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

    PubMed Central

    Agrawal, Vijayendra; Kim, Dong Young; Kwon, Young-Guen

    2017-01-01

    Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/− mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/− mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density. PMID:28127049

  2. Influence of total parenteral nutrition on tumor growth and polyamine biosynthesis of fibrosarcoma-bearing rats after induced cachexia.

    PubMed

    Grossie, V B; Ota, D M; Ajani, J A; Chang, T H; Patenia, D; Nishioka, K

    1988-01-01

    The effect of a protein-free diet (PF) or a restricted intake of chow (RI) and subsequent host repletion with total parenteral nutrition (PF-TPN, RI-TPN) on tumor growth and polyamine metabolism of fibrosarcoma-bearing rats was examined. Host weight was significantly reduced by PF and RI. Tumor growth was reduced in malnourished rats with the PF regimen resulting in the greatest decrease. Rats receiving TPN after 14 days of the RI or PF regimens had higher host weight and plasma albumin levels than malnourished rats. Tumor growth during TPN was evaluated as the percent increase and compared with that of the respective malnourished rats. The percent increase for RI-TPN rats was significantly greater although a trend toward an increase was also evident for PF-TPN rats. Tumor ornithine decarboxylase (ODC) activity and putrescine levels were increased for PF rats and decreased for RI rats while tumor ODC activity was consistently increased by TPN. Tumor growth, ODC activity, and putrescine levels were simultaneously increased only for those rats fed the RI regimen prior to TPN. These results show a disparity in tumor ODC activity, putrescine levels, and tumor growth in malnourished rats. The results of this study suggest that the nutritional origin of cachexia influences the response of the tumor to TPN and emphasizes the importance of considering the methods to induce malnutrition in designing therapuetic regimens.

  3. LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.

    PubMed

    Kuzmanov, Aleksandar; Hopfer, Ulrike; Marti, Patricia; Meyer-Schaller, Nathalie; Yilmaz, Mahmut; Christofori, Gerhard

    2014-03-01

    An epithelial-mesenchymal transition (EMT) is a critical process during embryonic development and the progression of epithelial tumors to metastatic cancers. Gene expression profiling has uncovered the transcription factor LIM homeobox gene 2 (Lhx2) with up-regulated expression during TGFβ-induced EMT in normal and cancerous breast epithelial cells. Loss and gain of function experiments in transgenic mouse models of breast cancer and of insulinoma in vivo and in breast cancer cells in vitro indicate that Lhx2 plays a critical role in primary tumor growth and metastasis. Notably, the transgenic expression of Lhx2 during breast carcinogenesis promotes vessel maturation, primary tumor growth, tumor cell intravasation and metastasis by directly inducing the expression of platelet-derived growth factor (PDGF)-B in tumor cells and by indirectly increasing the expression of PDGF receptor-β (PDGFRβ) on tumor cells and pericytes. Pharmacological inhibition of PDGF-B/PDGFRβ signaling reduces vessel functionality and tumor growth and Lhx2-induced cell migration and cell invasion. The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRβ loop required for cell migration, invasion and metastatic dissemination and paracrine PDGF-B/PDGFRβ signaling to support blood vessel functionality and, thus, primary tumor growth.

  4. CD73-Generated Adenosine: Orchestrating the Tumor-Stroma Interplay to Promote Cancer Growth

    PubMed Central

    Allard, Bertrand; Turcotte, Martin; Stagg, John

    2012-01-01

    Despite the coming of age of cancer immunotherapy, clinical benefits are still modest. An important barrier to successful cancer immunotherapy is that tumors employ a number of mechanisms to facilitate immune escape, including the production of anti-inflammatory cytokines, the recruitment of regulatory immune subsets, and the production of immunosuppressive metabolites. Significant therapeutic opportunity exists in targeting these immunosuppressive pathways. One such immunosuppressive pathway is the production of extracellular adenosine by CD73, an ectonucleotidase overexpressed in various types of cancer. We hereafter review the biology of CD73 and its role in cancer progression and metastasis. We describe the role of extracellular adenosine in promoting tumor growth through paracrine and autocrine action on tumor cells, endothelial cells, and immune cells. PMID:23125525

  5. Optimization of vascular-targeting drugs in a computational model of tumor growth

    NASA Astrophysics Data System (ADS)

    Gevertz, Jana

    2012-04-01

    A biophysical tool is introduced that seeks to provide a theoretical basis for helping drug design tea