Sample records for tumor growth delay

  1. 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 300kHz 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 (6V/cm, 150kHz) 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. PMID:25955102

  2. STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma

    SciTech Connect

    Geng Ling [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Shinohara, Eric T. [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Kim, Dong [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Tan Jiahuai [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Osusky, Kate [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States); Shyr, Yu [Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN (United States); Hallahan, Dennis E. [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN (United States) and Vanderbilt-Ingram Cancer Center, Nashville, TN (United States)]. E-mail: Dennis.Hallahan@mcmail.vanderbilt.edu

    2006-01-01

    Purpose: Glioblastoma multiforme (GBM) is a devastating brain neoplasm that is essentially incurable. Although radiation therapy prolongs survival, GBMs progress within areas of irradiation. Recent studies in invertebrates have shown that STI571 (Gleevec; Novartis, East Hanover, NJ) enhances the cytotoxicity of ionizing radiation. In the present study, the effectiveness of STI571 in combination with radiation was studied in mouse models of GBM. Methods and Materials: Murine GL261 and human D54 GBM cell lines formed tumors in brains and hind limbs of C57BL6 and nude mice, respectively. GL261 and D54 cells were treated with 5 {mu}mol/L of STI571 for 1 h and/or irradiated with 3 Gy. Protein was analyzed by Western immunoblots probed with antibodies to caspase 3, cleaved caspase 3, phospho-Akt, Akt, and platelet-derived growth factor receptor (PDGFR) {alpha} and {beta}. Tumor volumes were assessed in mice bearing GL261 or D54 tumors treated with 21 Gy administered in seven fractionated doses. Histologic sections from STI571-treated mice were stained with phospho-Akt and phospho-PDGFR {beta} antibodies. Kaplan-Meier survival curves were used to study the response of mice bearing intracranial implants of GL261. Results: STI571 penetrated the blood-brain barrier, which resulted in a reduction in phospho-PDGFR in GBM. STI571-induced apoptosis in GBM was significantly enhanced by irradiation. STI571 combined with irradiation induced caspase 3 cleavage in GBM cells. Glioblastoma multiforme response to therapy correlated with an increase in tumor growth delay and survival when STI571 was administered in conjunction with daily irradiation. Conclusion: These findings suggest that STI571 has the potential to augment radiotherapy and thereby improve median survival.

  3. Irradiation combined with SU5416: Microvascular changes and growth delay in a human xenograft glioblastoma tumor line

    SciTech Connect

    Schuuring, Janneke [Department of NeurologyUniversity Medical Center, Nijmegen (Netherlands); Department of Neurology, Groene Hart Hospital, Gouda (Netherlands); Bussink, Johan [Department of Radiation Oncology, University Medical Center, Nijmegen (Netherlands)]. E-mail: J.Bussink@rther.umcn.nl; Bernsen, Hans [Department ofRadiation Oncology, University Medical Center, Nijmegen (Netherlands); Canisius Wilhelmina Hospital, Nijmegen (Netherlands); Peeters, Wenny [Department ofRadiation Oncology, University Medical Center, Nijmegen (Netherlands); Kogel, Albert J. van der [Department ofRadiation Oncology, University Medical Center, Nijmegen (Netherlands)

    2005-02-01

    Purpose: The combination of irradiation and the antiangiogenic compound SU5416 was tested and compared with irradiation alone in a human glioblastoma tumor line xenografted in nude mice. The aim of this study was to monitor microenvironmental changes and growth delay. Methods and materials: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without SU5416. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after imunohistochemical staining. Tumor growth delay was monitored for up to 200 days after treatment. Results: SU5416, when combined with irradiation, has an additive effect over treatment with irradiation alone. Analysis of the tumor microenvironment showed a decreased vascular density during treatment with SU5416. In tumors regrowing after reaching only a partial remission, vascular characteristics normalized shortly after cessation of SU5416. However, in tumors regrowing after reaching a complete remission, permanent microenvironmental changes and an increase of tumor necrosis with a subsequent slower tumor regrowth was found. Conclusions: Permanent vascular changes were seen after combined treatment resulting in complete remission. Antiangiogenic treatment with SU5416 when combined with irradiation has an additive effect over treatment with irradiation or antiangiogenic treatment alone.

  4. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice.

    PubMed

    Zhou, Zhongjun; Wang, Jianming; Cao, Renhai; Morita, Hiroyuki; Soininen, Raija; Chan, Kui Ming; Liu, Baohua; Cao, Yihai; Tryggvason, Karl

    2004-07-15

    Perlecan, a modular proteoglycan carrying primary heparan sulfate (HS) side chains, is a major component of blood vessel basement membranes. It sequesters growth factors such as fibroblast growth factor 2 (FGF-2) and regulates the ligand-receptor interactions on the cell surface, and thus it has been implicated in the control of angiogenesis. Both stimulatory and inhibitory effects of perlecan on FGF-2 signaling have been reported. To understand the in vivo function of HS carried by perlecan, the perlecan gene heparan sulfate proteoglycan 2 (Hspg2) was mutated in mouse by gene targeting. The HS at the NH(2) terminus of perlecan was removed while the core protein remained intact. Perlecan HS-deficient (Hspg2(Delta3/Delta3)) mice survived embryonic development and were apparently healthy as adults. However, mutant mice exhibited significantly delayed wound healing, retarded FGF-2-induced tumor growth, and defective angiogenesis. In the mouse corneal angiogenesis model, FGF-2-induced neovascularization was significantly impaired in Hspg2(Delta3/Delta3) mutant mice. Our results suggest that HS in perlecan positively regulates the angiogenesis in vivo. PMID:15256433

  5. Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model.

    PubMed

    Foehr, Erik D; Lorente, Gustavo; Kuo, Jane; Ram, Rosie; Nikolich, Karoly; Urfer, Roman

    2006-02-15

    The receptor protein tyrosine phosphatase beta (RPTPbeta) is a functional biomarker for several solid tumor types. RPTPbeta expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPbeta is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPbeta is expressed in a variety of solid tumor types with low expression in normal tissue. To assess RPTPbeta as a potential target for treatment of glioblastoma and other cancers, antibodies directed to RPTPbeta have been developed and profiled in vitro and in vivo. The recombinant extracellular domain of human short RPTPbeta was used to immunize mice and generate monoclonal antibodies that selectively recognize RPTPbeta and bind to the antigen with low nanomolar affinities. Moreover, these antibodies recognized the target on living tumor cells as measured by flow cytometry. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody. Finally, in vivo studies showed that an anti-RPTPbeta immunotoxin (7E4B11-SAP) could significantly delay human U87 glioma tumors in a mouse xenograft model. Unconjugated 7E4B11 provides a modest but statistically significant tumor growth delay when delivered systemically in mice bearing U87 glioma tumors. PMID:16489031

  6. 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-? 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-? 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

  7. Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma.

    PubMed

    Gordon, Ira K; Lu, Jie; Graves, Christian A; Huntoon, Kristin; Frerich, Jason M; Hanson, Ryan H; Wang, Xiaoping; Hong, Christopher S; Ho, Winson; Feldman, Michael J; Ikejiri, Barbara; Bisht, Kheem; Chen, Xiaoyuan S; Tandle, Anita; Yang, Chunzhang; Arscott, W Tristram; Ye, Donald; Heiss, John D; Lonser, Russell R; Camphausen, Kevin; Zhuang, Zhengping

    2015-07-01

    Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased ?-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity. Mol Cancer Ther; 14(7); 1540-7. ©2015 AACR. PMID:25939762

  8. Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

    PubMed Central

    2014-01-01

    Background Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. Methods We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ? signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). Results PSCA-CAR T cells exhibit specific interferon (IFN)-? and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Conclusions Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer. PMID:24438073

  9. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.

    PubMed

    Yang, H; Pellegrini, L; Napolitano, A; Giorgi, C; Jube, S; Preti, A; Jennings, C J; De Marchis, F; Flores, E G; Larson, D; Pagano, I; Tanji, M; Powers, A; Kanodia, S; Gaudino, G; Pastorino, S; Pass, H I; Pinton, P; Bianchi, M E; Carbone, M

    2015-01-01

    High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information. PMID:26068794

  10. Targeting of the Receptor Protein Tyrosine Phosphatase B with a Monoclonal Antibody Delays Tumor Growth in a Glioblastoma Model

    Microsoft Academic Search

    Erik D. Foehr; Gustavo Lorente; Jane Kuo; Rosie Ram; Karoly Nikolich; Roman Urfer

    The receptor protein tyrosine phosphatase B (RPTPB )i s a functional biomarker for several solid tumor types. RPTPB expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPB is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPB is

  11. Non-competitive modulation of the proteasome by imidazoline scaffolds overcome bortezomib resistant and delay MM tumor growth in vivo

    PubMed Central

    Lansdell, Theresa A.; Hurchla, Michelle A.; Xiang, Jingyu; Hovde, Stacy; Weilbaecher, Katherine N.; Henry, R. William; Tepe, Jetze J.

    2012-01-01

    Multiple myeloma is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (~97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than one year. We describe herein the inhibition of the human proteasome via a non-competitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013 induces apoptosis a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative BM samples of MM patients. The cellular activity translated well in vivo where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib. PMID:23198928

  12. Impaired Angiogenesis, Delayed Wound Healing and Retarded Tumor Growth in Perlecan Heparan Sulfate-Deficient Mice

    Microsoft Academic Search

    Zhongjun Zhou; Jianming Wang; Renhai Cao; Hiroyuki Morita; Raija Soininen; Kui Ming Chan; Baohua Liu; Yihai Cao; Karl Tryggvason

    2004-01-01

    Perlecan, a modular proteoglycan carrying primary heparan sulfate (HS) side chains, is a major component of blood vessel basement mem- branes. It sequesters growth factors such as fibroblast growth factor 2 (FGF-2) and regulates the ligand-receptor interactions on the cell surface, and thus it has been implicated in the control of angiogenesis. Both stimulatory and inhibitory effects of perlecan on

  13. Correlation Between Tumor Growth Delay and Expression of Cancer and Host VEGF, VEGFR2, and Osteopontin in Response to Radiotherapy

    SciTech Connect

    Solberg, Timothy D. [University of Nebraska Medical Center, Omaha, NE (United States); University of Texas Southwestern Medical Center, Dallas, TX (United States); Nearman, Jessica; Mullins, John; Li Sicong [University of Nebraska Medical Center, Omaha, NE (United States); Baranowska-Kortylewicz, Janina [University of Nebraska Medical Center, Omaha, NE (United States)], E-mail: jbaranow@unmc.edu

    2008-11-01

    Purpose: To determine the late effects of radiotherapy (RT) on vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and osteopontin (OPN) expression in cancer and stromal cells. Methods and Materials: LS174T xenografted athymic mice were used as a tumor model. Radiation was delivered in two equivalent fractionation schemes: 5 x 7 Gy and 1 x 20 Gy, the latter at two dose rates. Results: Tumor growth arrest was similar in all treatment groups, with the exception of a better response of small-size tumors in the 5 x 7-Gy group. The host VEGF and OPN levels were directly proportional to the tumor doubling time and were independent of the fractionation scheme. The host and cancer cell VEGFR2 levels in tumor were also directly related to the tumor response to RT. Conclusion: Upregulated VEGFR2 in cancer cells suggest paracrine signaling in the VEGFR2 pathway of cancer cells as the factor contributing to RT failure. The transient activation of the host VEGF/VEGFR2 pathway in tumor supports the model of angiogenic regeneration and suggests that radiation-induced upregulation of VEGF, VEGFR2, and downstream proteins might contribute to RT failure by escalating the rate of vascular repair. Coexpression of host OPN and VEGF, two factors closely associated with angiogenesis, indicate that OPN can serve as a surrogate marker of tumor recovery after RT. Taken together, these results strongly support the notion that to achieve optimal therapeutic outcomes, the scheduling of RT and antiangiogenic therapies will require patient-specific post-treatment monitoring of the VEGF/VEGFR2 pathway and that tumor-associated OPN can serve as an indicator of tumor regrowth.

  14. The effects of ultra-high dose rate proton irradiation on growth delay in the treatment of human tumor xenografts in nude mice.

    PubMed

    Zlobinskaya, O; Siebenwirth, C; Greubel, C; Hable, V; Hertenberger, R; Humble, N; Reinhardt, S; Michalski, D; Röper, B; Multhoff, G; Dollinger, G; Wilkens, J J; Schmid, T E

    2014-02-01

    The new technology of laser-driven ion acceleration (LDA) has shown the potential for driving highly brilliant particle beams. Laser-driven ion acceleration differs from conventional proton sources by its ultra-high dose rate, whose radiobiological impact should be investigated thoroughly before adopting current clinical dose concepts. The growth of human FaDu tumors transplanted onto the hind leg of nude mice was measured sonographically. Tumors were irradiated with 20 Gy of 23 MeV protons at pulsed mode with single pulses of 1 ns duration or continuous mode (?100 ms) in comparison to controls and to a dose-response curve for 6 MV photons. Tumor growth delay and the relative biological effectiveness (RBE) were calculated for all irradiation modes. The mean target dose reconstructed from Gafchromic films was 17.4 ± 0.8 Gy for the pulsed and 19.7 ± 1.1 Gy for the continuous irradiation mode. The mean tumor growth delay was 34 ± 6 days for pulsed, 35 ± 6 days for continuous protons, and 31 ± 7 days for photons 20 ± 1.2 Gy, resulting in RBEs of 1.22 ± 0.19 for pulsed and 1.10 ± 0.18 for continuous protons, respectively. In summary, protons were found to be significantly more effective in reducing the tumor volume than photons (P < 0.05). Together with the results of previous in vitro experiments, the in vivo data reveal no evidence for a substantially different radiobiology that is associated with the ultra-high dose rate of protons that might be generated from advanced laser technology in the future. PMID:24524347

  15. Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

    PubMed Central

    Gehrmann, Mathias; Schönberger, Johann; Zilch, Tanja; Rossbacher, Lydia; Thonigs, Gerald; Eilles, Christoph; Multhoff, Gabriele

    2005-01-01

    Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX?) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 ?M, 1 ?M, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX? tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology. PMID:16038410

  16. Influence of Dendritic Cells on Tumor Growth

    NASA Astrophysics Data System (ADS)

    Knight, Stella C.; Hunt, Ruth; Dore, Caroline; Medawar, Peter B.

    1985-07-01

    Dendritic cells (DC) exposed to antigen are potent initiators of immune responses, and the numbers of DC and the dose of antigen control the level of response. The influence of these variables was tested on the growth of mouse sarcoma cells in vivo. When normal syngeneic DC (100,000) were given to mice with palpable tumors, tumor regression or delay in tumor growth was obtained. DC exposed to increasing doses of tumor extract in vitro before administration had progressively less effect. DC exposed to antigen delayed tumor growth significantly only when given on the same day as 500 tumor cells. The studies suggested that low doses of antigen on DC elicit immune responses and that high doses block them. The numbers of antigen-presenting cells and the dose of antigen modulate the degree of immunity to mouse sarcoma in vivo.

  17. An MMP13Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

    Microsoft Academic Search

    Manisha Shah; Dexing Huang; Tony Blick; Andrea Connor; Lawrence A. Reiter; Joel R. Hardink; Conor C. Lynch; Mark Waltham; Erik W. Thompson

    2012-01-01

    We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB\\/c Nu\\/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into

  18. Mechanics in Tumor Growth 1 Mechanics in Tumor Growth

    E-print Network

    Preziosi, Luigi

    Mechanics in Tumor Growth 1 1 Mechanics in Tumor Growth L. Graziano Polytechnic of Turin Department Torino, Italy Abstract. This chapter focuses on the mechanical aspects of tumor growth. After describing some of the main feature of tumor growth and in particular the phenomena involving stress

  19. Knockdown of platinum-induced growth differentiation factor 15 abrogates p27-mediated tumor growth delay in the chemoresistant ovarian cancer model A2780cis

    PubMed Central

    Meier, Julia C; Haendler, Bernard; Seidel, Henrik; Groth, Philip; Adams, Robert; Ziegelbauer, Karl; Kreft, Bertolt; Beckmann, Georg; Sommer, Anette; Kopitz, Charlotte

    2015-01-01

    Molecular mechanisms underlying the development of resistance to platinum-based treatment in patients with ovarian cancer remain poorly understood. This is mainly due to the lack of appropriate in vivo models allowing the identification of resistance-related factors. In this study, we used human whole-genome microarrays and linear model analysis to identify potential resistance-related genes by comparing the expression profiles of the parental human ovarian cancer model A2780 and its platinum-resistant variant A2780cis before and after carboplatin treatment in vivo. Growth differentiation factor 15 (GDF15) was identified as one of five potential resistance-related genes in the A2780cis tumor model. Although A2780-bearing mice showed a strong carboplatin-induced increase of GDF15 plasma levels, the basal higher GDF15 plasma levels of A2780cis-bearing mice showed no further increase after short-term or long-term carboplatin treatment. This correlated with a decreased DNA damage response, enhanced AKT survival signaling and abrogated cell cycle arrest in the carboplatin-treated A2780cis tumors. Furthermore, knockdown of GDF15 in A2780cis cells did not alter cell proliferation but enhanced cell migration and colony size in vitro. Interestingly, in vivo knockdown of GDF15 in the A2780cis model led to a basal-enhanced tumor growth, but increased sensitivity to carboplatin treatment as compared to the control-transduced A2780cis tumors. This was associated with larger necrotic areas, a lobular tumor structure and increased p53 and p16 expression of the carboplatin-treated shGDF15-A2780cis tumors. Furthermore, shRNA-mediated GDF15 knockdown abrogated p27 expression as compared to control-transduced A2780cis tumors. In conclusion, these data show that GDF15 may contribute to carboplatin resistance by suppressing tumor growth through p27. These data show that GDF15 might serve as a novel treatment target in women with platinum-resistant ovarian cancer. PMID:25490861

  20. Strange Attractor in Immunology of Tumor Growth

    E-print Network

    Margarita Voitikova

    1997-08-21

    The time delayed cytotoxic T-lymphocyte response on the tumor growth has been developed on the basis of discrete approximation (2-dimensional map). The growth kinetic has been described by logistic law with growth rate being the bifurcation parameter. Increase in the growth rate results in instability of the tumor state and causes period-doubling bifurcations in the immune+tumor system. For larger values of tumor growth rate a strange attractor has been observed. The model proposed is able to describe the metastable-state production when time series data of the immune state and the number of tumor cells are irregular and unpredictable. This metastatic disease may be caused not by exterior (medical) factors, but interior density dependent ones.

  1. Stochastic models for tumoral growth

    NASA Astrophysics Data System (ADS)

    Escudero, Carlos

    2006-02-01

    Strong experimental evidence has indicated that tumor growth belongs to the molecular beam epitaxy universality class. This type of growth is characterized by the constraint of cell proliferation to the tumor border and the surface diffusion of cells at the growing edge. Tumor growth is thus conceived as a competition for space between the tumor and the host, and cell diffusion at the tumor border is an optimal strategy adopted for minimizing the pressure and helping tumor development. Two stochastic partial differential equations are reported in this paper in order to correctly model the physical properties of tumoral growth in (1+1) and (2+1) dimensions. The advantage of these models is that they reproduce the correct geometry of the tumor and are defined in terms of polar variables. An analysis of these models allows us to quantitatively estimate the response of the tumor to an unfavorable perturbation during growth.

  2. The TCD[sub 50] and regrowth delay assay in human tumor xenografts: Differences and implications

    SciTech Connect

    Budach, W.; Budach, V.; Stuschke, M.; Dinges, S.; Sack, H. (Univ. of Essen (Germany))

    1993-01-15

    The response to irradiation of five human xenograft cell lines - a malignant paraganglioma, a neurogenic sarcoma, a malignant histiocytoma, a primary lymphoma of the brain, and a squamous cell carcinoma - were tested in nude mice. All mice underwent 5 Gy whole body irradiation prior to xenotransplantation to minimize the residual immune response. The subcutaneous tumors were irradiated at a tumor volume of 120 mm[sup 3] under acutely hypoxic conditions with single doses between 8 Gy and 80 Gy depending on the expected radiation sensitivity of the tumor line. Endpoints of the study were the tumor control dose 50% (TCD[sub 50]) and the regrowth delay endpoints growth delay, specific growth delay, and the tumor bed effect corrected specific growth delay. Specific growth delay and corrected specific growth delay at 76% of the TCD[sub 50] was used in order to compare the data to previously published data from spheroids. The lowest TCD[sub 50] was found in the lymphoma with 24.9 Gy, whereas the TCD[sub 50] of the soft tissue sarcomas and the squamous cell carcinoma ranged from 57.8 Gy to 65.6 Gy. The isoeffective dose levels for the induction of 30 days growth delay, a specific growth delay of 3, and a corrected specific growth delay of 3 ranged from 15.5 Gy (ECL1) to 37.1 Gy (FADU), from 7.2 Gy (ENE2) to 45.6 Gy (EPG1) and from 9.2 Gy (ENE2) to 37.6 Gy (EPG1), respectively. The corrected specific growth delay at 76% of the TCD[sub 50] was correlated with the number of tumor rescue units per 100 cells in spheroids, which was available for three tumor lines, and with the tumor doubling time in xenografts (n = 5). The TCD[sub 50] values corresponded better to the clinical experience than the regrowth delay data. There was no correlation between TCD[sub 50] and any of the regrowth delay endpoints. This missing correlation was most likely a result of large differences in the number of tumor rescue units in human xenografts of the same size.

  3. Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays

    SciTech Connect

    Bi, Ping [Department of Mathematics, Shanghai Key Laboratory of PMMP, East China Normal University, 500 Dongchuan Rd., Shanghai 200241 (China) [Department of Mathematics, Shanghai Key Laboratory of PMMP, East China Normal University, 500 Dongchuan Rd., Shanghai 200241 (China); Center for Partial Differential Equations, East China Normal University, 500 Dongchuan Rd., Shanghai 200241 (China); Ruan, Shigui, E-mail: ruan@math.miami.edu [Department of Mathematics, University of Miami, Coral Gables, Florida 33124-4250 (United States)] [Department of Mathematics, University of Miami, Coral Gables, Florida 33124-4250 (United States); Zhang, Xinan [School of Mathematics and Statistics, Central China Normal University, Wuhan 430079 (China)] [School of Mathematics and Statistics, Central China Normal University, Wuhan 430079 (China)

    2014-06-15

    In this paper, a tumor and immune system interaction model consisted of two differential equations with three time delays is considered in which the delays describe the proliferation of tumor cells, the process of effector cells growth stimulated by tumor cells, and the differentiation of immune effector cells, respectively. Conditions for the asymptotic stability of equilibria and existence of Hopf bifurcations are obtained by analyzing the roots of a second degree exponential polynomial characteristic equation with delay dependent coefficients. It is shown that the positive equilibrium is asymptotically stable if all three delays are less than their corresponding critical values and Hopf bifurcations occur if any one of these delays passes through its critical value. Numerical simulations are carried out to illustrate the rich dynamical behavior of the model with different delay values including the existence of regular and irregular long periodic oscillations.

  4. Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays

    NASA Astrophysics Data System (ADS)

    Bi, Ping; Ruan, Shigui; Zhang, Xinan

    2014-06-01

    In this paper, a tumor and immune system interaction model consisted of two differential equations with three time delays is considered in which the delays describe the proliferation of tumor cells, the process of effector cells growth stimulated by tumor cells, and the differentiation of immune effector cells, respectively. Conditions for the asymptotic stability of equilibria and existence of Hopf bifurcations are obtained by analyzing the roots of a second degree exponential polynomial characteristic equation with delay dependent coefficients. It is shown that the positive equilibrium is asymptotically stable if all three delays are less than their corresponding critical values and Hopf bifurcations occur if any one of these delays passes through its critical value. Numerical simulations are carried out to illustrate the rich dynamical behavior of the model with different delay values including the existence of regular and irregular long periodic oscillations.

  5. Tumor growth modeling based on cell and tumor lifespans

    E-print Network

    Paris-Sud XI, Université de

    Tumor growth modeling based on cell and tumor lifespans R. Keinj1 , T. Bastogne2,4,6 , P. Vallois3 September 9, 2012 Abstract This paper deals with the lifespan modeling of heterogenous tumors treated by radiotherapy. A bi-scale model describing the cell and tumor lifespans by random variables is proposed. First

  6. Assessing ODE models of tumor growth

    NASA Astrophysics Data System (ADS)

    Dobrovolny, Hana; Jaafari, Hana; Ellis, Michael

    2014-03-01

    Mathematical models are often used to study and optimize treatment of cancer. In order to accurately predict the efficacy of a particular treatment, the model must correctly describe tumor growth. Over the years, several differential equation models of tumor growth have been proposed and independently fit to experimental data sets. While all the models provide reasonable fits to tumor growth data, the models have never been confronted with the same experimental data to determine whether any of the models provides a more accurate description of tumor growth. We collected tumor growth data from the literature and fit the various tumor growth models to the data to determine which model best describes tumor growth. Our results indicate that no single model can capture the variety of growth behavior captured in experiments.

  7. Stochastic resonance in a tumor-immune system subject to bounded noises and time delay

    NASA Astrophysics Data System (ADS)

    Guo, Wei; Mei, Dong-Cheng

    2014-12-01

    Immunotherapy is one of the most recent approaches in cancer therapy. A mathematical model of tumor-immune interaction, subject to a periodic immunotherapy treatment (imitated by a periodic signal), correlative and bounded stochastic fluctuations and time delays, is investigated by numerical simulations for its signal power amplification (SPA). Within the tailored parameter regime, the synchronous response of tumor growth to the immunotherapy, stochastic resonance (SR), versus both the noises and delays is obtained. The details are as follows (i) the peak values of SPA versus the noise intensity (A) in the proliferation term of tumor cells decrease as the frequency of periodic signal increases, i.e. an increase of the frequency restrains the SR; (ii) an increase of the amplitude of periodic signal restrains the SR versus A, but boosts up the SR versus the noise intensity B in the immune term; (iii) there is an optimum cross-correlated degree between the two bounded noises, at which the system exhibits the strongest SR versus the delay time ??(the reaction time of tumor cell population to their surrounding environment constraints); (iv) upon increasing the delay time ??, double SR versus the delay time ?? (the time taken by both the tumor antigen identification and tumor-stimulated proliferation of effectors) emerges. These results may be helpful for an immunotherapy treatment for the sufferer.

  8. Delay eect in models of population growth

    Microsoft Academic Search

    Dang Vu Giang; Yongwimon Lenbury; Thomas I. Seidman

    First, we systematize earlier results on the global stability of the model ? x + µx = f(x(· )) of population growth. Second, we investigate the eect of delay on the asymptotic behavior when the nonlinearity f is a unimodal function. Our results can be applied to several population models (7, 9-13) because the function f does not need to

  9. MEDI3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models.

    PubMed

    Leow, Ching Ching; Coffman, Karen; Inigo, Ivan; Breen, Shannon; Czapiga, Meggan; Soukharev, Serguei; Gingles, Neill; Peterson, Norman; Fazenbaker, Christine; Woods, Rob; Jallal, Bahija; Ricketts, Sally-Ann; Lavallee, Theresa; Coats, Steve; Chang, Yong

    2012-05-01

    Angiopoietin 2 (Ang2) is an important regulator of angiogenesis, blood vessel maturation and integrity of the vascular endothelium. The correlation between the dynamic expression of Ang2 in tumors with regions of high angiogenic activity and a poor prognosis in many tumor types makes Ang2 an ideal drug target. We have generated MEDI3617, a human anti-Ang2 monoclonal antibody that neutralizes Ang2 by preventing its binding to the Tie2 receptor in vitro, and inhibits angiogenesis and tumor growth in vivo. Treatment of mice with MEDI3617 resulted in inhibition of angiogenesis in several mouse models including: FGF2-induced angiogenesis in a basement extract plug model, tumor and retinal angiogenesis. In xenograft tumor models, treatment with MEDI3617 resulted in a reduction in tumor angiogenesis and an increase in tumor hypoxia. The administration of MEDI3617 as a single agent to mice bearing human tumor xenografts resulted in tumor growth inhibition against a broad spectrum of tumor types. Combining MEDI3617 with chemotherapy or bevacizumab resulted in a delay in tumor growth and no body weight loss was observed in the combination groups. These results, combined with pharmacodynamic studies, demonstrate that treatment of tumor-bearing mice with MEDI3617 significantly inhibited tumor growth as a single agent by blocking tumor angiogenesis. Together, these data show that MEDI3617 is a robust antiangiogenic agent and support the clinical evaluation and biomarker development of MEDI3617 in cancer patients. PMID:22327175

  10. Inhibition of Vascularization in Tumor Growth

    NASA Astrophysics Data System (ADS)

    Scalerandi, M.; Sansone, B. Capogrosso

    2002-11-01

    The transition to a vascular phase is a prerequisite for fast tumor growth. During the avascular phase, the neoplasm feeds only from the (relatively few) existing nearby blood vessels. During angiogenesis, the number of capillaries surrounding and infiltrating the tumor increases dramatically. A model which includes physical and biological mechanisms of the interactions between the tumor and vascular growth describes the avascular-vascular transition. Numerical results agree with clinical observations and predict the influence of therapies aiming to inhibit the transition.

  11. Simulating tumor growth in confined heterogeneous environments

    NASA Astrophysics Data System (ADS)

    Gevertz, Jana L.; Gillies, George T.; Torquato, Salvatore

    2008-09-01

    The holy grail of computational tumor modeling is to develop a simulation tool that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies. In order to develop such a predictive model, one must account for many of the complex processes involved in tumor growth. One interaction that has not been incorporated into computational models of neoplastic progression is the impact that organ-imposed physical confinement and heterogeneity have on tumor growth. For this reason, we have taken a cellular automaton algorithm that was originally designed to simulate spherically symmetric tumor growth and generalized the algorithm to incorporate the effects of tissue shape and structure. We show that models that do not account for organ/tissue geometry and topology lead to false conclusions about tumor spread, shape and size. The impact that confinement has on tumor growth is more pronounced when a neoplasm is growing close to, versus far from, the confining boundary. Thus, any clinical simulation tool of cancer progression must not only consider the shape and structure of the organ in which a tumor is growing, but must also consider the location of the tumor within the organ if it is to accurately predict neoplastic growth dynamics.

  12. Ursolic acid-induced changes in tumor growth, O2 consumption, and tumor interstitial fluid pressure.

    PubMed

    Lee, I; Lee, J; Lee, Y H; Leonard, J

    2001-01-01

    The anti-tumor effect of ursolic acid (UA) and UA-induced changes in tumor physiology in tumor-bearing mice were examined. MTT colorimetric assay, clonogenic assay, and growth-delay assay for the determination of tumoricidal effects of UA were evaluated. UA-induced apoptosis was measured by fluorescent microscopy, stained by propidium iodide. Oxygen consumption (QO2) after treatment with UA was measured using a Clark-type electrode chamber. Systemic toxicity in mice was assayed by LD50(30). We also measured UA-induced changes in several tumor physiological parameters. Inhibitory effect of UA on various tumor cell lines was observed using MTT and clonogenic assays in vitro. UA-induced apoptosis significantly increased in a dose-dependent manner. Cellular QO2 values were significantly reduced by UA. In animal studies, UA significantly reduced tumor interstitial fluid pressure (TIFP) to approximately 40% of the control values at 2-3 days post-treatment (P<0.05). An i.p. administration of 100 mg/kg of UA significantly (P<0.01) inhibited tumor growth of FSaII. In conclusion, UA showed anti-tumor effect on various tumor cells in vitro as well as a moderate retardation of growth in two tumor models in vivo. We gained some insight regarding the pathophysiological benefits of UA (i.e., reduction in TIFP) as a cancer therapeutic agent. Consequently, these observations can be used for further study of UA or to facilitate clinical applications of UA for treating cancer patients. PMID:11724362

  13. Mathematical Modeling of Tumor Growth Kinetics

    Microsoft Academic Search

    Ž. Bajzer; S. Vuk-Pavlovi?; M. Huzak

    \\u000a The overall goal of this survey is to develop and present a coherent and integrated interpretation of mathematical models\\u000a which describe tumor growth. Rigorous description and quantitative understanding of tumor growth kinetics have been a focus\\u000a of mathematical modelers for more than five decades. Consequently, many models have been proposed, ranging from conceptually\\u000a and mathematically simple empirical models to complex

  14. Does tumor growth follow a "universal law" ? Caterina Guiot*,

    E-print Network

    Grether, Gregory

    1 Does tumor growth follow a "universal law" ? Caterina Guiot*, , Piero Giorgio Degiorgis , , Pier recently proposed. Here we investigate the extension of this model to the growth of solid malignant tumors, relating properly rescaled tumor masses and tumor growth times. The results support the notion that tumor

  15. Nod1-dependent control of tumor growth

    PubMed Central

    da Silva Correia, Jean; Miranda, Yvonne; Austin-Brown, Nikki; Hsu, Jenny; Mathison, John; Xiang, Rong; Zhou, Huamin; Li, Qinxi; Han, Jiahuai; Ulevitch, Richard J.

    2006-01-01

    Nod1, a cytosolic protein that senses meso-diaminopimelic acid-containing ligands derived from peptidoglycan, plays a role in host responses to invasive bacteria. Here we describe a function for Nod1, whereby it controls tumor formation. Cell lines derived from the human breast cancer epithelial cell line MCF-7 were used in a severe combined immune deficiency (SCID) mouse xenograft model to characterize a pathway linking Nod1 to the growth of estrogen-sensitive tumors. In MCF-7 cells, the absence of Nod1 correlates with tumor growth, an increased sensitivity to estrogen-induced cell proliferation, and a failure to undergo Nod1-dependent apoptosis. Conversely, overexpression of Nod1 in MCF-7 cells results in inhibition of estrogen-dependent tumor growth and reduction of estrogen-induced proliferative responses in vitro. PMID:16446438

  16. The non glycanated endocan polypeptide slows tumor growth by inducing stromal inflammatory reaction

    PubMed Central

    Depontieu, Florence; Scherpereel, Arnaud; Awad, Ali; Tsicopoulos, Anne; Leboeuf, Christophe; Janin, Anne; Duez, Catherine; Grigoriu, Bogdan; Lassalle, Philippe

    2015-01-01

    Endocan expression is increasingly studied in various human cancers. Experimental evidence showed that human endocan, through its glycan chain, is implicated in various processes of tumor growth. We functionally characterize mouse endocan which is also a chondroitin sulfate proteoglycan but much less glycanated than human endocan. Distant domains from the O-glycanation site, located within exons 1 and 2 determine the glycanation pattern of endocan. In opposite to the human homologue, overexpression of mouse endocan in HT-29 cells delayed the tumor appearance and reduced the tumor growth rate. This tumor growth inhibition is supported by non glycanated form of mouse endocan. Non glycanated human endocan overexpressed in HT-29, A549 or K1000 cells also exhibited an anti-tumor effect. Moreover, systemic delivery of non glycanated human endocan also results in HT-29 tumor growth delay. In vitro, endocan polypeptide did not affect HT-29 cell proliferation, nor cell viability. In tumor tissue sections, a stromal inflammatory reaction was observed only in tumors overexpressing endocan polypeptide, and depletion of CD122+ cells was able to delete partially the anti-tumor effect of endocan polypeptide. These results reveal a novel pathway for endocan in the control of tumor growth, which involves inflammatory cells of the innate immunity. PMID:25575808

  17. Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays

    E-print Network

    Ruan, Shigui

    Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays in a tumor and immune system interaction model with three delays Ping Bi,1,2 Shigui Ruan,3,a) and Xinan Zhang) In this paper, a tumor and immune system interaction model consisted of two differential equations with three

  18. Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.

    PubMed

    Dumon, K R; Ishii, H; Vecchione, A; Trapasso, F; Baldassarre, G; Chakrani, F; Druck, T; Rosato, E F; Williams, N N; Baffa, R; During, M J; Huebner, K; Croce, C M

    2001-06-15

    The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease. PMID:11406559

  19. Blood porphyrin luminescence and tumor growth correlation

    NASA Astrophysics Data System (ADS)

    Courrol, Lilia Coronato; Silva, Flávia Rodrigues de Oliveira; Bellini, Maria Helena; Mansano, Ronaldo Domingues; Schor, Nestor; Vieira, Nilson Dias, Jr.

    2007-02-01

    Fluorescence technique appears very important for the diagnosis of cancer. Fluorescence detection has advantages over other light-based investigation methods: high sensitivity, high speed, and safety. Renal cell carcinoma (RCC) accounts for approximately 3% of new cancer incidence and mortality in the United States. Unfortunately many RCC masses remain asymptomatic and nonpalpable until they are advanced. Diagnosis and localization of early carcinoma play an important role in the prevention and curative treatment of RCC. Certain drugs or chemicals such as porphyrin derivatives accumulate substantially more in tumors than normal tissues. The autofluorescence of blood porphyrin of healthy and tumor induced male SCID mice was analyzed using fluorescence and excitation spectroscopy. A significant contrast between normal and tumor blood could be established. Blood porphyrin fluorophore showed enhanced fluorescence band (around 630 nm) in function of the tumor growth. This indicates that either the autofluorescence intensity of the blood fluorescence may provide a good parameter for the "first approximation" characterization of the tumor stage.

  20. On the Distinction Between Lag and Delay in Population Growth

    Microsoft Academic Search

    Peter Vadasz; Alisa S. Vadasz

    2010-01-01

    The analysis and results presented in this paper provide conclusive evidence to distinguish between the delay effect and the\\u000a lag as two biologically distinct phenomena. It therefore dispels the incorrect notion that delay effects represented by delay\\u000a differential equations are the biological reason behind the lag phase in microorganism growth. The resulting consequence so\\u000a far is that the only other

  1. MATH100 PROJECT A SIMPLE MODEL FOR TUMOR GROWTH

    E-print Network

    Fasshauer, Greg

    MATH100 PROJECT A SIMPLE MODEL FOR TUMOR GROWTH Introduction. It has been observed experimentally that a tumor grows by dividing its cells, and at early stage the tumor grows at a rate proportional (1) is known as the law of natural growth. Given the initial tumor volume is V0 at the initial time t

  2. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis

    PubMed Central

    Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge; Melero-Martin, Juan M.; Lin, Ruei-Zeng; Klagsbrun, Michael

    2013-01-01

    Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory cells. We found that tumor-associated adipocytes also contribute to inflammation. We have analyzed peritumoral adipose tissue in a syngeneic mouse melanoma model. Compared to control adipose tissue, adipose tissue juxtaposed to implanted tumors exhibited reduced adipocyte size, extensive fibrosis, increased angiogenesis and a dense macrophage infiltrate. A mouse cytokine protein array revealed up-regulation of inflammatory mediators including IL-6, CXCL1, MCP-1, MIP-2 and TIMP-1 in peritumoral versus counterpart adipose tissues. CD11b+ macrophages contributed strongly to the inflammatory activity. These macrophages were isolated from peritumoral adipose tissue and found to overexpress ARG1, NOS2, CD301, CD163, MCP-1 and VEGF, which are indicative of both M1 and M2 polarization. Tumors implanted at a site distant from subcutaneous, anterior adipose tissue were strongly growth-delayed, had fewer blood vessels and were less populated by CD11b+ macrophages. In contrast to normal adipose tissue, micro-dissected peritumoral adipose tissue explants launched numerous vascular sprouts when cultured in an ex vivo model. Thus, inflamed tumor-associated adipose tissue fuels the growth of malignant cells by acting as a proximate source for vascular endothelium and activated pro-inflammatory cells, in particular macrophages. PMID:22614697

  3. Delayed adolescent growth in homozygous sickle cell disease.

    PubMed Central

    Singhal, A; Thomas, P; Cook, R; Wierenga, K; Serjeant, G

    1994-01-01

    Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth. PMID:7826110

  4. Blocking tumor cell eicosanoid synthesis by GPx4 impedes tumor growth and malignancy

    Microsoft Academic Search

    Ingeborg Heirman; Daisy Ginneberge; Regina Brigelius-Flohé; Nico Hendrickx; Patrizia Agostinis; Peter Brouckaert; Pieter Rottiers; Johan Grooten

    2006-01-01

    Using tumor cell-restricted overexpression of glutathione peroxidase 4 (GPx4), we investigated the contribution of tumor cell eicosanoids to solid tumor growth and malignant progression in two tumor models differing in tumorigenic potential. By lowering cellular lipid hydroperoxide levels, GPx4 inhibits cyclooxygenase (COX) and lipoxygenase (LOX) activities. GPx4 overexpression drastically impeded solid tumor growth of weakly tumorigenic L929 fibrosarcoma cells, whereas

  5. Diethylstilbestrol inhibits tumor growth and prolactin production in rat pituitary tumors.

    PubMed Central

    Lloyd, R. V.; Landefeld, T. D.; Maslar, I.; Frohman, L. A.

    1985-01-01

    Treatment of rats bearing transplantable MtT/W15 tumors with 10 mg of diethylstilbestrol (DES) for 3 weeks led to inhibition of tumor growth. The inhibition of tumor growth was reversible after removal of the DES. Histologic examination revealed decreased mitotic activity; however, DES did not produce cell necrosis. Concomitantly, the anterior pituitary glands of animals treated with DES became hyperplastic, with an increased number of prolactin (PRL)-producing cells. DES resulted in a decreased number of PRL cells in the tumor and decreased serum PRL/tumor weight, compared with that of control rats. There was also an increase in the number of growth hormone (GH) tumor cells and an increased serum GH/tumor weight. 17 beta-Estradiol had an effect similar to that of DES, while progesterone did not inhibit tumor growth or cause pituitary cell hyperplasia. Ovariectomy resulted in a decrease in the tumor growth rate, compared with that of control animals, suggesting that the MtT/W 15 tumors are relatively dependent on estrogens for optimal growth. These results indicate that DES inhibition of MtT/W 15 tumor growth is an excellent model for study of the mechanism of the inhibition of tumor growth and the modification of GH and PRL expression by the tumor cells. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3976841

  6. Potential new way to suppress tumor growth

    Cancer.gov

    Researchers at the University of California, San Diego School of Medicine (home of the Moores Comprehensive Cancer Center), with colleagues at the University of Rochester Medical Center, have identified a new mechanism that appears to suppress tumor growth, opening the possibility of developing a new class of anti-cancer drugs. Writing in this week’s online Early Edition of the Proceedings of the National Academy of Sciences (PNAS), the team reports that a particular form of a signaling protein called STAT5A stabilizes the formation of heterochromatin (a form of chromosomal DNA), which in turn suppresses the ability of cancer cells to issue instructions to multiply and grow.

  7. HSPA12B: a novel facilitator of lung tumor growth.

    PubMed

    Ma, He; Lu, Ting; Zhang, Xiaojin; Li, Chuanfu; Xiong, Jingwei; Huang, Lei; Liu, Ping; Li, Yuehua; Liu, Li; Ding, Zhengnian

    2015-04-30

    Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wild-type littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors. Interestingly, a significantly enhanced upregulation of Cox-2 was detected in Tg tumors than in WT tumors. Also, Tg tumors demonstrated upregulation of VEGF and angiopoietin-1, downregulation of AKAP12, and increased eNOS phosphorylation compared with WT tumors. Celecoxib, a selective Cox-2 inhibitor, suppressed the HSPA12B-induced increase in lung tumor burden. Moreover, celecoxib decreased angiogenesis and proliferation whereas increased apoptosis in Tg tumors. Additionally, celecoxib reduced angiopoietin-1 expression and eNOS phosphorylation but increased AKAP12 levels in Tg tumors. Our results indicate that HSPA12B stimulates lung tumor growth via a Cox-2-dependent mechanism. The present study identified HSPA12B as a novel facilitator of lung tumor growth and a potential therapeutic target for the treatment of lung cancer. PMID:25909170

  8. Rare cancers yield potential source of tumor growth

    Cancer.gov

    Researchers at the National Institutes of Health have discovered a genetic mutation that appears to increase production of red blood cells in tumors. The discovery, based on analysis of tissue from rare endocrine tumors, may help clarify how some tumors generate a new blood supply to sustain their growth, the researchers explained.

  9. Analysis of a Mathematical Model Describing Necrotic Tumor Growth

    E-print Network

    Matioc, Anca-Voichita

    regimes of vascularisation is studied. The tumor consists of a necrotic core of death cells region. The initial tumor domain is given by 0 and x is the position vector in R2. For a precise deAnalysis of a Mathematical Model Describing Necrotic Tumor Growth Joachim Escher, Anca

  10. ANALYSIS OF A MATHEMATICAL MODEL FOR THE GROWTH OF TUMORS

    E-print Network

    ANALYSIS OF A MATHEMATICAL MODEL FOR THE GROWTH OF TUMORS AVNER FRIEDMAN AND FERNANDO REITICH. In this paper we study a model of tumor which grows or shrinks due to proliferationof cells which depends on nutrient concentration modelled by a diusion equation. The tumor is assumed to be spherically symmetric

  11. ANALYSIS OF A MATHEMATICAL MODEL FOR THE GROWTH OF TUMORS

    E-print Network

    ANALYSIS OF A MATHEMATICAL MODEL FOR THE GROWTH OF TUMORS AVNER FRIEDMAN \\Lambda AND FERNANDO 55455. Abstract. In this paper we study a model of tumor which grows or shrinks due to proliferation of cells which depends on nutrient concentration modelled by a diffusion equation. The tumor is assumed

  12. P-selectin-mediated platelet adhesion promotes tumor growth

    PubMed Central

    Yang, Yang; Li, Bin; Guo, Simei; Li, Jialin; Ye, Jie; Li, Jiangchao; Zhang, Qianqian; Lan, Tian; He, Xiaodong; Cao, Liu; Zhou, Jia; Geng, Jianguo; Wang, Lijing

    2015-01-01

    Blood platelets foster carcinogenesis. We found that platelets are accumulated in human tumors. P-selectin deficiency and soluble P-selectin abolish platelet deposition within tumors, decreasing secretion of vascular endothelial growth factor and angiogenesis, thereby suppressing tumor growth. Binding of the P-selectin cytoplasmic tail to talin1 triggers the talin1 N-terminal head to interact with the ?3 cytoplasmic tail. This activates ?IIb?3 and recruits platelets into tumors. Platelet infiltration into solid tumors occurs through a P-selectin-dependent mechanism. PMID:25762641

  13. Osteoblastogenesis and tumor growth in myeloma

    PubMed Central

    YACCOBY, SHMUEL

    2010-01-01

    Myeloma is associated with suppression of osteoblastogenesis, consequentially resulting in increased osteoclast activity and induction of typical osteolytic bone disease. The molecular mechanisms by which myeloma cells suppress osteoblastogenesis and the consequences of increased osteoblast activity on myeloma cell growth have been partially delineated only recently. Reduced osteoblastogenesis is a consequence of abnormal properties and impaired osteogenic potential of osteoprogenitor cells from myeloma patients and is also the result of production of multiple osteoblastogenesis inhibitors by myeloma cells and by microenvironmental cells within the myelomatous bone. Nevertheless, novel osteoblast-activating agents (e.g. proteasome inhibitor bortezomib) are capable of inducing bone formation in myeloma animal models and clinically. These agents induce increased osteoblast activity, often coupled with a concomitant reduction in osteoclastogenesis, that is strongly associated with reduced myeloma tumor burden. In vitro, osteoblasts, in contrast to osteoclasts, attenuate the growth of myeloma cells from a large subset of patients; potential molecular mechanisms are discussed. These studies suggest that myeloma cells suppress osteoblastogenesis to their advantage and that increased osteoblast activity is a promising approach to treat myeloma bone disease and simultaneously control myeloma development and progression. PMID:20038269

  14. Somatostatin analog Sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors

    Microsoft Academic Search

    Rudolf Arnold; Christian Neuhaus; Ralph Benning; Wolf B. Schwerk; Michael E. Trautmann; Klaus Joseph; Christian Bruns

    1993-01-01

    A prospective study was performed to determine the efficacy of octreotide (Sandostatin®; SMS 201–995) 200 µg tid in controlling tumor growth. The study included 21 patients with metastasized endocrine GEP tumors: 6 gastrinomas, 8 carcinoid syndromes, 7 nonfunctioning tumors. Treatment was performed for 3 to 59 months (median 15 months). Evaluation of the response to octreotide was facilitated in 12

  15. Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth

    PubMed Central

    Williams, Cassin Kimmel; la Luz Sierra, Maria de; Bernardo, Marcelino; McCormick, Peter J.; Maric, Dragan; Regino, Celeste; Choyke, Peter; Tosato, Giovanna

    2008-01-01

    Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)–induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors. PMID:18577711

  16. Vascular Endothelial Growth Factor C–Induced Lymphangiogenesis DecreasesTumor Interstitial Fluid Pressure and Tumor Growth1

    PubMed Central

    Hofmann, Matthias; Pflanzer, Ralph; Zoller, Nadja Nicole; Bernd, August; Kaufmann, Roland; Thaci, Diamant; Bereiter-Hahn, Jurgen; Hirohata, Satoshi; Kippenberger, Stefan

    2013-01-01

    Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo. PMID:23908682

  17. Joint tumor growth prediction and tumor segmentation on therapeutic follow-up PET images.

    PubMed

    Mi, Hongmei; Petitjean, Caroline; Vera, Pierre; Ruan, Su

    2015-07-01

    Tumor response to treatment varies among patients. Patient-specific prediction of tumor evolution based on medical images during the treatment can help to build and adapt patient's treatment planning in a non-invasive way. Personalized tumor growth modeling allows patient-specific prediction by estimating model parameters based on individual's images. The model parameters are often estimated by optimizing a cost function constructed based on the tumor delineations. In this paper, we propose a joint framework for tumor growth prediction and tumor segmentation in the context of patient's therapeutic follow ups. Throughout the treatment, a series of sequential positron emission tomography (PET) images are acquired for tumor response monitoring. We propose to take into account the predicted information, which is used in combination with the random walks (RW) algorithm, to develop an automatic tumor segmentation method on PET images. Moreover, we propose an iterative scheme of RW, making the segmentation more performant. Furthermore, the obtained segmentation is applied to the process of model parameter estimation so as to get the model based prediction of tumor evolution. We evaluate our methods on 7 lung tumor patients, totaling 29 PET exams, under radiotherapy by comparing the obtained tumor prediction and tumor segmentation with manual tumor delineation by expert. Our system produces promising results when compared to the state-of-the-art methods. PMID:25988489

  18. IRP2 regulates breast tumor growth

    PubMed Central

    Wang, Wei; Deng, Zhiyong; Hatcher, Heather; Miller, Lance D.; Di, Xiumin; Tesfay, Lia; Sui, Guangchao; D'Agostino, Ralph B.; Torti, Frank M.; Torti, Suzy V.

    2014-01-01

    Experimental and epidemiological evidence suggest that dysregulation of proteins involved in iron metabolism plays a critical role in cancer. The mechanisms by which cancer cells alter homeostatic iron regulation are just beginning to be understood. Here we demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast cancer. Although both IRP1 and IRP2 are over-expressed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferritin H and increased transferrin receptor 1 (TfR1). Knock-down of IRP2 in triple negative MDA-MB-231 human breast cancer cells increases ferritin H expression and decreases TfR1 expression, resulting in a decrease in the labile iron pool. Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the mouse mammary fat pad. Gene expression microarray profiles of breast cancer patients demonstrate that increased IRP2 expression is associated with high grade cancer. Increased IRP2 expression is observed in luminal A, luminal B and basal breast cancer subtypes, but not in breast tumors of the ERBB2 molecular subtype. These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some breast cancer patients. PMID:24285726

  19. Avitalized bacteria mediate tumor growth control via activation of innate immunity.

    PubMed

    Klier, Ulrike; Maletzki, Claudia; Göttmann, Nadeshda; Kreikemeyer, Bernd; Linnebacher, Michael

    2011-01-01

    Acute bacterial infections have beneficial effects on tumor patients. To eliminate side effects evoked by viable microbes, we here assessed the immunotherapeutic potential of inactivated bacteria on colorectal carcinomas. Our In vitro results indicate a cell-specific direct cytotoxicity towards tumor cells presented by G1-arrest. Antitumoral activity was boosted in the presence of leukocytes. Long time stimulations revealed massive activation of NK cells even in complete autologous settings. In vivo, repetitive local treatment mediated tumor growth control. Evaluation of residual tumors identified increased infiltrates, with NK cells (CD49b(+), NKG2D(+)) being the main responding cell population. Substantial NK cell-mediated delay of tumor growth was also achieved in T-cell deficient mice xenografted with human colorectal carcinomas. Of note, local as well as systemic therapy mediated tumor growth control. These data highlight the potential of avitalized bacteria to especially activate the immune system's innate arm and they should be considered for future integrated immunotherapy. PMID:21463858

  20. VEGF-integrin interplay controls tumor growth and vascularization

    NASA Astrophysics Data System (ADS)

    de, Sarmishtha; Razorenova, Olga; McCabe, Noel Patrick; O'Toole, Timothy; Qin, Jun; Byzova, Tatiana V.

    2005-05-01

    Cross-talk between the major angiogenic growth factor, VEGF, and integrin cell adhesion receptors has emerged recently as a critical factor in the regulation of angiogenesis and tumor development. However, the molecular mechanisms and consequences of this intercommunication remain unclear. Here, we define a mechanism whereby integrin v3, through activation, clustering, and signaling by means of p66 Shc (Src homology 2 domain containing), regulates the production of VEGF in tumor cells expressing this integrin. Tumors with "activatable" but not "inactive" 3 integrin secrete high levels of VEGF, which in turn promotes extensive neovascularization and augments tumor growth in vivo. This stimulation of VEGF expression depends upon the ability of v3 integrin to cluster and promote phosphorylation of p66 Shc. These observations identify a link between 3 integrins and VEGF in tumor growth and angiogenesis and, therefore, may influence anti-integrin as well as anti-VEGF therapeutic strategies. activation | angiogenesis | Src homology 2 domain containing

  1. Stroke from Delayed Embolization of Polymerized Glue Following Percutaneous Direct Injection of a Carotid Body Tumor

    PubMed Central

    Gupta, Arun Kumar; Rajan, Jayadevan E; Thomas, Bejoy

    2007-01-01

    A 52-year-old male with right carotid body tumor underwent direct percutaneous glue (n-butylcyanoacrylate [NBCA]) embolization. Several hours later, he developed left hemiparesis from embolization of the polymerized glue cast. Migration of glue during percutaneous tumor embolization is presumed to occur only in the liquid state, which may lead to stroke or cranial nerve deficits. To the best of our knowledge, this is the first report of delayed glue embolization from a treated hypervascular tumor of the head and neck. PMID:17554195

  2. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma.

    PubMed

    Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yanfei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

    2014-07-30

    X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment. PMID:24980821

  3. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma

    PubMed Central

    Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yan Fei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

    2014-01-01

    X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment. PMID:24980821

  4. Tumor growth inhibition through targeting liposomally bound curcumin to tumor vasculature.

    PubMed

    Mondal, Goutam; Barui, Sugata; Saha, Soumen; Chaudhuri, Arabinda

    2013-12-28

    Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~500 ?g/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures. PMID:24036260

  5. Tumor-induced osteomalacia due to a recurrent mesenchymal tumor overexpressing several growth factor receptors

    PubMed Central

    Gerothanasi, Nikolina; Frydas, Athanasios; Triantafyllou, Evangelia; Poulios, Chris; Hytiroglou, Prodromos; Apostolou, Panagiotis; Papasotiriou, Ioannis; Tournis, Symeon; Kesisoglou, Isaak; Yovos, John G

    2015-01-01

    Summary Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. These tumors typically follow a benign clinical course and local recurrence occurs in <5% of cases. We investigated a 49-year-old man with a recurrent mesenchymal phosphaturic tumor showing no signs of malignancy. The patient suffered from chronic muscle weakness, myalgia and cramps. His medical record included the diagnosis of oncogenic osteomalacia, for which he was submitted to tumor resection in the left leg three times before. Laboratory examination showed hypophosphatemia, hyperphosphaturia and an elevated serum FGF23 level. A radical surgical approach (amputation) was advised, however, complete biochemical and clinical remission was not reached. Molecular analysis of the tumor cells demonstrated overexpression of growth factor receptors implicated in tumor angiogenesis and metastatic potential (platelet derived growth factor type A (PDGFRA), PDGFRB and vascular endothelial growth factor receptor) together with increased expression of FGF23, x-linked-phosphate-regulating endopeptidase and KLOTHO. TIO is usually associated with benign phosphauturic tumors and, when identified, resection of the tumor leads to complete remission in the majority of cases. The underlying pathophysiology of recurrences in these tumors is not known. This is the first report showing increased expression of growth factor receptors in a locally aggressive but histopathologically benign phosphaturic mesenchymal tumor. Learning points TIO is usually associated with benign soft tissue or bone neoplasms of mesenchymal origin.These tumors typically follow a benign clinical course and even in the rare malignant cases local recurrence occurs in <5%.Successful identification and removal of the tumor leads to full recovery in the majority of cases.

  6. 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.

  7. Bioavailable copper modulates oxidative phosphorylation and growth of tumors

    PubMed Central

    Ishida, Seiko; Andreux, Pénélope; Poitry-Yamate, Carole; Auwerx, Johan; Hanahan, Douglas

    2013-01-01

    Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment. PMID:24218578

  8. Patient Specific Tumor Growth Prediction Using Multimodal Images

    PubMed Central

    Liu, Yixun; Sadowski, Samira M.; Weisbrod, Allison B.; Kebebew, Electron; Summers, Ronald M.; Yao, Jianhua

    2014-01-01

    Personalized tumor growth model is valuable in tumor staging and therapy planning. In this paper, we present a patient specific tumor growth model based on longitudinal multimodal imaging data including dual-phase CT and FDG-PET. The proposed Reaction-Advection-Diffusion model is capable of integrating cancerous cell proliferation, infiltration, metabolic rate and extracellular matrix biomechanical response. To bridge the model with multimodal imaging data, we introduce intracellular volume fraction (ICVF) measured from dual-phase CT and Standardized Uptake Value (SUV) measured from FDG-PET into the model. The patient specific model parameters are estimated by fitting the model to the observation, which leads to an inverse problem formalized as a coupled Partial Differential Equations (PDE)-constrained optimization problem. The optimality system is derived and solved by the Finite Difference Method. The model was evaluated by comparing the predicted tumors with the observed tumors in terms of average surface distance (ASD), root mean square difference (RMSD) of the ICVF map, average ICVF difference (AICVFD) of tumor surface and tumor relative volume difference (RVD) on six patients with pathologically confirmed pancreatic neuroendocrine tumors. The ASD between the predicted tumor and the reference tumor was 2.4±0.5 mm, the RMSD was 4.3±0.4%, the AICVFD was 2.6±0.6%, and the RVD was 7.7±1.3%. PMID:24607911

  9. Growth of human urologic tumors on extracellular matrix.

    PubMed

    Bulbul, M A; Pavelic, K; Slocum, H K; Frankfurt, O S; Rustum, Y M; Huben, R P; Bernacki, R J

    1986-08-01

    Surgical specimens of fifty urologic tumors, 19 renal, 19 bladder, nine prostate and three testicular, were disaggregated into a cell suspension by a two step mechanical and enzymatic method. Viability, cytology and flow cytometry (FCM) for DNA ploidy were subsequently determined. Growth of urological tumors on extracellular matrix (ECM) was carried out as follows: 2.5 to 5 X 10(5) cells were placed in plastic T25 flasks in RPMI 1640 + 10 per cent fetal bovine serum (FBS). 1.0 to 5 X 10(4) cells were plated in wells coated with ECM derived from bovine corneal endothelial cells with RPMI 1640 + 10 per cent FBS. Cultures were incubated for seven to 10 days at 37 degrees C. Only one (renal) out of 28 tumors grew on plastic. Forty out of 50 tumors (80 per cent) established primary cultures on ECM as determined by cell counting, protein determination, and/or [3H]thymidine incorporation. Previous experience with 106 urologic tumors grown on double layer agar demonstrated an overall success rate of 48 per cent. On ECM renal tumors showed 95 per cent growth success, prostate 89 per cent, bladder 63 per cent and testicular 67 per cent. Unlike viability by trypan blue exclusion, tumor DNA ploidy and percentage of malignant cells plated on ECM had no effect on growth success. The malignant nature of the cultured cells was confirmed by cytology. Twelve high grade and metastatic tumors caused degradation of the ECM. DNA ploidy was similar in four and different in six tumors before and after culture. Five tumors underwent in vitro drug testing on ECM with significant growth inhibition observed in three cases. The extracellular matrix seems to be a promising model for growing urologic tumors with excellent potential for drug testing in vitro. PMID:3735526

  10. Dual Role of ?6?4 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function

    PubMed Central

    Raymond, Karine; Kreft, Maaike; Song, Ji-Ying; Janssen, Hans

    2007-01-01

    An increased expression of the integrin ?6?4 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of ?6?4 in the early stages of tumor development. We have isolated cells from mouse skin (mouse tumor-initiating cells [mTICs]) that are deficient in both p53 and Smad4 and carry conditional alleles of the ?4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that ?6?4 mediates a tumor-suppressive effect. Reconstitution experiments with ?4-chimeras showed that this effect is not dependent on ligation of ?6?4 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of ?4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, ?6?4 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector-loop mutants of RasV12 suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, ?6?4 can either mediate an adhesion-independent tumor-suppressive effect or act as a tumor promotor. PMID:17699601

  11. DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency

    Microsoft Academic Search

    Timothy Hoey; Wan-Ching Yen; Fumiko Axelrod; Jesspreet Basi; Lucas Donigian; Scott Dylla; Maureen Fitch-Bruhns; Sasha Lazetic; In-Kyung Park; Aaron Sato; Sanjeev Satyal; Xinhao Wang; Michael F. Clarke; John Lewicki; Austin Gurney

    2009-01-01

    SUMMARY Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xeno- graft models derived from primary human tumors. We found that each

  12. COX2\\/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

    Microsoft Academic Search

    Satoko Yoshida; Hideki Amano; Izumi Hayashi; Hidero Kitasato; Mariko Kamata; Madoka Inukai; Hirokuni Yoshimura; Masataka Majima

    2003-01-01

    Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis

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

    PubMed

    Lee, Hye Lim; Park, Sang Ho; 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

    2015-03-30

    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-?B) 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 ?g/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-?B 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-?B inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-?B pathway. PMID:25730901

  14. 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-?B) 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 ?g/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-?B 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-?B inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-?B pathway. PMID:25730901

  15. 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. PMID:25665006

  16. Existence of Limit Cycles in the Solow Model with Delayed-Logistic Population Growth

    PubMed Central

    2014-01-01

    This paper is devoted to the existence and stability analysis of limit cycles in a delayed mathematical model for the economy growth. Specifically the Solow model is further improved by inserting the time delay into the logistic population growth rate. Moreover, by choosing the time delay as a bifurcation parameter, we prove that the system loses its stability and a Hopf bifurcation occurs when time delay passes through critical values. Finally, numerical simulations are carried out for supporting the analytical results. PMID:24592147

  17. 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 ?m, 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 infiltration is predicted for the opposite condition. Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM. In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a three-dimensional geometry. It is shown that TCs tend to migrate among adjacent vessels seeking new oxygen and nutrients. This model can predict and optimize the efficacy of anticancer therapeutic strategies. It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on TC proliferation.

  18. Sclareol modulates the Treg intra-tumoral infiltrated cell and inhibits tumor growth in vivo.

    PubMed

    Noori, Shokoofe; Hassan, Zuhair M; Mohammadi, Mehdi; Habibi, Zohre; Sohrabi, Nooshin; Bayanolhagh, Saeed

    2010-01-01

    A regulatory or suppressor T cell is functionally defined as a T cell that inhibits an immune response by influencing the activity of another cell type. On the other hand, Th1 cells express IFN-gamma and mediate cellular immunity. Sclareol exhibits growth inhibition and cytotoxic activity against a variety of human cancer cell lines. In the first set of experiments, Sclareol was isolated from the plant Salvia sclarea and our study assessed the immuno-therapeutic effectiveness of Sclareol by direct intra-tumoral injection. Secondly, several immunological parameters such as splenocytes proliferation, intra-tumor CD4+CD25+Foxp3+ Treg cells, IFN-gamma and IL-4 secretion and tumor size were assessed to evaluate the anti-tumoral immune response. By all means, the findings confirmed that the activity of Sclareol could reduce the tumor growth in vivo against breast cancer. PMID:20409537

  19. TNF? 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 (TNF?) 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, TNF? 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 TNF? neutralization with an anti-TNF? monoclonal antibody (mAb) successfully inhibited NO2(-) synthesis by blood mononuclear cells and tumor explants. Recombinant TNF? (rTNF?) enhanced NO2(-) synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNF? antagonization with an anti-TNF? mAb potently inhibited rTNF? induced C666-1 proliferation and NO2(-) production. Importantly, primary tumors treated with the anti-TNF? 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 TNF?/NOS2 pathway may alter NPC tumor growth. PMID:25912222

  20. The zinc finger transcription factor EGR-1 impedes interleukin-1-inducible tumor growth arrest.

    PubMed Central

    Sells, S F; Muthukumar, S; Sukhatme, V P; Crist, S A; Rangnekar, V M

    1995-01-01

    Interleukin-1 (IL-1) is a growth arrest signal for diverse human tumor cell lines. We report here that the action of this cytokine in melanoma cells is associated with induction of EGR-1, a zinc finger protein that activates gene transcription. Both growth arrest and EGR-1 are induced via the type I receptor of IL-1. To determine the role of EGR-1 in IL-1 action in melanoma cells, we used a chimera expressing the transrepression domain of the Wilm's tumor gene, WT1, and the DNA binding domain of Egr-1. This chimera competitively inhibited EGR-1-dependent transactivation via the GC-rich DNA binding sequence, indicating that it acted as a functional dominant negative mutant of Egr-1. Melanoma cell lines stably transfected with the dominant negative mutant construct were supersensitive to IL-1 and showed accelerated G0/G1 growth arrest compared with the parental cell line. The effect of the dominant negative mutant construct was mimicked by addition of an antisense Egr-1 oligomer to the culture medium of the parental cells: the oligomer inhibited EGR-1 expression and accelerated the growth-inhibitory response to IL-1. These data imply that EGR-1 acts to delay IL-1-mediated tumor growth arrest. PMID:7823937

  1. RGD-Tachyplesin Inhibits Tumor Growth1

    Microsoft Academic Search

    Yixin Chen; Xueming Xu; Shuigen Hong; Jinguo Chen; Ningfei Liu; Charles B. Underhill; Karen Creswell; Lurong Zhang

    2001-01-01

    Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining

  2. Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition.

    PubMed

    Maity, Gargi; De, Archana; Das, Amlan; Banerjee, Snigdha; Sarkar, Sandipto; Banerjee, Sushanta K

    2015-07-01

    Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-?/SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-? in breast carcinogenesis. PMID:25867761

  3. Delayed Frost Growth on Jumping-Drop Superhydrophobic Surfaces

    SciTech Connect

    Boreyko, Jonathan B [ORNL; Collier, Pat [ORNL

    2013-01-01

    Self-propelled jumping drops are continuously removed from a condensing superhydrophobic surface to enable a micrometric steady-state drop size. Here, we report that subcooled condensate on a chilled superhydrophobic surface are able to repeatedly jump off the surface before heterogeneous ice nucleation occurs. Frost still forms on the superhydrophobic surface due to ice nucleation at neighboring edge defects, which eventually spreads over the entire surface via an inter-drop frost wave. The growth of this inter-drop frost front is shown to be up to three times slower on the superhydrophobic surface compared to a control hydrophobic surface, due to the jumping-drop effect dynamically minimizing the average drop size and surface coverage of the condensate. A simple scaling model is developed to relate the success and speed of inter-drop ice bridging to the drop size distribution. While other reports of condensation frosting on superhydrophobic surfaces have focused exclusively on liquid-solid ice nucleation for isolated drops, these findings reveal that the growth of frost is an inter-drop phenomenon that is strongly coupled to the wettability and drop size distribution of the surface. A jumping-drop superhydrophobic condenser was found to be superior to a conventional dropwise condenser in two respects: preventing heterogeneous ice nucleation by continuously removing subcooled condensate, and delaying frost growth by minimizing the success of interdrop ice bridge formation.

  4. Tumor angiogenesis and accessibility: role of vascular endothelial growth factor.

    PubMed

    Jain, Rakesh K

    2002-12-01

    Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through a process known as angiogenesis. Unlike normal blood vessels, tumor blood vessels are chaotic, irregular, and leaky, which leads to uneven delivery of nutrients and therapeutic agents to the tumor. Conventional therapies target neoplastic cells within a tumor; however, tumor vasculature is emerging as an important target for anticancer therapy. Antiangiogenic therapy offers several potential advantages as an approach to cancer treatment, notably physical accessibility and genetic stability of target cells. Vascular endothelial growth factor (VEGF), a central mediator of angiogenesis, has emerged as an important target for antiangiogenic therapy. In preclinical studies, treatment of human tumor xenografts in immunodeficient mice with the anti-VEGF monoclonal antibody A4.6.1 led to reduced tumor vessel permeability and caused vascular regression. The reduced vascular permeability, resulting from inhibition of VEGF, led to increased delivery of oxygen and therapeutic agents to tumors. Anti-VEGF therapy was effectively combined with other treatment modalities, including radiation, antihormonal, antibody, and chemotherapies in multiple preclinical models. Currently, several phase 3 clinical trials in various cancer types are under way to establish the efficacy of antiangiogenic therapy with a recombinant humanized anti-VEGF monoclonal antibody, bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA), in combination with chemotherapeutic agents. PMID:12516032

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

    PubMed Central

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

    2015-01-01

    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. PMID:26193241

  6. Immunosuppressive drugs and their effect on experimental tumor growth

    Microsoft Academic Search

    Itsuo Yokoyama; Shuji Hayashi; Takaaki Kobayashi; Motohiko Yasutomi; Kazuharu Uchida; Hiroshi Takagi

    1995-01-01

    The effect of cyclosporin (CyA), FK 506, and mycophenolate mofetil (MPM) on tumor growth was investigated using syngeneic mouse colon carcinoma 38. Mice were laparotomized and the tumor cells were injected into the portal vein to establish liver metastasis. The animals were grouped as follows: groups A-1, B-1, and C-1 were given CyA [15 mg\\/kg body weight (BW)], FK 506

  7. 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.

  8. Multiphase modeling of tumor growth and extracellular matrix interaction: Mathematical tools and applications

    E-print Network

    Preziosi, Luigi

    Multiphase modeling of tumor growth and extracellular matrix interaction: Mathematical tools modeling framework tumors are described as a mixture of tumor and host cells within a porous structure of the growing tumor with the host tissue, their influence on tumor growth, and the attachment

  9. Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression

    SciTech Connect

    Chen, M.-F. [Department of Radiation Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan (China); Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taipei, Taiwan (China); Keng, Peter C. [Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York (United States); Shau Hungyi [Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States); Wu, C.-T. [Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taipei, Taiwan (China); Hu, Y.-C. [Division of Surgical Oncology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA (United States); Liao, S.-K. [Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taipei, Taiwan (China); Chen, W.-C. [Department of Radiation Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan (China)]. E-mail: miaofen@adm.cgmh.org.tw

    2006-02-01

    Purpose: In this study, we examined the role of peroxiredoxin I (Prx I) in lung cancer cell growth in vitro and in vivo and its influence on these tumor cells' sensitivity to radiotherapy. Methods and materials: We established stable transfectants of A549 (p53+) and H1299 (p53-) lung carcinoma cell lines with Prx I antisense to downregulate their Prx I protein. We then examined their in vitro biologic changes and used nude mice xenografts of these cell lines to compare tumor invasion, spontaneous metastatic capacity, and sensitivity to radiotherapy. Results: The Prx I antisense transfectants of both cell lines showed a significant reduction in Prx I protein production. Prx I antisense transfectants grew more slowly than did the wild type. As xenografts in mice, A549 Prx I antisense transfectants showed a threefold delay in the generation of palpable tumors. The incidence of spontaneous metastasis of Prx I antisense transfectants was significantly less than that of the wild-type cells. Furthermore, irradiation of Prx I antisense transfectants caused more than twice the growth delay compared with the wild type. Conclusion: The results of these studies suggest that inactivation of Prx I may be a promising approach to improve the treatment outcome of patients with lung cancer.

  10. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    PubMed Central

    De Veirman, Kim; Rao, Luigia; De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els; Van Riet, Ivan; Frassanito, Maria Antonia; Di Marzo, Lucia; Vacca, Angelo; Vanderkerken, Karin

    2014-01-01

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease. PMID:24978438

  11. Preliminary investigation of the inhibitory effects of mechanical stress in tumor growth

    E-print Network

    Miga, Michael I.

    Preliminary investigation of the inhibitory effects of mechanical stress in tumor growth Ishita the growth of the tumor as two separate components- a proliferative component and an invasive component to describe tumor growth, and the affect of mechanical stresses caused by the mass effect of tumor cells

  12. Promotion of lung tumor growth by interleukin-17.

    PubMed

    Xu, Beibei; Guenther, James F; Pociask, Derek A; Wang, Yu; Kolls, Jay K; You, Zongbing; Chandrasekar, Bysani; Shan, Bin; Sullivan, Deborah E; Morris, Gilbert F

    2014-09-15

    Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-Ras(LA1) mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K-Ras(LA1) mice at 8-10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasiveness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNA-resistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53- and SRSF1-dependent manner. PMID:25038189

  13. Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth.

    PubMed

    Xuan, Zi-Xue; Li, Lin-Na; Zhang, Qi; Xu, Cheng-Wang; Yang, De-Xuan; Yuan, Ye; An, Ying-Hong; Wang, Shan-Shan; Li, Xiao-Wen; Yuan, Shou-Jun

    2014-12-01

    The critical role of VEGFR2 in tumor neovascularization and progression has allowed the design of clinically beneficial therapies based on it. Here we show that BC001, a new fully human anti-VEGFR2 monoclonal antibody, inhibits VEGF-stimulated endothelial cell migration, tube formation, and effectively suppressed the transdifferentiation of cancer stem cells into endothelial cells in vitro. Since BC001 exhibited no activity against the mouse VEGFR2 and mouse based study was required to confirm its efficacy in vivo, BC101, the mouse analogue of BC001, was developed. BC101 significantly attenuated angiogenesis according to Matrigel plug assay and resulted in ~80% growth inhibition of mouse B16F10 homograft tumors relative to vehicle control. Similarly, human analogue BC001 suppressed the growth of human xenograft tumors HCT116 and BGC823. Furthermore, immunohistochemical results showed reduced expression of CD31, VEGFR2 and Ki-67, as well as increased expression of Caspase 3 in BC001-treated tumor, which indicated BC001 was able to significantly decrease microvessel density, suppress proliferation and promote apoptosis. These results demonstrate the fully human VEGFR2 monoclonal antibody BC001 can work as an effective inhibitor of tumor angiogenesis and tumor growth both in vitro and in vivo. PMID:25269419

  14. Molecular Cochaperones: Tumor Growth and Cancer Treatment

    PubMed Central

    Calderwood, Stuart K.

    2013-01-01

    Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90) and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents. PMID:24278769

  15. 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. PMID:21908797

  16. Progressive Deceleration in Growth as an Early Sign of Delayed Puberty in Boys

    Microsoft Academic Search

    M. V. L. Du Caju; L. Op De Beeck; S. U. Sys; M. M. Hagendorens; R. P. A. Rooman

    2000-01-01

    Objective: To describe the prepubertal growth pattern in boys with delayed puberty. Methods: Growth curves for height and height velocity covering the age range 4–14 years were constructed on the basis of retrospectively obtained data in 85 boys with delayed puberty, who attained a normal final height. Results: Between the age of 4 and 14 years the height in this

  17. Transforming Growth Factor B Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin17

    Microsoft Academic Search

    Jeong-Seok Nam; Masaki Terabe; Mi-Jin Kang; Helen Chae; Nga Voong; Yu-an Yang; Arian Laurence; Aleksandra Michalowska; Mizuko Mamura; Scott Lonning; Jay A. Berzofsky; Lalage M. Wakefield

    2008-01-01

    Overexpression of the immunosuppressive cytokine trans- forming growth factor B (TGF-B) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-B. We showed that CD8+ splenocytes from tumor-bearing

  18. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

    PubMed

    Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

    2015-01-01

    Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-? production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. PMID:25429071

  19. Joint fitting reveals hidden interactions in tumor growth.

    PubMed

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

    2015-01-21

    Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Crucial to the system evolution are the interactions between these populations. To obtain information about these interactions we apply the recently developed vector universality (VUN) formalism to various instances of competition between tumor populations. The formalism allows us (a) to quantify the growth mechanisms of a HeLa cell colony, describing the phenotype switching responsible for its fast expansion, (b) to reliably reconstruct the evolution of the necrotic and viable fractions in both in vitro and in vivo tumors using data for the time dependences of the total masses alone, and (c) to show how the shedding of cells leading to subspheroid formation is beneficial to both the spheroid and subspheroid populations, suggesting that shedding is a strong positive influence on cancer dissemination. PMID:25451531

  20. Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth properties and gene expression

    PubMed Central

    Sussan, Thomas E; Pletcher, Mathew T; Murakami, Yoshinori; Reeves, Roger H

    2005-01-01

    Background Introduction of cDNA or genomic clones of the tumor suppressor in lung cancer 1 (TSLC1) gene into the non-small cell lung cancer line, A549, reverses tumorigenic growth properties of these cells. These results and the observation that TSLC1 is down-regulated in a number of tumors suggest that TSLC1 functions as a critical switch mediating repression of tumorigenesis. Results To investigate this mechanism, we compared growth properties of A549 with the TSLC1-containing derivative. We found a G1/S phase transition delay in 12.2. Subtractive hybridization, quantitative PCR, and TranSignal Protein/DNA arrays were used to identify genes whose expression changed when TSLC1 was up-regulated. Members of common G1/S phase regulatory pathways such as TP53, MYC, RB1 and HRAS were not differentially expressed, indicating that TSLC1 may function through an alternative pathway(s). A number of genes involved in cell proliferation and tumorigenesis were differentially expressed, notably genes in the Ras-induced senescence pathway. We examined expression of several of these key genes in human tumors and normal lung tissue, and found similar changes in expression, validating the physiological relevance of the A549 and 12.2 cell lines. Conclusion Gene expression and cell cycle differences provide insights into potential downstream pathways of TSLC1 that mediate the suppression of tumor properties in A549 cells. PMID:16083501

  1. Inhibition of Tumor Growth by Dietary Zinc Deficiency1

    Microsoft Academic Search

    James T. McQuitty; William D. DeWys; Liberatore Monaco; William H. Strain; Charles G. Rob; Jean Apgar; Walter J. Pories

    SUMMARY The effect of different levels of zinc intake on tumor growth was studied by implanting Walker 256 carcino- sarcoma into weanling Sprague-Dawley rats maintained on laboratory chow or on a zinc-deficient synthetic diet. Three experimental groups receiving this synthetic diet were given 0, 50, or 500 parts per million, respectively, of zinc ion in the drinking water. The latter

  2. 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…

  3. Tumor growth instability and the onset of invasion.

    PubMed

    Castro, Mario; Molina-París, Carmen; Deisboeck, Thomas S

    2005-10-01

    Motivated by experimental observations, we develop a mathematical model of chemotactically directed tumor growth. We present an analytical study of the model as well as a numerical one. The mathematical analysis shows that: (i) tumor cell proliferation by itself cannot generate the invasive branching behavior observed experimentally, (ii) heterotype chemotaxis provides an instability mechanism that leads to the onset of tumor invasion, and (iii) homotype chemotaxis does not provide such an instability mechanism but enhances the mean speed of the tumor surface. The numerical results not only support the assumptions needed to perform the mathematical analysis but they also provide evidence of (i), (ii), and (iii). Finally, both the analytical study and the numerical work agree with the experimental phenomena. PMID:16383420

  4. Incorporating spatial dependence into a multicellular tumor spheroid growth model

    NASA Astrophysics Data System (ADS)

    Garner, Allen L.; Lau, Y. Y.; Jackson, Trachette L.; Uhler, Michael D.; Jordan, David W.; Gilgenbach, Ronald M.

    2005-12-01

    Recent models for organism and tumor growth yield simple scaling laws based on conservation of energy. Here, we extend such a model to include spatial dependence to model necrotic core formation. We adopt the allometric equation for tumor volume with a reaction-diffusion equation for nutrient concentration. In addition, we assume that the total metabolic energy and average cellular metabolic rate depend on nutrient concentration in a Michaelis-Menten-like manner. From experimental results, we relate the necrotic volume to nutrient consumption and estimate both the time and nutrient concentration at necrotic core formation. Based on experimental results, we demand that the necrotic core radius varies linearly with tumor radius after core formation and extend the equations for tumor volume and nutrient concentration to the postnecrotic core regime. In particular, we obtain excellent agreement with experimental data and the final steady-state viable rim thickness.

  5. Testosterone treatment in adolescent boys with constitutional delay of growth and development

    Microsoft Academic Search

    Ashraf T. Soliman; Mohammed M. Abdul Khadir; Maurice Asfour

    1995-01-01

    Administration of androgens to adolescent boys with constitutional delay in growth has been highly controversial. One hundred forty.eight adolescent boys with constitutional delay of growth and puberty with a mean age of 14.3 ± 0.7 years were treated with testosterone enanthate 100 mg intramuscularly each month for 6 months. Growth parameters, sexual maturation, and circulating concentrations of testosterone and insulin-like

  6. Hedgehog signaling in myofibroblasts directly promotes prostate tumor cell growth

    PubMed Central

    Domenech, Maribella; Bjerregaard, Robert; Bushman, Wade; Beebe, David J.

    2012-01-01

    Despite strong evidence for the involvement of the stroma in Hedgehog signaling, little is known about the identity of the stromal cells and the signaling mechanisms that mediate the growth promoting effect of Hh signaling. We developed an in vitro co-culture model using microchannel technology to examine the effect of paracrine Hh signaling on proliferation of prostate cancer cells. We show here that activation of Hh signaling in myofibroblasts is sufficient to accelerate tumor cell growth. This effect was independent of any direct effect of Hh ligand on tumor cells or other cellular components of the tumor stroma. Further, the trophic effect of Hh pathway activation in myofibroblasts does not require collaboration of other elements of the stroma or direct physical interaction with the cancer cells. By isolating the tropic effect of Hh pathway activation in prostate stroma, we have taken the first step toward identifying cell-specific mechanisms that mediate the effect of paracrine Hh signaling on tumor growth. PMID:22234342

  7. Time delay and noise explaining the behaviour of the cell growth in fermentation process

    NASA Astrophysics Data System (ADS)

    Ayuobi, Tawfiqullah; Rosli, Norhayati; Bahar, Arifah; Salleh, Madihah Md

    2015-02-01

    This paper proposes to investigate the interplay between time delay and external noise in explaining the behaviour of the microbial growth in batch fermentation process. Time delay and noise are modelled jointly via stochastic delay differential equations (SDDEs). The typical behaviour of cell concentration in batch fermentation process under this model is investigated. Milstein scheme is applied for solving this model numerically. Simulation results illustrate the effects of time delay and external noise in explaining the lag and stationary phases, respectively for the cell growth of fermentation process.

  8. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling

    PubMed Central

    Pasula, Satish; Cai, Xiaofeng; Dong, Yunzhou; Messa, Mirko; McManus, John; Chang, Baojun; Liu, Xiaolei; Zhu, Hua; Mansat, Robert Silasi; Yoon, Seon-Joo; Hahn, Scott; Keeling, Jacob; Saunders, Debra; Ko, Genevieve; Knight, John; Newton, Gail; Luscinskas, Francis; Sun, Xiaohong; Towner, Rheal; Lupu, Florea; Xia, Lijun; Cremona, Ottavio; De Camilli, Pietro; Min, Wang; Chen, Hong

    2012-01-01

    Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, however, loss of epsins 1 and 2 resulted in disorganized vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promoted binding of epsin to ubiquitinated VEGFR2. Loss of epsins 1 and 2 specifically impaired endocytosis and degradation of VEGFR2, which resulted in excessive VEGF signaling that compromised tumor vascular function by exacerbating nonproductive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Promotion of excessive VEGF signaling within tumors via a block of epsin 1 and 2 function may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies. PMID:23187125

  9. Piecewise Constant Suboptimal Controls for a System Describing Tumor Growth under Angiogenic Treatment

    E-print Network

    Ledzewicz, Urszula

    approach that aims at depriving a growing tumor of the blood vessel network it needs for growth. Initially to allow for cell duplication and tumor growth. However, after this state of avascular growth is over, at the size of about 1 - 2 mm in diameter, this no longer is true and most tumor cells enter the dormant stage

  10. Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth

    E-print Network

    Boyer, Edmond

    ! 1! Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth2013 #12;! 2! Abstract Tumor growth is a complex process involving a large number of biological formalized with the help of mathematical models. Based on experimental data of in vivo syngeneic tumor growth

  11. Formal asymptotic limit of a diffuse-interface tumor-growth

    E-print Network

    Paris-Sud XI, Université de

    Formal asymptotic limit of a diffuse-interface tumor-growth model Danielle Hilhorst , Johannes-interface tumor-growth model, which has the form of a phase-field system. We discuss the singular limit perturbation, interface mo- tion, matched asymptotic expansion, tumor-growth model. 1 Introduction Diffuse

  12. Classical Mathematical Models for Description and Prediction of Experimental Tumor Growth

    E-print Network

    Paris-Sud XI, Université de

    1 Classical Mathematical Models for Description and Prediction of Experimental Tumor Growth complexity, tumor growth kinetics follow relatively simple macroscopic laws that have been quantified for the purpose of comparing alternative models for their abilities to describe and predict tumor growth

  13. Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells.

    PubMed

    De Vlieghere, Elly; Gremonprez, Félix; Verset, Laurine; Mariën, Lore; Jones, Christopher J; De Craene, Bram; Berx, Geert; Descamps, Benedicte; Vanhove, Christian; Remon, Jean-Paul; Ceelen, Wim; Demetter, Pieter; Bracke, Marc; De Geest, Bruno G; De Wever, Olivier

    2015-06-01

    Peritoneal metastasis is life threatening and is the result of an extensive communication between disseminated cancer cells, mesothelial cells and cancer-associated fibroblasts (CAF). CAFs secrete extracellular matrix (ECM) proteins creating a receptive environment for peritoneal implantation. Considering cancer as an ecosystem may provide opportunities to exploit CAFs to create biomimetic traps to deceive and redirect cancer cells. We have designed microparticles (MP) containing a CAF-derived ECM-surface that is intended to compete with natural niches. CAFs were encapsulated in alginate/gelatine beads (500-750 ?m in diameter) functionalised with a polyelectrolyte coating (MP[CAF]). The encapsulated CAFs remain viable and metabolically active (?35 days), when permanently encapsulated. CAF-derived ECM proteins are retained by the non-biodegradable coating. Adhesion experiments mimicking the environment of the peritoneal cavity show the selective capture of floating cancer cells from different tumor origins by MP[CAF] compared to control MP. MP[CAF] are distributed throughout the abdominal cavity without attachment to intestinal organs and without signs of inflammatory reaction. Intraperitoneal delivery of MP[CAF] and sequential removal redirects cancer cell adhesion from the surgical wound to the MP[CAF], delays peritoneal metastasis formation and prolongs animal survival. Our experiments suggest the use of a biomimetic trap based on tumor-environment interactions to delay peritoneal metastasis. PMID:25907048

  14. Effects of Noise Correlation and Time Delay on Transient Properties of a Cancer Growth System with Immunization

    NASA Astrophysics Data System (ADS)

    Jia, Zheng-Lin

    The effects of noise correlation and time delay on the transient properties of a cancer growth system are studied in terms of the mean first-passage time (MFPT), which provides a measure of the mean extinction time of the tumor cell population. The results indicate that the additive and multiplicative noises can induce the noise-enhanced stability (NES) effect. The increasing of the delay time weakens the NES effect in the presence of two noise sources and induces a shift of the maximum of the MFPT towards smaller values of the noise intensities. The increasing of cross-correlation strength between noises can only restrain the NES effect induced by the multiplicative noise and can induce a shift of the peak of the MFPT towards larger values of the noise intensities.

  15. A recombinant endogenous retrovirus amplified in a mouse neuroblastoma is involved in tumor growth in vivo.

    PubMed

    Pothlichet, Julien; Heidmann, Thierry; Mangeney, Marianne

    2006-08-15

    The theory of immunoediting postulates that tumor cells exhibit a reduced immunogenicity to escape eradication by the host immune system. It has been proposed that endogenous retroviruses--provided that they are active--could play a role in this process, via the immunosuppressive domain carried by their envelope protein. Here, we demonstrate that the Neuro-2a tumor cell line--originating from a spontaneous A/J mouse neuroblastoma--produces an infectious retrovirus that most probably results from a recombination event between 2 mouse endogenous retroviral elements. This Neuro-2a-associated recombinant retrovirus derives from the unique ecotropic provirus located at the Emv-1 locus, but with a gag sequence conferring B-tropism, thus allowing its high-level amplification in Neuro-2a cells. We show that knocking down -by RNA interference- this endogenous retrovirus in Neuro-2a cells has no effect on the transformed phenotype of the cells, but results in delayed tumor growth and prolonged animal survival, following engraftment of the cells into immunocompetent mice. Recombination between endogenous retroviruses, amplification of the resulting element and high-level expression of its immunosuppressive activity are therefore likely steps of an immunoediting process, leading to an invading tumor. PMID:16550601

  16. Homeostatic competition drives tumor growth and metastasis nucleation

    PubMed Central

    Basan, Markus; Risler, Thomas; Joanny, Jean-François; Sastre-Garau, Xavier; Prost, Jacques

    2009-01-01

    We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths. PMID:20119483

  17. Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth

    Microsoft Academic Search

    Michael S O'Reilly; Thomas Boehm; Yuen Shing; Naomi Fukai; George Vasios; Evelyn Flynn; James R Birkhead; Bjorn R Olsen; Judah Folkman

    1997-01-01

    We previously identified the angiogenesis inhibitor angiostatin. Using a similar strategy, we have identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli–derived endostatin was administered as a nonrefolded suspen- sion.

  18. Interfacial properties in a discrete model for tumor growth

    NASA Astrophysics Data System (ADS)

    Moglia, Belén; Guisoni, Nara; Albano, Ezequiel V.

    2013-03-01

    We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent ?=0.32(2) that governs the early time regime, (ii) the roughness exponent ?=0.49(2) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z=?/??1.49(2), which measures the propagation of correlations in the direction parallel to the interface, e.g., ??t1/z, where ? is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.

  19. Delayed Effects of Whole Brain Radiotherapy in Germ Cell Tumor Patients With Central Nervous System Metastases

    SciTech Connect

    Doyle, Danielle M. [Department of Medicine, Division of Hematology and Oncology, Indiana University, Indianapolis, IN (United States); Walther Cancer Institute, Indianapolis, IN (United States)], E-mail: dpeoni@iupui.edu; Einhorn, Lawrence H. [Department of Medicine, Division of Hematology and Oncology, Indiana University, Indianapolis, IN (United States); Walther Cancer Institute, Indianapolis, IN (United States)

    2008-04-01

    Purpose: Central nervous system (CNS) metastases are uncommon in patients with germ cell tumors, with an incidence of 2-3%. CNS metastases have been managed with whole brain radiotherapy (WBRT) and concomitant cisplatin-based combination chemotherapy. Our previous study did not observe serious CNS toxicity (Int J Radiat Oncol Biol Phys 1991;22:17-22). We now report on 5 patients who developed delayed significant CNS toxicity. Patients and Methods: We observed 5 patients with delayed CNS toxicity. The initial diagnosis was between 1981 and 2003. All patients had poor-risk disease according to the International Germ Cell Consensus Collaborative Group criteria. Of the 5 patients, 3 had CNS metastases at diagnosis and 2 developed relapses with CNS metastases. These 5 patients underwent WBRT to 4,000-5,000 cGy in 18-28 fractions concurrently with cisplatin-based chemotherapy. Results: All 5 patients developed delayed symptoms consistent with progressive multifocal leukoencephalopathy. The symptoms included seizures, hemiparesis, cranial neuropathy, headaches, blindness, dementia, and ataxia. The median time from WBRT to CNS symptoms was 72 months (range, 9-228). Head imaging revealed multiple abnormalities consistent with gliosis and diffuse cerebral atrophy. Of the 5 patients, 3 had progressive and 2 stable symptoms. Treatment with surgery and/or steroids had modest benefit. The progressive multifocal leukoencephalopathy resulted in significant debility in all 5 patients, resulting in death (3 patients), loss of work, steroid-induced morbidity, and recurrent hospitalizations. Conclusion: Whole brain radiotherapy is not innocuous in young patients with germ cell tumors and can cause late CNS toxicity.

  20. 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 (?-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 ?-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.

  1. Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1.

    PubMed

    Kerl, Kornelius; Moreno, Natalia; Holsten, Till; Ahlfeld, Julia; Mertins, Julius; Hotfilder, Marc; Kool, Marcel; Bartelheim, Kerstin; Schleicher, Sabine; Handgretinger, Rupert; Schüller, Ulrich; Meisterernst, Michael; Frühwald, Michael C

    2014-08-15

    Rhabdoid tumors are highly aggressive tumors occurring in infants and very young children. Despite multimodal and intensive therapy prognosis remains poor. Molecular analyses have uncovered several deregulated pathways, among them the CDK4/6-Rb-, the WNT- and the Sonic hedgehog (SHH) pathways. The SHH pathway is activated in rhabdoid tumors by GLI1 overexpression. Here, we demonstrate that arsenic trioxide (ATO) inhibits tumor cell growth of malignant rhabdoid tumors in vitro and in a mouse xenograft model by suppressing Gli1. Our data uncover ATO as a promising therapeutic approach to improve prognosis for rhabdoid tumor patients. PMID:24420698

  2. Environmental enrichment does not impact on tumor growth in mice.

    PubMed

    Westwood, Jennifer A; Darcy, Phillip K; Kershaw, Michael H

    2013-01-01

    The effect of environmental enrichment (EE) on a variety of physiologic and disease processes has been studied in laboratory mice. During EE, a large group of mice are housed in larger cages than the standard cage and are given toys and equipment, enabling more social contact, and providing a greater surface area per mouse, and a more stimulating environment. Studies have been performed into the effect of EE on neurogenesis, brain injury, cognitive capacity, memory, learning, neuronal pathways, diseases such as Alzheimer's, anxiety, social defeat, emotionality, depression, drug addiction, alopecia, and stereotypies. In the cancer field, three papers have reported effects on mice injected with tumors and housed in enriched environments compared with those housed in standard conditions. One paper reported a significant decrease in tumor growth in mice in EE housing. We attempted to replicate this finding in our animal facility, because the implications of repeating this finding would have profound implications for how we house all our mice in our studies on cancer. We were unable to reproduce the results in the paper in which B16F10 subcutaneous tumors of mice housed in EE conditions were smaller than those of mice housed in standard conditions. The differences in results could have been due to the different growth rate of the B16F10 cultures from the different laboratories, the microbiota of the mice housed in the two animal facilities, variations in noise and handling between the two facilities, food composition, the chemical composition of the cages or the detergents used for cleaning, or a variety of other reasons. EE alone does not appear to consistently result in decreased tumor growth, but other factors would appear to be able to counteract or inhibit the effects of EE on cancer progression. PMID:24555065

  3. HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.

    PubMed

    Moore, Richard G; Hill, Emily K; Horan, Timothy; Yano, Naohiro; Kim, KyuKwang; MacLaughlan, Shannon; Lambert-Messerlian, Geralyn; Tseng, YiTang Don; Padbury, James F; Miller, M Craig; Lange, Thilo S; Singh, Rakesh K

    2014-01-01

    Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1?. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer. PMID:24389815

  4. HE4 (WFDC2) gene overexpression promotes ovarian tumor growth

    PubMed Central

    Moore, Richard G.; Hill, Emily K.; Horan, Timothy; Yano, Naohiro; Kim, KyuKwang; MacLaughlan, Shannon; Lambert-Messerlian, Geralyn; Tseng, YiTang Don; Padbury, James F.; Miller, M. Craig; Lange, Thilo S.; Singh, Rakesh K.

    2014-01-01

    Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1?. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer. PMID:24389815

  5. Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.

    PubMed

    Pavani, M; Fones, E; Oksenberg, D; Garcia, M; Hernandez, C; Cordano, G; Muñoz, S; Mancilla, J; Guerrero, A; Ferreira, J

    1994-11-16

    The effects of nordihydroguaiaretic acid (NDGA), best known as an inhibitor of lipoxygenase activities, on the culture growth, oxygen consumption, ATP level, viability, and redox state of some electron carriers of intact TA3 and 786A ascites tumor cells have been studied. NDGA inhibited the respiration rate of these two tumor cell lines by preventing electron flow through the respiratory chain. Consequently, ATP levels, cell viability and culture growth rates were decreased. NDGA did not noticeably inhibit electron flow through both cytochrome oxidase and ubiquinone-cytochrome b-c1 complex. Also, the presence of NDGA changed to redox state of NAD(P)+ to a more reduced level, and the redox states of ubiquinone, cytochrome b and cytochromes c + c1 changed to a more oxidized level. These observations suggest that the electron transport in the tumor mitochondria was inhibited by NDGA at the NADH-dehydrogenase-ubiquinone level (energy-conserving site 1). As a consequence, mitochondrial ATP synthesis would be interrupted. This event could be related to the cytotoxic effect of NDGA. PMID:7986205

  6. Transplanted tumor growth inhibition by functionalized short single-walled carbon nanotubules.

    PubMed

    Kit, O I; Zlatnik, E Yu; Peredreyeva, L V; Chervonobrodov, S P

    2014-01-01

    The effects of short single-walled carbon nanotubules functionalized by COOH- and NH2- containing groups (NT-COOH and NT-NH2), on the dynamics of transplanted Pliss lymphosarcoma growth were studied after tumor cell preincubation with nanotubules and after injection of nanotubules into the developing tumor. Tumor growth was inhibited and the lifespan of rats with tumors was prolonged by 1.7 times after transplantation of tumor preincubated with NT-NH2, while NT-COOH caused no effect of this kind. Intratumor injection of NT-NH2 inhibited tumor growth over 3 weeks and prolonged animal lifespan. PMID:24771378

  7. A High-Performance Cellular Automaton Model of Tumor Growth with Dynamically Growing Domains.

    PubMed

    Poleszczuk, Jan; Enderling, Heiko

    2014-01-01

    Tumor growth from a single transformed cancer cell up to a clinically apparent mass spans many spatial and temporal orders of magnitude. Implementation of cellular automata simulations of such tumor growth can be straightforward but computing performance often counterbalances simplicity. Computationally convenient simulation times can be achieved by choosing appropriate data structures, memory and cell handling as well as domain setup. We propose a cellular automaton model of tumor growth with a domain that expands dynamically as the tumor population increases. We discuss memory access, data structures and implementation techniques that yield high-performance multi-scale Monte Carlo simulations of tumor growth. We discuss tumor properties that favor the proposed high-performance design and present simulation results of the tumor growth model. We estimate to which parameters the model is the most sensitive, and show that tumor volume depends on a number of parameters in a non-monotonic manner. PMID:25346862

  8. Hybrid Cellular Continuum Simulations of Heterogeneity in Tumor Growth

    NASA Astrophysics Data System (ADS)

    Hentschel, H. G. E.; Family, Fereydoon; van Meir, Erwin; Grossniklaus, Hans

    2010-03-01

    We will discuss simulations of pre-angiogenic tumor growth using a class of hybrid cellular-continuum models. A lattice site can be occupied either by a cell of a specific tumor cell population or consist of extracellular matrix. The local concentrations of oxygen is described by continuum reaction-diffusion equations. Dynamic linked lists of cells are evolved in time and contain information on cell type, position, age, concentration of oxygen at cell site. When cells proliferate via mitosis or differentiate, new cells are added to the list, if mutation occurs the cell types are altered, and if the cell dies via apoptosis the cells are removed from the linked list. The motion of individual cells consist of random walks subject to caging and chemotaxis away from regions of low oxygen concentration. We will describe the heterogenous spatial segregation of different cell types in the tumor, the development of necrotic cores as well as micronecrotic regions, and the effects of externally applied drugs on cell populations and overall tumor shape.

  9. The Constitutive Photomorphogenesis 9 Signalosome Directs Vascular Endothelial Growth Factor Production in Tumor Cells1

    Microsoft Academic Search

    Christian Pollmann; Xiaohua Huang; Julian Mall; Dawadschargal Bech-Otschir; Michael Naumann; Wolfgang Dubiel

    2001-01-01

    Angiogenesis is a prerequisite for solid tumor growth and metastasis. Elucidation of the signaling pathways that control tumor angiogenesis constitutes the basis for a rational antiangiogenic tumor therapy. Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN). The CSN is a kinase complex

  10. Asymmetric non-Gaussian effects in a tumor growth model with immunization q

    E-print Network

    Song, Renming

    . For various initial densities of tumor cells, the mean residence time and the escape probability are computedAsymmetric non-Gaussian effects in a tumor growth model with immunization q Mengli Hao a , Jinqiao 2013 Accepted 13 February 2014 Available online 5 March 2014 Keywords: Tumor growth with immunization

  11. Adapting a transforming growth factor -related tumor protection strategy to enhance antitumor immunity

    Microsoft Academic Search

    Catherine M. Bollard; Claudia Rossig; M. Julia Calonge; M. Helen; Hans-Joachim Wagner Huls; Joan Massague; Malcolm K. Brenner; Helen E. Heslop; Cliona M. Rooney

    2002-01-01

    Transforming growth factor (TGF-), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhib- its tumor-specific cellular immunity. Tu- mors can avoid the differentiating and apoptotic effects of TGF- by expressing a nonfunctional TGF- receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes

  12. A Chebyshev method for a free boundary problem modeling tumor growth

    E-print Network

    Sommese, Andrew J.

    A Chebyshev method for a free boundary problem modeling tumor growth Wenrui Hao Oliver Kernell Andrew Sommese May 23, 2013 1 Mathematical model Mathematical models of tumor growth, which consider the tumor tissue as a density of proliferating cells, have been developed and studied in many papers; see [1

  13. MULTIPHASE MODELING AND QUALITATIVE ANALYSIS OF THE PROBLEM OF THE GROWTH OF TUMOR CORDS

    E-print Network

    Ceragioli, Francesca

    MULTIPHASE MODELING AND QUALITATIVE ANALYSIS OF THE PROBLEM OF THE GROWTH OF TUMOR CORDS ANDREA TOSIN Abstract. In this paper a macroscopic model of tumor cords growth is developed, relying on the mathematical theory of deformable porous media. Tumor is modeled as a saturated mixture of proliferating cells

  14. ANALYSIS OF A MATHEMATICAL MODEL OF THE EFFECT OF INHIBITORS ON THE GROWTH OF TUMORS

    E-print Network

    ANALYSIS OF A MATHEMATICAL MODEL OF THE EFFECT OF INHIBITORS ON THE GROWTH OF TUMORS SHANGBIN CUI Church St. SE, Minneapolis, MN 55455. Abstract. In this paper we study a model of tumor growth in the presence of inhibitors. The tumor is assumed to be spherically symmetric and its boundary is an unknown

  15. A Generative Approach for Image-Based Modeling of Tumor Growth

    E-print Network

    Paris-Sud XI, Université de

    A Generative Approach for Image-Based Modeling of Tumor Growth Bjoern H. Menze1,2 , Koen Van tumor patients to monitor the state of the disease and to evaluate therapeutic options. A large number points. In this work we propose a joint generative model of tumor growth and of image observation

  16. Evolving interfaces via gradients of geometry-dependent interior Poisson problems: application to tumor growth

    E-print Network

    Lowengrub, John

    to tumor growth Paul Macklin, John Lowengrub * Department of Mathematics, 103 MSTB, University to a model for tumor growth and present several 2D simula- tions. Our algorithm is validated by comparison accurate simulations of complex, evolving tumor morphologies that demonstrate the repeated encapsulation

  17. Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis

    Microsoft Academic Search

    M. Muehlemann; K. D. Miller; M. Dauphinee; G. J. Mizejewski

    2005-01-01

    This review surveys the biological activities of an alpha-fetoprotein (AFP) derived peptide termed the Growth Inhibitory Peptide (GIP), which is a synthetic 34 amino acid segment produced from the full length 590 amino acid AFP molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult terminally-differentiated cells. The mechanism of action

  18. ANALYSIS OF A TWO-PHASE MODEL DESCRIBING THE GROWTH OF SOLID TUMORS

    E-print Network

    Matioc, Anca-Voichita

    ANALYSIS OF A TWO-PHASE MODEL DESCRIBING THE GROWTH OF SOLID TUMORS JOACHIM ESCHER AND ANCA tumors when taking into account the eects of cell-to-cell adhesion and taxis due to nutrient. The tumor is surrounded by healthy tissue which is the source of nutrient for the tumor cells. In a three

  19. Tumor Growth Parameters Estimation and Source Localization From a Unique Time Point: Application to

    E-print Network

    Paris-Sud XI, Université de

    Tumor Growth Parameters Estimation and Source Localization From a Unique Time Point: Application provided interesting ways to better understand the proliferative-invasive aspect of glial cells in tumors of a non-swollen brain tumor, estimate the tumor source location and the diffusivity ratio between white

  20. The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.

    PubMed

    To, Ciric; Kim, Eun-Hee; Royce, Darlene B; Williams, Charlotte R; Collins, Ryan M; Risingsong, Renee; Sporn, Michael B; Liby, Karen T

    2014-07-01

    Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. PMID:24817481

  1. Delayed adolescent growth in homozygous sickle cell disease

    Microsoft Academic Search

    A Singhal; P Thomas; R Cook; K Wierenga; G Serjeant

    1994-01-01

    Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1).

  2. The effect of prolonged administration of an anabolic steroid (oxandrolone) on growth in boys with constitutionally delayed growth and puberty

    Microsoft Academic Search

    Eelco J. Schroor; Mirjam M. van Weissenbruch; Pieter Knibbe; Henriette A. Delemarre-van de Waal

    1995-01-01

    Short-term oxandrolone treatment is used to stimulate growth in boys with constitutional delay of growth and puberty (CDGP). Oxandrolone stimulates growth, but a beneficial effect on final height has not been established. In our study, we report the effect of long-term treatment (30–57 months) with oxandrolone in 18 boys with CDGP, compared with nine puberty-matched, untreated controls (group 1). The

  3. Genetic separation of tumor growth and hemorrhagic phenotypes in an estrogen-induced tumor.

    PubMed Central

    Wendell, D L; Herman, A; Gorski, J

    1996-01-01

    Chronic administration of estrogen to the Fischer 344 (F344) rat induces growth of large, hemorrhagic pituitary tumors. Ten weeks of diethylstilbestrol (DES) treatment caused female F344 rat pituitaries to grow to an average of 109.2 +/- 6.3 mg (mean +/- SE) versus 11.3 +/- 1.4 mg for untreated rats, and to become highly hemorrhagic. The same DES treatment produced no significant growth (8.9 +/- 0.5 mg for treated females versus 8.7 +/- 1.1 for untreated females) or morphological changes in Brown Norway (BN) rat pituitaries. An F1 hybrid of F344 and BN exhibited significant pituitary growth after 10 weeks of DES treatment with an average mass of 26.3 +/- 0.7 mg compared with 8.6 +/- 0.9 mg for untreated rats. Surprisingly, the F1 hybrid tumors were not hemorrhagic and had hemoglobin content and outward appearance identical to that of BN. Expression of both growth and morphological changes is due to multiple genes. However, while DES-induced pituitary growth exhibited quantitative, additive inheritance, the hemorrhagic phenotype exhibited recessive, epistatic inheritance. Only 5 of the 160 F2 pituitaries exhibited the hemorrhagic phenotype; 36 of the 160 F2 pituitaries were in the F344 range of mass, but 31 of these were not hemorrhagic, indicating that the hemorrhagic phenotype is not merely a consequence of extensive growth. The hemorrhagic F2 pituitaries were all among the most massive, indicating that some of the genes regulate both phenotypes. Images Fig. 1 PMID:8755612

  4. Macrophage Migration Inhibitory Factor promotes tumor growth and metastasis by inducing Myeloid Derived Suppressor Cells in the tumor microenvironment

    PubMed Central

    Simpson, Kendra D.; Templeton, Dennis J.; Cross, Janet V.

    2012-01-01

    The Macrophage Migration Inhibitory Factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show here that, in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion, and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response, and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches. PMID:23125418

  5. Radiotherapy planning for glioblastoma based on a tumor growth model: Improving target volume delineation

    E-print Network

    Unkelbach, Jan; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A

    2013-01-01

    Glioblastoma are known to infiltrate the brain parenchyma 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 clinical practice, a uniform margin is applied to account for microscopic spread of disease. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth: 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...

  6. Dynamic density functional theory of solid tumor growth: Preliminary models

    PubMed Central

    Chauviere, Arnaud; Hatzikirou, Haralambos; Kevrekidis, Ioannis G.; Lowengrub, John S.; Cristini, Vittorio

    2012-01-01

    Cancer is a disease that can be seen as a complex system whose dynamics and growth result from nonlinear processes coupled across wide ranges of spatio-temporal scales. The current mathematical modeling literature addresses issues at various scales but the development of theoretical methodologies capable of bridging gaps across scales needs further study. We present a new theoretical framework based on Dynamic Density Functional Theory (DDFT) extended, for the first time, to the dynamics of living tissues by accounting for cell density correlations, different cell types, phenotypes and cell birth/death processes, in order to provide a biophysically consistent description of processes across the scales. We present an application of this approach to tumor growth. PMID:22489279

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

    PubMed Central

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

    2014-01-01

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

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

    Microsoft Academic Search

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

    1993-01-01

    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

  9. 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

  10. Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors

    PubMed Central

    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. PMID:25111061

  11. Perfluorochemical emulsions can increase tumor radiosensitivity

    Microsoft Academic Search

    B. A. Teicher; C. M. Rose

    1984-01-01

    An oxygen-carrying perfluorochemical emulsion enhanced the effectiveness of radiation therapy in two transplantable solid tumors in mice. The perfluorochemical emulsion had no effect on tumor growth after x-irradiation, but delayed tumor growth significantly when administered to oxygen-breathing mice before or during irradiation.

  12. Resistance of a VEGF-producing tumor to anti-VEGF antibody: Unimpeded growth of human rhabdoid tumor xenografts

    Microsoft Academic Search

    Samuel Z. Soffer; Eugene Kim; Jianzhong Huang; Kimberly McCrudden; Akiko Yokoi; James T. Moore; Christina Manley; Kathleen O'Toole; William Middlesworth; Charles Stolar; Darrell J. Yamashiro; Jessica J. Kandel

    2002-01-01

    Background\\/Purpose: Rhabdoid tumor of the kidney (RTK) is a lethal malignancy of childhood for which there currently are no effective therapies. Because vascular endothelial growth factor (VEGF) is nearly ubiquitous in human tumors, the authors hypothesized that a xenograft model of RTK would (1) express VEGF and (2) respond to anti-VEGF intervention. Methods: A total of 2 [times ] 106

  13. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases.

    PubMed

    Aoyama, Yumi; Avruch, Joseph; Zhang, Xian-Feng

    2004-04-22

    Nore1, a noncatalytic protein identified by its ability to bind selectively to active Ras, is most closely related in amino-acid sequence to the tumor suppressor RASSF1. Both are expressed predominantly as a longer (Nore1A/RASSF1A) and/or shorter (Nore1B/RASSF1C) polypeptide; all four polypeptides contain a Ras-association domain and bind, through their conserved carboxytermini, the proapoptotic protein kinases MST1 and MST2. Moreover, the expression of the longer polypeptide is downregulated in human tumor cell lines through promoter methylation (frequently for RASSF1A, less regularly for Nore1A). Forced expression of RASSF1A in several such lines (including the NSCLC line A549) has been shown to suppress tumorigenicity; herein we inquire whether Nore has growth inhibitory activity. Four tumor cell lines were tested, selected for their low expression of both Nore1A and Nore1B; the two NSCLC lines, A549 and NCI-H460, each have a mutant active Ras oncogene, whereas the two melanoma lines G361 and M14 each contain the constitutively active BRaf(V599E) oncogene and wild-type Ras. The expression of Nore1A or Nore1B suppresses colony formation by the A549 and G361 lines, as effectively in A549 as does RASSF1A; colony formation in the NCI-H460 and M14 lines is unaffected. Nore1A inhibits anchorage-independent growth by A549 cells and delays A549 progression through G1 without evidence of increased apoptosis. The growth suppressive action of Nore1A is largely unaffected by deletion of both the MST- and Ras-binding domains, as well as by mutation of the Nore1A zinc finger. Thus, Nore1 suppresses the growth of some tumor cell lines through as yet unidentified effectors, independent of Ras-like proteins or MST1/2. PMID:15007383

  14. Heat-activated thermosensitive liposomal cisplatin (HTLC) results in effective growth delay of cervical carcinoma in mice.

    PubMed

    Dou, Yannan N; Zheng, Jinzi; Foltz, Warren D; Weersink, Robert; Chaudary, Naz; Jaffray, David A; Allen, Christine

    2014-03-28

    Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of cervical cancer, but dose limiting toxicity is a key issue associated with its clinical application. A suite of liposome formulations of CDDP has been developed in efforts to reduce systemic toxicity, but their therapeutic advantage over the free drug has been modest due to insufficient drug release at the tumor site. This report describes the development of a novel heat-activated thermosensitive liposome formulation containing CDDP (HTLC) designed to release approximately 90% of the loaded drug in less than 5min under mild heating conditions (42°C). Physico-chemical characteristics of HTLC were assessed in terms of gel to liquid crystalline phase transition temperature (Tm), drug loading efficiency, particle size, and stability. The pharmacokinetic profile and biodistribution of HTLC in non-tumor-bearing mice were evaluated over a 24h period. A sophisticated spatio-temporal elucidation of HTLC release in tumor-bearing mice was achieved by way of real-time monitoring using a magnetic resonance (MR) imaging protocol, wherein a custom-built laser-based conformal heat source was applied at the tumor volume to trigger the release of HTLC co-encapsulated with the MR contrast agent gadoteridol (Gd-HP-DO3A). MR thermometry (MRT) demonstrated that a relatively uniform temperature distribution was achieved in the tumor volume using the external laser-based heating setup. In mice bearing subcutaneously-implanted ME-180 cervical tumors, the combination of HTLC and heat resulted in a 2-fold increase in tumor drug levels at 1h post-administration compared to HTLC without heating. Furthermore, the overall tumor accumulation levels for the HTLC groups (with and without heat) at 1h post-injection were significantly higher than the corresponding free CDDP group. This translated into a significant improvement in therapeutic efficacy evaluated as tumor growth delay (p<0.05) for the heated HTLC treatment group compared to the unheated HTLC, heated or unheated free CDDP, and saline groups. Overall, findings from this study demonstrate that a heat-activated, triggered release formulation of CDDP results in a significant enhancement in the therapeutic index of this drug. PMID:24440663

  15. A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization During Tumor Growth and Metastasis

    PubMed Central

    Dong, Dezheng; Stapleton, Christopher; Luo, Biquan; Xiong, Shigang; Ye, Wei; Zhang, Yi; Jhaveri, Niyati; Zhu, Genyuan; Ye, Risheng; Liu, Zhi; Bruhn, Kevin W.; Craft, Noah; Groshen, Susan; Hofman, Florence M.; Lee, Amy S.

    2011-01-01

    GRP78/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we demonstrated that Grp78 heterozygosity not only impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis, the Grp78+/? mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this report, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models where wild-type, syngeneic mammary tumor cells were injected into the host, we showed that Grp78+/? mice suppressed tumor growth and angiogenesis during the early but not late phase of tumor growth. Growth of metastatic lesions of wild-type, syngeneic melanoma cells in the Grp78+/? mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and demonstrated severe reduction of tumor angiogenesis and metastatic growth with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells demonstrated that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression and metastasis. PMID:21467168

  16. 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 suppressor function of LSAMP is most likely exerted by reducing the proliferation rate of the tumor cells, possibly by indirectly upregulating one or more of the genes HES1, CTAG2 or KLF10. To our knowledge, this study describes novel functions of LSAMP, a first step to understanding the functional role of this specific deletion in osteosarcomas. PMID:24885297

  17. 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

  18. Inhibition of vascular endothelial cell growth factor suppresses the in vivo growth of human prostate tumors

    Microsoft Academic Search

    Alexander Kirschenbaum; Jin-Ping Wang; Meiyue Ren; Jonathan D. Schiff; Stuart A. Aaronson; Michael J. Droller; Napoleone Ferrara; James F. Holland; Alice C. Levine

    1997-01-01

    The LNCaP human prostate cancer cell line is androgenand stromal-dependent for in vivo growth. We co-inoculated LNCaP cells with human fetal fibroblasts, isolated from prostate, bone (male), and lung (male and female) derived from 18- to 22-week-old human fetal tissue, into non-castrate male nude mice. Co-inoculation of LNCaP with fetal prostatic fibroblasts resulted in high tumor take rates (27 of

  19. Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis.

    PubMed

    Qi, Cuiling; Lan, Haimei; Ye, Jie; Li, Weidong; Wei, Ping; Yang, Yang; Guo, Simei; Lan, Tian; Li, Jiangchao; Zhang, Qianqian; He, Xiaodong; Wang, Lijing

    2014-07-01

    Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2'-deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression. PMID:24840330

  20. Targeting Gli transcription activation by small molecule suppresses tumor growth.

    PubMed

    Bosco-Clément, G; Zhang, F; Chen, Z; Zhou, H-M; Li, H; Mikami, I; Hirata, T; Yagui-Beltran, A; Lui, N; Do, H T; Cheng, T; Tseng, H-H; Choi, H; Fang, L-T; Kim, I-J; Yue, D; Wang, C; Zheng, Q; Fujii, N; Mann, M; Jablons, D M; He, B

    2014-04-17

    Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer 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 coactivator TBP-associated factor 9 (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 downregulate 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, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy. PMID:23686308

  1. 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

  2. Modelling hematopoiesis mediated by growth factors: Delay equations describing periodic

    E-print Network

    Boyer, Edmond

    and reg- ulation of blood cells. It is based upon differentiation of stem cells under the action of growth factors. A mathematical approach of this process is proposed to carry out explanation on some blood diseases, characterized by oscillations in circulating blood cells. A system of three differential

  3. 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.

  4. Phosphocaveolin-1 Enforces Tumor Growth and Chemoresistance in Rhabdomyosarcoma

    PubMed Central

    Faggi, Fiorella; Mitola, Stefania; Sorci, Guglielmo; Riuzzi, Francesca; Donato, Rosario; Codenotti, Silvia; Poliani, Pietro Luigi; Cominelli, Manuela; Vescovi, Raffaella; Rossi, Stefania; Calza, Stefano; Colombi, Marina; Penna, Fabio; Costelli, Paola; Perini, Ilaria; Sampaolesi, Maurilio; Monti, Eugenio; Fanzani, Alessandro

    2014-01-01

    Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS. PMID:24427291

  5. M-HIFU Inhibits Tumor Growth, Suppresses STAT3 Activity and Enhances Tumor Specific Immunity in a Transplant Tumor Model of Prostate Cancer

    PubMed Central

    Huang, Xiaoyi; Yuan, Fang; Liang, Meihua; Lo, Hui-Wen; Shinohara, Mari L.; Robertson, Cary; Zhong, Pei

    2012-01-01

    Objective In this study, we explored the use of mechanical high intensity focused ultrasound (M-HIFU) as a neo-adjuvant therapy prior to surgical resection of the primary tumor. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in M-HIFU elicited anti-tumor immune response using a transplant tumor model of prostate cancer. Methods RM-9, a mouse prostate cancer cell line with constitutively activated STAT3, was inoculated subcutaneously in C57BL/6J mice. The tumor-bearing mice (with a maximum tumor diameter of 5?6 mm) were treated by M-HIFU or sham exposure two days before surgical resection of the primary tumor. Following recovery, if no tumor recurrence was observed in 30 days, tumor rechallenge was performed. The growth of the rechallenged tumor, survival rate and anti-tumor immune response of the animal were evaluated. Results No tumor recurrence and distant metastasis were observed in both treatment groups employing M-HIFU + surgery and surgery alone. However, compared to surgery alone, M-HIFU combined with surgery were found to significantly inhibit the growth of rechallenged tumors, down-regulate intra-tumoral STAT3 activities, increase cytotoxic T cells in spleens and tumor draining lymph nodes (TDLNs), and improve the host survival. Furthermore, M-HIFU combined with surgery was found to significantly decrease the level of immunosuppression with concomitantly increased number and activities of dendritic cells, compared to surgery alone. Conclusion Our results demonstrate that M-HIFU can inhibit STAT3 activities, and when combined synergistically with surgery, may provide a novel and promising strategy for the treatment of prostate cancers. PMID:22911830

  6. Scheduling of Angiogenic Inhibitors for Gompertzian and Logistic Tumor Growth Models

    E-print Network

    Ledzewicz, Urszula

    for a cancer therapy which would primarily target healthy cells and cancerous ones only indirectly. Tumor anti endostatin target those cells preventing the tumor from developing its 1 #12;own blood vessel system and thus follow this path initiated by Hahnfeldt et al. in [18] where a model for tumor growth under the action

  7. A Synthesis of Optimal Controls for a Model of Tumor Growth under Angiogenic Inhibitors1

    E-print Network

    Ledzewicz, Urszula

    A Synthesis of Optimal Controls for a Model of Tumor Growth under Angiogenic Inhibitors1 Urszula for the scheduling of angio- genic inhibitors to control a vascularized tumor is considered as an optimal control for the newly forming blood vessels of the tumor. Angiogenic inhibitors like endostatin target those cells

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

    PubMed Central

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

    2007-01-01

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

  9. Inhibition of Cysteine Cathepsin Protease Activity Enhances Chemotherapy Regimens by Decreasing Tumor Growth and

    E-print Network

    Bogyo, Matthew

    Tumor Growth and Invasiveness in a Mouse Model of Multistage Cancer Katherine M. Bell-McGuinn, 1 Alfred. Inhibition of the cysteine cathepsin family using a pan-cathepsin inhibitor, JPM-OEt, led to tumor regression at a defined end point and tumor burden was assessed followed by a detailed analysis of cell proliferation

  10. Simulating complex tumor dynamics from avascular to vascular growth using a general level-set method

    E-print Network

    Sethian, James A.

    Simulating complex tumor dynamics from avascular to vascular growth using a general level Science Foundation Abstract A comprehensive continuum model of solid tumor evolution and development represents both the avascular and the vascular phase of tumor evolution, and is able to simulate when

  11. Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth.

    PubMed

    Gacche, Rajesh N; Meshram, Rohan J

    2013-11-01

    Angiogenesis: a process of generation of new blood vessels has been proved to be necessary for sustained tumor growth and cancer progression. Inhibiting angiogenesis pathway has long been remained a significant hope for the development of novel, effective and target orientated antitumor agents arresting the tumor proliferation and metastasis. The process of neoangiogenesis as a biological process is regulated by several pro- and anti-angiogenic factors, especially vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor 1 and transforming growth factor. Every endothelial cell destined for vessel formation is equipped with receptors for these angiogenic peptides. Moreover, numerous other angiogenic cytokines such as platelet derived growth factor (PGDF), placenta growth factor (PGF), nerve growth factor (NGF), stem-cell factor (SCF), and interleukins-2, 4, 6 etc. These molecular players performs critical role in regulating the angiogenic switch. Couple of decade's research in molecular aspects of tumor biology has unraveled numerous structural and functional mysteries of these angiogenic peptides. In present article, a detailed update on the functional and structural peculiarities of the various angiogenic peptides is described focusing on structural opportunities made available that has potential to be used to modulate function of these angiogenic peptides in developing therapeutic agents targeting neoplastic angiogenesis. The data may be useful in the mainstream of developing novel anticancer agents targeting tumor angiogenesis. We also discuss major therapeutic agents that are currently used in angiogenesis associated therapies as well as those are subject of active research or are in clinical trials. PMID:24139944

  12. Evaluating the role of substance P in the growth of brain tumors.

    PubMed

    Harford-Wright, E; Lewis, K M; Vink, R; Ghabriel, M N

    2014-03-01

    Recent research has investigated the expression and secretion of neuropeptides by tumors, and the potential of these peptides to facilitate tumor growth and spread. In particular, substance P (SP) and its receptor NK1 have been implicated in tumor cell growth and evasion of apoptosis, although few studies have examined this relationship in vivo. The present study used both in vitro and in vivo models to characterize the role of SP in tumor pathogenesis. Immunohistochemical assessment of human primary and secondary brain tumor tissue demonstrated a marked increase in SP and its NK1 receptor in all tumor types investigated. Of the metastatic tumors, melanoma demonstrated particularly elevated SP and NK1 receptor staining. Subsequently, A-375 human melanoma cell line was examined in vitro and found to express both SP and the NK1 receptor. Treatment with the NK1 receptor antagonist Emend IV resulted in decreased cell viability and an increase in cell death in this cell line in vitro. An animal model of brain tumors using the same cell line was employed to assess the effect of Emend IV on tumor growth in vivo. Administration of Emend IV was found to decrease tumor volume and decrease cellular proliferation indicating that SP may play a role in tumor pathogenesis within the brain. We conclude that SP may provide a novel therapeutic target in the treatment of certain types of brain tumors, with further research required to determine whether the role of SP in cancer is tumor-type dependent. PMID:24374326

  13. Radiographically determined growth kinetics of primary lung tumors in the dog

    SciTech Connect

    Perry, R.E. (Michigan State Univ., East Lansing, MI (USA). Coll. of Veterinary Medicine Pacific Northwest Lab., Richland, WA (USA)); Weller, R.E.; Buschbom, R.L.; Dagle, G.E.; Park, J.F. (Pacific Northwest Lab., Richland, WA (USA))

    1989-10-01

    Tumor growth rate patterns especially tumor doubling time (TDT), have been extensively evaluated in man. Studies involving the determination of TDT in humans are limited, however, by the number of cases, time consistent radiographic tumor measurements, and inability to perform experimental procedures. In animals similar constraints do not exist. Lifespan animal models lend themselves well to tumor growth pattern analysis. Experimental studies have been designed to evaluate both the biological effects and growth patterns of induced and spontaneous tumors. The purpose of this study was to calculate the tumor volume doubling times (TCDT) for radiation-induced and spontaneous primary pulmonary neoplasms in dogs to see if differences existed due to etiology, sex or histologic cell type, and to determine if the time of tumor onset could be extrapolated from the TVDT. 3 refs.

  14. Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles on Tumor Growth

    PubMed Central

    Bruno, Stefania; Collino, Federica; Iavello, Alessandra; Camussi, Giovanni

    2014-01-01

    Extracellular vesicles (EVs) are membrane vesicles, which are secreted by a variety of cells that have a relevant role in intercellular communication. EVs derived from various cell types exert different effects on target cells. Mesenchymal stromal cells (MSCs) are stem cells that are ubiquitously present in different tissues of the human body, and MSC-derived EVs take part in a wide range of biological processes. Of particular relevance is the effect of MSCs on tumor growth and progression. MSCs have opposing effects on tumor growth, being able either to favor angiogenesis and tumor initiation, or to inhibit progression of established tumors, according to the conditions. Different studies have reported that EVs from MSCs may exert either an anti- or a pro-tumor growth effect depending on tumor type and stage of development. In this review, we will discuss the data presented in the literature on EV-mediated interactions between MSCs and tumors. PMID:25157253

  15. On the Probability of Random Genetic Mutations for Various Types of Tumor Growth

    PubMed Central

    2013-01-01

    In this work, we consider the problem of estimating the probability for a specific random genetic mutation to be present in a tumor of a given size. Previous mathematical models have been based on stochastic methods where the tumor was assumed to be homogeneous and, on average, growing exponentially. In contrast, we are able to obtain analytical results for cases where the exponential growth of cancer has been replaced by other, arguably more realistic types of growth of a heterogeneous tumor cell population. Our main result is that the probability that a given random mutation will be present by the time a tumor reaches a certain size, is independent of the type of curve assumed for the average growth of the tumor, at least for a general class of growth curves. The same is true for the related estimate of the expected number of mutants present in a tumor of a given size, if mutants are indeed present. PMID:22311065

  16. Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

    PubMed Central

    Zhang, Guodong; Panigrahy, Dipak; Hwang, Sung Hee; Yang, Jun; Mahakian, Lisa M.; Wettersten, Hiromi I.; Liu, Jun-Yan; Wang, Yanru; Ingham, Elizabeth S.; Tam, Sarah; Kieran, Mark W.; Weiss, Robert H.; Ferrara, Katherine W.; Hammock, Bruce D.

    2014-01-01

    Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy. PMID:25024195

  17. Testosterone treatment in adolescent boys with constitutional delay of growth and development.

    PubMed

    Soliman, A T; Khadir, M M; Asfour, M

    1995-08-01

    Administration of androgens to adolescent boys with constitutional delay in growth has been highly controversial. One hundred forty-eight adolescent boys with constitutional delay of growth and puberty with a mean age of 14.3 +/- 0.7 years were treated with testosterone enanthate 100 mg intramuscularly each month for 6 months. Growth parameters, sexual maturation, and circulating concentrations of testosterone and insulin-like growth factor-I (IGF-I) were compared with those for 50 age-matched adolescent boys with constitutional delay of growth and puberty with a mean age of 14.1 +/- 0.9 years who did not receive any treatment. The mean height growth velocity, height standard deviation score, weight gain, and IGF-I concentration were significantly greater in the treatment group after 1 year of follow-up evaluation. The advancement in bone age equaled that in chronologic age in the treatment group, with no significant change in the bone age to chronologic age ratio (BA/CA) before versus after therapy. All subjects in the treatment group had clearly entered puberty by the end of 1 year. Testicular size increased significantly in the treatment group and they had significantly higher serum testosterone concentrations 6 months after the end of testosterone therapy as compared with the control group, denoting activation of the hypothalamic-pituitary testicular axis. All subjects in the treatment group were psychologically satisfied with the enhanced growth and increased muscle mass, versus only 40% of those in the control group. In conclusion, our regimen appears to be efficacious and safe for treatment of boys with constitutional delay of growth and puberty and has no deleterious effect on skeletal age. PMID:7637642

  18. Tumor Volume and Growth Kinetics in Hypothalamic-Chiasmatic Pediatric Low Grade Gliomas

    Microsoft Academic Search

    Jorge A. Lazareff; Rafal Suwinski; Roberto De Rosa; Charles E. Olmstead

    1999-01-01

    Pediatric low grade gliomas evidence a tendency towards quiescent growth, thus complicating the clinical management of nonresected tumors whose clinical behavior may be difficult to predict. We decided to explore the hypothesis of possible correlation in pediatric low grade glioma between tumor volume and growth rate. We identified 6 children with hypothalamic chiasmatic lesions. Five of these patients were treated

  19. Pubertal growth of the medial amygdala delayed by short photoperiods in the Siberian hamster, Phodopus sungorus

    E-print Network

    Breedlove, Marc

    Pubertal growth of the medial amygdala delayed by short photoperiods in the Siberian hamster nucleus of the amygdala (MeA) by comparing Siberian hamsters (Phodopus sungorus) that had been raised from birth in either long day (LD; 16:8 h light:dark) or short day (SD; 8:16) photoperiods. Hamsters were

  20. Impulsive exponential stabilization of discrete population growth models with time delays

    Microsoft Academic Search

    Yu Zhang; Jitao Sun

    2010-01-01

    The purpose of this paper is to investigate the impulsive exponential stabilization for the positive equilibrium points of a class of discrete population growth models with time delays. By using Lyapunov functionals, some new exponential stability criteria are given. It is shown that impulses can indeed make unstable equilibrium points exponentially stable, and when the impulses are employed to stabilize

  1. Stochastic resonance induced by Lévy noise in a tumor growth model with periodic treatment

    NASA Astrophysics Data System (ADS)

    Xu, Wei; Hao, Mengli; Gu, Xudong; Yang, Guidong

    2014-05-01

    In this paper, the stochastic resonance phenomenon in a tumor growth model under subthreshold periodic therapy and Lévy noise excitation is investigated. The possible reoccurrence of tumor due to stochastic resonance is discussed. The signal-to-noise ratio (SNR) is calculated numerically to measure the stochastic resonance. It is found that smaller stability index is better for avoiding tumor reappearance. Besides, the effect of the skewness parameter on the tumor regrowth is related to the stability index. Furthermore, increasing the intensity of periodic treatment does not always facilitate tumor therapy. These results are beneficial to the optimization of periodic tumor therapy.

  2. Chronic supplementation with shark liver oil for reducing tumor growth and cachexia in walker 256 tumor-bearing rats.

    PubMed

    Iagher, Fabíola; de Brito Belo, Sérgio Ricardo; Naliwaiko, Katya; Franzói, Andressa Machado; de Brito, Gleisson Alisson Pereira; Yamazaki, Ricardo Key; Muritiba, Ana Lúcia; Muehlmann, Luis Alexandre; Steffani, Jovani Antonio; Fernandes, Luiz Cláudio

    2011-11-01

    We investigated the effect of chronic supplementation with shark liver oil (SLO), an antitumor supplement source of n-3 fatty acids and 1-O-alkylglycerols, alone and combined with coconut fat (CF), a source of saturated fatty acids, on Walker 256 tumor growth and cachexia. Male rats were supplemented daily and orally with SLO and/or CF (1 g per kg body weight) for 7 wk. After 7 wk, 50% of animals were subcutaneously inoculated with 3 × 10(7) Walker 256 tumor cells. After 14 days, the rats were killed, the tumors were removed for lipid peroxidation measurement, and blood was collected for glycemia, triacylglycerolemia, and lacticidemia evaluation. Liver samples were obtained for glycogen measurement. Unlike CF, supplementation with SLO promoted gain in body weight, reduction of tumor weight, and maintained glycemia, triacylglycerolemia, lacticidemia, and liver glycogen content to values similar to non-tumor-bearing rats. Combined supplementation of SLO with CF also showed a reversion of cachexia with gain in body mass, reduction of lacticidemia, maintaining the liver glycogen store, and reduction in tumor weight. SLO, alone or combined with CF, promoted increase of tumor lipid peroxidation. In conclusion, SLO supplemented chronically, alone or associated with CF, was able to reduce tumor growth and cachexia. PMID:21981555

  3. Effect of Protein Intake on Tumor Growth and Cell Cycle Kinetics

    Microsoft Academic Search

    Michael H. Torosian

    1995-01-01

    Previous research has documented significant acceleration of tumor growth in animals receiving shorttern parenteral nutrition. This study was performed to determine the effect of long-term enteral protein intake on tumor cell cycle kinetics in the tumor-bearing host. Fifty Lewis\\/Wistar rats with subcutaneous mammary tumor implants (AC-33) were randomized to receive a standard protein diet (22.0% protein; 4.20 kcal\\/g) or protein-depleted

  4. The role of proteoglycans in the reactive stroma on tumor growth and progression.

    PubMed

    Coulson-Thomas, Yvette May; Gesteira, Tarsis Ferreira; Norton, Andrew Lawrence; Kao, Winston W-Y; Nader, Helena Bonciani; Coulson-Thomas, Vivien Jane

    2015-01-01

    The stroma surrounding tumors can either restrict or promote tumor growth and progression, and both the cellular and non-cellular components of the stroma play an active role. The cellular components in the surrounding stroma include tumor-associated fibroblasts, host tissue cells and immune cells. The non-cellular components, which form the extracellular matrix (ECM) scaffold, include proteoglycans, collagen, proteinases, growth factors and cytokines. For tumorigenesis to occur it is necessary for tumor cells to modify the surrounding stroma. Tumor cells have mechanisms for achieving this, such as co-opting fibroblasts and modifying the ECM they produce, degrading the surrounding ECM and/or synthesizing a favorable ECM to support invasion. Proteoglycans are an important component of the ECM and play an active role in tumor growth and progression. The expression and glycosylation patterns of proteoglycans are altered in the stroma surrounding tumors and these molecules may support or restrict tumor growth and progression depending on the type and stage of tumor. In the present review we discuss the difference between the tumor promoting and restricting stromal reactions surrounding tumors and the role proteoglycans play. PMID:24931397

  5. Sunitinib inhibits tumor vascularity and growth but does not affect Akt and ERK phosphorylation in xenograft tumors.

    PubMed

    Voce, Pasquale; D'Agostino, Maria; Moretti, Sonia; Sponziello, Marialuisa; Rhoden, Kerry; Calcinaro, Filippo; Tamburrano, Giulia; Tallini, Giovanni; Puxeddu, Efisio; Filetti, Sebastiano; Russo, Diego; Durante, Cosimo

    2011-11-01

    Sunitinib is a multikinase inhibitor approved for use in some human solid malignancies, including renal clear cell and gastrointestinal stromal cancer, and under investigation for many other neoplasias. In many preclinical cancer models sunitinib has shown anti-angiogenic and antitumor effects, acting mainly by inhibiting the activity of pro-angiogenic growth factor receptors. However, a percentage of tumors develop resistance to this treatment. The aim of this study was to identify novel potential molecular targets for the non- responsive tumors. The effects of sunitinib were investigated in xenograft tumors obtained by injecting HEK293 cells into NOD-SCID mice, focusing on the activity of growth-regulating pathways involved in tumorigenesis. During 11 days of oral administration of sunitinib (40 mg/kg/day), the growth of tumors was monitored by measuring the mass volume by a caliper. At the end of the treatment, tumor specimens were histologically examined for microvessel density (MVD) and presence of necrosis, and the phosphorylation of ERK and Akt was analyzed in protein extracts by Western blotting. Moreover, the mRNA levels of VEGF and its receptor genes were measured by quantitative RT-PCR. Treatment with sunitinib elicited a clear reduction of the tumor growth, associated with a reduction of MVD, correlated with an increased number of necrotic cells. In contrast, the levels of phosphorylated Akt and ERK proteins were similar in treated and non-treated animals. The VEGF and VEGFR-1 and 2 transcripts were not affected by sunitinib treatment. In conclusion, these findings confirm the anti-angiogenic action as the major effect of sunitinib against tumor growth. In contrast, other important growth regulatory pathways involved in malignant trans-formation, such as the ERK-MAPK and Akt/mTOR pathways are not affected by such a treatment, suggesting the use of specific inhibitors of these pathways as valid candidates for combinatorial therapies in sunitinib-resistant malignancies. PMID:21850379

  6. Question 2.7: Logistic growth of a tumor. Zobl et al. [1] have studied the growth functions of tumors by inducing novel sarcomas in the kidneys of rats with Polyoma virus. These tumors

    E-print Network

    Utrecht, Universiteit

    exponentially and then approach a steady state volume. This growth function can therefore potentially linearly with the population size, i.e., (1 - N/K) gives a linear decline of the growth rate, which becomesQuestion 2.7: Logistic growth of a tumor. Zobl et al. [1] have studied the growth functions

  7. Histologic variability in solitary fibrous tumors reflects angiogenic and growth factor signaling pathway alterations.

    PubMed

    Demicco, Elizabeth G; Wani, Khalida; Fox, Patricia S; Bassett, Roland L; Young, Eric D; Lev, Dina; Aldape, Kenneth D; Lazar, Alexander J; Wang, Wei-Lien

    2015-07-01

    This study aimed to evaluate expression of receptor tyrosine kinases, their ligands, and mutational status in solitary fibrous tumors, with correlation to histopathologic variants, tumor stage, and aggressive behavior. Immunohistochemical staining for PDGF?; PDGF?; PDGFR-?; PDGFR-?; IGF1R; EGFR; VEGF; IGF2; c-Met; c-kit; c-erbB2; PTEN; and phosphorylated (p)AKT, pS6, and p4EBP1 was analyzed in 114 cases of solitary fibrous tumor using tissue microarray. Mutational analysis was performed using Sequenom MassARRAY-based platform. Multiple growth factors were overexpressed in most tumors, and increased numbers of overexpressed factors correlated with activation of the AKT pathway as measured by increased expression of p4EBP1(P = .0005). Compared to hypocellular tumors, localized hypercellular tumors were associated with high vascular endothelial growth factor (32% versus 8%; P = .008) and PDGF? (41% versus 13%; P = .008). Metastatic tumors more frequently overexpressed PDGFR-? compared to localized tumors (75% versus 31%; P < .001). None of the factors examined had prognostic significance in primary tumors. Single-nucleotide polymorphisms involving MET were identified in 4 patients; these do not appear to drive tumor behavior and were not reflected in c-Met expression levels. Simultaneous overexpression of multiple growth factors is common in solitary fibrous tumors; variability in expression may contribute to tumor phenotype and aggressive behavior. PMID:25976141

  8. Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer

    PubMed Central

    de Heer, Pieter; Sandel, Maro H.; Guertens, Gunther; de Boeck, Gert; Koudijs, Margaretha M.; Nagelkerke, J. Fred; Junggeburt, Jan M. C.; de Bruijn, Ernst A.; van de Velde, Cornelis J. H.

    2008-01-01

    Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer in cyclooxygenase-2 (COX-2) overexpressing colorectal cancers. The present study was designed to evaluate the inhibitory effects of the COX-2 inhibitor celecoxib on the growth of colorectal cancer liver metastases in a syngeneic rat model, CC531. Materials and methods The effects of celecoxib on cell viability in vitro were evaluated by treatment of CC531 tumor cell cultures with celecoxib. In vivo, Wag/Rij rats were inoculated with CC531 tumor cells at two sites in the liver and treated with celecoxib starting one week before, or directly after tumor inoculation. Control rats were inoculated without treatment. Three weeks after tumor inoculation rats were sacrificed. Tumor size, immune cell infiltration, caspase-3 activity, PGE2 and celecoxib levels were determined. Results CC531 tumors did not show COX-2 expression. Tumor growth was significantly inhibited by celecoxib treatment in a dose dependent manner. Immune cell infiltration was decreased after celecoxib treatment, indicating that the immune system was not involved in preventing tumor growth. Tumor caspase-3 levels were only significantly increased if treatment was started before tumor inoculation. Celecoxib serum concentration starting at 0.84 ?g/ml significantly inhibited the outgrowth of CC531 liver tumors. In contrast, in vitro concentrations of celecoxib of at least 12 ?g/ml were needed to affect tumor cell viability. Conclusion These results suggest that the inhibitory effects of celecoxib on tumor growth are not by direct cytotoxicity, but by creating an unfavorable environment for tumor growth. PMID:18247029

  9. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice

    PubMed Central

    Esteva-Font, Cristina; Jin, Byung-Ju; Verkman, A. S.

    2014-01-01

    Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1+/+ MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm3 (se, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm3, 12 mice) were greatly reduced in AQP1?/? MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1?/? MMTV-PyVT mice, with reduced vessel density. HIF-1? expression was increased in tumors in AQP1?/? MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1+/+ MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.—Esteva-Font, C., Jin, B.-J., Verkman, A. S. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. PMID:24334548

  10. Inhibitory effect of recombinant endostatin on angiogenesis and tumor growth of hepatoma.

    PubMed

    Li, Peiyuan; Feng, Zuohua; Zhang, Guimei; Zhang, Hui; Xue, Shengli; Huang, Bo; Lin, Jusheng

    2003-01-01

    To study the influence of recombinant endostatin on angiogenesis and tumor growth of mice H22 hepatoma, tumor models were constructed by injecting H22 hepatoma cells into the leg muscle of mice. Recombinant endostatin was produced by gene engineering in E. coli. The recombinant protein was injected subcutaneously to treat transplanted hepatoma faraway. The weight of tumors was measured, and the changes of necrosis of tumor cells and vessel density were observed by immunohistochemistry. The results suggested that the growth of hepatoma models transplanted in the muscle of legs was suppressed by recombinant endostatin. The density of vascularity was decreased, but the necrosis of tumor cells increased. The inhibitory effect of recombinant endostatin on angiogenesis and tumor growth of hepatoma was not affected after chemotherapy. PMID:14526417

  11. Inhibition of Wilms' tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA.

    PubMed

    Celiker, M Y; Wang, M; Atsidaftos, E; Liu, X; Liu, Y E; Jiang, Y; Valderrama, E; Goldberg, I D; Shi, Y E

    2001-07-19

    Extracellular matrix (ECM) degrading matrix metalloproteinases (MMPs) lead to ECM turnover, a key event in cancer growth and progression. The tissue inhibitors of matrix metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use for cancer gene therapy. Here we report that systemic administration of naked TIMP-4 DNA significantly inhibited Wilms' tumor growth in nude mice. TIMP-4, whose expression was lost in Wilms' tumor, inhibited the growth of G401 Wilms' tumor cells at a concentration lower than those required for MMP inhibition. This inhibition was associated with internalization of exogenous recombinant TIMP-4. Electroporation-mediated intramuscular injection of TIMP-4 expression plasmid resulted in sustained plasma TIMP-4 levels and significant tumor suppression. Our data demonstrate a tumor suppressive effect of TIMP-4 against Wilms' tumor and the potential utility of intramuscular delivery of TIMP gene for treatment of kidney derived cancers. PMID:11466614

  12. VEGF-Targeted RNA Interference Suppresses Angiogenesis and Tumor Growth of Retinoblastoma

    Microsoft Academic Search

    R. B. Jia; P. Zhang; Y. X. Zhou; X. Song; H. Y. Liu; L. Z. Wang; M. Luo; J. Lu; S. F. Ge; X. Q. Fan

    2007-01-01

    Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors for tumor angiogenesis which has been verified to be involved in neovascularization of retinoblastoma. Here, we sought to explore whether RNA interference (RNAi) targeting VEGF could inhibit retinoblastoma angiogenesis and tumor growth. Stable transfection of the two human retinoblastoma cell lines SO-RB50 and HXO-RB44 with VEGF-targeted

  13. Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts.

    PubMed

    Ackermann, Maximilian; Carvajal, Irvith M; Morse, Brent A; Moreta, Miguel; O'Neil, Steven; Kossodo, Sylvie; Peterson, Jeffrey D; Delventhal, Vera; Marsh, H Nicholas; Furfine, Eric S; Konerding, Moritz A

    2011-01-01

    Antiangiogenesis has become a promising pillar in modern cancer therapy. This study investigates the antiangiogenic effects of the PEGylated Adnectin™, CT-322, in a murine Colo-205 xenograft tumor model. CT-322 specifically binds to and blocks vascular endothelial growth factor receptor (VEGFR-2). Adnectins are a novel class of targeted biologics engineered from the 10th domain of human fibronectin. CT-322 treated tumors exhibited a significant reduction in tumor growth of 69%, a 2.8 times lower tumor surface area and fewer necrotic areas. Control tumors showed a 2.36-fold higher microvessel density (MVD) and a 2.42 times higher vessel volume in corrosion casts. The vascular architecture in CT-322-treated tumors was characterized by a strong normalization of vasculature. This was quantified in corrosion casts of CT-322 treated tumors in which the intervascular distance (a reciprocal parameter indicative of vessel density) and the distance between two consecutive branchings were assessed, with these distances being 2.21 times and 2.37 times greater than in controls, respectively. Fluorescence molecular tomography (FMT) equally affirmed the inhibitory effects of CT-322 on tumor vasculature as indicated by a 60% reduction of the vascular probe, AngioSense, accumulating in tumor tissue, as a measurement of vascular permeability. Moreover, AngioSense accumulation was reduced as early as 24 h after starting treatment. The sum of these effects on tumor vasculature illustrates the anti-angiogenic mechanism underlying the antitumor activity of CT-322 and provides support for further evaluation of this Adnectin in combinatorial strategies with standard of care therapies. PMID:21109927

  14. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors

    PubMed Central

    Papaioannou, Marilena; Lopez-Casas, Pedro Pablo; Llonch, Elisabet; Hidalgo, Manuel; Gorgoulis, Vassilis G.; Nebreda, Angel R.

    2015-01-01

    Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment. PMID:25890501

  15. Neutrophils but not eosinophils are involved in growth suppression of IL-4-secreting tumors.

    PubMed

    Noffz, G; Qin, Z; Kopf, M; Blankenstein, T

    1998-01-01

    Local expression of IL-4 by gene-modified tumor cells increases their immunogenicity by inducing an inflammatory response that is dominated by eosinophils. Eosinophils have been implicated as antitumor effector cells because the application of a granulocyte-depleting Ab inhibited rejection of IL-4 transfected tumors. This Ab did not discriminate between eosinophils and neutrophils and, therefore, this experiment could not exclude neutrophils as primary effector cells, whereas eosinophils were innocent bystander cells in IL-4 transfected tumors. We analyzed tumor growth suppression and granulocyte infiltration in IL-5-deficient (IL-5(-/-)) mice that had a deficiency of eosinophils, using two tumor lines (B16-F10 and MCA205) transfected to secrete IL-4. IL-4-expressing tumors were at least as efficiently rejected in IL-5(-/-) mice as in wild-type mice, despite an almost complete absence of tumor-infiltrating eosinophils. However, neutrophils were present in undiminished amounts and their depletion partially restored tumor growth. Furthermore, the growth of IL-5-secreting tumors was not impaired in either wild-type or IL-5(-/-) mice, even though it induced eosinophilia in both mouse strains. These findings demonstrate that eosinophils can be induced in IL-5(-/-) mice by exogenous IL-5 and argue against a compensatory effect of neutrophils in the absence of eosinophils. We conclude that 1) infiltration of IL-4 transfected tumors by eosinophils is completely IL-5 dependent, 2) eosinophils have no tumoricidal activity, and 3) neutrophils are responsible, at least in part, for tumor suppression. PMID:9551990

  16. COMPUTATIONAL MODELING OF SOLID TUMOR GROWTH: THE AVASCULAR STAGE

    E-print Network

    Boyer, Edmond

    to proliferate without limitation leading to the formation of an initial tumor nodule. To proliferate, cells need, we use a multiscale model using PDEs to describe the evolution of the tumor cell densities. In our cells motion and tumor expansion. According to biology, cells grow against a basal membrane which

  17. Characterization of Nocturnal Ultradian Rhythms of Melatonin in Children with Growth Hormone-Dependent and Independent Growth Delay

    Microsoft Academic Search

    A. Munoz-Hoyos; R. JALDO; A. MOLINA-CARBALLO; G. ESCAMES; M. MACIAS; J. M. FERNANDEZ-GARCIA; R. J. REITER; D. ACUNA-CASTROVIEJO

    2001-01-01

    To assess the existence of a possible nocturnal ultradian rhythm of melatonin in children, we analyzed 28 pediatric patients (mean age, 9.08 6 2.2 yr) with GH-dependent and GH-independent growth delay. Plasma melatonin was measured by RIA in children sampled every 30 min between 2100 - 0900 h. Statistical analysis consisted of cluster analysis to examine the presence of peaks

  18. 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 anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a "lethal" aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia. PMID:21051947

  19. 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 NF?B, 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/NF?B 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. PMID:22918248

  20. Control of Tumor Growth in Animals by Infusion of an Angiogenesis Inhibitor

    NASA Astrophysics Data System (ADS)

    Langer, Robert; Conn, Howard; Vacanti, Joseph; Haudenschild, Christian; Folkman, Judah

    1980-07-01

    Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were <3% of those in control animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weighed <2.5% of implants in mice receiving Ringer's solution, Trasylol, or albumin. Histologic study of major organs and standard blood tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.

  1. Integrin ?v?6 sustains and promotes tumor invasive growth in colon cancer progression

    PubMed Central

    Yang, Guang-Yun; Guo, Sen; Dong, Cong-Ying; Wang, Xian-Qiang; Hu, Bing-Yang; Liu, Yang-Feng; Chen, Yong-Wei; Niu, Jun; Dong, Jia-Hong

    2015-01-01

    AIM: To detect the mechanism by which colon tumor escapes the growth constraints imposed on normal cells by cell crowding and dense pericellular matrices. METHODS: An immunohistochemical study of integrin ?v?6 and matrix metalloproteinase-9 (MMP-9) was performed on tissue microarrays of 200 spots, including 100 cases of colon tumors. RESULTS: High immunoreactivity for ?v?6 (73.7%; 28/38) and MMP-9 (76.5%; 52/68) was observed in invasive tumor portions. Furthermore, the effects of integrin ?v?6 on tumor invasive growth in nude mice were detected. Tumor invasive growth and high expression of both ?v?6 and MMP-9 were only seen in tumors resulting from WiDr cells expressing ?v?6 in the tumorigenicity assay. Flow cytometry was applied to analyze ?v?6 expression in colon cancer WiDr and SW480 cells. The effects of cell density on ?v?6 expression and MMP-9 secretion were also detected by Biotrak MMP-9 activity assay and gelatin zymography assay. High cell density evidently enhanced ?v?6 expression and promoted MMP-9 secretion compared with low density. CONCLUSION: Integrin ?v?6 sustains and promotes tumor invasive growth in tumor progression via a self-perpetuating mechanism. Integrin ???6-mediated MMP-9 secretion facilitates pericellular matrix degradation at high cell density, which provides the basis of invasive growth.

  2. Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.

    PubMed

    Wu, Xuesong; Schulte, Brian C; Zhou, Youwen; Haribhai, Dipica; Mackinnon, Alexander C; Plaza, Jose A; Williams, Calvin B; Hwang, Sam T

    2014-11-01

    Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL. PMID:24780929

  3. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling.

    PubMed

    Pai, Rama; Dunlap, Debra; Qing, Jing; Mohtashemi, Iman; Hotzel, Kathy; French, Dorothy M

    2008-07-01

    Fibroblast growth factors (FGF) play important roles in development, angiogenesis, and cancer. FGF19 uniquely binds to FGF receptor 4 (FGFR4). Our previous study has shown that FGF19 transgenic tumors have an activated Wnt-pathway phenotype. Wnt signaling is implicated in initiating or promoting FGF signaling in various cell types and organs. In this study, we examined whether FGF19 or inhibition of FGF19 affects the beta-catenin signaling pathway using human colon cancer cell lines (HCT116, Colo201). Our results show that FGF19 increases tyrosine phosphorylation of beta-catenin and causes loss of beta-catenin-E-cadherin binding. FGF19 increases p-GSK3beta and active beta-catenin levels and anti-FGF19 antibody (1A6) treatment abrogates this effect of FGF19. Anti-FGF19 antibody treatment increases S33/S37/T41 phosphorylation and ubiquitination of beta-catenin. Ion-trap mass spectrometric analysis confirmed that 1A6 increases phosphorylation of beta-catenin in the NH(2) terminus. Using HCT116-paired beta-catenin knockout cells, we show that FGF19 induces TCF/LEF reporter activity in parental (WT/Delta45) and in WT/--but not in mutant (-/Delta45) cells, and that inhibition of endogenous FGF19 reduces this reporter activity, indicating that wild-type beta-catenin is accessible for modulation. FGFR4 knockdown using inducible short hairpin RNA significantly reduces the colony-forming ability in vitro and tumor growth in vivo. Although cleaved caspase-3 immunoreactivity remains unchanged, the number of ki67-positive nuclei is reduced in FGFR4 knockdown tumor xenograft tissues. Consistent with the reduced beta-catenin activation, Taqman analyses show that FGF19/FGFR4 inhibition reduced beta-catenin target gene (cyclin D1, CD44, c-jun, Cox-2, UPAR) expression. These findings highlight that FGF19/FGFR4 cross-talk with beta-catenin and that pathway intervention reduces tumor growth. PMID:18593907

  4. Protection of mice against tumor growth by immunization with an oncogene-encoded growth factor.

    PubMed Central

    Talarico, D; Ittmann, M; Balsari, A; Delli-Bovi, P; Basch, R S; Basilico, C

    1990-01-01

    The K-fgf/hst oncogene encodes a growth factor of the fibroblast growth factor (FGF) family that is secreted and transforms cells through a mechanism of autocrine cell proliferation. K-fgf-transformed cells are highly tumorigenic in immunocompetent allogeneic and syngeneic animals. BALB/c mice were immunized with a bacterial fusion protein consisting of a portion of the MS2 polymerase and of the human K-FGF precursor lacking only the first 4 amino acids or with a recombinant protein corresponding to the mature, secreted form of K-FGF (176 amino acids). They were then challenged with syngeneic K-fgf- or H-ras-transformed cells. Vaccinated animals exhibited a significant degree of protection against tumor induction, which was specific for K-fgf-transformed cells and correlated with the ability of the immunized mice to produce high titers of anti-K-FGF antibodies. Thus immunization with a single oncogene product can protect animals against tumor cells expressing this oncogene. Images PMID:2190216

  5. Methionine enkephalin (MENK) inhibits tumor growth through regulating CD4+Foxp3+ regulatory T cells (Tregs) in mice.

    PubMed

    Li, Xuan; Meng, Yiming; Plotnikoff, Nicolas P; Youkilis, Gene; Griffin, Noreen; Wang, Enhua; Lu, Changlong; Shan, Fengping

    2015-01-01

    Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-? (TGF-?) mediated conversion from naïve CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-?induction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy. PMID:25701137

  6. 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. PMID:25976379

  7. Preclinical Development of a Novel Class of CXCR4 Antagonist Impairing Solid Tumors Growth and Metastases

    PubMed Central

    Portella, Luigi; Vitale, Rosamaria; De Luca, Stefania; D’Alterio, Crescenzo; Ieranò, Caterina; Napolitano, Maria; Riccio, Anna; Polimeno, Maria Neve; Monfregola, Luca; Barbieri, Antonio; Luciano, Antonio; Ciarmiello, Andrea; Arra, Claudio; Castello, Giuseppe; Amodeo, Pietro; Scala, Stefania

    2013-01-01

    The CXCR4/CXCL12 axis plays a role in cancer metastases, stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in stem cell mobilization prior to autologous transplantation in hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer therapy are not available. To develop new CXCR4 antagonists a rational, ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the vMIP-II inhibitory chemokine formed the core of nineteen cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and calcium efflux. Peptides R, S and I were chosen for evaluation in in vivo models of lung metastases (B16-CXCR4 and KTM2 murine osteosarcoma cells) and growth of a renal cells xenograft. Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced calcium efflux. The four peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human melanoma cells. Intraperitoneal treatment with peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung metastases in C57/BL mice. KTM2 osteosarcoma lung metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three peptides significantly inhibited subcutaneous growth of SN12C-EGFP renal cancer cells. A novel class of CXCR4 inhibitory peptides was discovered. Three peptides, R, I and S inhibited lung metastases and primary tumor growth and will be evaluated as anticancer agents. PMID:24058588

  8. Treatment of large low-grade oligodendroglial tumors with upfront procarbazine, lomustine, and vincristine chemotherapy with long follow-up: a retrospective cohort study with growth kinetics.

    PubMed

    Taal, Walter; van der Rijt, Carin C D; Dinjens, Winand N M; Sillevis Smitt, Peter A E; Wertenbroek, Agnes A A C M; Bromberg, Jacoline E C; van Heuvel, Irene; Kros, Johan M; van den Bent, Martin J

    2015-01-01

    We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, CCNU and vincristine (PCV) in order to delay radiotherapy. Patients were treated with PCV for a maximum of 6 cycles. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. Thirty-two patients were treated between 1998 and 2006, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years (range 0.5-13 years). The median overall survival (mOS) was 120 months and the median progression-free survival (mPFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months, but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (mOS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (mPFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34 % and the radiotherapy in these patients was postponed for a median period of more than 6 years. This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss. PMID:25344884

  9. Noninvasive photoacoustic imaging of the developing vasculature during early tumor growth

    NASA Astrophysics Data System (ADS)

    Lao, Yeqi; Xing, Da; Yang, Sihua; Xiang, Liangzhong

    2008-08-01

    In this study, we monitor the progress of vasculature in early tumor growth using photoacoustic imaging over a 20 day period after subcutaneous inoculation of breast cancer tumor cells in a mouse. With 532 nm laser pulses employed as an irradiation source, the photoacoustic images were obtained through the photoacoustic signals received by a hydrophone in orthogonal mode. The morphological characteristics of vasculature in tumor region are clearly resolved in the photoacoustic images, and the change in structure as well as the increase in density can be identified. Moreover, the average photoacoustic signal strength of vasculature in tumor region, which is highly correlated with the total hemoglobin concentration of blood, is enhanced during early tumor growth. These results indicate the feasibility of detecting early stage tumor and monitoring the progress of anti-angiogenic therapy by photoacoustic imaging.

  10. 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.

  11. On a Nonlinear Model for Tumor Growth: Global in Time Weak Solutions

    NASA Astrophysics Data System (ADS)

    Donatelli, Donatella; Trivisa, Konstantina

    2014-07-01

    We investigate the dynamics of a class of tumor growth models known as mixed models. The key characteristic of these type of tumor growth models is that the different populations of cells are continuously present everywhere in the tumor at all times. In this work we focus on the evolution of tumor growth in the presence of proliferating, quiescent and dead cells as well as a nutrient. The system is given by a multi-phase flow model and the tumor is described as a growing continuum ? with boundary ?? both of which evolve in time. Global-in-time weak solutions are obtained using an approach based on penalization of the boundary behavior, diffusion and viscosity in the weak formulation.

  12. Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth

    PubMed Central

    Li, Xin; Ling, Wen; Khan, Sharmin; Yaccoby, Shmuel

    2012-01-01

    The cytotherapeutic potential of mesenchymal stem cells (MSCs) has been evaluated in various disorders including those involving inflammation, autoimmunity, bone regeneration, and cancer. Multiple myeloma (MM) is a systemic malignancy associated with induction of osteolytic lesions that often are not repaired even after prolonged remission. The aims of the study were to evaluate the effects of intrabone and systemic injections of mesenchymal stem cells (MSCs) on MM bone disease, tumor growth, and tumor regrowth in the SCID-rab model and to shed light on the exact localization of systemically injected MSCs. Intrabone injection of MSCs, but not hematopoietic stem cells, into myelomatous bones prevented MM-induced bone disease, promoted bone formation, and inhibited MM growth. After remission was induced with melphalan treatment, intrabone-injected MSCs promoted bone formation and delayed myeloma cell regrowth in bone. Most intrabone or systemically injected MSCs were undetected 2–4 weeks after injection. The bone-building effects of MSCs were mediated through activation of endogenous osteoblasts and suppression of osteoclast activity. While a single intravenous injection of MSCs had no effect on MM, sequential weekly intravenous injections of MSCs prevented MM-induced bone disease but had no effect on tumor burden. MSCs expressed high levels of anti-inflammatory (e.g. HMOX1), and bone remodeling (e.g. Decorin, CYR61) mediators. In vitro, MSCs promoted osteoblast maturation and suppressed osteoclast formation, and these effects were partially prevented by blocking decorin. A subset of intravenously or intracardially injected MSCs trafficked to myelomatous bone in SCID-rab mice. While the majority of intravenously injected MSCs were trapped in lungs, intracardially injected MSCs were mainly localized in draining mesenteric lymph nodes. This study shows that exogenous MSCs act as bystander cells to inhibit MM-induced bone disease and tumor growth and that systemically injected MSCs are attracted to bone by myeloma cells or conditions induced by MM and inhibit bone disease. PMID:22460389

  13. The effect of interstitial pressure on tumor growth: coupling with the blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; McDougall, Steven R.; Chaplain, Mark A.J.; Cristini, Vittorio; Lowengrub, John

    2013-01-01

    The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. PMID:23220211

  14. The effect of interstitial pressure on tumor growth: coupling with the blood and lymphatic vascular systems.

    PubMed

    Wu, Min; Frieboes, Hermann B; McDougall, Steven R; Chaplain, Mark A J; Cristini, Vittorio; Lowengrub, John

    2013-03-01

    The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. PMID:23220211

  15. Mechanism of delayed frost growth on superhydrophobic surfaces with jumping condensates: more than interdrop freezing.

    PubMed

    Hao, Quanyong; Pang, Yichuan; Zhao, Ying; Zhang, Jing; Feng, Jie; Yao, Shuhuai

    2014-12-30

    Delayed frost growth on superhydrophobic surfaces (SHSs) with jumping condensates has been found by many researchers recently. However, the mechanism of this phenomenon has not been elucidated clearly. In this study, copper SHSs with or without jumping condensates were selected as the substrates for observing condensation icing at a relative humidity (RH) of 60%. The results showed that only SHS with jumping condensates showed delayed condensation icing. Moreover, when such SHSs were placed upward and the surface temperature was held at -10 °C, some discrete frozen drops first appeared on the SHSs. The following icing mainly occurred on these discrete global crystals and then expanded around them until covering the entire surface. Little macroscopic interdrop freezing phenomenon was found. The growth of the frost front is mainly dominated by jumping freezing (the condensed droplets jumped onto the ice crystals and were frozen) or direct vapor-ice deposition. Using microscopy, we found interdrop freezing occurred, in addition to the two mechanisms mentioned above. By placing the SHS downward at -10 °C and intentionally introducing or eliminating tiny dusts, we confirmed that there were no superhydrophobic defects on our SHSs. The discrete frozen drops first appearing on the SHSs were triggered by tiny dusts falling on the surface before or during condensation icing. The key approach in delaying or resisting frost growth on SHSs with jumping condensates is to retard initial ice crystal formation, e.g., eliminating the edge effect and keeping the SHSs clean. PMID:25466489

  16. Bone Marrow Derived Mesenchymal Stem\\/Stromal Cells and Tumor Growth

    Microsoft Academic Search

    Pravin J. Mishra; Debabrata Banerjee

    \\u000a Carcinoma associated fibroblasts (CAFs) play an important role in the growth of epithelial solid tumors. The origin of these\\u000a tumor or CAFs has not been conclusively established. There is experimental evidence to suggest that part of the tumor or CAFs\\u000a may arise from bone marrow derived mesenchymal stromal\\/stem cells or MSCs. It is well known that bone marrow derived MSCs

  17. Substance-P-Mediated Immunomodulation of Tumor Growth in a Murine Model

    Microsoft Academic Search

    Jill M. Manske; Summer E. Hanson

    2005-01-01

    Background\\/Objective: Substance P (SP) has been reported to have immunoregulatory properties including effects on many of the mediators involved in anti-tumor immunity. In this study, we investigated the effect of SP on tumor development in a murine model of melanoma. In addition, we examined the role of natural killer (NK) and T cells in SP-mediated modulation of tumor growth. Materials

  18. Co-implanting orthotopic tissue creates stroma microenvironment enhancing growth and angiogenesis of multiple tumors.

    PubMed

    Borgstrom, Per; Oh, Phil; Czarny, Malgorzata; Racine, Brian; Schnitzer, Jan E

    2013-01-01

    Tumor models are needed to study cancer. Noninvasive imaging of tumors under native conditions in vivo is critical but challenging. Intravital microscopy (IVM) of subcutaneous tumors provides dynamic, continuous, long-term imaging at high resolution. Although popular, subcutaneous tumor models are often criticized for being ectopic and lacking orthotopic tissue microenvironments critical for proper development. Similar IVM of orthotopic and especially spontaneous tumors is seldom possible. Here, we generate and characterize tumor models in mice for breast, lung, prostate and ovarian cancer by co-engrafting tumor spheroids with orthotopic tissue in dorsal skin window chambers for IVM. We use tumor cells and tissue, both genetically engineered to express distinct fluorescent proteins, in order to distinguish neoplastic cells from engrafted tissue. IVM of this new, two-colored model reveals classic tumor morphology with red tumor cell nests surrounded by green stromal elements. The co-implanted tissue forms the supportive stroma and vasculature of these tumors. Tumor growth and angiogenesis are more robust when tumor cells are co-implanted with orthotopic tissue versus other tissues, or in the skin alone. The orthotopic tissue promotes tumor cell mitosis over apoptosis. With time, tumor cells can adapt to new environments and ultimately even grow better in the non-orthotopic tissue over the original orthotopic tissue. These models offer a significant advance by recreating an orthotopic microenvironment in an ectopic location that is still easy to image by IVM. These "ectopic-orthotopic" models provide an exceptional way to study tumor and stroma cells in cancer, and directly show the critical importance of microenvironment in the development of multiple tumors. PMID:24715954

  19. Co-implanting orthotopic tissue creates stroma microenvironment enhancing growth and angiogenesis of multiple tumors

    PubMed Central

    Schnitzer, Jan E

    2013-01-01

    Tumor models are needed to study cancer. Noninvasive imaging of tumors under native conditions in vivo is critical but challenging. Intravital microscopy (IVM) of subcutaneous tumors provides dynamic, continuous, long-term imaging at high resolution. Although popular, subcutaneous tumor models are often criticized for being ectopic and lacking orthotopic tissue microenvironments critical for proper development. Similar IVM of orthotopic and especially spontaneous tumors is seldom possible. Here, we generate and characterize tumor models in mice for breast, lung, prostate and ovarian cancer by co-engrafting tumor spheroids with orthotopic tissue in dorsal skin window chambers for IVM. We use tumor cells and tissue, both genetically engineered to express distinct fluorescent proteins, in order to distinguish neoplastic cells from engrafted tissue. IVM of this new, two-colored model reveals classic tumor morphology with red tumor cell nests surrounded by green stromal elements. The co-implanted tissue forms the supportive stroma and vasculature of these tumors. Tumor growth and angiogenesis are more robust when tumor cells are co-implanted with orthotopic tissue versus other tissues, or in the skin alone. The orthotopic tissue promotes tumor cell mitosis over apoptosis. With time, tumor cells can adapt to new environments and ultimately even grow better in the non-orthotopic tissue over the original orthotopic tissue. These models offer a significant advance by recreating an orthotopic microenvironment in an ectopic location that is still easy to image by IVM. These “ectopic-orthotopic” models provide an exceptional way to study tumor and stroma cells in cancer, and directly show the critical importance of microenvironment in the development of multiple tumors. PMID:24715954

  20. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

    E-print Network

    Martin, John D.

    The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress ...

  1. Combination of Clinical Factors Predictive of Growth of Small Choroidal Melanocytic Tumors

    Microsoft Academic Search

    Carol L. Shields; Jacqueline Cater; Jerry A. Shields; Arun D. Singh; Maria Carmen; M. Santos; Cynthia Carvalho

    2000-01-01

    Objective: To better define the effect of individual risk factors and combinations thereof on the growth of small choroidal melanocytic tumors. Design: Retrospective analysis. Setting: Clinical practice of ocular oncology. Patients: The study included 1287 patients with small suspicious choroidal melanocytic tumors, measuring 3 mm or less in thickness, managed with observation. Results: On multivariate analysis, the clinical risk factors

  2. Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose

    E-print Network

    Paris-Sud XI, Université de

    Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose to a homogeneous dose - the standard in current clinical practice. We discuss the use of the Fisher for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model

  3. 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

  4. 2'-hydroxyflavanone inhibits prostate tumor growth through inactivation of AKT/STAT3 signaling and induction of cell apoptosis.

    PubMed

    Wu, Kaijie; Ning, Zhongyun; Zhou, Jiancheng; Wang, Bin; Fan, Jinhai; Zhu, Jianning; Gao, Yang; Wang, Xinyang; Hsieh, Jer-Tsong; He, Dalin

    2014-07-01

    Although there have been advances in therapeutic regimes for metastatic castration-resistant prostate cancer (CRPC), these recent developments have not led to improved cure rates. Thus, more novel agents to prolong patient survival are desired. 2'-Hydroxyflavanone (2HF), a nontoxic natural flavonoid, has been shown to exhibit pleiotropic anticancer effects in many cancer types, including prostate cancer (PCa). However, the therapeutic effects of 2HF on tumor growth and its potential mechanisms in CRPC have not been completely elucidated. In the present study, utilizing three different metastatic and androgen-independent PCa cell models (PC-3, DU145 and C4-2), we found that 2HF treatment not only resulted in inhibition of cell proliferation and colony formation in vitro, but also delayed subcutaneous tumor growth in vivo. Mechanistically, besides its known inhibitory effects on aldo?keto reductase activity and de novo androgen synthesis, 2HF also markedly suppressed AKT phosphorylation, signal transducer and activator of transcription-3 (STAT3) phosphorylation and transactivation subsequently regulating the expression of members of the BCL-2 family (i.e., Mcl-1, Bcl-2 and Bax) and modulating caspase-mediated cell apoptosis. Overall, this study revealed a novel mechanism for 2HF targeting metastatic CRPC, in which inactivation of AKT/STAT3 signaling led to cell apoptosis and growth inhibition. PMID:24859932

  5. A multinomial model of tumor growth treated by radiotherapy

    E-print Network

    Paris-Sud XI, Université de

    of the radioactive treatments on cancer and healthy cells are characterized by two probabilities: (i) the tumor during the radiotherapy k discrete time m number of targets in the cancer cells n0 initial number of cancer cells in the tumor p survival probability of a target after treatment pc survival probability

  6. Conditions supporting repair of potentially lethal damage cause a significant reduction of ultraviolet light-induced division delay in synchronized and plateau-phase Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.; Nusse, M.

    1982-09-01

    Repair of potentially lethal damage (PLD) induced by uv light in synchronized and in plateau-phase cultures of Ehrlich ascites tumor cells was studied by measuring cell survival. In particlar the influence of conditions supporting repair of PLD on growth kinetics was investigated. In synchronized G/sub 1/, S, or G/sub 2/ + M cells as well as in plateau-phase cells, uv light induced, almost exclusively, delay in the next S phase. A significant decrease of this delay was observed when the cells were incubated for 24 hr in balanced salt solution. Repair of PLD after uv irradiation was found to occur in plateau-phase cells and in cells in different phases of the cell cycle provided that after irradiation these were kept under conditions inhibiting cell multiplication (incubation in balanced salt solution or in conditioned medium). The repair time constant t/sub 50/ was significantly higher than those found for X irradiation (5-10 hr compared to 2 hr), and repair was not significantly inhibited by either 20 ..mu..g/ml cycloheximide or 2 mM caffeine in 24 hr.

  7. The Functionalized Human Serine Protease Granzyme B/VEGF121 Targets Tumor Vasculature and Ablates Tumor Growth

    PubMed Central

    Mohamedali, Khalid A.; Cao, Yu; Cheung, Lawrence H.; Hittelman, Walter N.; Rosenblum, Michael G.

    2014-01-01

    The serine protease granzyme B (GrB) induces apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. Vascular endothelial growth factor 121 (VEGF121) binds to both VEGFR-1 and VEGFR-2 receptors. We engineered a unique GrB/VEGF121 fusion protein and characterized its properties in vitro and in vivo. Endothelial and tumor cells lines demonstrated varying levels of sensitivity to GrB/VEGF121 that correlated closely to total VEGFR-2 expression. GrB/VEGF121 localized efficiently into VEGFR-2 expressing cells while the internalization into VEGFR-1 expressing cells was significantly reduced. Treatment of VEGFR-2+ cells caused mitochondrial depolarization in 48% of cells by 48 h. Exposure to GrB/VEGF121 induced apoptosis in VEGFR-2+, but not in VEGFR-1+, cells and rapid caspase activation was observed that could not be inhibited by treatment with a pan-caspase inhibitor. In vivo, GrB/VEGF121 localized in perivascular tumor areas adjacent to microvessels and in other areas in the tumor less well vascularized, while free GrB did not specifically localize to tumor tissue. Administration (i.v.) of GrB/VEGF121 to mice at doses up to 40 mg/kg showed no toxicity. Treatment of mice bearing established PC-3 tumor xenografts with GrB/VEGF121 showed significant antitumor effect vs. treatment with GrB or saline. Treatment with GrB/VEGF121 at 27 mg/kg resulted in the regression of 4 of 5 tumors in this group. Tumors showed a two-fold lower Ki-67 labeling index compared to controls. Our results demonstrate that targeted delivery of granzyme B to tumor vascular endothelial cells or to tumor cells activates apoptotic cascades and this completely human construct may have significant therapeutic potential. PMID:23858102

  8. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    PubMed Central

    Lai, Wen-Lin; Harn, Horng-jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man

    2013-01-01

    Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer. PMID:24319475

  9. Inhibition of Tumor Angiogenesis and Growth by Nanoparticle-Mediated p53 Gene Therapy in Mice

    PubMed Central

    Prabha, Swayam; Sharma, Blanka; Labhasetwar, Vinod

    2012-01-01

    Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53NPs. We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs. controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this is accomplished is disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition. PMID:22595792

  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

    2015-06-01

    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. PMID:26024008

  11. Celecoxib prevents tumor growth in an animal model by a COX2 independent mechanism

    Microsoft Academic Search

    Amanda Leite Bastos-Pereira; Daiana Lugarini; Adriana de Oliveira-Christoff; Thiago Vinicius Ávila; Simone Teixeira; Amanda do Rocio Andrade Pires; Sílvia Maria Suter Correia Cadena; Lucélia Donatti; Helena Cristina da Silva de Assis; Alexandra Acco

    2010-01-01

    Purpose  Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to reduce cell growth in several tumors. Among these possible\\u000a antineoplastic drugs are cyclooxygenase-2 (COX-2)-selective drugs, such as celecoxib, in which antitumoral mechanisms were\\u000a evaluated in rats bearing Walker-256 (W256) tumor.\\u000a \\u000a \\u000a \\u000a Methods  W256 carcinosarcoma cells were inoculated subcutaneously (107 cells\\/rat) in rats submitted to treatment with celecoxib (25 mg kg?1) or vehicle for 14 days. Tumor growth,

  12. Tumor Microenvironments Correspond to Unique Metabolic Signatures that Affect Tumor Growth | Physical Sciences in Oncology

    Cancer.gov

    Using a genetic construct that produces a green glow as a tumor responds to microenvironmental stresses, a team of investigators at Stanford University have shown that the way in which a tumor responds to stress can predict how it will grow in the body. This work, led by Albert Koong, M.D., was published in the journal Cancer Research.

  13. Cyanidin 3Glucoside and Peonidin 3Glucoside Inhibit Tumor Cell Growth and Induce Apoptosis In Vitro and Suppress Tumor Growth In Vivo

    Microsoft Academic Search

    Pei-Ni Chen; Shu-Chen Chu; Hui-Ling Chiou; Chui-Liang Chiang; Shun-Fa Yang; Yih-Shou Hsieh

    2005-01-01

    Dietary polyphenols, including anthocyanins, are suggested to be involved in the protective effects of fruits and vegetables against cancer. However, anticancer effects of peonidin 3-glucoside have not been clearly demonstrated, with only limited studies being available concerning the in- hibitory effect of cyanidin 3-glucoside for tumor cell growth. Therefore, in this study, we have isolated and identified the two bioactive

  14. Regulation of Tumor Growth and Metastasis: The Role of Tumor Microenvironment

    PubMed Central

    Goubran, Hadi A; Kotb, Rami R; Stakiw, Julie; Emara, Mohamed E; Burnouf, Thierry

    2014-01-01

    The presence of abnormal cells with malignant potential or neoplastic characteristics is a relatively common phenomenon. The interaction of these abnormal cells with their microenvironment is essential for tumor development, protection from the body’s immune or defence mechanisms, later progression and the development of life-threatening or metastatic disease. The tumor microenvironment is a collective term that includes the tumor’s surrounding and supportive stroma, the different effectors of the immune system, blood platelets, hormones and other humoral factors. A better understanding of the interplay between the tumor cells and its microenvironment can provide efficient tools for cancer management, as well as better prevention, screening and risk assessment protocols. PMID:24926201

  15. 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. PMID:22174618

  16. 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

  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. PMID:23221082

  18. AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo

    PubMed Central

    Faubert, Brandon; Boily, Gino; Izreig, Said; Griss, Takla; Samborska, Bozena; Dong, Zhifeng; Dupuy, Fanny; Chambers, Christopher; Fuerth, Benjamin J.; Viollet, Benoit; Mamer, Orval A.; Avizonis, Daina; DeBerardinis, Ralph J.; Siegel, Peter M.; Jones, Russell G.

    2012-01-01

    Summary AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells, and suppresses tumor growth in vivo. Genetic ablation of the ?1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPK? in both transformed and non-transformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1? (HIF-1?), as silencing HIF-1? reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPK? signaling. Together our findings suggest that AMPK activity opposes tumor development, and its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation. PMID:23274086

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

    NASA Astrophysics Data System (ADS)

    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.

    2003-11-01

    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. Placenta Growth Factor Overexpression Inhibits Tumor Growth, Angiogenesis, and Metastasis by Depleting Vascular Endothelial Growth Factor Homodimers in Orthotopic Mouse Models

    Microsoft Academic Search

    Lei Xu; David M. Cochran; Ricky T. Tong; Frank Winkler; Satoshi Kashiwagi; Rakesh K. Jain; Dai Fukumura

    The role of placenta growth factor (PlGF) in pathologic angiogenesis is controversial. The effects of PlGF on growth, angiogenesis, and metastasis from orthotopic tumors are not known. To this end, we stably transfected three human cancer cell lines (A549 lung, HCT116 colon, and U87-MG glioblasto- ma) with human plgf-2 full-length cDNA. Overexpression of PlGF did not affect tumor cell proliferation

  1. Primitive neuroectodermal tumor presenting as a delayed sequela to cranial irradiation and intrathecal methotrexate

    SciTech Connect

    Barasch, E.S.; Altieri, D.; Decker, R.E.; Ahmed, S.; Lin, J.

    1988-11-01

    A patient developed a primitive neuroectodermal tumor (PNET) many years after therapeutic cerebral radiation and methotrexate treatment for leukemia. The differential radiologic and histologic diagnoses, as well as the possible co-oncogenic effects of radiation and methotrexate, are evaluated.

  2. Endogenous T Cell Responses to Antigens Expressed in Lung Adenocarcinomas Delay Malignant Tumor Progression

    E-print Network

    DuPage, Michel

    Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse ...

  3. Antiangiogenic and proapoptotic activities of allyl isothiocyanate inhibit ascites tumor growth in vivo.

    PubMed

    Kumar, Akhilesh; D'Souza, Saritha S; Tickoo, Sanjay; Salimath, Bharathi P; Singh, H B

    2009-03-01

    The authors investigate the antiangiogenic and proapoptotic effects of mustard essential oil containing allyl isothiocyanate (AITC) and explore its mechanism of action on Ehrlich ascites tumor (EAT) cells. Swiss albino mice transplanted with EAT cells were used to study the effect of AITC. AITC was effective at a concentration of 10 mum as demonstrated by the inhibition of proliferation of EAT cells when compared with the normal HEK293 cells. It significantly reduced ascites secretion and tumor cell proliferation by about 80% and inhibited vascular endothelial growth factor expression in tumor-bearing mice in vivo. It also reduced vessel sprouting and exhibited potent antiangiogenic activity in the chorioallantoic membrane and cornea of the rat. AITC arrested the growth of EAT cells by inducing apoptosis and effectively arrested cell cycle progression at the G1 phase. The results clearly suggest that AITC inhibits tumor growth by both antiangiogenic and proapoptotic mechanisms. PMID:19223371

  4. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo.

    PubMed

    Yang, Lihua; Jackson, Erin; Woerner, B Mark; Perry, Arie; Piwnica-Worms, David; Rubin, Joshua B

    2007-01-15

    The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted. PMID:17234775

  5. 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-1? and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1? 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-1? 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-1?, PGC-1?, 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. PMID:23070475

  6. Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromal cells

    Microsoft Academic Search

    Chia-Ling Hsieh; Thomas A Gardner; Li Miao; Gary Balian; Leland W K Chung; Leland WK Chung

    2004-01-01

    Stromal–epithelial interaction contributes to local prostate tumor growth, androgen-independent progression and distant metastasis. We have established in vitro coculture and in vivo chimeric tumor models to evaluate the roles of stromal cells isolated from either osteosarcoma or normal bone, a site where prostate cancer cells frequently metastasize, in contributing to the growth and survival of human prostate cancer cells. We

  7. 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 crucial model input. We conclude that the tumor growth model provides a method to account for anisotropic growth patterns of glioma, and may therefore provide a tool to make target delineation more objective and automated.

  8. Stochastic Resonance in a Bacterium Growth System with Time Delay and Colored Noise

    NASA Astrophysics Data System (ADS)

    Li, Shenghong; Wu, Jiancheng

    2015-04-01

    The phenomenon of stochastic resonance in a bacterium growth system that is with two different kinds of time delays and is driven by colored noises is investigated. Based on the extended unified colored noise theory and the method of the probability density approximation, the Fokker-Planck equation and the stationary probability density function are derived. Then via the theory of adiabatic limit, the analytical expression of the signal-to-noise ratio (SNR) is obtained. The different effects of the time delays existed in the nonlinear system and the noise correlation times on the stationary probability density and the signal-to-noise rate are discussed respectively. Finally, numerical simulations are offered and are consistent with approximate analytical results.

  9. 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 proliferation, as well as in the inhibition of angiogenesis. PMID:24416386

  10. 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 (TNF?, IL1?) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects. PMID:25893810

  11. The role of bone-marrow-derived cells in tumor growth, metastasis initiation and progression.

    PubMed

    Gao, Dingcheng; Mittal, Vivek

    2009-08-01

    Emerging evidence from murine models suggests that tumor-specific endocrine factors systemically stimulate the quiescent bone marrow (BM) compartment, resulting in the expansion, mobilization and recruitment of BM progenitor cells. Discrete subsets of tumor-instigated BM-derived progenitor cells support tumor progression and metastasis by regulating angiogenesis, inflammation and immune suppression. Notably, clinical studies have begun to reveal that increased BM recruitment in tumors is associated with poor prognosis. Thus, the BM-derived tumor microenvironment is an attractive therapeutic target, and drugs targeting the components of the microenvironment are currently in clinical trials. Here, we focus on recent advances and emerging concepts regarding the intriguing role of BM-derived cells in tumor growth, metastasis initiation and progression, and we discuss future directions in the context of novel diagnostic and therapeutic opportunities. PMID:19665928

  12. Pazopanib, a Receptor Tyrosine Kinase Inhibitor, Suppresses Tumor Growth through Angiogenesis in Dedifferentiated Liposarcoma Xenograft Models123

    PubMed Central

    Li, Haifu; Wozniak, Agnieszka; Sciot, Raf; Cornillie, Jasmien; Wellens, Jasmien; Van Looy, Thomas; Vanleeuw, Ulla; Stas, Marguerite; Hompes, Daphne; Debiec-Rychter, Maria; Schöffski, Patrick

    2014-01-01

    INTRODUCTION: The rarity of dedifferentiated liposarcoma (DDLPS) and the lack of experimental DDLPS models limit the development of novel therapeutic strategies. Pazopanib (PAZ) is a tyrosine kinase inhibitor that is approved for the treatment of non-adipocytic advanced soft tissue sarcoma. The activity of this agent has not yet been properly explored in preclinical liposarcoma models nor in a randomized phase ? clinical trial in this entity. The aim of the present study was to investigate whether PAZ had antitumor activity in DDLPS models in vivo. MATERIAL AND METHODS: We established two patient-derived DDLPS xenograft models (UZLX-STS3 and UZLX-STS5) through implantation of tumor material from sarcoma patients in athymic nude NMRI mice. An animal model of the SW872 liposarcoma cell line was also used. To investigate the efficacy of PAZ in vivo, mice bearing tumors were treated for 2 weeks with sterile water, doxorubicin (1.2 mg/kg, intraperitoneally, twice per week), PAZ [40 mg/kg, orally (p.o.), twice per day], or PAZ plus doxorubicin (same schedules as for single treatments). RESULTS: Patient-derived xenografts retained the histologic and molecular features of DDLPS. PAZ significantly delayed tumor growth by decreasing proliferation and inhibited angiogenesis in all models tested. Combining the angiogenesis inhibitor with an anthracycline did not show superior efficacy. CONCLUSION: These results suggest that PAZ has potential antitumor activity in DDLPS primarily through antiangiogenic effects and therefore should be explored in clinical trials. PMID:25500074

  13. Targeted inhibition of histone deacetylases and hedgehog signaling suppress tumor growth and homologous recombination in aerodigestive cancers

    PubMed Central

    Chun, Stephen G; Park, Hyunsil; Pandita, Raj K; Horikoshi, Nobuo; Pandita, Tej K; Schwartz, David L; Yordy, John S

    2015-01-01

    Standard combined modality therapies for aerodigestive tract malignancies have suboptimal outcomes, and targeting cancer-specific molecular pathways in combination with radiation could improve the therapeutic ratio. Dysregulation of epigenetic modulators such as histone deacetylases (HDACs), and developmental morphogens such as the hedgehog (HH) pathway have been implicated in aerodigestive tumor progression and metastasis. We hypothesized that simultaneous targeting of HDACs and the HH-pathway mediator Smoothened (Smo) represents an opportunity to overcome therapeutic resistance in these cancers. We evaluated the effects of the HDAC inhibitor SAHA and Smo inhibitor GDC-0449 with radiation in multiple aerodigestive cancer cell lines. Isobologram analyses showed that SAHA and GDC-0449 synergistically suppressed cancer cell proliferation in vitro. SAHA and GDC-0449 cooperatively enhanced G0/G1 cell cycle arrest which was associated with up-regulation of p21waf. GDC-0449 prevented SAHA-induced up-regulation of Gli-1 and Gli-2. Both Smo and Ptc-1 expression was cooperatively suppressed by SAHA and GDC-0449. The combination of SAHA and GDC-0449 induced radiation sensitization with 2 Gy as determined by colony formation assays and cytogenetic analyses, which correlated with higher residual ?-H2AX and 53BP1 foci. In mouse tumor xenografts of the SqCC/Y1 cell line, SAHA and GDC-0449 delayed tumor growth longer and prolonged survival more than either agent alone. In summary, we have identified synergistic effect of HDAC and HH signaling for radiosensitization to improve therapeutic outcomes for aerodigestive malignancies.

  14. The effect of partial hepatectomy on tumor growth in rats: in vivo and in vitro studies

    Microsoft Academic Search

    Koert P. De Jong; Harold E. Lont; Amelie M. Bijma; Mark A. M. Brouwers; Elisabeth G. E. De Vries; Marco L. Van Veen; Richard L. Marquet; Maarten J. H. Slooff; Onno T. Terpstra

    1995-01-01

    Residual tumor in the remnant liver after partial hepatectomy (PH) for colorectal liver metastases is a serious clinical problem. This fact is reflected by the high number of recurrences after potentially curative liver resections. Liver regeneration, it appears, might influence the growth of remaining micrometastases in the liver. Using rats, we demonstrated enhancement of growth of a syngeneic colon carcinoma

  15. Receptor tyrosine kinase inhibition suppresses growth of pediatric renal tumor cells in vitro

    Microsoft Academic Search

    Shalizeh Naraghi; Sami Khoshyomn; Joseph A DeMattia; Dennis W Vane

    2000-01-01

    Purpose: Children who undergo standard therapy for renal tumors are at an increased risk for treatment sequelae such as congestive heart failure, abnormal trunk development, and secondary malignancies. Therefore, research on the use of novel chemotherapeutic agents with fewer side effects is justified. Recent experimental evidence suggests that growth factor receptors such as epidermal growth factor receptor (EGFR) and platelet-derived

  16. Inhibition of Wilms' tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA

    Microsoft Academic Search

    M Y Çeliker; M Wang; E Atsidaftos; X Liu; Y E Liu; Y Jiang; E Valderrama; I D Goldberg; Y E Shi

    2001-01-01

    Extracellular matrix (ECM) degrading matrix metalloproteinases (MMPs) lead to ECM turnover, a key event in cancer growth and progression. The tissue inhibitors of matrix metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use for cancer gene therapy. Here we report that systemic administration of naked TIMP-4 DNA significantly inhibited Wilms' tumor growth in nude mice. TIMP-4, whose expression

  17. Dopamine receptor antagonist thioridazine inhibits tumor growth in a murine breast cancer model.

    PubMed

    Yin, Tao; He, Sisi; Shen, Guobo; Ye, Tinghong; Guo, Fuchun; Wang, Yongsheng

    2015-09-01

    Neuropsychological factors have been shown to influence tumor progression and therapeutic response. The present study investigated the effect of the dopamine receptor antagonist thioridazine on murine breast cancer. The anti?tumor efficacy of thioridazine was assessed using a murine breast cancer model. Cell apoptosis and proliferation were analyzed in vitro using flow cytometry (FCM) and the MTT assay, respectively. Western blot analysis was performed to assess Akt, phosphorylated (p)?Akt, signal transducer and activator of transcription (STAT) 3, p?STAT3 and p?p65 in tumor cells following treatment with thioridazine. The Ki67 index and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)?positive apoptotic cells were assessed in the tumor sections. Thioridazine was found to reduce tumor growth, inhibit tumor cell proliferation and induce apoptosis in a dose? and time?dependent manner in vitro. Thioridazine was also found to markedly inhibit tumor proliferation and induce tumor cell apoptosis in vivo as shown by the lower Ki67 index and increase in TUNEL?positive cells. In addition, thioridazine was observed to inhibit the activation of the canonical nuclear factor ??light?chain?enhancer of activated B cells pathway and exert anti?tumor effects by remodeling the tumor stroma, as well as inhibit angiogenesis in the tumor microenvironment. In conclusion, thioridazine was found to significantly inhibit breast tumor growth and the potential for thioridazine to be used in cancer therapy may be re?evaluated and investigated in clinical settings. PMID:26095429

  18. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis

    PubMed Central

    Lee, Sang Hun; Jeong, Dongjun; Han, Yong-Seok

    2015-01-01

    The shaping of new blood vessels is a significant event in cancer growth and metastasis. Therefore, the molecular system of cancer angiogenesis has garnered considerable interest in cancer research. The vascular endothelial growth factor (VEGF) and VEGF receptor pathway are recognized as the key regulators of the angiogenic process. Activation of the VEGF/VEGF-receptor pathway initiates signaling cascades that promote endothelial cell growth, migration, and differentiation. Recently, VEGF was shown to play a role in the recruitment of bone marrow-derived endothelial progenitor cells to neovascularization sites. The role of VEGF in promoting tumor angiogenesis and the occurrence of human cancers has led to the rational design and development of agents that selectively target this pathway. Moreover, these anti-VEGF/VEGF receptor agents show therapeutic potential by inhibition of angiogenesis and tumor growth in preclinical models. In this review, we summarize the role of the VEGF pathway during tumor angiogenesis.

  19. Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation

    Microsoft Academic Search

    Takashi Sasamura; Shigenobu Nakamura; Yuko Iida; Hideki Fujii; Jun Murata; Ikuo Saiki; Hiroshi Nojima; Yasushi Kuraishi

    2002-01-01

    The present study was conducted to clarify whether relief from cancer pain by morphine would suppress tumor growth and metastasis. When given orthotopic inoculation of B16–BL6 melanoma cells into the hind paw, C57BL\\/6 mice showed moderate and marked hyperalgesia on days 7–10 and from day 14 post-inoculation, respectively. The volume of inoculated hind paw was increased exponentially as a function

  20. Developmental hypothyroxinaemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring.

    PubMed

    Wei, W; Wang, Y; Wang, Y; Dong, J; Min, H; Song, B; Teng, W; Xi, Q; Chen, J

    2013-09-01

    Iodine is essential for the biosynthesis of thyroid hormones, including triiodothyronine and thyroxine. Thyroid hormones are important for central nervous system development. Mild maternal iodine deficiency (ID)-induced hypothyroxinaemia causes neurological deficits and mental retardation of the foetus. However, the detailed mechanism underlying these deficits is still largely unknown. Given that the growth-associated protein of 43 kDa (GAP-43), semaphorin 3A (Sema3A) and the glycogen synthase kinase 3? (GSK3?)/collapsin response mediator protein 2 (CRMP2) pathway are essential for axonal development, we hypothesise that hippocampal axonal growth-related proteins may be impaired, which may contribute to hippocampal axonal growth delay in rat offspring exposed to maternal hypothyroxinaemia. To test this hypothesis, maternal hypothyroxinaemia models were established in Wistar rats using a mild ID diet. Besides a negative control group, two maternal hypothyroidism models were created with either a severe ID diet or methimazole in the water. Our results showed that maternal hypothyroxinaemia exposure delayed offspring axonal growth on gestational day 19, postnatal day (PN) 7, PN14 and PN21. Consistent with this, the mean intensity of hippocampal CRMP2 and Tau1 immunofluorescence axonal protein was reduced in the mild ID group. Moreover, maternal hypothyroxinaemia disrupted expressions of GAP-43 and Sema3A. Furthermore, the phosphorylation of GSK3? and CRMP2 was also affected in the treated offspring, implying a potential mechanism by which hypothyroxinaemia-exposure affects neurodevelopment. Taken together, our data support the hypothesis that maternal hypothyroxinaemia may impair axonal growth of the offspring. PMID:23763342

  1. 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. PMID:24636868

  2. Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

    PubMed Central

    D’Amico, Gabriela; Korhonen, Emilia A.; Anisimov, Andrey; Zarkada, Georgia; Holopainen, Tanja; Hägerling, René; Kiefer, Friedemann; Eklund, Lauri; Sormunen, Raija; Elamaa, Harri; Brekken, Rolf A.; Adams, Ralf H.; Koh, Gou Young; Saharinen, Pipsa; Alitalo, Kari

    2014-01-01

    The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy. PMID:24430181

  3. Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth

    PubMed Central

    Sarkisyan, Gor; Gay, Laurie J.; Nguyen, Nhan; Felding, Brunhilde H.

    2014-01-01

    Understanding vascular growth and maturation in developing tumors has important implications for tumor progression, spread, and ultimately host survival. Modulating the signaling of endothelial G protein-coupled receptors (GPCRs) in blood and lymphatic vessels can enhance or limit tumor progression. Sphingosine 1-phosphate receptor 1 (S1PR1) is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR1- enhanced green fluorescent protein (eGFP) mouse model in combination with intravital imaging and pharmacologic modulation of S1PR1 signaling, we show that boundary conditions of high and low S1PR1 signaling retard tumor progression by enhancing or destabilizing neovasculature integrity, respectively. In contrast, midrange S1PR1 signaling, achieved by receptor antagonist titration, promotes abundant growth of small, organized vessels and thereby enhances tumor progression. Furthermore, in vivo S1PR1 antagonism supports lung colonization by circulating tumor cells. Regulation of endothelial S1PR1 dynamically controls vascular integrity and maturation and thus modulates angiogenesis, tumor growth, and hematogenous metastasis. PMID:24740542

  4. Elevated epidermal growth factor receptor binding in plutonium-induced lung tumors from dogs

    SciTech Connect

    Leung, F.C.; Bohn, L.R.; Dagle, G.E. (Pacific Northwest Lab., Richland, WA (USA))

    1991-04-01

    The objective of this study is to examine and characterize epidermal growth factor receptor (EGF-R) binding in inhaled plutonium-induced canine lung-tumor tissue and to compare it with that in normal canine lung tissue. Crude membrane preparations from normal and lung-tumor tissue from beagle dogs were examined in a radioreceptor assay, using {sup 125}I-labeled epidermal growth factor (EGF) as a ligand. Specific EGF receptor binding was determined in the presence of excess unlabeled EGF. We have examined EGF receptor binding in eight lung-tumor samples obtained from six dogs. Epidermal growth factor receptor binding was significantly greater in lung-tumor samples (31.38%) compared with that in normal lung tissue (3.76%). Scatchard plot analysis from the displacement assay revealed that there was no statistical difference in the binding affinity but significantly higher concentration of EGF-R sites in the lung-tumor tissue (619 fmol/mg) than in normal lung tissue (53 fmol/mg). The increase in EGF-R number in plutonium-induced dog lung tumors does not seem to correlate with increase in the initial lung burden exposure to plutonium. Our results demonstrate that there is a significant increase in EGF-R binding in inhaled plutonium-induced dog lung tumors.

  5. Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth.

    PubMed

    Ma, Xiaojun; Aoki, Tomohiro; Tsuruyama, Tatsuaki; Narumiya, Shuh

    2015-07-15

    Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNF? and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNF?, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNF?, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer. Cancer Res; 75(14); 2822-32. ©2015 AACR. PMID:26018088

  6. Dynamic tumor growth patterns in a novel murine model of colorectal cancer.

    PubMed

    Paul Olson, Terrah J; Hadac, Jamie N; Sievers, Chelsie K; Leystra, Alyssa A; Deming, Dustin A; Zahm, Christopher D; Albrecht, Dawn M; Nomura, Alice; Nettekoven, Laura A; Plesh, Lauren K; Clipson, Linda; Sullivan, Ruth; Newton, Michael A; Schelman, William R; Halberg, Richard B

    2014-01-01

    Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc(Min/+) mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of ?-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies. PMID:24196829

  7. Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies

    NASA Astrophysics Data System (ADS)

    Kohandel, M.; Kardar, M.; Milosevic, M.; Sivaloganathan, S.

    2007-07-01

    Tumors cannot grow beyond a certain size (about 1-2 mm in diameter) through simple diffusion of oxygen and other essential nutrients into the tumor. Angiogenesis, the formation of blood vessels from pre-existing vessels, is a crucial and observed step, through which a tumor obtains its own blood supply. Thus, strategies that interfere with the development of this tumor vasculature, known as anti-angiogenic therapy, represent a novel approach to controlling tumor growth. Several pre-clinical studies have suggested that currently available angiogenesis inhibitors are unlikely to yield significant sustained improvements in tumor control on their own, but rather will need to be used in combination with conventional treatments to achieve maximal benefit. Optimal sequencing of anti-angiogenic treatment and radiotherapy or chemotherapy is essential to the success of these combined treatment strategies. Hence, a major challenge to mathematical modeling and computer simulations is to find appropriate dosages, schedules and sequencing of combination therapies to control or eliminate tumor growth. Here, we present a mathematical model that incorporates tumor cells and the vascular network, as well as their interplay. We can then include the effects of two different treatments, conventional cytotoxic therapy and anti-angiogenic therapy. The results are compared with available experimental and clinical data.

  8. The permanence and extinction of a nonlinear growth rate single-species non-autonomous dispersal models with time delays

    Microsoft Academic Search

    ChunLing Shi; Zhong Li; Fengde Chen

    2007-01-01

    In this paper, we consider the effect of diffusion on the permanence and extinction of a non-autonomous nonlinear growth rate single-species dispersal model with time delays. Firstly, the sufficient conditions of the permanence and extinction of the species are established, which shows if the growth rate and dispersal coefficients is suitable, the species is permanent, on the contrary, it is

  9. Association of ghrelin and leptin with reproductive hormones in constitutional delay of growth and puberty

    PubMed Central

    2010-01-01

    Background Constitutional delay of growth and puberty (CDGP) is a variation of the onset and timing of pubertal development without a defined endocrine abnormality. Recently published studies indicate that leptin and ghrelin play a role in puberty initiation and progress. They have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that elevated ghrelin and reduced leptin concentrations could be implicated in altering the tempo of puberty in adolescents with CDGP. So in the current study we evaluate variations in leptin and ghrelin levels in adolescent boys with CDGP, the relationships between both hormones and reproductive hormones including LH, FSH and testosterone were also evaluated. Methods The study enrolled 23 adolescent boys with CDGP and 20 healthy controls matched for age and sex. Weight, height, BMI, testicular volume, bone age, bone age delay, serum FSH, LH, testosterone, leptin and ghrelin were assessed. Results Adolescent boys with CDGP had significantly lower leptin and higher ghrelin than normal controls. Leptin was positively correlated with BMI, bone age, testicular volume, FSH, LH and testosterone and negatively correlated with delayed bone age and ghrelin. Ghrelin was negatively correlated with BMI, bone age, testicular volume, FSH, LH and testosterone. With multiple regression analysis BMI, FSH, LH, testosterone and ghrelin remained independently correlated with leptin while BMI, LH and testosterone remained independently correlated with ghrelin. Conclusion Elevated serum ghrelin and decreased leptin concentrations and their associations with reproductive hormones may explain the sexual immaturity in adolescent boys with CDGP. PMID:21176234

  10. Timed daily administration of prolactin and corticosteroid hormone reduces murine tumor growth and enhances immune reactivity.

    PubMed

    Keisari, Y; Cincotta, E; Meier, A H; Cincotta, A H

    1999-05-01

    In the present study, we investigated the time-dependent interactive effects of daily injections of prolactin (PRL) and corticosterone (CORT) on the activation of lymphocyte function and inhibition of tumor growth in vivo in mice. BALB/c mice were injected subcutaneously with EMT-6 fibrosarcoma cells (a murine connective tissue tumor cell derived from mammary gland), and then different groups of animals were treated with PRL (1 microg/g body weight [BW] ip) at Oh, 4h, 8h, 12h, 16h, or 20h after CRT (1 microg/g BW ip) daily for 10 days. Different control groups were vehicle treated or treated with either hormone alone. Mice were kept in constant light 1 week before and during injections and in a 14:10 light-dark cycle thereafter. Tumor progression was monitored for up to 21 days after the cessation of treatment, and thereafter spleen lymphocytes were harvested and tested for mitogen-triggered proliferation. Prolactin administration at 8h or 16-20h after corticosteroid treatment reduced tumor volume by 77% and 49%, respectively, relative to vehicle-treated controls. Other time relations of hormone treatment were ineffectual. Further studies indicated that the immunosuppressant cyclosporin A (CSA) substantially stimulated tumor growth; this effect was completely abrogated by a simultaneous 8h related hormone treatment. How ever, the 8h hormone treatment was ineffective in inhibiting tumor growth in T-cell-deficient nude mice. Spleen lymphocytes from tumor-bearing (TB) mice showed an elevated basal proliferative capacity stimulated by concanavalin A (ConA; a stimulus for T-cell proliferation) and lipopolysaccharide (LPS; a stimulus for B-cell proliferation) compared to non-TB mice. Spleen lymphocytes from TB mice treated with CORT and PRL at 8h intervals exhibited an increased spontaneous (as well as LPS- and ConA- triggered) proliferation (by 104%, 48%, and 70%, respectively) compared with vehicle control TB mice. Fluorescence-activated cell sorting (FACS) analysis of splenocytes from hormone-treated animals indicated a 34-100% increase in the CD4+ (e.g., T helper cell) population. Treatment of animals with either hormone alone did not inhibit tumor growth or stimulate immune function relative to vehicle controls. The daily rhythms of plasma PRL, CORT, and thyroxine were all substantially altered by the presence of tumor in these mice. These results indicate that appropriately timed daily treatment of PRL and CORT can attenuate tumor growth, in part, via activation of antitumor immune mechanisms. Collectively, these data suggest that circadian neuroendocrine activities must be temporally organized appropriately to inhibit tumor growth. PMID:10373101

  11. Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone.

    PubMed

    Li, Xin; Liao, Jinhui; Park, Serk In; Koh, Amy J; Sadler, William D; Pienta, Kenneth J; Rosol, Thomas J; McCauley, Laurie K

    2011-06-01

    Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important regulator of cancer cell proliferation. The goal of this investigation was to elucidate the role of calcium released during bone resorption and to determine the impact of drugs which suppress bone resorption on tumor growth in bone. To compare tumor growth in a skeletal versus non-skeletal site, equal numbers of canine prostate cancer cells expressing luciferase (ACE-1(luc)) were inoculated into a simple collagen matrix, neonatal mouse vertebrae (vossicles), human de-proteinized bone, or a mineralized collagen matrix. Implants were placed subcutaneously into athymic mice. Luciferase activity was used to track tumor growth weekly, and at one month tumors were dissected for histologic analysis. Luciferase activity and tumor size were greater in vossicles, de-proteinized bone and mineralized collagen matrix versus non-mineralized collagen implants. The human osteoblastic prostate carcinoma cell line C4-2b also grew better in a mineral rich environment with a greater proliferation of C4-2b cells reflected by Ki-67 staining. Zoledronic acid (ZA), a bisphosphonate, and recombinant OPG-Fc, a RANKL inhibitor, were administered to mice bearing vertebral implants (vossicles) containing ACE-1 osteoblastic prostate cancer cells. Vossicles or collagen matrices were seeded with ACE-1(luc) cells subcutaneously in athymic mice (2 vossicles, 2 collagen implants/mouse). Mice received ZA (5 ?g/mouse, twice/week), (OPG-Fc at 10mg/kg, 3 times/week) or vehicle, and luciferase activity was measured weekly. Histologic analysis of the tumors, vossicles and endogenous bones and serum biochemistry were performed. Antiresorptive administration was associated with decreased serum TRAP5b, reduced osteoclast numbers, and increased tibia and vossicle bone areas. ZA significantly decreased bone marrow calcium concentrations without affecting serum calcium. ZA and OPG-Fc significantly inhibited tumor growth in bone but not in collagen implants. In conclusion, the inhibitory effects of ZA or OPG-Fc on prostate tumor growth in bone are mediated via blocking bone resorption and calcium release from bone. PMID:21419883

  12. Drugs Which Inhibit Osteoclast Function Suppress Tumor Growth through Calcium Reduction in Bone

    PubMed Central

    Li, Xin; Liao, Jinhui; Park, Serk In; Koh, Amy J; Sadler, William D; Pienta, Kenneth J; Rosol, Thomas J; McCauley, Laurie K

    2011-01-01

    Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important regulator of cancer cell proliferation. The goal of this investigation was to elucidate the role of calcium released during bone resorption and to determine the impact of drugs which suppress bone resorption on tumor growth in bone. To compare tumor growth in a skeletal versus non-skeletal site, equal numbers of canine prostate cancer cells expressing luciferase (ACE-1luc) prostate cancer cells were inoculated into a simple collagen matrix, neonatal mouse vertebrae (vossicles), human de-proteinized bone, or a mineralized collagen matrix. Implants were placed subcutaneously into athymic mice. Luciferase activity was used to track tumor growth weekly and at one month tumors were dissected for histologic analysis. Luciferase activity and tumor size were greater in vossicles, de-proteinized bone and mineralized collagen matrix versus non-mineralized collagen implants. The human osteoblastic prostate carcinoma cell line C4-2b also grew better in a mineral rich environment with a greater proliferation of C4-2b cells reflected by Ki-67 staining. Zoledronic acid (ZA), a bisphosphonate, and recombinant OPG-Fc, a RANKL inhibitor, were administered to mice bearing vertebral implants (vossicles) containing ACE-1 osteoblastic prostate cancer cells. Vossicles or collagen matrices were seeded with ACE-1luc cells subcutaneously in athymic mice (2 vossicles, 2 collagen implants/mouse). Mice received ZA (5?g/mouse, twice/week), (OPG-Fc at 10mg/kg, 3 times/week) or vehicle, and luciferase activity was measured weekly. Histologic analysis of the tumors, vossicles and endogenous bones and serum biochemistry were performed. Antiresorptive administration was associated with decreased serum TRAP5b and reduced osteoclast numbers, increased tibia and vossicle bone areas. ZA significantly decreased bone marrow calcium concentrations without affecting serum calcium. ZA and OPG-Fc significantly inhibited tumor growth in bone but not in collagen implants. In conclusion, the inhibitory effects of ZA or OPG-Fc on prostate tumor growth in bone are mediated via blocking bone resorption and calcium release from bone. PMID:21419883

  13. 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.

  14. Inhibition of Prostate Tumor Growth and Bone Remodeling by the Vascular Targeting Agent VEGF121\\/rGel

    Microsoft Academic Search

    Khalid A. Mohamedali; Ann T. Poblenz; Charles R. Sikes; Nora M. Navone; Philip E. Thorpe; Bryant G. Darnay; Michael G. Rosenblum

    2006-01-01

    The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF121\\/recombinant gelonin (rGel) strongly

  15. A Comparison of Imaging Techniques to Monitor Tumor Growth and Cancer Progression in Living Animals

    PubMed Central

    Puaux, Anne-Laure; Ong, Lai Chun; Jin, Yi; Teh, Irvin; Hong, Michelle; Chow, Pierce K. H.; Golay, Xavier; Abastado, Jean-Pierre

    2011-01-01

    Introduction and Purpose. Monitoring solid tumor growth and metastasis in small animals is important for cancer research. Noninvasive techniques make longitudinal studies possible, require fewer animals, and have greater statistical power. Such techniques include FDG positron emission tomography (FDG-PET), magnetic resonance imaging (MRI), and optical imaging, comprising bioluminescence imaging (BLI) and fluorescence imaging (FLI). This study compared the performance and usability of these methods in the context of mouse tumor studies. Methods. B16 tumor-bearing mice (n = 4 for each study) were used to compare practicality, performance for small tumor detection and tumor burden measurement. Using RETAAD mice, which develop spontaneous melanomas, we examined the performance of MRI (n = 6 mice) and FDG-PET (n = 10 mice) for tumor identification. Results. Overall, BLI and FLI were the most practical techniques tested. Both BLI and FDG-PET identified small nonpalpable tumors, whereas MRI and FLI only detected macroscopic, clinically evident tumors. FDG-PET and MRI performed well in the identification of tumors in terms of specificity, sensitivity, and positive predictive value. Conclusion. Each of the four methods has different strengths that must be understood before selecting them for use. PMID:22121481

  16. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia

    Microsoft Academic Search

    E. A. Imel; M. Peacock; P. Pitukcheewanont; H. J. Heller; L. M. Ward; D. Shulman; M. Kassem; P. Rackoff; M. Zimering; A. Dalkin; E. Drobny; G. Colussi; J. L. Shaker; E. H. Hoogendoorn; S. L. Hui; M. J. Econs

    2006-01-01

    CONTEXT: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors that cause TIO and is, at least partly, responsible for the manifestations of TIO. OBJECTIVE: The objective of this study was to determine the sensitivity

  17. Dietary fish oil suppresses tumor growth and metastasis of Lewis lung carcinoma in mice

    Microsoft Academic Search

    Daniel Yam; Alpha Peled; Monica Huszar; Meir Shinitzky

    1997-01-01

    In this study we examined the influence of different polyunsaturated fatty acid (PUFA) diets on the tumor growth and metastatic dissemination of the well-characterized Lewis Lung Carcinoma (3LL) in C57BL6J mice. The tumor-bearing mice were fed ad libitum with three different diets of 5% oil; either soybean oil (SO), which is rich in omega-6 (?-6); perilla oil (PO), which is

  18. 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-3? activation, while p38? 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. PMID:24789042

  19. Recombinant canstatin inhibits tumor growth in an orthotopic AT84 oral squamous cell carcinoma model

    Microsoft Academic Search

    Jeon Hwang-BoKi Hyun; Ki Hyun Yoo; Han-Sin Jeong; In Sik Chung

    2010-01-01

    The inhibitory effect of recombinant canstatin on tumor growth was investigated using an orthotopic oral squamous cell carcinoma\\u000a (AT-84 cells) animal (C3H\\/HeN) model. Recombinant canstatin from stably transfected Drosophila S2 cells was purified to homogeneity using a simple one-step Ni NTA affinity fractionation. In our oral cancer model, the\\u000a final volume and weight of tumors in groups treated with purified

  20. Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors

    Microsoft Academic Search

    Gary M. K. Tse; Philip C. W. Lui; Joaquim S. L. Vong; Kin-Mang Lau; Thomas C. Putti; Rooshdiya Karim; Richard A. Scolyer; C-Soon Lee; Alex M. C. Yu; David C. H. Ng; Agnes K. Y. Tse; Puay-Hoon Tan

    2009-01-01

    Mammary phyllodes tumors are uncommon stromal-epithelial neoplasms, and are divided into benign, borderline malignant and\\u000a frankly malignant groups on the basis of their histological features. Accumulating evidence shows that epidermal growth factor\\u000a receptor (EGFR) is involved in the pathogenesis and progression of many malignancies. This study investigated 453 phyllodes\\u000a tumors (296 benign, 98 borderline, 59 malignant) for EGFR expression using

  1. [Clear Cell Tumor of the Lung Showing Gradual Growth for 6 years].

    PubMed

    Fukui, Takamasa; Wakatsuki, Yusuke; Yutaka, Yojiro; Katakura, Hiromichi; Yamanaka, Akira

    2015-03-01

    Clear cell tumor of the lung( CCTL) is a rare benign tumor that originates from the lung. We report a case of CCTL which had grown for 6 years. The patient was a 25-year-old woman and her chest roentgenogram detected a well-circumscribed coin-like shadow in the left lower lung field. Its size was 30 mm in diameter at consultation, and retrospectively we recognized a nodule of 13 mm in diameter in the same location on the health checkup roentgenogram 6 years before. The growth of the tumor suggested the possibility of malignancy, and the tumor was surgically resected by partial resection of the lung. Post operative course was uneventful. The tumor was clearly separated from pulmonary parenchyma, and was immunohistochemically diagnosed as CCTL. PMID:25743552

  2. WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant.

    PubMed

    Haber, D A; Park, S; Maheswaran, S; Englert, C; Re, G G; Hazen-Martin, D J; Sens, D A; Garvin, A J

    1993-12-24

    A human Wilms tumor cell line (RM1) was developed to test the tumor suppressor activity of WT1, a zinc finger transcription factor that is expressed in the developing human kidney and is mutationally inactivated in a subset of Wilms tumors. Transfection of each of four wild-type WT1 isoforms suppressed the growth of RM1 cells. The endogenous WT1 transcript in these cells was devoid of exon 2 sequences, a splicing alteration that was also detected in varying amounts in all Wilms tumors tested but not in normal kidney. Production of this abnormal transcript, which encodes a functionally altered protein, may represent a distinct mechanism for inactivating WT1 in Wilms tumors. PMID:8266105

  3. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread.

    PubMed

    Wong, Ping-Pui; Demircioglu, Fevzi; Ghazaly, Essam; Alrawashdeh, Wasfi; Stratford, Michael R L; Scudamore, Cheryl L; Cereser, Biancastella; Crnogorac-Jurcevic, Tatjana; McDonald, Stuart; Elia, George; Hagemann, Thorsten; Kocher, Hemant M; Hodivala-Dilke, Kairbaan M

    2015-01-12

    Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment. PMID:25584895

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

    PubMed

    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

    2014-12-28

    Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and anti-inflammatory 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

  5. Magnolol-induced inhibition of tumor growth in systemic malignancies.

    PubMed

    Kapoor, Shailendra

    2013-12-01

    The commentary illustrates the significant tumor attenuating effects of magnolol and refers to the article on "Screening active anti-breast cancer compounds from Cortex Magnolia officinalis by 2D LC-MS" (X. Hou, et al., J. Sep. Sci. 2013, 36 (4), 706-712). On the basis of the literature, there is definitively need for further studies to fully understand the magnolol reation pathways and to harness the antineoplastic effects. PMID:24115640

  6. Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide

    PubMed Central

    Quann, Kevin; Gonzales, Donna M.; Mercier, Isabelle; Wang, Chenguang; Sotgia, Federica; Pestell, Richard G.; Lisanti, Michael P.; Jasmin, Jean-François

    2013-01-01

    Caveolin-1 (Cav-1) is a critical regulator of tumor progression in a variety of cancers where it has been shown to act as either a tumor suppressor or tumor promoter. In glioblastoma multiforme, it has been previously demonstrated to function as a putative tumor suppressor. Our studies here, using the human glioblastoma-derived cell line U-87MG, further support the role of Cav-1 as a negative regulator of tumor growth. Using a lentiviral transduction approach, we were able to stably overexpress Cav-1 in U-87MG cells. Gene expression microarray analyses demonstrated significant enrichment in gene signatures corresponding to downregulation of MAPK, PI3K/AKT and mTOR signaling, as well as activation of apoptotic pathways in Cav-1-overexpressing U-87MG cells. These same gene signatures were later confirmed at the protein level in vitro. To explore the ability of Cav-1 to regulate tumor growth in vivo, we further show that Cav-1-overexpressing U-87MG cells display reduced tumorigenicity in an ectopic xenograft mouse model, with marked hypoactivation of MAPK and PI3K/mTOR pathways. Finally, we demonstrate that Cav-1 overexpression confers sensitivity to the most commonly used chemotherapy for glioblastoma, temozolomide. In conclusion, Cav-1 negatively regulates key cell growth and survival pathways and may be an effective biomarker for predicting response to chemotherapy in glioblastoma. PMID:23598719

  7. Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide.

    PubMed

    Quann, Kevin; Gonzales, Donna M; Mercier, Isabelle; Wang, Chenguang; Sotgia, Federica; Pestell, Richard G; Lisanti, Michael P; Jasmin, Jean-François

    2013-05-15

    Caveolin-1 (Cav-1) is a critical regulator of tumor progression in a variety of cancers where it has been shown to act as either a tumor suppressor or tumor promoter. In glioblastoma multiforme, it has been previously demonstrated to function as a putative tumor suppressor. Our studies here, using the human glioblastoma-derived cell line U-87MG, further support the role of Cav-1 as a negative regulator of tumor growth. Using a lentiviral transduction approach, we were able to stably overexpress Cav-1 in U-87MG cells. Gene expression microarray analyses demonstrated significant enrichment in gene signatures corresponding to downregulation of MAPK, PI3K/AKT and mTOR signaling, as well as activation of apoptotic pathways in Cav-1-overexpressing U-87MG cells. These same gene signatures were later confirmed at the protein level in vitro. To explore the ability of Cav-1 to regulate tumor growth in vivo, we further show that Cav-1-overexpressing U-87MG cells display reduced tumorigenicity in an ectopic xenograft mouse model, with marked hypoactivation of MAPK and PI3K/mTOR pathways. Finally, we demonstrate that Cav-1 overexpression confers sensitivity to the most commonly used chemotherapy for glioblastoma, temozolomide. In conclusion, Cav-1 negatively regulates key cell growth and survival pathways and may be an effective biomarker for predicting response to chemotherapy in glioblastoma. PMID:23598719

  8. 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-1?, 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 PPAR? 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-1? axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

  9. Tumor-induced osteomalacia with normal systemic fibroblast growth factor-23 level.

    PubMed

    Amblee, Ambika; Uy, Juanito; Senseng, Carmencita; Hart, Peter

    2014-04-01

    A 38-year-old man presenting with long bone/rib fractures was diagnosed with tumor-induced osteomalacia (TIO) caused by a giant cell tumor in the right foot with normal systemic fibroblast growth factor-23 (FGF23) levels. Multiple imaging modalities done initially and one year later were unable to localize the tumor. New-onset foot pain discovered a right foot mass with resolution of metabolic abnormalities post-surgery. Sampling from both femoral veins showed an elevated FGF23 value on the right side. This case is unique in that the patient had a normal systemic FGF23 level even with severe clinical manifestations of TIO. PMID:25852869

  10. 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.

  11. Non-diffeomorphic registration of brain tumor images by simulating tissue loss and tumor growth

    Microsoft Academic Search

    Evangelia I. Zacharaki; Cosmina S. Hogea; Dinggang Shen; George Biros; Christos Davatzikos

    2009-01-01

    Although a variety of diffeomorphic deformable registration methods exist in the literature, application of these methods in the presence of space-occupying lesions is not straightforward. The motivation of this work is spatial normalization of MR images from patients with brain tumors in a common stereotaxic space, aiming to pool data from different patients into a common space in order to

  12. Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice.

    PubMed

    Koodie, Lisa; Yuan, Hongyan; Pumper, Jeffery A; Yu, Haidong; Charboneau, Richard; Ramkrishnan, Sundaram; Roy, Sabita

    2014-04-01

    Tumor cells secrete factors that stimulate the migration of peripheral blood leukocytes and enhance tumor progression by affecting angiogenesis. In these studies, we investigated the effect of morphine, a known immunosuppressant, on leukocyte migration and recruitment to conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells. Our results indicate that morphine treatment reduced the migration and recruitment of tumor-infiltrating leukocytes into Matrigel plugs and polyvinyl alcohol sponges containing conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells when compared with placebo. A reciprocal increase in peripheral blood leukocytes was observed at the time of plug or sponge removal in morphine-treated mice. Decreased angiogenesis was observed in conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells Matrigel plugs taken from morphine-treated wild-type mice when compared with placebo but was abolished in morphine-treated ?-opioid receptor knockout mice. In addition, in vitro studies using trans-well and electric cell substrate impedance sensing system studies reveal for the first time morphine's inhibitory effects on leukocyte migration and their ability to transmigrate across an activated endothelial monolayer. Taken together, these studies indicate that morphine treatment can potentially decrease leukocyte transendothelial migration and reduce angiogenesis associated with tumor growth. The use of morphine for cancer pain management may be beneficial through its effects on angiogenesis. PMID:24495739

  13. Lipid dependence of nuclear glucose-6-phosphatase during tumor growth and changes in its nature after irradiation of tumor bearers

    SciTech Connect

    Pal'mina, N.P.; Mal'tseva, E.L.; Burlakova, E.B.

    1982-01-01

    Since nuclear glucose-6-phosphatase has both general and distinguishing features in comparison with the microsomal enzyme, its activity was studied at different periods of tumor growth and these data compare with the composition and antioxidant activity of the nuclear lipids (AOA). The enzyme activity was determined by the Swanson method, consisting of a measurement of the amount of inorganic phosphate liberated as a result of enzymatic hydrolysis of glucose-6-phosphate in 15 min after addition of a suspension of nuclei to it. The antioxidant activity of the lipids (AOA) was determined on a methyl-oleate oxidation model, the composition of phospholipids by the method of two-dimensional thin-layer chromatography, and the amount of protein by the Lowry method. Ehrlich's ascites carcinoma was transplanted on the seventh day of its development, dose of inoculum 10/sup 6/ cells. Tumor cells were irradiated with 650 roentgens on the fifth day after transplantation. The data obtained are evidence that in the nuclei of liver cells of the tumor bearer the phosphohydrolase activity of glucose-6-phosphatase is regulated by the change in the content of phosphatidylethanolamine and level of development of oxidation reactions in lipids, while in the nuclei of tumor cells this system of regulation is impaired, and despite its presence in the membrane, the enzyme does not function. (JMT)

  14. Morphine Inhibits Migration of Tumor-Infiltrating Leukocytes and Suppresses Angiogenesis Associated with Tumor Growth in Mice

    PubMed Central

    Koodie, Lisa; Yuan, Hongyan; Pumper, Jeffery A.; Yu, Haidong; Charboneau, Richard; Ramkrishnan, Sundaram; Roy, Sabita

    2015-01-01

    Tumor cells secrete factors that stimulate the migration of peripheral blood leukocytes and enhance tumor progression by affecting angiogenesis. In these studies, we investigated the effect of morphine, a known immunosuppressant, on leukocyte migration and recruitment to conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells. Our results indicate that morphine treatment reduced the migration and recruitment of tumor-infiltrating leukocytes into Matrigel plugs and polyvinyl alcohol sponges containing conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells when compared with placebo. A reciprocal increase in peripheral blood leukocytes was observed at the time of plug or sponge removal in morphine-treated mice. Decreased angiogenesis was observed in conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells Matrigel plugs taken from morphine-treated wild-type mice when compared with placebo but was abolished in morphine-treated ?-opioid receptor knockout mice. In addition, in vitro studies using trans-well and electric cell substrate impedance sensing system studies reveal for the first time morphine's inhibitory effects on leukocyte migration and their ability to transmigrate across an activated endothelial monolayer. Taken together, these studies indicate that morphine treatment can potentially decrease leukocyte transendothelial migration and reduce angiogenesis associated with tumor growth. The use of morphine for cancer pain management may be beneficial through its effects on angiogenesis. PMID:24495739

  15. Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma

    PubMed Central

    Van Beijnum, Judy R.; Cerisoli, Francesco; Scaria, Puthupparampil V.; Verheul, Mark; Van Berkel, Maaike P.; Pieters, Ebel H. E.; Van Haastert, Rick J.; Yousefi, Afrouz; Mastrobattista, Enrico; Storm, Gert; Berezikov, Eugene; Cuppen, Edwin; Woodle, Martin; Schaapveld, Roel Q. J.; Prevost, Gregoire P.; Griffioen, Arjan W.; Van Noort, Paula I.; Schiffelers, Raymond M.

    2014-01-01

    Tumor-angiogenesis is the multi-factorial process of sprouting of endothelial cells (EC) into micro-vessels to provide tumor cells with nutrients and oxygen. To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. Introduction of miR-7 in EC resulted in strongly reduced cell viability, tube formation, sprouting and migration. Application of miR-7 in the chick chorioallantoic membrane assay led to a profound reduction of vascularization, similar to anti-angiogenic drug sunitinib. Local administration of miR-7 in an in vivo murine neuroblastoma tumor model significantly inhibited angiogenesis and tumor growth. Finally, systemic administration of miR-7 using a novel integrin-targeted biodegradable polymeric nanoparticles that targets both EC and tumor cells, strongly reduced angiogenesis and tumor proliferation in mice with human glioblastoma xenografts. Transcriptome analysis of miR-7 transfected EC in combination with in silico target prediction resulted in the identification of OGT as novel target gene of miR-7. Our study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic. PMID:25149532

  16. Three-dimensional multispecies nonlinear tumor growth–I. Model and numerical method

    PubMed Central

    Wise, S.M.; Lowengrub, J.S.; Frieboes, H.B.; Cristini, V.

    2012-01-01

    This is the first paper in a two-part series in which we develop, analyze and simulate a diffuse interface continuum model of multispecies tumor growth and tumor-induced angiogenesis in two and three dimensions. Three dimensional simulations of nonlinear tumor growth and neovascularization using this diffuse interface model were recently presented in Frieboes et al. (2007), but that paper did not describe the details of the model or the numerical algorithm. This is done here. In this diffuse interface approach, sharp interfaces are replaced by narrow transition layers that arise due to differential adhesive forces among the cell-species. Accordingly, a continuum model of adhesion is introduced. The model is thermodynamically consistent, is related to recently developed mixture models, and thus is capable of providing a detailed description of tumor progression. The model is well-posed and 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. We demonstrate analytically and numerically that when the diffuse interface thickness tends to zero, the system reduces to a classical sharp interface model. Using a new fully adaptive, nonlinear multigrid/finite difference method the system is simulated efficiently. In this first paper, we present simulations of unstable avascular tumor growth in two and three dimensions and demonstrate that our techniques now make large-scale three dimensional simulations of tumors with complex morphologies computationally feasible. In Part II of this study, we will investigate multispecies tumor invasion, tumor-induced angiogenesis and focus on the morphological instabilities that may underlie invasive phenotypes. PMID:18485374

  17. 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

  18. Control of ocular tumor growth and metastatic spread by soluble and membrane Fas ligand.

    PubMed

    Gregory, Meredith S; Saff, Rebecca R; Marshak-Rothstein, Ann; Ksander, Bruce R

    2007-12-15

    Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions-membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage. PMID:18089826

  19. 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

  20. Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function.

    PubMed

    Norden, Diana M; Bicer, Sabahattin; Clark, Yvonne; Jing, Runfeng; Henry, Christopher J; Wold, Loren E; Reiser, Peter J; Godbout, Jonathan P; McCarthy, Donna O

    2015-01-01

    Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1? mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1? in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth. PMID:25102452

  1. Dynamic Quantitative Intravital Imaging of Glioblastoma Progression Reveals a Lack of Correlation between Tumor Growth and Blood Vessel Density

    PubMed Central

    Ricard, Clément; Stanchi, Fabio; Rodriguez, Thieric; Amoureux, Marie-Claude; Rougon, Geneviève; Debarbieux, Franck

    2013-01-01

    The spatiotemporal and longitudinal monitoring of cellular processes occurring in tumors is critical for oncological research. We focused on glioblastoma multiforme (GBM), an untreatable highly vascularized brain tumor whose progression is thought to critically depend on the oxygen and metabolites supplied by blood vessels. We optimized protocols for orthotopic GBM grafting in mice that were able to recapitulate the biophysical constraints normally governing tumor progression and were suitable for intravital multiphoton microscopy. We repeatedly imaged tumor cells and blood vessels during GBM development. We established methods for quantitative correlative analyses of dynamic imaging data over wide fields in order to cover the entire tumor. We searched whether correlations existed between blood vessel density, tumor cell density and proliferation in control tumors. Extensive vascular remodeling and the formation of new vessels accompanied U87 tumor cell growth, but no strong correlation was found between local cell density and the extent of local blood vessel density irrespective of the tumor area or time points. The technique moreover proves useful for comparative analysis of mice subjected either to Bevacizumab anti-angiogenic treatment that targets VEGF or to AMD3100, an antagonist of CXCR4 receptor. Bevacizumab treatment massively reduced tumoral vessel densities but only transiently reduced U87 tumor growth rate. Again, there was no correlation between local blood vessel density and local cell density. Moreover, Bev applied only prior to tumor implantation inhibited tumor growth to the same extent as post-grafting treatment. AMD3100 achieved a potent inhibition of tumor growth without significant reduction in blood vessel density. These results indicate that in the brain, in this model, tumor growth can be sustained without an increase in blood vessel density and suggest that GBM growth is rather governed by stromal properties. PMID:24069154

  2. 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

  3. Overexpression of hypoxia-inducible factor-1? and vascular endothelial growth factor in sacral giant cell tumors and the correlation with tumor microvessel density

    PubMed Central

    FU, SHAOFENG; BAI, RUI; ZHAO, ZHENQUN; ZHANG, ZHIFENG; ZHANG, GANG; WANG, YUXIN; WANG, YONG; JIANG, DIANMING; ZHU, DEZHI

    2014-01-01

    Although classified as benign, giant cell tumors of the bone (GCTB) may be aggressive, recur and even metastasize to the lungs. In addition, the pathogenesis and histogenesis remain unclear; thus, the driving factors behind the strong tumor growth capacity of GCTB require investigation. In the present study, the expression levels of hypoxia-inducible factor (HIF)-1? and vascular endothelial growth factor (VEGF), which are promoted by hypoxic conditions, were determined in 22 sacral GCTB samples using immunohistochemistry and western blot analysis. Furthermore, CD34 expression was analyzed using these methods. The correlation between HIF-1? or VEGF expression and the tumor microvessel density (MVD) was then determined. The results demonstrated that HIF-1?, VEGF and CD34 were overexpressed in the 22 sacral GCTB specimens, and overexpression of HIF-1? and VEGF correlated with the tumor MVD. Thus, the present study has provided novel indicators for the tumor growth capacity of GCTBs. PMID:25289039

  4. Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model

    PubMed Central

    HUNG, MING-SZU; XU, ZHIDONG; CHEN, YU; SMITH, EMMANUEL; MAO, JIAN-HUA; HSIEH, DAVID; LIN, YU-CHING; YANG, CHENG-TA; JABLONS, DAVID M.; YOU, LIANG

    2013-01-01

    Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2? in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer. PMID:24008396

  5. Prevention of in vivo lung tumor growth by prolonged local delivery of hydroxycamptothecin using poly(ester-carbonate)-collagen composites

    E-print Network

    Prevention of in vivo lung tumor growth by prolonged local delivery of hydroxycamptothecin using February 2010 Available online 22 February 2010 Keywords: Prevention Lung tumors Recurrence Films Local delivery Local tumor recurrence has a major impact on long-term patient survival following the surgical

  6. NKG2D CAR T cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors

    PubMed Central

    Spear, Paul; Barber, Amorette; Rynda-Apple, Agnieszka; Sentman, Charles L.

    2013-01-01

    Tumor heterogeneity presents a substantial barrier to increasing clinical responses mediated by targeted therapies. Broadening the immune response elicited by treatments that target a single antigen is necessary for the elimination of tumor variants that fail to express the targeted antigen. In this study, it is shown that adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) inhibited the growth of target-expressing and –deficient tumor cells within ovarian and lymphoma tumors. Mice bearing the ID8 ovarian or RMA lymphoma tumors were treated with T cells transduced with a NKG2D-based CAR (chNKG2D). NKG2D CAR T cell therapy protected mice from heterogeneous RMA tumors. Moreover, adoptive transfer of chNKG2D T cells mediated tumor protection against highly heterogeneous ovarian tumors in which 50%, 20%, or only 7% of tumor cells expressed significant amounts of NKG2D ligands. CAR T cells did not mediate an in vivo response against tumor cells that did not express sufficient amounts of NKG2D ligands, and the number of ligand-expressing tumor cells correlated with therapeutic efficacy. In addition, tumor-free surviving mice were protected against a tumor re-challenge with NKG2D ligand-negative ovarian tumor cells. These data indicate that NKG2D CAR T cell treatment can be an effective therapy against heterogeneous tumors and induce tumor-specific immunity against ligand-deficient tumor cells. PMID:23628805

  7. Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy.

    PubMed

    Daniel, L; Trouillas, J; Renaud, W; Chevallier, P; Gouvernet, J; Rougon, G; Figarella-Branger, D

    2000-01-01

    Pituitary adenomas are usually benign neuroendocrine tumors. However, some of those that are histopathologically undistinguishable behave aggressively and metastasize. The polysialylated neural cell adhesion molecule (PSA-NCAM), which is highly expressed during the development of the brain and pituitary, is detected in some neuroendocrine tumors and might be relevant as a prognostic marker in pituitary tumors. In the present study, we have searched for PSA-NCAM expression in four lineages of rat pituitary transplantable tumors (SMtTW). Each lineage, maintained by serial tumor grafts under the kidney capsule and skin, differed in its GH/Prl secretion, growth rate, and malignant behavior. PSA-NCAM expression, detected by immunohistochemistry and Western blotting and quantified by ELISA, varied according to the SMtTW lineage. The benign tumors, SMtTW2, with a low growth rate never expressed PSA-NCAM. Another benign lineage, SMtTW3, with a high growth rate expressed a low amount of PSA-NCAM. The highest PSA-NCAM expression was seen in tumors that grew beneath the skin, invaded the kidney, and metastasized (SMtTW4). Tumors of the SMtTW10 lineage, which behaved as either benign or malignant tumors, were heterogeneous in terms of PSA-NCAM expression. In this rat transplantable pituitary tumor model, PSA-NCAM expression correlated in decreasing order with: (a) invasiveness (P < 0.0001), (b) metastases (P = 0.004), (c) ability to grow under the skin (P = 0.006), and (d) growth rate under the kidney capsule (P < 0.01), but not with hormone secretion (r = 0.207). This model, which is very similar to the human pathology, suggests that PSA-NCAM evaluation is of interest in the diagnosis of malignancy and the prognosis of human pituitary tumors. In addition, the SMtTW tumors could be instrumental in evaluating the effects of new therapeutic agents modulating PSA-NCAM expression. PMID:10646857

  8. Effect of Cyclooxygenase and Nitric Oxide Synthase Inhibitors on Tumor Growth in Mouse Tumor Models with and without Cancer Cachexia Related to Prostanoids1

    Microsoft Academic Search

    Christian Cahlin; Johan Gelin; Dick Delbro; Christina Lonnroth; Chiharu Doi; Kent Lundholm

    The potential interaction between cyclooxygenase (Cox) and NO met- abolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57Bl; MCG 101) or a malig- nant melanoma (C3H\\/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and

  9. Some Cancer Mutations Slow Tumor Growth | Physical Sciences in Oncology

    Cancer.gov

    A typical cancer cell has thousands of mutations scattered throughout its genome and hundreds of mutated genes. However, only a handful of those genes, known as drivers, are responsible for cancerous traits such as uncontrolled growth. Cancer biologists have largely ignored these so-called passenger mutations, believing they had little or no impact on cancer progression.

  10. Cancer as a moving target: understanding the composition and rebound growth kinetics of recurrent tumors

    PubMed Central

    Foo, Jasmine; Leder, Kevin; Mumenthaler, Shannon M

    2013-01-01

    We introduce a stochastic branching process model of diversity in recurrent tumors whose growth is driven by drug resistance. Here, an initially declining population can escape certain extinction via the production of mutants whose fitness is drawn at random from a mutational fitness landscape. Using a combination of analytical and computational techniques, we study the rebound growth kinetics and composition of the relapsed tumor. We find that the diversity of relapsed tumors is strongly affected by the shape of the mutational fitness distribution. Interestingly, the model exhibits a qualitative shift in behavior depending on the balance between mutation rate and initial population size. In high mutation settings, recurrence timing is a strong predictor of the diversity of the relapsed tumor, whereas in the low mutation rate regime, recurrence timing is a good predictor of tumor aggressiveness. Analysis reveals that in the high mutation regime, stochasticity in recurrence timing is driven by the random survival of small resistant populations rather than variability in production of resistance from the sensitive population, whereas the opposite is true in the low mutation rate setting. These conclusions contribute to an evolutionary understanding of the suitability of tumor size and time of recurrence as prognostic and predictive factors in cancer. PMID:23396647

  11. Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor.

    PubMed

    Hu, Xian-Wen; Duan, Hai-Feng; Gao, Li-Hua; Pan, Shu-Yuan; Li, Yong-Mei; Xi, Yongyi; Zhao, Su-Rong; Yin, Liang; Li, Jin-Feng; Chen, Hui-Peng; Wu, Chu-Tse

    2008-05-01

    Urokinase (uPA) and its receptor (uPAR) play an important role in tumor growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumors. In this study, ATF-Fc, an antibody-like molecule comprising the amino-terminal fragment of human uPA (ATF) linked to the Fc fragment of human IgG1 via a flexible linker was developed. Its antitumor activities were evaluated in vitro and in vivo. The results showed that ATF-Fc had obvious cytotoxic effect on several types of tumor cells, which is dependent on cellular expression of uPAR and its Fc fragment. Treatment with ATF-Fc caused a significant suppression on tumor growth and metastasis of xenograft human tumors (MCF-7 breast cancer and BGC-823 gastric cancer) in athymic nude mice. Furthermore, we demonstrated that ATF-Fc had an anti-angiogenesis activity both in vitro and in vivo. In conclusion, we provided a novel therapeutic antibody-like molecule in the management of a variety of solid tumors by disrupting the uPA/uPAR interaction. PMID:18245952

  12. Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo

    PubMed Central

    Wang, Ping; Song, Liqiang; Ge, Hui; Jin, Pule; Jiang, Yifang; Hu, Wenxia; Geng, Nan

    2014-01-01

    Platelet-derived growth factor (PDGF) and its receptors (PDGFR), including PDGFR? and PDGFR?, play important roles in tumorigenesis, tumor progression, and the regulation of stromal cell function. Constitutive activation of PDGFR signaling, gene rearrangement, and activating mutations of PDGFR have been identified in various types of human tumors and malignancies. PDGFR? and PDGFR? belong to the family of type III receptor tyrosine kinases and, upon stimulation, activate downstream signaling cascades. Crenolanib is a specific tyrosine kinase inhibitor that targets and inhibits the kinase activity of PDGFR and the FMS-related tyrosine kinase 3. Its clinical efficacy in several human tumors is currently under investigation in Phase II clinical trials. In this study, we examined the potential role of crenolanib in the treatment of non-small-cell lung cancer (NSCLC). Using A549 cells as a model system, we have shown that crenolanib is capable of suppressing proliferation and inducing apoptosis in a dose-dependent manner. Crenolanib-treated cells have reduced migratory activity in response to inducers of chemotaxis. Furthermore, the in vivo antitumor activity of crenolanib was confirmed in an NSCLC xenograft tumor model. Injection of crenolanib significantly inhibited the growth of tumor mass by inducing apoptosis in tumor cells. Our results provide strong evidence supporting the use of crenolanib as a potential therapeutic agent in treating NSCLC. This work sets a foundation for further development of targeted and personalized therapeutics for lung cancer. PMID:25328409

  13. Multiphase modeling and qualitative analysis of the growth of tumor cords

    E-print Network

    Andrea Tosin

    2009-06-27

    In this paper a macroscopic model of tumor cord growth is developed, relying on the mathematical theory of deformable porous media. Tumor is modeled as a saturated mixture of proliferating cells, extracellular fluid and extracellular matrix, that occupies a spatial region close to a blood vessel whence cells get the nutrient needed for their vital functions. Growth of tumor cells takes place within a healthy host tissue, which is in turn modeled as a saturated mixture of non-proliferating cells. Interactions between these two regions are accounted for as an essential mechanism for the growth of the tumor mass. By weakening the role of the extracellular matrix, which is regarded as a rigid non-remodeling scaffold, a system of two partial differential equations is derived, describing the evolution of the cell volume ratio coupled to the dynamics of the nutrient, whose higher and lower concentration levels determine proliferation or death of tumor cells, respectively. Numerical simulations of a reference two-dimensional problem are shown and commented, and a qualitative mathematical analysis of some of its key issues is proposed.

  14. Honokiol thwarts gastric tumor growth and peritoneal dissemination by inhibiting Tpl2 in an orthotopic model.

    PubMed

    Pan, Hung-Chuan; Lai, De-Wei; Lan, Keng-Hsin; Shen, Chin-Chang; Wu, Sheng-Mao; Chiu, Chien-Shan; Wang, Keh-Bin; Sheu, Meei-Ling

    2013-11-01

    Honokiol is known to suppress the growth of cancer cells; however, to date, its antiperitoneal dissemination effects have not been studied in an orthotopic mouse model. In the present study, we evaluated the antiperitoneal dissemination potential of Honokiol in an orthotopic mouse model and assessed associations with tumor growth factor-?1 (TGF?1) and cells stimulated by a carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Our results demonstrate that tumor growth, peritoneal dissemination and peritoneum or organ metastasis of orthotopically implanted MKN45 cells were significantly decreased in Honokiol-treated mice and that endoplasmic reticulum (ER) stress was induced. Honokiol-treated tumors showed increased epithelial signatures such as E-cadherin, cytokeratin-18 and ER stress marker. In contrast, decreased expression of vimentin, Snail and tumor progression locus 2 (Tpl2) was also noted. TGF?1 and MNNG-induced downregulation of E-cadherin and upregulation of Tpl2 were abrogated by Honokiol treatment. The effect of Tpl2 inhibition in cancer cells or endothelial cells was associated with inactivation of CCAAT/enhancer binding protein B, nuclear factor kappa-light-chain-enhancer of activated B cell and activator protein-1 and suppression of vascular endothelial growth factor. Inhibition of Tpl2 in gastric cancer cells by small interfering RNA or pharmacological inhibitor was found to effectively reduce growth ability and vessel density in vivo. Honokiol-induced reversal of epithelial-to-mesenchymal transition (EMT) and ER stress-induced apoptosis via Tp12 may involve the paralleling processes. Taken together, our results suggest that the therapeutic inhibition of Tpl2 by Honokiol thwarts both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT. PMID:23828905

  15. Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

    Microsoft Academic Search

    Fengshuo Jin; Zhihui Xie; Calvin J Kuo; Leland W K Chung; Chia-Ling Hsieh

    2005-01-01

    Tumor–endothelial interaction contributes to local prostate tumor growth and distant metastasis. In this communication, we designed a novel approach to target both cancer cells and their “crosstalk” with surrounding microvascular endothelium in an experimental hormone refractory human prostate cancer model. We evaluated the in vitro and in vivo synergistic and\\/or additive effects of a combination of conditional oncolytic adenovirus plus

  16. Mast cells protect from skin tumor development and limit tumor growth during cutaneous de novo carcinogenesis in a Kit-dependent mouse model.

    PubMed

    Siebenhaar, Frank; Metz, Martin; Maurer, Marcus

    2014-03-01

    Epidermal tumors belong to the most frequent type of neoplasms, and tumor-associated accumulation of mast cells (MCs) has first been observed more than a century ago. Therefore, MCs have been implicated in tumor development and growth; however, the results regarding the role of MC in cutaneous de novo carcinogenesis are still controversially discussed. Here, we subjected MC-deficient Kit(W) /Kit(W-v) mice to chemical skin carcinogenesis. Tumors were induced using the carcinogen 7,12-dimethylbenz[a]-anthracene and subsequent treatment with the tumor promoter 12-tetradecanoyl-phorbol-13-acetat. The treatment resulted in pronounced inflammatory cell infiltrates that were diminished in MC-deficient animals. Unexpectedly, tumor development and growth was significantly increased in MC-deficient Kit(W) /Kit(W-v) mice. The repair of their MC deficiency by local adoptive transfer of MCs normalized tumor incidence and growth. The recruitment of skin-infiltrating immune cells, particularly of F4/80+ monocytes, Gr-1+ granulocytes, B220+ B cells and CD8+ T lymphocytes, to sites of tumor development was, in part, also controlled by MCs. Recent evidence indicated the importance of local antitumor tissue immunity which prevents tumor development. These findings suggest a critical role for MCs in mediating these host antitumor immune responses in the skin. PMID:24444017

  17. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression

    Microsoft Academic Search

    Dingcheng Gao; Daniel Nolan; Kevin McDonnell; Linda Vahdat; Robert Benezra; Nasser Altorki; Vivek Mittal

    2009-01-01

    Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic

  18. IFN-beta restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation.

    PubMed

    Sims, Thomas L; McGee, Mackenzie; Williams, Regan F; Myers, Adrianne L; Tracey, Lorraine; Hamner, J Blair; Ng, Catherine; Wu, Jianrong; Gaber, M Waleed; McCarville, Beth; Nathwani, Amit C; Davidoff, Andrew M

    2010-03-01

    Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS. PMID:20197402

  19. Inhibitory effect of Capsella bursa-pastoris extract on growth of Ehrlich solid tumor in mice.

    PubMed

    Kuroda, K; Akao, M; Kanisawa, M; Miyaki, K

    1976-06-01

    The treatment of ICR mice with i.p. injections (0.14 g/kg/day) of the extract of Capsella bursa-pastoris herb (Cruciferae) caused 50 to 80% inhibition of the solid growth of Ehrlich tumor cells that had been inoculated into the s.c. tissue of the animals. The tumor lumps in the treated mice showed multifocal necroses and the infiltartion of host fibrous tissue cells. Experiments were also performed to isolate and identify the active component for the antitumor action, and an acidic substance was isolated in crystalline form from the herb extract. This acidic substance was identified as fumaric acid and was effective in inhibiting the growth of Ehrlich solid tumor at a dose of 10 mg/kg/day. The 50% lethal dose (i.p.) of this acid was 266 mg/kg. PMID:1268843

  20. Luteolin and its inhibitory effect on tumor growth in systemic malignancies

    SciTech Connect

    Kapoor, Shailendra, E-mail: shailendrakapoor@yahoo.com [74 crossing place, Mechanicsville, VA (United States)

    2013-04-01

    Lamy et al have provided interesting data in their recent article in your esteemed journal. Luteolin augments apoptosis in a number of systemic malignancies. Luteolin reduces tumor growth in breast carcinomas. Luteolin mediates this effect by up-regulating the expression of Bax and down-regulating the expression of Bcl-xL. EGFR-induced MAPK activation is also attenuated. As a result there is increased G2/ M phase arrest. These effects have been seen both in vivo as well as in vitro. It also reduces ER? expression and causes inhibition of IGF-1 mediated PI3K–Akt pathway. Luteolin also activates p38 resulting in nuclear translocation of the apoptosis-inducing factor. Simultaneously it also activates ERK. As a result there is increased intra-tumoral apoptosis which is caspase dependent as well as caspase independent. - Highlights: ? Luteolin and tumor growth in breast carcinomas. ? Luteolin and pulmonary cancer. ? Luteolin and colon cancer.

  1. A stable scheme for a nonlinear, multiphase tumor growth model with an elastic membrane.

    PubMed

    Chen, Ying; Wise, Steven M; Shenoy, Vivek B; Lowengrub, John S

    2014-07-01

    In this paper, we extend the 3D multispecies diffuse-interface model of the tumor growth, which was derived in Wise et al. (Three-dimensional multispecies nonlinear tumor growth-I: model and numerical method, J. Theor. Biol. 253 (2008) 524-543), and incorporate the effect of a stiff membrane to model tumor growth in a confined microenvironment. We then develop accurate and efficient numerical methods to solve the model. When the membrane is endowed with a surface energy, the model is variational, and the numerical scheme, which involves adaptive mesh refinement and a nonlinear multigrid finite difference method, is demonstrably shown to be energy stable. Namely, in the absence of cell proliferation and death, the discrete energy is a nonincreasing function of time for any time and space steps. When a simplified model of membrane elastic energy is used, the resulting model is derived analogously to the surface energy case. However, the elastic energy model is actually nonvariational because certain coupling terms are neglected. Nevertheless, a very stable numerical scheme is developed following the strategy used in the surface energy case. 2D and 3D simulations are performed that demonstrate the accuracy of the algorithm and illustrate the shape instabilities and nonlinear effects of membrane elastic forces that may resist or enhance growth of the tumor. Compared with the standard Crank-Nicholson method, the time step can be up to 25 times larger using the new approach. PMID:24443369

  2. Traveling wave solution of the Hele-Shaw model of tumor growth with nutrient

    E-print Network

    Traveling wave solution of the Hele-Shaw model of tumor growth with nutrient Beno^it Perthame¶ Min incorporate mechanical laws for tissue compression combined with rules for nutrients availability which can profiles are rather complex, both in one and two dimensions. We study a simple free boundary model formed

  3. The Hippo tumor-suppressor pathway regulates apical-domain size in parallel to tissue growth

    Microsoft Academic Search

    Fisun Hamaratoglu; Kathleen Gajewski; Leticia Sansores-Garcia; Clayton Morrison; Chunyao Tao; Georg Halder

    2009-01-01

    The Hippo tumor-suppressor pathway controls tissue growth in Drosophila and mammals by regulating cell proliferation and apoptosis. The Hippo pathway includes the Fat cadherin, a transmembrane protein, which acts upstream of several other components that form a kinase cascade that culminates in the regulation of gene expression through the transcriptional coactivator Yorkie (Yki). Our previous work in Drosophila indicated that

  4. Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

    E-print Network

    Hammock, Bruce D.

    Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis from omega-6 ARA and epoxydocosapentaenoic acids (EDPs) from omega-3 docosahexaenoic acid (DHA) (14­16). DHA, which is the most abundant omega-3 fatty acid in most tissues (17, 18), can efficiently compete

  5. Realistic Simulation of the 3D Growth of Brain Tumors in MR Images Coupling Diffusion with

    E-print Network

    Ayache, Nicholas

    1 Realistic Simulation of the 3D Growth of Brain Tumors in MR Images Coupling Diffusion Centre Antoine Lacassagne, Nice, France Computational Radiology Laboratory, Brigham and Women's Hospital or the ventricles. These different structures are introduced into the model using an atlas matching technique

  6. VEGFR-1 Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Growth

    PubMed Central

    Frank, Natasha Y.; Schatton, Tobias; Kim, Soo; Zhan, Qian; Wilson, Brian J.; Ma, Jie; Saab, Karim R.; Osherov, Veronika; Widlund, Hans R.; Gasser, Martin; Waaga-Gasser, Ana-Maria; Kupper, Thomas S.; Murphy, George F.; Frank, Markus H.

    2011-01-01

    Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5+ melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31? vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5+ MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5+ tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5+ subpopulations that constitutively expressed VEGFR-1 but not in ABCB5? bulk populations that were predominantly VEGFR-1?. In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5+ VM morphology and inhibited ABCB5+ VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. PMID:21212411

  7. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth.

    PubMed

    Frank, Natasha Y; Schatton, Tobias; Kim, Soo; Zhan, Qian; Wilson, Brian J; Ma, Jie; Saab, Karim R; Osherov, Veronika; Widlund, Hans R; Gasser, Martin; Waaga-Gasser, Ana-Maria; Kupper, Thomas S; Murphy, George F; Frank, Markus H

    2011-02-15

    Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5(+) melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31(-) vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5(+) MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5(+) tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5(+) subpopulations that constitutively expressed VEGFR-1 but not in ABCB5(-) bulk populations that were predominantly VEGFR-1(-). In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5(+) VM morphology and inhibited ABCB5(+) VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by > 90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. PMID:21212411

  8. A stable scheme for a nonlinear, multiphase tumor growth model with an elastic membrane

    PubMed Central

    Chen, Ying; Wise, Steven M.; Shenoy, Vivek B.; Lowengrub, John S.

    2014-01-01

    Summary In this paper, we extend the 3D multispecies diffuse-interface model of the tumor growth, which was derived in Wise et al. (Three-dimensional multispecies nonlinear tumor growth-I: model and numerical method, J. Theor. Biol. 253 (2008) 524–543), and incorporate the effect of a stiff membrane to model tumor growth in a confined microenvironment. We then develop accurate and efficient numerical methods to solve the model. When the membrane is endowed with a surface energy, the model is variational, and the numerical scheme, which involves adaptive mesh refinement and a nonlinear multigrid finite difference method, is demonstrably shown to be energy stable. Namely, in the absence of cell proliferation and death, the discrete energy is a nonincreasing function of time for any time and space steps. When a simplified model of membrane elastic energy is used, the resulting model is derived analogously to the surface energy case. However, the elastic energy model is actually nonvariational because certain coupling terms are neglected. Nevertheless, a very stable numerical scheme is developed following the strategy used in the surface energy case. 2D and 3D simulations are performed that demonstrate the accuracy of the algorithm and illustrate the shape instabilities and nonlinear effects of membrane elastic forces that may resist or enhance growth of the tumor. Compared with the standard Crank–Nicholson method, the time step can be up to 25 times larger using the new approach. PMID:24443369

  9. Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model

    SciTech Connect

    Yin, Shu-Cheng [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China) [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Department of Otolaryngology – Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Guo, Wei [Department of Otolaryngology – Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China)] [Department of Otolaryngology – Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Tao, Ze-Zhang, E-mail: zezhangtao@gmail.com [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China)] [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China)

    2013-09-13

    Highlights: •We identified that PPP inhibits IGF-1R/Akt pathway in NPC cells. •PPP dose-dependently inhibits NPC cell proliferation in vitro. •PPP suppresses tumor growth of NPC in nude mice. •PPP have little effect on microtubule assembly. -- Abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor with tyrosine kinase activity and plays important roles in cell transformation, tumor growth, tumor invasion, and metastasis. Picropodophyllin (PPP) is a selective IGF-1R inhibitor and shows promising antitumor effects for several human cancers. However, its antitumor effects in nasopharyngeal carcinoma (NPC) remain unclear. The purpose of this study is to investigate the antitumor activity of PPP in NPC using in vitro cell culture and in vivo animal model. We found that PPP dose-dependently decreased the IGF-induced phosphorylation and activity of IGF-1R and consequently reduced the phosphorylation of Akt, one downstream target of IGF-1R. In addition, PPP inhibited NPC cell proliferation in vitro. The half maximal inhibitory concentration (IC50) of PPP for NPC cell line CNE-2 was ?1 ?M at 24 h after treatment and ?0.5 ?M at 48 h after treatment, respectively. Moreover, administration of PPP by intraperitoneal injection significantly suppressed the tumor growth of xenografted NPC in nude mice. Taken together, these results suggest targeting IGF-1R by PPP may represent a new strategy for treatment of NPCs with positive IGF-1R expression.

  10. A multicompartment mathematical model of cancer stem cell-driven tumor growth dynamics.

    PubMed

    Weekes, Suzanne L; Barker, Brian; Bober, Sarah; Cisneros, Karina; Cline, Justina; Thompson, Amanda; Hlatky, Lynn; Hahnfeldt, Philip; Enderling, Heiko

    2014-07-01

    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 reinitiate 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

  11. Extinction Effects of Multiplicative Non-Gaussian Lévy Noise in a Tumor Growth System with Immunization

    NASA Astrophysics Data System (ADS)

    Hao, Meng-Li; Xu, Wei; Li, Dong-Xi; Liu, Di

    2014-05-01

    The extinction phenomenon induced by multiplicative non-Gaussian Lévy noise in a tumor growth model with immune response is discussed. Under the influence of the stochastic immune rate, the model is analyzed in terms of a stochastic differential equation with multiplicative noise. By means of the theory of the infinitesimal generator of Hunt processes, the escape probability, which is used to measure the noise-induced extinction probability of tumor cells, is explicitly expressed as a function of initial tumor cell density, stability index and noise intensity. Based on the numerical calculations, it is found that for different initial densities of tumor cells, noise parameters play opposite roles on the escape probability. The optimally selected values of the multiplicative noise intensity and the stability index are found to maximize the escape probability.

  12. Growth delay as an index of allostatic load in young children: predictions to disinhibited social approach and diurnal cortisol activity.

    PubMed

    Johnson, Anna E; Bruce, Jacqueline; Tarullo, Amanda R; Gunnar, Megan R

    2011-08-01

    The goal of this study was to examine whether growth delay can serve as an index of allostatic load during early development, as it is well known that the activity of stress-mediating systems inhibits growth. The participants were children adopted internationally from institutional care (n = 36), children adopted internationally from foster care (n = 26), and nonadopted children (n = 35). For the adopted children, height for age and weight for height were assessed at adoption; for all children, disinhibited social approach (DSA; termed elsewhere as "indiscriminate friendliness") and diurnal cortisol were assessed at 6-8 years (M = 6.9 years). For internationally adopted children in general, and postinstitutionalized children specifically, linear growth delay assessed at the time of adoption was associated with more dysregulated behavior in response to an unfamiliar adult (i.e., greater DSA) and a more dysregulated diurnal cortisol rhythm (i.e., higher late afternoon and evening values). Further, among the most growth-delayed children, higher cortisol levels later in the day were correlated with DSA. The potential for using growth delay as an allostatic load indicator and the possible problems and limitations in its use in child populations are discussed. PMID:21756437

  13. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis.

    PubMed

    Liu, Lei; Sun, Lu; Wu, Qinjie; Guo, Wenhao; Li, Ling; Chen, YiShan; Li, Yuchen; Gong, Changyang; Qian, Zhiyong; Wei, Yuquan

    2013-02-25

    This work aims to develop curcumin (Cur) loaded biodegradable self-assembled polymeric micelles (Cur-M) to overcome poor water solubility of Cur and to meet the requirement of intravenous administration. Cur-M were prepared by solid dispersion method, which was simple and easy to scale up. Cur-M had a small particle size of 28.2 ± 1.8 nm and polydisperse index (PDI) of 0.136 ± 0.050, and drug loading and encapsulation efficiency of Cur-M were 14.84 ± 0.11% and 98.91 ± 0.70%, respectively. Besides, in vitro release profile showed a significant difference between rapid release of free Cur and much slower and sustained release of Cur-M. Cytotoxicity study showed that the encapsulated Cur remained its potent anti-tumor effect. Furthermore, Cur-M were more effective in inhibiting tumor growth and spontaneous pulmonary metastasis in subcutaneous 4T1 breast tumor model, and prolonged survival of tumor-bearing mice. In addition, immunofluorescent and immunohistochemical studies also showed that tumors of Cur-M-treated mice had more apoptosis cells, fewer microvessels, and fewer proliferation-positive cells. In conclusion, polymeric micelles encapsulating Cur were developed with enhanced anti-tumor and anti-metastasis activity on breast tumor, and Cur-M is excellent water-based formulation of Cur which may serve as a candidate for breast cancer therapy. PMID:23287774

  14. A nanoparticle system specifically designed to deliver short interfering RNA inhibits tumor growth in vivo.

    PubMed

    Yagi, Nobuhiro; Manabe, Ichiro; Tottori, Tsuneaki; Ishihara, Atsushi; Ogata, Fusa; Kim, Jong Heon; Nishimura, Satoshi; Fujiu, Katsuhito; Oishi, Yumiko; Itaka, Keiji; Kato, Yasuki; Yamauchi, Masahiro; Nagai, Ryozo

    2009-08-15

    Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the "wrapsome" (WS), which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. WS protected siRNA from enzymatic digestion, providing a long half-life in the systemic circulation. Moreover, siRNA/WS leaked from blood vessels within tumors into the tumor tissue, where it accumulated and was subsequently transfected into the tumor cells. Because the transcription factor KLF5 is known to play a role in tumor angiogenesis, we designed KLF5-siRNA to test the antitumor activity of siRNA/WS. KLF5-siRNA/WS exhibited significant antitumor activity, although neither WS containing control scrambled-siRNA nor saline containing KLF5-siRNA affected tumor growth. KLF5-siRNA/WS inhibited Klf5 expression within tumors at both mRNA and protein levels, significantly reducing angiogenesis, and we detected no significant acute or long-term toxicity. Our findings support the idea that siRNA/WS can be used to knock down specific genes within tumors and thereby exert therapeutic effects against cancers. PMID:19654315

  15. Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer12

    PubMed Central

    Park, Jae-Hyun; Rasch, Morten Grønbech; Qiu, Jing; Lund, Ida Katrine; Egeblad, Mikala

    2015-01-01

    The stroma of breast cancer can promote the disease’s progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV)–Neu] and a triple-negative/basal-like [C3(1)–Simian virus 40 large T antigen (Tag)] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9), an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1)-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1), an MMP9 substrate, were increased in C3(1)-Tag;Mmp9?/? compared to C3(1)-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1)-Tag;Mmp9?/? mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed. PMID:26025665

  16. Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth

    Microsoft Academic Search

    David Lyden; Koichi Hattori; Sergio Dias; Carla Costa; Pamela Blaikie; Linda Butros; Amy Chadburn; Beate Heissig; Willy Marks; Larry Witte; Yan Wu; Daniel Hicklin; Zhenping Zhu; Neil R. Hackett; Ronald G. Crystal; Malcolm A. S. Moore; Katherine A. Hajjar; Katia Manova; Robert Benezra; Shahin Rafii

    2001-01-01

    The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and

  17. 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. PMID:19726870

  18. Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer

    PubMed Central

    Rastelli, Antonella L.; Miles, Kiersten Marie; Ciamporcero, Eric; Longo, Valter D.; Nguyen, Holly; Vessella, Robert; Pili, Roberto

    2013-01-01

    Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer. Experimental Design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models. Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet. Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications. PMID:24353195

  19. Efficacy of local delivery of ardipusilloside I using biodegradable implants against cerebral tumor growth.

    PubMed

    Dang, Huan; Wang, Ji; Cheng, Jiang-Xue; Wang, Peng-Yuan; Wang, Ying; Cheng, Li-Fei; Du, Caigan; Wang, Xiao-Juan

    2015-01-01

    Ardipusilloside I (ADS-I) is a natural compound that can be isolated from the Chinese medicinal herb Ardisiapusilla A.DC, and has been reported to inhibit the growth of glioblastoma cells in cultures. This study was designed to test its efficacy by the delivery using biodegradable implants against glioblastoma in vivo. ADS-I was incorporated into polymer microspheres, which were prepared by a mixture of poly (D, L-lactic acid) and poly (D, L-lactic-co-glycolic acid) polymers and then fabricated into wafers. The anti-glioma activities of ADS-I-loaded wafers were examined by methylthiazol tetrazolium (MTT) assay in cultured rat C6 glioma cells, and by magnetic resonance imaging (MRI) and survival monitoring in C6 glioma-bearing rats. Here, we showed that ADS-I-loaded wafers sustained ADS-I release in vitro for 36 days in Higuchi model of kinetics, and had the same cytotoxic activity as ADS-I in the solution against the growth of C6 glioma cells in cultures. In C6 glioma-bearing rats, ADS-I wafer implants inhibited tumor growth in a dose-dependent matter, and were more effective than the same dosage of ADS-I in the solution. The tumor suppression efficacies of ADS-I wafer implants were positively correlated with an increase in tumor cell apoptosis and prolonged animal survival, and were associated with a decrease in vascular endothelial growth factor, C-reactive protein, tumor necrosis factor-? and interleukin-6, and an increase in interleukin-2 expression. In conclusion, this study demonstrates significant efficacy of local delivery of ADS-I using polymer implants against glioma tumor growth in vivo, suggesting the potential of ADS-I-loaded wafers for glioma treatment. PMID:25628934

  20. Sclareol modulates the Treg intra-tumoral infiltrated cell and inhibits tumor growth in vivo

    Microsoft Academic Search

    Shokoofe Noori; Zuhair M. Hassan; Mehdi Mohammadi; Zohre Habibi; Nooshin Sohrabi; Saeed Bayanolhagh

    2010-01-01

    A regulatory or suppressor T cell is functionally defined as a T cell that inhibits an immune response by influencing the activity of another cell type. On the other hand, Th1 cells express IFN-? and mediate cellular immunity.Sclareol exhibits growth inhibition and cytotoxic activity against a variety of human cancer cell lines. In the first set of experiments, Sclareol was

  1. miR-205 is frequently downregulated in prostate cancer and acts as a tumor suppressor by inhibiting tumor growth

    PubMed Central

    Wang, Ning; Li, Qi; Feng, Ning-Han; Cheng, Gong; Guan, Zhao-Long; Wang, Yang; Qin, Chao; Yin, Chang-Jun; Hua, Li-Xin

    2013-01-01

    The purpose of this study was to elucidate the molecular mechanisms of microRNA-205 (miR-205) as a tumor suppressor in prostate cancer (PCa). In the present study, microRNA microarray analysis suggested that the expression of miR-205 was significantly decreased in advanced PCa compared with early PCa. Real-time PCR analysis also indicated that miR-205 expression was significantly decreased in PCa tissues compared with non-cancerous tissues. Moreover, the expression of miR-205 has been demonstrated to be associated with the clinicopathological stage and total/free prostate-specific antigen (PSA) level of PCa. Functional analyses showed that both the overexpression of miR-205 and the knockdown of c-SRC in PCa cell lines could inhibit cell growth, colony formation, migration, invasion and the cell cycle as well as induce cell apoptosis in vitro. Furthermore, over-expressing miR-205 reduced tumorigenicity in vivo. Through a luciferase activity assay and Western blotting, c-SRC was identified as a target of miR-205 in cells. The overexpression of miR-205 suppressed c-SRC and its downstream signaling molecules, including FAK, p-FAK, ERK1/2 and p-ERK1/2, and attenuated cell proliferation, invasion and tumor growth. PMID:23974361

  2. Prostate-Specific Antigen Modulates the Expression of Genes Involved in Prostate Tumor Growth1

    PubMed Central

    Bindukumar, B; Schwartz, Stanley A; Nair, Madhavan P N; Aalinkeel, Ravikumar; Kawinski, Elzbieta; Chadha, Kailash C

    2005-01-01

    Abstract Prostate-specific antigen (PSA) is a serine protease that is widely used as a surrogate marker in the early diagnosis and management of prostate cancer. The physiological relevance of tissue PSA levels and their role in prostate tumor growth and metastasis are not known. Free-PSA (f-PSA) was purified to homogeneity from human seminal plasma by column chromatography, eliminating hk2 and all known PSA complexes and retaining its protease activity. Confluent mono-layers of prostate cancer cell lines, PC-3M and LNCaP, were treated with f-PSA in a series of in vitro experiments to determine the changes in expression of various genes that are known to regulate tumor growth and metastasis. Gene array, quantitative polymerase chain reaction (QPCR), and enzyme-linked immunosorbent assay (ELISA) results show significant changes in the expression of various cancer-related genes in PC-3M and LNCaP cells treated with f-PSA. In a gene array analysis of PC-3M cells treated with 10 µM f-PSA, 136 genes were upregulated and 137 genes were downregulated. In LNCaP cells treated with an identical concentration of f-PSA, a total of 793 genes was regulated. QPCR analysis reveals that the genes for urokinase-type plasminogen activator (uPA), VEGF, and Pim-1 oncogene, known to promote tumor growth, were significantly downregulated, whereas IFN-?, known to be a tumor-suppressor gene, was significantly upregulated in f-PSA-treated PC-3M cells. The effect of f-PSA on VEGF and IFN-? gene expression and on protein release in PC-3M cells was distinctly dose-dependent. In vivo studies showed a significant reduction (P = .03) in tumor load when f-PSA was administered in the tumor vicinity of PC-3M tumor-bearing BALB/c nude mice. Our data support the hypothesis that f-PSA plays a significant role in prostate tumor growth by regulating various proangiogenic and antiangiogenic growth factors. PMID:15799824

  3. Mean 24-hour growth hormone and testosterone concentrations in relation to pubertal growth spurt in boys with normal or delayed puberty

    Microsoft Academic Search

    O. Butenandt; R. Eder; K. Wohlfarth; F. Bidlingmaier; D. Knorr

    1976-01-01

    The mean growth hormone concentration during a 24-hour period in 7 boys of short familial stature and a growth rate of 3.2–5.4 cm\\/year was between 1.0 and 4.6 ng\\/ml serum. In 7 boys with pubertal growth spurt and familial tallness (growth rate 7.2–11.0 cm\\/year) it varied from 0.97 to 4.4 ng\\/ml and in 6 boys with constitutional delay of puberty

  4. Inhibition of Receptor Signaling and of Glioblastoma-derived Tumor Growth by a Novel PDGFR? Aptamer

    PubMed Central

    Camorani, Simona; Esposito, Carla L; Rienzo, Anna; Catuogno, Silvia; Iaboni, Margherita; Condorelli, Gerolama; de Franciscis, Vittorio; Cerchia, Laura

    2014-01-01

    Platelet-derived growth factor receptor ? (PDGFR?) is a cell-surface tyrosine kinase receptor implicated in several cellular processes including proliferation, migration, and angiogenesis. It represents a compelling therapeutic target in many human tumors, including glioma. A number of tyrosine kinase inhibitors under development as antitumor agents have been found to inhibit PDGFR?. However, they are not selective as they present multiple tyrosine kinase targets. Here, we report a novel PDGFR?-specific antagonist represented by a nuclease-resistant RNA-aptamer, named Gint4.T. This aptamer is able to specifically bind to the human PDGFR? ectodomain (Kd: 9.6?nmol/l) causing a strong inhibition of ligand-dependent receptor activation and of downstream signaling in cell lines and primary cultures of human glioblastoma cells. Moreover, Gint4.T aptamer drastically inhibits cell migration and proliferation, induces differentiation, and blocks tumor growth in vivo. In addition, Gint4.T aptamer prevents PDGFR? heterodimerization with and resultant transactivation of epidermal growth factor receptor. As a result, the combination of Gint4.T and an epidermal growth factor receptor–targeted aptamer is better at slowing tumor growth than either single aptamer alone. These findings reveal Gint4.T as a PDGFR?-drug candidate with translational potential. PMID:24566984

  5. Investigation of HT1080 tumor growth dynamics and ECM invasion in 3D

    NASA Astrophysics Data System (ADS)

    Yogurtcu, Osman; Jimenez Valencia, Angela; Lee, Meng-Horng; Sun, Sean; Wirtz, Denis

    2013-03-01

    Tumors are complex arrangements of tissues made up of several components, including dense masses of cancer cells and re-organized extracellular matrix (ECM). Recent studies have revealed the crucial role that extracellular matrix components have on single cancer cell behavior, but how the interaction of ECM components affects the growth dynamics of an entire tumor is not fully understood. Here, we use human derived fibrosarcoma cell (HT1080) aggregates in combination with live cell imaging, cryo-stat sectioning, immunostaining, and confocal imaging to study changes in cell aggregate size, proliferation, and spatial distribution within 3 dimensional (3D) matrices. We compare our experimental observations with a coupled partial differential equations based mathematical model to predict cell aggregate growth and cell density distribution and determine how cell interactions play a significant role in this dynamic growth. Using this model, we investigate the distinct contributions from cell migration, proliferation, cell-matrix interactions, and matrix remodeling to the aggregate dynamics.

  6. A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.

    PubMed

    Fontenot, Emily; Rossi, Emma; Mumper, Russell; Snyder, Stephanie; Siamakpour-Reihani, Sharareh; Ma, Ping; Hilliard, Eleanor; Bone, Bradley; Ketelsen, David; Santos, Charlene; Patterson, Cam; Klauber-DeMore, Nancy

    2013-05-01

    Secreted frizzled-related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer and stimulates angiogenesis via activation of the calcineurin/NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of ?-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling and to evaluate whether SFRP2 is a viable therapeutic target. The antiangiogenic and antitumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, tube formation assays, and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor-bearing and nontumor-bearing mice. SFRP2 mAb was shown to induce antitumor and antiangiogenic effects in vitro and inhibit activation of ?-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared with control (P = 0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (P = 0.03) compared with control, whereas bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of ?-catenin and NFATc3 in endothelial and tumor cells and is a novel therapeutic approach for inhibiting angiosarcoma and triple-negative breast cancer. PMID:23604067

  7. Tumor-promoting functions of transforming growth factor-? in progression of cancer

    PubMed Central

    2012-01-01

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

  8. Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver.

    PubMed

    Bayón, L G; Izquierdo, M A; Sirovich, I; van Rooijen, N; Beelen, R H; Meijer, S

    1996-05-01

    Metastasis to the liver is a common event in clinical oncology. Blood-borne tumor cells (TCs) arriving to the liver sinusoids run into a special vascular bed. The lining of liver sinusoids is shared by Kupffer cells (KCs) and endothelial cells. KCs, liver-fixed macrophages, are responsible for detection and removal of "non-self" particles. To investigate their role in arresting blood-borne TCs and controlling tumor growth, we injected a syngeneic colon carcinoma cell line into a mesenteric vein of two groups of rats; one group was without Kupffer cells and the other normal controls. We removed the liver of these animals at different time intervals and performed immunohistochemical analysis with monoclonal antibodies (MoAbs) against our tumor cell line, three macrophage subpopulations, natural killer cells, and B and T lymphocytes. Additionally, we showed in vitro spontaneous cytotoxicity of KCs against our tumor cell line. Results suggest that KCs play a relevant role in arresting circulating TCs at the liver sinusoid, although it is limited to a small number of malignant cells. They also seem to play a major role in clearing neoplastic cells from the liver parenchyma, in controlling tumor growth in the very early stages of metastatic development, and in modulating the host immune response to cancer cells. PMID:8621157

  9. Blocking IL1? Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis.

    PubMed

    Voloshin, Tali; Alishekevitz, Dror; Kaneti, Limor; Miller, Valeria; Isakov, Elina; Kaplanov, Irena; Voronov, Elena; Fremder, Ella; Benhar, Moran; Machluf, Marcelle; Apte, Ron N; Shaked, Yuval

    2015-06-01

    Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here, we show that the proinflammatory cytokine IL1? is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL1?, or its receptor, using either genetic or pharmacologic approach, results in slight retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL1 receptor antagonist anakinra exhibit increased number of M2 macrophages and vessel leakiness when compared with paclitaxel monotherapy-treated mice, indicating a prometastatic role of M2 macrophages in the IL1?-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL1 pathway on tumor growth. Accordingly, treatments using "add-on" drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases. Mol Cancer Ther; 14(6); 1385-94. ©2015 AACR. PMID:25887886

  10. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.

    PubMed Central

    Pezzella, F.; Pastorino, U.; Tagliabue, E.; Andreola, S.; Sozzi, G.; Gasparini, G.; Menard, S.; Gatter, K. C.; Harris, A. L.; Fox, S.; Buyse, M.; Pilotti, S.; Pierotti, M.; Rilke, F.

    1997-01-01

    Neoplastic growth is usually dependent on blood supply, and it is commonly accepted that this is provided by the formation of new vessels. However, tumors may be able to grow without neovascularization if they find a suitable vascular bed available. We have investigated the pattern of vascularization in a series of 500 primary stage I non-small-cell lung carcinomas. Immunostaining of endothelial cells has highlighted four distinct patterns of vascularization. Three patterns (which we called basal, papillary, and diffuse) have in common the destruction of normal lung and the production of newly formed vessels and stroma. The fourth pattern, which we called alveolar or putative nonangiogenic, was observed in 16% (80/500) of the cases and is characterized by lack of parenchymal destruction and absence of both tumor associated stroma and new vessels. The only vessels present were the ones in the alveolar septa, and their presence highlighted, through the whole tumor, the lung alveoli filled up by the neoplastic cells. This observation suggests that, if an appropriate vascular bed is available, a tumor can exploit it and grows without inducing neo-angiogenesis. This could have implications for strategies aimed at inhibiting tumor growth by vascular targeting or inhibition of angiogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9358768

  11. Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich’s Ascites Tumor in Mice

    PubMed Central

    Singh, Saurabh; Pandey, Sanjay; Bhatt, Anant Narayan; Chaudhary, Richa; Bhuria, Vikas; Kalra, Namita; Soni, Ravi; Roy, Bal Gangadhar; Saluja, Daman; Dwarakanath, Bilikere S.

    2015-01-01

    Background Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis. Methodology/Principal Findings Swiss albino strain ‘A’ mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich’s ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1?) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function. Conclusion/Significance These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy. PMID:26135741

  12. Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects.

    PubMed

    Luo, Xiaoji; Chen, Jin; Song, Wen-Xin; Tang, Ni; Luo, Jinyong; Deng, Zhong-Liang; Sharff, Katie A; He, Gary; Bi, Yang; He, Bai-Cheng; Bennett, Erwin; Huang, Jiayi; Kang, Quan; Jiang, Wei; Su, Yuxi; Zhu, Gao-Hui; Yin, Hong; He, Yun; Wang, Yi; Souris, Jeffrey S; Chen, Liang; Zuo, Guo-Wei; Montag, Anthony G; Reid, Russell R; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan

    2008-12-01

    Osteosarcoma (OS) is the most common primary malignancy of bone. Here, we investigated a possible role of defective osteoblast differentiation in OS tumorigenesis. We found that basal levels of the early osteogenic marker alkaline phosphatase (ALP) activity were low in OS lines. Osteogenic regulators Runx2 and OSX, and the late marker osteopontin (OPN) expressed at low levels in most OS lines, indicating that most OS cells fail to undergo terminal differentiation. Furthermore, OS cells were refractory to osteogenic BMP-induced increases in ALP activity. Osteogenic BMPs were shown to upregulate early target genes, but not late osteogenic markers OPN and osteocalcin (OC). Furthermore, osteogenic BMPs failed to induce bone formation from human OS cells, rather effectively promoted OS tumor growth in an orthotopic OS model. Exogenous expression of early target genes enhanced BMP-stimulated OS tumor growth, whereas osteogenic BMP-promoted OS tumor growth was inhibited by exogenous Runx2 expression. These results suggest that alterations in osteoprogenitors may disrupt osteogenic differentiation pathway. Thus, identifying potential differentiation defects in OS tumors would allow us to reconstruct the tumorigenic events in osteoprogenitors and to develop rational differentiation therapies for clinical OS management. PMID:18838962

  13. In vivo tumor growth inhibition and biodistribution studies of locked nucleic acid (LNA) antisense oligonucleotides

    PubMed Central

    Fluiter, Kees; ten Asbroek, Anneloor L. M. A.; de Wissel, Marit B.; Jakobs, Marja E.; Wissenbach, Margit; Olsson, Håkan; Olsen, Otto; Oerum, Henrik; Baas, Frank

    2003-01-01

    Locked nucleic acids (LNA) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. The LNA oligonucleotides (LNA PO ODNs) are very stable in vitro and in vivo without the need for a phosphorothiolated backbone. In this study we tested the biological fate and the efficacy in tumor growth inhibition of antisense oligonucleotides directed against the gene of the large subunit of RNA polymerase II (POLR2A) that are completely synthesized as LNA containing diester backbones. These full LNA oligonucleotides strongly reduce POLR2A protein levels. Full LNA PO ODNs appeared to be very stable compounds when injected into the circulation of mice. Full LNA PO ODNs were continuously administered for 14 days to tumor-bearing nude mice. Tumor growth was inhibited sequence specifically at dosages from 1 mg/kg/day. LNA PO ODNs appeared to be non-toxic at dosages <5 mg/kg/day. Biodistribution studies showed the kidneys to have the highest uptake of LNA PO ODNs and urinary secretion as the major route of clearance. This report shows that LNA PO ODNs are potent genotype-specific drugs that can inhibit tumor growth in vivo. PMID:12560491

  14. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis

    PubMed Central

    XIAN, SHU-LIN; CAO, WEI; ZHANG, XIAO-DONG; LU, YUN-FEI

    2015-01-01

    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. PMID:25621044

  15. Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth

    PubMed Central

    Hitosugi, Taro; Kang, Sumin; Vander Heiden, Matthew G.; Chung, Tae-Wook; Elf, Shannon; Lythgoe, Katherine; Dong, Shaozhong; Lonial, Sagar; Wang, Xu; Chen, Georgia Z.; Xie, Jianxin; Gu, Ting-Lei; Polakiewicz, Roberto D.; Roesel, Johannes L.; Boggon, Titus J.; Khuri, Fadlo R.; Gilliland, D. Gary; Cantley, Lewis C.; Kaufman, Jonathan; Chen, Jing

    2010-01-01

    The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth. PMID:19920251

  16. LXR-dependent and -independent effects of oxysterols on immunity and tumor growth.

    PubMed

    Traversari, Catia; Sozzani, Silvano; Steffensen, Knut R; Russo, Vincenzo

    2014-07-01

    Oxysterols are involved in maintaining cellular cholesterol levels. Recently, oxysterols have been demonstrated to modulate the function of immune cells and tumor growth. These effects can be dependent on the activation of the oxysterol-binding liver X receptors (LXRs) or, as recently demonstrated for T and B cells, DCs and neutrophils, can be independent of LXR activation. LXR-dependent oxysterol effects can be ascribed to the activation of LXR?, LXR? or LXR?? isoforms, which induces transcriptional activation or trans-repression of target genes. The prevalent activation of one isoform seems to be cell-, tissue-, or context-specific, as shown in some pathologic processes, i.e., infectious diseases, atherosclerosis, and autoimmunity. Oxysterol-LXR signaling has recently been shown to inhibit antitumor immune responses, as well as to modulate tumor cell growth. Here, we review the mechanisms that link oxysterols to tumor growth, and discuss possible networks at the basis of LXR-dependent and -independent oxysterol effects on immune cells and tumor development. PMID:24777958

  17. Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis.

    PubMed

    Chen, Sidi; Sanjana, Neville E; Zheng, Kaijie; Shalem, Ophir; Lee, Kyungheon; Shi, Xi; Scott, David A; Song, Jun; Pan, Jen Q; Weissleder, Ralph; Lee, Hakho; Zhang, Feng; Sharp, Phillip A

    2015-03-12

    Genetic screens are powerful tools for identifying genes responsible for diverse phenotypes. Here we describe a genome-wide CRISPR/Cas9-mediated loss-of-function screen in tumor growth and metastasis. We mutagenized a non-metastatic mouse cancer cell line using a genome-scale library with 67,405 single-guide RNAs (sgRNAs). The mutant cell pool rapidly generates metastases when transplanted into immunocompromised mice. Enriched sgRNAs in lung metastases and late-stage primary tumors were found to target a small set of genes, suggesting that specific loss-of-function mutations drive tumor growth and metastasis. Individual sgRNAs and a small pool of 624 sgRNAs targeting the top-scoring genes from the primary screen dramatically accelerate metastasis. In all of these experiments, the effect of mutations on primary tumor growth positively correlates with the development of metastases. Our study demonstrates Cas9-based screening as a robust method to systematically assay gene phenotypes in cancer evolution in vivo. PMID:25748654

  18. Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

    NASA Astrophysics Data System (ADS)

    Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

    2014-03-01

    Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

  19. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases.

    PubMed

    Sottnik, Joseph L; Dai, Jinlu; Zhang, Honglai; Campbell, Brittany; Keller, Evan T

    2015-06-01

    Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. Cancer Res; 75(11); 2151-8. ©2015 AACR. PMID:25855383

  20. Casein kinase 2? regulates glioblastoma brain tumor-initiating cell growth through the ?-catenin pathway.

    PubMed

    Nitta, R T; Gholamin, S; Feroze, A H; Agarwal, M; Cheshier, S H; Mitra, S S; Li, G

    2015-07-01

    Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2?, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2? had enhanced proliferation and anchorage-independent growth. Inhibition of CK? using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2? decreased the activity of a well-known GBM-initiating cell regulator, ?-catenin. Loss of CK2? decreased two ?-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2? in GBM stem cell maintenance, we reduced CK2? activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2? activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2? is involved in GBM tumorigenesis by maintaining BTIC through the regulation of ?-catenin. PMID:25241897

  1. Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth.

    PubMed

    Munguia, A; Ota, T; Miest, T; Russell, S J

    2008-05-01

    Multiple myeloma (MM) is a disseminated malignancy of antibody secreting plasma cells that localize primarily to the bone marrow. Several studies have illustrated the potential of utilizing oncolytic viruses (measles, vaccinia, Vesicular Stomatitis Virus and coxsackievirus A21) for the treatment of MM, but there are significant barriers that prevent the viruses from reaching sites of myeloma tumor growth after intravenous delivery. The most important barriers are failure to extravasate from tumor blood vessels, mislocalization of the viruses in liver and spleen and neutralization by antiviral antibodies. In this review, we discuss the use of various cell types as carriers to overcome these barriers, emphasizing their relative susceptibilities to virus infection and their variable trafficking properties. Mesenchymal progenitor cells, monocytes and T cells have all shown promise as virus-delivery vehicles capable of accessing sites of myeloma growth. However, a previously unexplored alternative would be to use primary myeloma cells, or even myeloma cell lines, as delivery vehicles. Advantages of this approach are the natural ability of myeloma cells to home to sites of myeloma tumor growth and their compatibility with tumor-specific viruses that cannot propagate in other carrier cell lineages. A potential difficulty associated with the use of myeloma cells for virus delivery is that they must be exposed to supralethal doses of ionizing radiation before they can be safely administered to patients. Preliminary studies are presented in which we demonstrate the feasibility of using irradiated myeloma cells as carriers to deliver oncolytic viruses to sites of myeloma tumor growth in an orthotopic human myeloma model. PMID:18356812

  2. 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

  3. THE BISPHOSPHONATE ZOLEDRONIC ACID DECREASES TUMOR GROWTH IN BONE IN MICE WITH DEFECTIVE OSTEOCLASTS*

    PubMed Central

    Hirbe, Angela C.; Roelofs, Anke J.; Floyd, Desiree H.; Deng, Hongju; Becker, Stephanie N.; Lanigan, Lisa G.; Apicelli, Anthony J.; Xu, Zhiqiang; Prior, Julie L.; Eagleton, Mark C.; Piwnica-Worms, David; Rogers, Michael J.; Weilbaecher, Katherine

    2009-01-01

    Bisphosphonates (BPs), bone targeted drugs that disrupt osteoclast function, are routinely used to treat complications of bone metastasis. Studies in preclinical models of cancer have shown that BPs reduce skeletal tumor burden and increase survival. Similarly, we observed in the present study that administration of the Nitrogen-containing BP (N-BP), zoledronic acid (ZA) to osteolytic tumor-bearing Tax+ mice beginning at 6 months of age led to resolution of radiographic skeletal lesions. N-BPs inhibit farnesyl diphosphate (FPP) synthase, thereby inhibiting protein prenylation and causing cellular toxicity. We found that ZA decreased Tax+ tumor and B16 melanoma viability and caused the accumulation of unprenylated Rap1a proteins in vitro. However, it is presently unclear whether N-BPs exert anti-tumor effects in bone independent of inhibition of osteoclast (OC) function in vivo. Therefore, we evaluated the impact of treatment with ZA on B16 melanoma bone tumor burden in irradiated mice transplanted with splenic cells from src-/- mice, which have non-functioning OCs. OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis. PMID:19442620

  4. A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth.

    PubMed

    Farnsworth, Rae H; Karnezis, Tara; Shayan, Ramin; Matsumoto, Masataka; Nowell, Cameron J; Achen, Marc G; Stacker, Steven A

    2011-10-15

    Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4-expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D-driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent. PMID:21868759

  5. Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

    PubMed Central

    Bird, Lina J.; Coleman, Maureen L.

    2013-01-01

    Transition metals are known to cause toxic effects through their interaction with oxygen, but toxicity under anoxic conditions is poorly understood. Here we investigated the effects of iron (Fe) and copper (Cu) on the anaerobic growth and gene expression of the purple phototrophic bacterium Rhodopseudomonas palustris TIE-1. We found that Fe(II) and Cu(II) act synergistically to delay anaerobic growth at environmentally relevant metal concentrations. Cu(I) and Cu(II) had similar effects both alone and in the presence of ascorbate, a Cu(II) reductant, indicating that reduction of Cu(II) to Cu(I) by Fe(II) is not sufficient to explain the growth inhibition. Addition of Cu(II) increased the toxicity of Co(II) and Ni(II); in contrast, Ni(II) toxicity was diminished in the presence of Fe(II). The synergistic anaerobic toxicity of Fe(II) and Cu(II) was also observed for Escherichia coli MG1655, Shewanella oneidensis MR-1, and Rhodobacter capsulatus SB1003. Gene expression analyses for R. palustris identified three regulatory genes that respond to Cu(II) and not to Fe(II): homologs of cueR and cusR, two known proteobacterial copper homeostasis regulators, and csoR, a copper regulator recently identified in Mycobacterium tuberculosis. Two P-type ATPase efflux pumps, along with an FoF1 ATP synthase, were also upregulated by Cu(II) but not by Fe(II). An Escherichia coli mutant deficient in copA, cus, and cueO showed a smaller synergistic effect, indicating that iron might interfere with one or more of the copper homeostasis systems. Our results suggest that interactive effects of transition metals on microbial physiology may be widespread under anoxic conditions, although the molecular mechanisms remain to be more fully elucidated. PMID:23563938

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

    SciTech Connect

    Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)] [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China)] [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)] [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China)] [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China)] [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States)] [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China) [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    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 been studied in vitro and in vivo. ? CYP4Z1 regulates expression and production of VEGF-A and TIMP-2. ? CYP4Z1-induced angiogenesis is associated with PI3K and ERK1/2 activation. ? CYP4Z1 may be an attractive target for anti-cancer therapy.

  7. Oral administration of Polypodium leucotomos delays skin tumor development and increases epidermal p53 expression and the anti-oxidant status of UV-irradiated hairless mice.

    PubMed

    Rodríguez-Yanes, Esperanza; Cuevas, Jesús; González, Salvador; Mallol, Jordi

    2014-07-01

    Chronic exposure to ultraviolet radiation (UVR) induces skin tumors in hairless mice. Daily oral administration of a Polypodium leucotomos (PL) extract significantly delayed tumor development in PL-treated versus non-PL-treated mice. UVR and/or PL treatment modified several oxidative stress markers. In all irradiated mice, erythrocytic glutathione S-transferase (GST) activity and glutathione disulphide (GSSG) content increased and in all PL-treated mice GSSG content decreased, specially in non-irradiated animals, and total plasma anti-oxidant capacity (ORAC) increased. In dorsolateral non-tumoral skin of all irradiated mice, glutathione reductase (GR) and glutathione peroxidase (GPx) activities increased and GSSG decreased in non-irradiated PL-treated animals. UVR induced a steep increase of p53 expression in epidermal cells. In non-tumoral skin, this increase was significantly higher in PL-treated animals than in non-treated mice and can contribute in delaying tumor development, either by repairing the damaged DNA or by increasing apoptosis. These results reinforce the usefulness of PL as systemic photoprotective agent, especially in patients highly sensitive to UVR. PMID:24862559

  8. Targeted Resequencing of the Pericentromere of Chromosome 2 Linked to Constitutional Delay of Growth and Puberty

    PubMed Central

    Cousminer, Diana L.; Leinonen, Jaakko T.; Sarin, Antti-Pekka; Chheda, Himanshu; Surakka, Ida; Wehkalampi, Karoliina; Ellonen, Pekka; Ripatti, Samuli; Dunkel, Leo; Palotie, Aarno; Widén, Elisabeth

    2015-01-01

    Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79–124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP. PMID:26030606

  9. Targeted resequencing of the pericentromere of chromosome 2 linked to constitutional delay of growth and puberty.

    PubMed

    Cousminer, Diana L; Leinonen, Jaakko T; Sarin, Antti-Pekka; Chheda, Himanshu; Surakka, Ida; Wehkalampi, Karoliina; Ellonen, Pekka; Ripatti, Samuli; Dunkel, Leo; Palotie, Aarno; Widén, Elisabeth

    2015-01-01

    Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP. PMID:26030606

  10. Involvement of growth factors and their receptors in radon-induced rat lung tumors

    SciTech Connect

    Leung, F.C.; Dagle, G.E.; Cross, F.T. [Pacific Northwest Lab., Richland, WA (United States)

    1992-12-31

    In this paper we examine the role of growth factors (GF) and their receptors (GFR) in radon-induced rat lung tumors. Inhalation exposure of radon and its daughters induced lung tumors in rats, but the molecule/cellular mechanisms are not known. Recent evidence suggests that GF/GFR play a critical role in the growth and development of lung cancer in humans and animals. We have developed immunocytochemical methods for identifying sites of production and action of GF/GFR at the cellular level; for example, the avidin-biotin horseradish peroxidase technique. In radon-induced rat epidermoid carcinomas, epidermal growth factor (EGF), EGF-receptors (EGF-R), transforming growth factor alpha (TGF-{alpha}), and bombesin were found to be abnormally expressed. These abnormal expressions, mainly associated with epidermoid carcinomas of the lung, were not found in any other lung tumor types. Our data suggest that EGF, EGF-R, TGF-{alpha}, and bombesin are involved in radon oncogenesis in rat lungs, especially in epidermoid carcinomas, possibly through the autocrine/paracrine pathway.

  11. Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor.

    PubMed

    Wyder, Lorenza; Suply, Thomas; Ricoux, Bérangère; Billy, Eric; Schnell, Christian; Baumgarten, Birgit U; Maira, Sauveur Michel; Koelbing, Claudia; Ferretti, Mireille; Kinzel, Bernd; Müller, Matthias; Seuwen, Klaus; Ludwig, Marie-Gabrielle

    2011-12-01

    The G protein-coupled receptor GPR4 is activated by acidic pH and recent evidence indicates that it is expressed in endothelial cells. In agreement with these reports, we observe a high correlation of GPR4 mRNA expression with endothelial marker genes, and we confirm expression and acidic pH dependent function of GPR4 in primary human vascular endothelial cells. GPR4-deficient mice were generated; these are viable and fertile and show no gross abnormalities. However, these animals show a significantly reduced angiogenic response to VEGF (vascular endothelial growth factor), but not to bFGF (basic fibroblast growth factor), in a growth factor implant model. Accordingly, in two different orthotopic models, tumor growth is strongly reduced in mice lacking GPR4. Histological analysis of tumors indicates reduced tumor cell proliferation as well as altered vessel morphology, length and density. Moreover, GPR4 deficiency results in reduced VEGFR2 (VEGF Receptor 2) levels in endothelial cells, accounting, at least in part, for the observed phenotype. Our data suggest that endothelial cells sense local tissue acidosis via GPR4 and that this signal is required to generate a full angiogenic response to VEGF. PMID:22045552

  12. Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53.

    PubMed

    Komarova, E A; Diatchenko, L; Rokhlin, O W; Hill, J E; Wang, Z J; Krivokrysenko, V I; Feinstein, E; Gudkov, A V

    1998-09-01

    p53 tumor suppressor gene controls cell response to a variety of stresses inducing growth arrest or apoptosis in damaged cells. It largely determines the sensitivity of tumor and normal cells to radiation and chemotherapy, and, therefore, defines both the efficacy and limitations of anti-cancer treatment. To determine molecular mechanisms of p53-dependent stress response in normal tissues we identified and compared the spectra of radiation-responsive genes in cells of different origin and p53 status using a cDNA array hybridization technique. The majority of genes identified were p53-dependent and cell type specific. Several of the new p53 responders encode known secreted growth inhibitory factors. This suggests that p53, in addition to its intrinsic antiproliferation activity, can cause 'bystander effect' by inducing export of growth suppressive stimuli from damaged cells to neighboring cells. Consistently, a p53-dependent accumulation of factors, which causes growth inhibitory effects in a variety of cell lines, was found after gamma irradiation in the media from established and primary cell cultures and in the urine of irradiated mice. Moreover, p53-dependent factors released by normal human fibroblasts potentiated the cytotoxic effect of a chemotherapeutic drug on co-cultivated tumor cells. This suggests a previously unknown role for normal cells in chemo- and radiation therapy of cancer. PMID:9764819

  13. 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

  14. Oridonin inhibits tumor growth in glioma by inducing cell cycle arrest and apoptosis.

    PubMed

    Zhang, X-H; Liu, Y-X; Jia, M; Han, J-S; Zhao, M; Ji, S-P; Li, A-M

    2014-01-01

    Glioma is the most common malignant intracranial tumors. Despite newly developed therapies, these treatments mainly target oncogenic signals, and unfortunately, fail to provide enough survival benefit in both human patients and mouse xenograft models, especially the first-generation therapies. Oridonin is purified from the Chinese herb Rabdosia rubescens and considered to exert extensive anti-cancer effects on human tumorigenesis. In this study, we systemically investigated the role of Oridonin in tumor growth and the underlying mechanisms in human glioma. We found that Oridonin inhibited cell proliferations in a dose- and time-dependent manner in both glioma U87 and U251 cells. Moreover, these anti-cancer effects were also confirmed in a mouse model bearing glioma. Furthermore, cell cycle arrest in S phase was observed in Oridonin-mediated growth inhibition by flow cytometry. Cell cycle arrest in S phase led to eventual cell apoptosis, as revealed by Hoechst 33342 staining and annexin V/PI double-staining. The cell apoptosis might be accomplished through a mitochondrial manner. In all, we were the first to our knowledge to report that Oridonin could exert anti-cancer effects on tumor growth in human glioma by inducing cell cycle arrest and eventual cell apoptosis. The identification of Oridonin as a critical mediator of glioma growth may potentiate Oridonin as a novel therapeutic strategies in glioma treatments. PMID:25553351

  15. The Epstein-Barr Virus Encoded BART miRNAs Potentiate Tumor Growth In Vivo

    PubMed Central

    Qiu, Jin; Smith, Pamela; Leahy, Leah; Thorley-Lawson, David A.

    2015-01-01

    The human herpes virus Epstein-Barr virus (EBV) latently infects and drives the proliferation of B lymphocytes in vitro and is associated with several forms of lymphoma and carcinoma in vivo. The virus encodes ~30 miRNAs in the BART region, the function of most of which remains elusive. Here we have used a new mouse xenograft model of EBV driven carcinomagenesis to demonstrate that the BART miRNAs potentiate tumor growth and development in vivo. No effect was seen on invasion or metastasis, and the growth promoting activity was not seen in vitro. In vivo tumor growth was not associated with the expression of specific BART miRNAs but with up regulation of all the BART miRNAs, consistent with previous observations that all the BART miRNAs are highly expressed in all of the EBV associated cancers. Based on these observations, we suggest that deregulated expression of the BART miRNAs potentiates tumor growth and represents a general mechanism behind EBV associated oncogenesis. PMID:25590614

  16. Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing

    PubMed Central

    Coutelle, Oliver; Hornig-Do, Hue-Tran; Witt, Axel; Andree, Maria; Schiffmann, Lars M; Piekarek, Michael; Brinkmann, Kerstin; Seeger, Jens M; Liwschitz, Maxim; Miwa, Satomi; Hallek, Michael; Krönke, Martin; Trifunovic, Aleksandra; Eming, Sabine A; Wiesner, Rudolf J; Hacker, Ulrich T; Kashkar, Hamid

    2014-01-01

    In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment. PMID:24648500

  17. Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice

    PubMed Central

    Bhandarkar, Sulochana S.; Jaconi, Marisa; Fried, Levi E.; Bonner, Michael Y.; Lefkove, Benjamin; Govindarajan, Baskaran; Perry, Betsy N.; Parhar, Ravi; Mackelfresh, Jamie; Sohn, Allie; Stouffs, Michael; Knaus, Ulla; Yancopoulos, George; Reiss, Yvonne; Benest, Andrew V.; Augustin, Hellmut G.; Arbiser, Jack L.

    2009-01-01

    Hemangiomas are the most common type of tumor in infants. As they are endothelial cell–derived neoplasias, their growth can be regulated by the autocrine-acting Tie2 ligand angiopoietin 2 (Ang2). Using an experimental model of human hemangiomas, in which polyoma middle T–transformed brain endothelial (bEnd) cells are grafted subcutaneously into nude mice, we compared hemangioma growth originating from bEnd cells derived from wild-type, Ang2+/–, and Ang2–/– mice. Surprisingly, Ang2-deficient bEnd cells formed endothelial tumors that grew rapidly and were devoid of the typical cavernous architecture of slow-growing Ang2-expressing hemangiomas, while Ang2+/– cells were greatly impaired in their in vivo growth. Gene array analysis identified a strong downregulation of NADPH oxidase 4 (Nox4) in Ang2+/– cells. Correspondingly, lentiviral silencing of Nox4 in an Ang2-sufficient bEnd cell line decreased Ang2 mRNA levels and greatly impaired hemangioma growth in vivo. Using a structure-based approach, we identified fulvenes as what we believe to be a novel class of Nox inhibitors. We therefore produced and began the initial characterization of fulvenes as potential Nox inhibitors, finding that fulvene-5 efficiently inhibited Nox activity in vitro and potently inhibited hemangioma growth in vivo. In conclusion, the present study establishes Nox4 as a critical regulator of hemangioma growth and identifies fulvenes as a potential class of candidate inhibitor to therapeutically interfere with Nox function. PMID:19620773

  18. Tumor Growth Rate (TGR) is an early indicator of anti-tumor drug activity in phase I clinical trials

    PubMed Central

    Ferté, Charles; Fernandez, Marianna; Hollebecque, Antoine; Koscielny, Serge; Levy, Antonin; Massard, Christophe; Balheda, Rastislav; Bot, Brian; Gomez-Roca, Carlos; Dromain, Clarisse; Ammari, Samy; Soria, Jean-Charles

    2013-01-01

    Purpose RECIST evaluation does not take into account the pre-treatment tumor kinetics and may provide incomplete information regarding experimental drug activity. Tumor Growth Rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Experimental designs Medical records from all patients (n=253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pre-treatment period (REFERENCE) and the EXPERIMENTAL period. Associations between TGR, standard prognostic scores (RMH score) and outcome (PFS, OS) were computed (multivariate analysis). Results We observed a reduction of TGR between the REFERENCE vs. EXPERIMENTAL periods (38% vs. 4.4%, P<.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analyses, only the decrease of TGR was associated with PFS (P=.004), whereas the RMH score was the only variable associated with OS (P=.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P<.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity. Conclusions Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) indpendent association with PFS; and (iii) It reveals drug-specific profiles; suggesting potential utility for guiding the further development of the investigational drugs. PMID:24240109

  19. The phosphoinositide 3-kinase pathway is crucial for the growth of canine mast cell tumors.

    PubMed

    Amagai, Yosuke; Tanaka, Akane; Matsuda, Akira; Oida, Kumiko; Jung, Kyungsook; Matsuda, Hiroshi

    2013-01-01

    Mast cell tumors (MCTs) are the most common tumors in dogs, accounting for 16-21% of cutaneous tumors. Although several small molecule inhibitors, including imatinib mesylate, have been used for the treatment of MCTs, the response rate remains less than 50%. In this study, the effects of different selective signal inhibitors on MCT cell growth were evaluated using 4 different cell lines derived from dogs. We found that the phosphoinositide 3-kinase (PI3K) signaling pathway is crucial for the proliferation of MCT cells in the presence or absence of c-kit gene mutations. Here, we propose a novel therapeutic strategy to target the PI3K pathway for the treatment of canine MCTs. PMID:23328607

  20. Inhibition of NF-?B in cancer cells converts inflammation- induced tumor growth mediated by TNF? to TRAIL-mediated tumor regression

    Microsoft Academic Search

    Jun-Li Luo; Shin Maeda; Li-Chung Hsu; Hideo Yagita; Michael Karin

    2004-01-01

    We used an experimental murine cancer metastasis model in which a colon adenocarcinoma cell line generates lung metastases, whose growth is stimulated in response to injection of bacterial lipopolysaccharide (LPS), to investigate the role of NF-?B in inflammation-induced tumor growth. We found that LPS-induced metastatic growth response in this model depends on both TNF? production by host hematopoietic cells and

  1. Inhibition of Notch Signaling in Combination with Paclitaxel Reduces Platinum-Resistant Ovarian Tumor Growth

    PubMed Central

    Groeneweg, Jolijn W.; DiGloria, Celeste M.; Yuan, Jing; Richardson, William S.; Growdon, Whitfield B.; Sathyanarayanan, Sriram; Foster, Rosemary; Rueda, Bo R.

    2014-01-01

    Introduction: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a ?-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p?tumors (p?=?0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p?tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. Conclusion: Inhibiting the Notch signaling cascade with a GSI reduces primary human xenograft growth in vivo. GSI synergized with conventional cytotoxic chemotherapy only in the platinum-resistant OvCa models with single agent paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa. PMID:25072022

  2. Chinese Red Yeast Rice Inhibition of Prostate Tumor Growth in SCID mice

    PubMed Central

    Hong, Mee Young; Henning, Susanne; Moro, Aune; Seeram, Navindra P.; Zhang, Yanjun; Heber, David

    2011-01-01

    Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but lovastatin unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and AR-overexpressing androgen-independent prostate cancer cell proliferation in vitro. The present study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared to animals receiving vehicle alone (P<0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR demonstrating that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P<0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3 and SRD5A1) in both type of tumors (P<0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. PMID:21278313

  3. Chinese red yeast rice inhibition of prostate tumor growth in SCID mice.

    PubMed

    Hong, Mee Young; Henning, Susanne; Moro, Aune; Seeram, Navindra P; Zhang, Yanjun; Heber, David

    2011-04-01

    Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but LV unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and androgen receptor-overexpressing androgen-independent prostate cancer cell proliferation in vitro. This study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared with animals receiving vehicle alone (P < 0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR, showing that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P < 0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3, and SRD5A1) in both type of tumors (P < 0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. PMID:21278313

  4. Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

    PubMed Central

    2011-01-01

    Vascular endothelial growth factor (VEGF) blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2). We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA) indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature. PMID:21978392

  5. The novel herbal cocktail MA128 suppresses tumor growth and the metastatic potential of highly malignant tumor cells.

    PubMed

    Kim, Aeyung; Im, Minju; Yim, Nam-Hiu; Hwang, Youn-Hwan; Yang, Hye Jin; Ma, Jin Yeul

    2015-08-01

    MA128, a novel herbal medicine, was previously identified and its effectiveness in the treatment of asthma and atopic dermatitis (AD) was demonstrated. In particular, post-inflammatory hyperpigmentation (PIH) in AD mice was improved by treatment with MA128. In addition, MA128 exhibited anti-melanogenic activity by inhibiting tyrosinase activity via the p38 MAPK and protein kinase A signaling pathways in B16F10 cells. In the present study, we examined whether oral administration of MA128 suppressed the in vivo tumor growth of HT1080 cells in athymic nude mice. The results showed that the daily oral administration of 75 and 150 mg/kg MA128 suppressed the tumorigenic growth of HT1080 cells efficiently. Since metastasis is a major cause of cancer-associated mortality and the greatest challenge during cancer treatment, we investigated the effect of non-toxic concentrations of MA128 on the metastatic potential of HT1080 cells. MA128 inhibited anchorage-independent colony formation, migration and invasion. Matrix metalloproteinase-9 (MMP-9) activity under resting and PMA-stimulated conditions was decreased in a dose-dependent manner by MA128 in HT1080 cells. In addition, the daily oral administration of MA128 at doses of 75 and 150 mg/kg efficiently blocked the lung metastasis of B16F10 cells that had been injected into the tail veins of C57BL/6 mice. In particular, none of the mice treated with MA128 exhibited systemic toxicity, such as body weight loss or liver and kidney dysfunction. MA128 also inhibited tumor?induced angiogenesis. Taken together, the results suggest that MA128 is a potential therapeutic agent and a safe herbal medicine for controlling malignant and metastatic cancer. PMID:26035620

  6. Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

    PubMed Central

    2013-01-01

    Background Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety. Methods In this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer. Results ES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice. Conclusions The ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin-based fusion proteins and their enediyne-energized analogs probably provides a promising modality in cancer therapy. PMID:24128285

  7. Control of solid tumor growth in mice using EGF receptor targeted RNA replicase-based plasmid DNA

    PubMed Central

    Rodriguez, B. Leticia; Li, Xinran; Kiguchi, Kaoru; DiGiovanni, John; Unger, Evan C.; Cui, Zhengrong

    2012-01-01

    Previously, it was shown that treatment of tumor-bearing mice with an RNA replicase-based plasmid that produces double-stranded RNA when transfected into tumor cells significantly inhibited the tumor growth. In the present study, the feasibility of further improving the anti-tumor activity of the RNA replicase-based plasmid by targeting it into tumors cells was evaluated. An epidermal growth factor (EGF)-conjugated, PEGylated cationic liposome was developed to deliver the RNA replicase-based plasmid, pSIN-?, into EGFR-over-expressing human breast cancer cells (MDA-MB-468) in vitro and in vivo. Delivery of the pSIN-? using the EGF receptor-targeted liposome more effectively controlled the growth of MDA-MB-468 tumors (and human epidermoid carcinoma A431 tumors) in mice than using un-targeted liposome. The pSIN-? carried by the EGFR-targeted liposome caused the complete regression of MDA-MB-468 tumors in mice, likely due to the enhancement of its pro-apoptotic, anti-proliferative, and anti-angiogenic activities. Tumor-targeted RNA replicase-based plasmid holds a strong potential in tumor therapy. PMID:22296186

  8. 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) ?, protein kinase C (PKC) ?, 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 PLC?/PKC/ERK signaling. PMID:26126534

  9. Metastasis Suppressor Genes: At the Interface Between the Environment and Tumor Cell Growth

    PubMed Central

    Hurst, Douglas R.; Welch, Danny R.

    2013-01-01

    The molecular mechanisms and genetic programs required for cancer metastasis are sometimes overlapping, but components are clearly distinct from those promoting growth of a primary tumor. Every sequential, rate-limiting step in the sequence of events leading to metastasis requires coordinated expression of multiple genes, necessary signaling events, and favorable environmental conditions or the ability to escape negative selection pressures. Metastasis suppressors are molecules that inhibit the process of metastasis without preventing growth of the primary tumor. The cellular processes regulated by metastasis suppressors are diverse and function at every step in the metastatic cascade. As we gain knowledge into the molecular mechanisms of metastasis suppressors and cofactors with which they interact, we learn more about the process, including appreciation that some are potential targets for therapy of metastasis, the most lethal aspect of cancer. Until now, metastasis suppressors have been described largely by their function. With greater appreciation of their biochemical mechanisms of action, the importance of context is increasingly recognized especially since tumor cells exist in myriad microenvironments. In this review, we assemble the evidence that selected molecules are indeed suppressors of metastasis, collate the data defining the biochemical mechanisms of action, and glean insights regarding how metastasis suppressors regulate tumor cell communication to–from microenvironments. PMID:21199781

  10. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.

    PubMed

    Roesch, Alexander; Fukunaga-Kalabis, Mizuho; Schmidt, Elizabeth C; Zabierowski, Susan E; Brafford, Patricia A; Vultur, Adina; Basu, Devraj; Gimotty, Phyllis; Vogt, Thomas; Herlyn, Meenhard

    2010-05-14

    Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation. PMID:20478252

  11. Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells12

    PubMed Central

    Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

    2013-01-01

    The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy. PMID:23814493

  12. Biodegradable polymeric micelles encapsulated JK184 suppress tumor growth through inhibiting Hedgehog signaling pathway

    NASA Astrophysics Data System (ADS)

    Zhang, Nannan; Liu, Shichang; Wang, Ning; Deng, Senyi; Song, Linjiang; Wu, Qinjie; Liu, Lei; Su, Weijun; Wei, Yuquan; Xie, Yongmei; Gong, Changyang

    2015-01-01

    JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity.JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06300g

  13. Sudden cold temperature delays plant carbon transport and shifts allocation from growth to respiratory demand

    NASA Astrophysics Data System (ADS)

    Barthel, M.; Cieraad, E.; Zakharova, A.; Hunt, J. E.

    2014-03-01

    Since substrates for respiration are supplied mainly by recent photo-assimilates, there is a strong but time-lagged link between short-term above- and belowground carbon (C) cycling. However, regulation of this coupling by environmental variables is poorly understood. Whereas recent studies focussed on the effect of drought and shading on the link between above- and belowground short-term C cycling, the effect of temperature remains unclear. We used a 13CO2 pulse-chase labelling experiment to investigate the effect of a sudden temperature change from 25 to 10 °C on the short-term coupling between assimilatory C uptake and respiratory loss. The study was done in the laboratory using two-month-old perennial rye-grass plants (Lolium perenne L.). After label application, the ?13C signal of respired shoot and root samples was analysed at regular time intervals using laser spectroscopy. In addition, ?13C was analysed in bulk root and shoot samples. Cold temperature (10 °C) reduced the short-term coupling between shoot and roots by delaying belowground transfer of recent assimilates and its subsequent respiratory use, as indicated by the ?13C signal of root respiration (?13CRR). That is, the time lag from the actual shoot labelling to the first appearance of the label in 13CRR was about 1.5 times longer under cold temperature. Moreover, analysis of bulk shoot and root material revealed that plants at cold temperature invest relatively more carbon into respiration compared to growth or storage. While the whole plant C turnover increased under cold temperature, the turnover time of the labile C pool decreased, probably because less 13C is used for growth and/or storage. That is, (almost) all recent C remained in the labile pool serving respiration under these conditions. Overall, our results highlight the importance of temperature as a driver of C transport and relative C allocation within the plant-soil system.

  14. HIGH INTERSTITIAL FLUID PRESSURE REGULATES TUMOR GROWTH AND DRUG UPTAKE IN HUMAN GLIOBLASTOMA

    PubMed Central

    Persson, Anders I.; Ilkhanizadeh, Shirin; Miroshnikova, Yekaterina A.; Frantz, Aaron; Lakins, John N.; James, C. David; McKnight, Tracy R.; Berger, Mitchel S.; Bergers, Gabriele; Weiss, William A.; Weaver, Valerie M.

    2014-01-01

    BACKGROUND: (blind field). METHODS: We developed methodology to measure IFP in human GBM xenografts and mechanical compression in 3D-cultures. We used a cell counter and calcein-AM-loaded cells to measure cell volume following treatment with temozolomide and/or blockade of NKCC1 activity. Fluorescent MQAE-loaded cells were recorded to measure intracellular chloride levels. To study uptake of chemotherapy following IFP-reduction in GBM xenografts following AF-induction or treatment with bumetanide, we injected doxorubicin and measured fluorescent doxorubicin levels in tissue sections. RESULTS: Elevated compression increased proliferation in GBM cultures and IFP levels rapidly increased during the exponential growth phase in GBM xenografts. In contrast to Avastin that targets the vasculature, SPC diet induced AF expression only in tumor cells. In addition to reducing IFP levels, AF-induction also inhibited proliferation, induced apoptosis, and increased survival in mice xenografted with human GBM cells. SPC diet and intranasal injection of AF increased uptake of doxorubicin in GBM xenografts. In vitro, AF augmented TMZ-induced apoptosis and reduced proliferation at both baseline and increased hydrostatic compression. CONCLUSIONS: In contrast to IFP-reducing therapies targeting the vasculature, treatments that reduced osmotic pressure in GBM cells effectively reduced tumor growth and invasion in vivo. AF and bumetanide increased uptake and cytotoxic response from chemotherapies by inhibiting NKCC1 activity in GBM cells. Our studies suggest that elevated IFP promotes tumor growth, reduces drug uptake, and limits therapy-response in GBM. AF-induction represents an attractive strategy to reduce invasion, inhibit tumor growth, increase drug uptake, and ultimately improve the survival of GBM patients. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.

  15. Escape from Transforming Growth Factor beta Control and Oncogene Cooperation in Skin Tumor Development

    Microsoft Academic Search

    Caterina Missero; Santiago Ramon Y. Cajal; G. Paolo Dotto

    1991-01-01

    Control of tumor development by surrounding normal cells has been suggested by a number of in vitro studies. In vivo, tumorigenicity of ras-transformed primary keratinocytes can be suppressed by addition of normal dermal fibroblasts. Here, we report that dermal fibroblasts produce a diffusible inhibitory factor belonging to the transforming growth factor beta (TGF-beta) family and possibly corresponding to TGF-beta3. This

  16. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions

    PubMed Central

    Dai, Jinlu; Zhang, Honglai; Karatsinides, Andreas; Keller, Jill M.; Kozloff, Kenneth M.; Aftab, Dana T.; Schimmoller, Frauke; Keller, Evan T.

    2013-01-01

    Purpose Cabozantinib, an orally available multi-tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct anti-tumor effect, an indirect effect through modulating bone, or both. Experimental Design Using human prostate cancer xenograft studies in mice we determined cabozantinib's impact on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (1) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability and MET and (2) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2. Results Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1,C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro, that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively. Conclusion These data indicate that cabozantinib has direct anti-tumor activity; and that its ability to modulate osteoblast activity may contribute to its anti-tumor efficacy. PMID:24097861

  17. The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth

    Microsoft Academic Search

    Christopher M. Cabello; Warner B. Bair; Sarah D. Lamore; Stephanie Ley; Alexandra S. Bause; Sara Azimian; Georg T. Wondrak

    2009-01-01

    Redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by pro-oxidant redox intervention. Dietary constituents that contain an electrophilic Michael acceptor pharmacophore may therefore display promising chemopreventive and chemotherapeutic anti-cancer activity. Here, we demonstrate that the cinnamon-derived dietary Michael acceptor trans-cinnamic aldehyde (CA) impairs melanoma cell proliferation and tumor growth. Feasibility of therapeutic intervention using high

  18. In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imaging

    PubMed Central

    Evans, Conor L.; Rizvi, Imran; Hasan, Tayyaba; de Boer, Johannes F.

    2010-01-01

    In vitro three-dimensional models for metastatic ovarian cancer have been useful for recapitulating the human disease. These spheroidal tumor cultures, however, can grow in excess of 1 mm in diameter, which are difficult to visualize without suitable imaging technology. Optical coherence tomography (OCT) is an ideal live imaging method for non-perturbatively visualizing these complex systems. OCT enabled detailed observations of the model at both nodular and cellular levels, revealing growth dynamics not previously observed. The development of a time-lapse OCT system, capable of automated, multidimensional acquisition, further provided insights into the growth and chemotherapeutic response of ovarian cancer. PMID:19466138

  19. Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromal cells.

    PubMed

    Hsieh, Chia-Ling; Gardner, Thomas A; Miao, Li; Balian, Gary; Chung, Leland W K

    2004-02-01

    Stromal-epithelial interaction contributes to local prostate tumor growth, androgen-independent progression and distant metastasis. We have established in vitro coculture and in vivo chimeric tumor models to evaluate the roles of stromal cells isolated from either osteosarcoma or normal bone, a site where prostate cancer cells frequently metastasize, in contributing to the growth and survival of human prostate cancer cells. We have evaluated extensively the effects of toxic gene therapy using luciferase-tagged chimeric human prostate cancer models both in vitro and in vivo. In the in vitro cocultured cell model, we assessed cancer cell growth and residual cellular proteins after targeting either prostate cancer epithelial cells alone or both prostate cancer and bone stromal cells. In the in vivo animal model, we measured tumor volume and serum prostate-specific antigen (PSA) in mice bearing chimeric prostate tumors comprised of human prostate tumor cells and normal bone stromal cells. Our results demonstrated that: (1) The rate of human prostate cancer cell growth in vitro is accelerated by coculturing with human and rat osteosarcoma or normal mouse bone marrow stromal cell lines. No growth stimulation was noted when cocultured with a human prostate epithelial cell line. (2) Disabling the growth of normal bone stromal cells using transgenic targeting with a bystander gene, herpes simplex virus thymidine kinase (hsv-TK), plus the pro-drug ganciclovir (GCV) or acyclovir markedly depressed the growth of cocultured human prostate cancer cells in vitro and human prostate cancer-mouse normal bone stroma chimeric tumors in vivo. (3) By cotargeting both human prostate cancer and normal mouse bone stromal cells in vitro with an adenoviral construct, Ad-hOC-TK (a replication-defective Ad5 vector with the bystander transgene hsv-TK under the control of a human osteocalcin (hOC) promoter) plus GCV4, we observed greater inhibition of tumor cell growth than by targeting a single cell compartment with Ad-PSA-TK (a vector construct similar to Ad-hOC-TK except that the transgene expression is under regulation by a full-length human PSA promoter). These results, taken together, established a basic principle that cotargeting both tumor and its supporting stroma is more efficacious than targeting a single cell compartment in the treatment of human prostate cancer bone metastasis. This principle can be applied to other clinical conditions of cancer growth where stroma contribute to the overall growth and survival potential of the cancer. PMID:14695756

  20. Glucagon-induced angiogenesis and tumor growth through the HIF-1-VEGF-dependent pathway in hyperglycemic nude mice.

    PubMed

    Wang, Y; Zhu, Y D; Gui, Q; Wang, X D; Zhu, Y X

    2014-01-01

    In this study, we examined the effect glucagon-induced hyperglycemia on tumor growth as well as the role of the hypoxia-inducible factor 1 (HIF-1)-vascular endothelial growth factor (VEGF) pathway in this condition. A high concentration of glucose (HG) was utilized to treat HeLa cells under hypoxic or normoxic conditions, and transcriptional levels of HIF-1, VEGF, and basic fibroblast growth factor (bFGF) were evaluated. Moreover, the ability of an HIF-1 inhibitor to block the effect induced by HG was examined. By contrast, hyperglycemia was induced in nude mice by glucagon released from an osmotic pump, and microvessel density was determined with CD31 staining. Thus, the relationship among hyperglycemia, microvessel density, tumor growth, and the HIF-1 inhibitor were analyzed. We found that HG increased transcription of the VEGF gene, which is downstream of HIF-1. Moreover, HG impaired the function of HIF-1 inhibitors [HIF-1 small interfering RNA (siRNA) and berberine] to affect the VEGF transcription level in tumor cells. By contrast, hyperglycemia increased tumor microvessel density and promoted tumor growth, which was inhibited by the HIF-1 inhibitor. However, hyperglycemia attenuated the effect of the HIF-1 inhibitor. Glucagon-induced hyperglycemia influenced tumor microenvironments through the HIF-1-VEGF-dependent pathway and promoted tumor growth and resistance to HIF-1 inhibition treatments. PMID:25222223

  1. Biological Stoichiometry in Tumor Micro-environments

    PubMed Central

    Kareva, Irina

    2013-01-01

    Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH), increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy. PMID:23349677

  2. A polysaccharide from Trametes robiniophila inhibits human osteosarcoma xenograft tumor growth in vivo.

    PubMed

    Zhao, Xingkai; Ma, Shuo; Liu, Ning; Liu, Jiakun; Wang, Wenbo

    2015-06-25

    In the present study, we isolated and purified one polysaccharide (TRP) from Trametes robiniophila, which had a backbone of 1,3,6- and 1,4-linked glucpyranosyl moieties, with 1-linked arabinofuranosyl and galactopyranosyl terminal at the O-3 position of 1,3,6-linked glucpyranosyl residues. TRP was further evaluated for its antitumor activity against xenografted U-2 OS osteosarcoma in BALB/c nude mice together with the possible mechanism of action. We found that oral administration of TRP significantly suppressed U-2 OS tumor growth in mice via the induction of apoptosis, as evidenced by the increased number of TUNEL-positive cells in tumor tissues. Moreover, TRP administration increased the levels of the proapoptotic Bax protein and decreased the level of the antiapoptotic Bcl-2 protein, thus resulting in a rise of Bax/Bcl-2 ratio. Furthermore, the protein expression of caspase-9, caspase-3 and cleaved PARP became evident in tumor tissues from mice following TRP treatment, but caspase-8 keep unchanged. Besides, overexpression of metadherin (MTDH) was attenuated in tumor tissues of TRP-fed mice. Taken together, these findings suggest that the TRP-induced apoptosis of tumor tissues is through a mitochondria-mediated intrinsic apoptotic pathway. PMID:25839806

  3. Oridonin Inhibits Tumor Growth and Metastasis through Anti-Angiogenesis by Blocking the Notch Signaling

    PubMed Central

    Li, Jingjie; Deng, Huayun; Song, Yajuan; Zhai, Dong; Peng, Yi; Lu, Xiaoling; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

    2014-01-01

    While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases. PMID:25485753

  4. CD24 is an effector of HIF-1 driven primary tumor growth and metastasis

    PubMed Central

    Thomas, Shibu; Harding, Michael; Smith, Steven C.; Overdevest, Jonathan B.; Nitz, Matthew D.; Frierson, Henry F.; Tomlins, Scott A.; Kristiansen, Glen; Theodorescu, Dan

    2012-01-01

    Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor HIF-1? in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element (HRE) in the CD24 promoter. HIF-1? overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1? to the CD24 promoter. shRNA mediated-attenuation of HIF-1? or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1?-depleted cancer cells rescued this decrease while HIF-1? overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1? and CD24 levels and an association of their co-expression to decreased patient survival. Our results establish a mechanistic linkage between two critically important molecules in cancer, identifying CD24 as a critical HIF-1? transcriptional target and biological effector, strengthening the rationale to target CD24 for cancer therapy. PMID:22926560

  5. Bayesian calibration, validation, and uncertainty quantification of diffuse interface models of tumor growth.

    PubMed

    Hawkins-Daarud, Andrea; Prudhomme, Serge; van der Zee, Kristoffer G; Oden, J Tinsley

    2013-12-01

    The idea that one can possibly develop computational models that predict the emergence, growth, or decline of tumors in living tissue is enormously intriguing as such predictions could revolutionize medicine and bring a new paradigm into the treatment and prevention of a class of the deadliest maladies affecting humankind. But at the heart of this subject is the notion of predictability itself, the ambiguity involved in selecting and implementing effective models, and the acquisition of relevant data, all factors that contribute to the difficulty of predicting such complex events as tumor growth with quantifiable uncertainty. In this work, we attempt to lay out a framework, based on Bayesian probability, for systematically addressing the questions of Validation, the process of investigating the accuracy with which a mathematical model is able to reproduce particular physical events, and Uncertainty quantification, developing measures of the degree of confidence with which a computer model predicts particular quantities of interest. For illustrative purposes, we exercise the process using virtual data for models of tumor growth based on diffuse-interface theories of mixtures utilizing virtual data. PMID:23053536

  6. Suppression of tumor growth by Pleurotus ferulae ethanol extract through induction of cell apoptosis, and inhibition of cell proliferation and migration.

    PubMed

    Wang, Weilan; Chen, Kaixu; Liu, Qing; Johnston, Nathan; Ma, Zhenghai; Zhang, Fuchun; Zheng, Xiufen

    2014-01-01

    Cancer is the second leading cause of death worldwide. Edible medicinal mushrooms have been used in traditional medicine as regimes for cancer patients. Recently anti-cancer bioactive components from some mushrooms have been isolated and their anti-cancer effects have been tested. Pleurotus ferulae, a typical edible medicinal mushroom in Xinjiang China, has also been used to treat cancer patients in folk medicine. However, little studies have been reported on the anti-cancer components of Pleurotus ferulae. This study aims to extract bioactive components from Pleurotus ferulae and to investigate the anti-cancer effects of the extracts. We used ethanol to extract anti-cancer bioactive components enriched with terpenoids from Pleurotus ferulae. We tested the anti-tumour effects of ethanol extracts on the melanoma cell line B16F10, the human gastric cancer cell line BGC 823 and the immortalized human gastric epithelial mucosa cell line GES-1 in vitro and a murine melanoma model in vivo. Cell toxicity and cell proliferation were measured by MTT assays. Cell cycle progression, apoptosis, caspase 3 activity, mitochondrial membrane potential (MMP), migration and gene expression were studied in vitro. PFEC suppressed tumor cell growth, inhibited cell proliferation, arrested cells at G0/G1 phases and was not toxic to non-cancer cells. PFEC also induced cell apoptosis and necrosis, increased caspase 3 activity, reduced the MMP, prevented cell invasion and changed the expression of genes associated with apoptosis and the cell cycle. PFEC delayed tumor formation and reduced tumor growth in vivo. In conclusion, ethanol extracted components from Pleurotus ferulae exert anti-cancer effects through direct suppression of tumor cell growth and invasion, demonstrating its therapeutic potential in cancer treatment. PMID:25029345

  7. Suppression of Tumor Growth by Pleurotus ferulae Ethanol Extract through Induction of Cell Apoptosis, and Inhibition of Cell Proliferation and Migration

    PubMed Central

    Wang, Weilan; Chen, Kaixu; Liu, Qing; Johnston, Nathan; Ma, Zhenghai; Zhang, Fuchun; Zheng, Xiufen

    2014-01-01

    Cancer is the second leading cause of death worldwide. Edible medicinal mushrooms have been used in traditional medicine as regimes for cancer patients. Recently anti-cancer bioactive components from some mushrooms have been isolated and their anti-cancer effects have been tested. Pleurotus ferulae, a typical edible medicinal mushroom in Xinjiang China, has also been used to treat cancer patients in folk medicine. However, little studies have been reported on the anti-cancer components of Pleurotus ferulae. This study aims to extract bioactive components from Pleurotus ferulae and to investigate the anti-cancer effects of the extracts. We used ethanol to extract anti-cancer bioactive components enriched with terpenoids from Pleurotus ferulae. We tested the anti-tumour effects of ethanol extracts on the melanoma cell line B16F10, the human gastric cancer cell line BGC 823 and the immortalized human gastric epithelial mucosa cell line GES-1 in vitro and a murine melanoma model in vivo. Cell toxicity and cell proliferation were measured by MTT assays. Cell cycle progression, apoptosis, caspase 3 activity, mitochondrial membrane potential (MMP), migration and gene expression were studied in vitro. PFEC suppressed tumor cell growth, inhibited cell proliferation, arrested cells at G0/G1 phases and was not toxic to non-cancer cells. PFEC also induced cell apoptosis and necrosis, increased caspase 3 activity, reduced the MMP, prevented cell invasion and changed the expression of genes associated with apoptosis and the cell cycle. PFEC delayed tumor formation and reduced tumor growth in vivo. In conclusion, ethanol extracted components from Pleurotus ferulae exert anti-cancer effects through direct suppression of tumor cell growth and invasion, demonstrating its therapeutic potential in cancer treatment. PMID:25029345

  8. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides

    PubMed Central

    Otto, Christoph; Kaemmerer, Ulrike; Illert, Bertram; Muehling, Bettina; Pfetzer, Nadja; Wittig, Rainer; Voelker, Hans Ullrich; Thiede, Arnulf; Coy, Johannes F

    2008-01-01

    Background Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT). Methods Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume). Results The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 ± 8.5 days versus only 23.3 ± 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. Conclusion Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further studies are needed to address the impact of this diet on other tumour-relevant functions such as invasive growth and metastasis. PMID:18447912

  9. Flaxseed oil enhances the effectiveness of trastuzumab in reducing the growth of HER2-overexpressing human breast tumors (BT-474).

    PubMed

    Mason, Julie K; Fu, Minghua; Chen, Jianmin; Thompson, Lilian U

    2015-01-01

    Flaxseed oil (FSO) reduces breast tumorigenesis and HER2 expression in animal models of luminal breast cancer. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). We aimed to determine the effect of 4% FSO alone and combined with TRAS on HER2-overexpressing tumor (BT-474) growth and to explore potential mechanisms with a specific focus on HER2, mitogen-activated protein kinase (MAPK) and Akt signaling and fatty acid profile. Athymic mice with established tumors were fed the basal diet (control) or 4% FSO diet, with or without TRAS (1 or 2.5 mg/kg) treatment for 4 weeks. Tumor growth, HER2 signaling biomarkers (mRNA and protein) and fatty acid profile were measured. Tumors treated with FSO alone showed no difference in tumor growth compared to control; however, compared to TRAS2.5 and other groups, FSO+TRAS2.5 caused significantly lower tumor growth and cell proliferation and higher apoptosis and the greatest lowering of signaling biomarker expressions (MAPK2, HER2 mRNA; pHER2 protein). Both TRAS and FSO had main effects of reducing the phosphorylated/total expression of Akt and MAPK protein expression. Dietary FSO altered the tumor fatty acid profile. In conclusion, 4% dietary FSO alone does not affect BT-474 tumor growth but enhances the tumor-reducing effect of TRAS (2.5 mg/kg). FSO×TRAS interactive effect may be modulated by their combined reductions of HER2 signaling through the Akt and MAPK pathways leading to reduced cell proliferation and increased apoptosis. FSO alters tumor fatty acid profile that likely contributes to effects on signaling pathways. This supports FSO as a complementary treatment for HER2+ breast cancer treated with TRAS. PMID:25441844

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

    PubMed Central

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

    2015-01-01

    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-1? 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. PMID:25354695

  11. 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-1? 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. PMID:25354695

  12. Functional Interaction of the Retinoblastoma and Ini1\\/Snf5 Tumor Suppressors in Cell Growth and Pituitary Tumorigenesis

    Microsoft Academic Search

    Cynthia J. Guidi; Rajini Mudhasani; Kathleen Hoover; Irwin Leav; Anthony N. Imbalzano; Stephen N. Jones

    2006-01-01

    The Ini1 subunit of the SWI\\/SNF chromatin remodeling complex suppresses formation of malignant rhabdoid tumors in humans and mice. Transduction of Ini1 into Ini1-deficient tumor-derived cell lines has indicated that Ini1 arrests cell growth,controls chromosomal ploidy,and suppresses tumor- igenesis by regulating components of the retinoblastoma (Rb) signaling pathway. Furthermore,conditional inactivation of Ini1 in mouse fibroblasts alters the expression of various

  13. Expression Pattern and Functional Relevance of Epidermal Growth Factor Receptor and Cyclooxygenase2: Novel Chemotherapeutic Targets in Pancreatic Endocrine Tumors?

    Microsoft Academic Search

    Frank Bergmann; Marco Breinig; Michael Höpfner; Ralf J Rieker; Lars Fischer; Christian Köhler; Irene Esposito; Jörg Kleeff; Esther Herpel; Volker Ehemann; Helmut Friess; Peter Schirmacher; Michael A Kern

    2009-01-01

    OBJECTIVES:Pancreatic endocrine tumors represent morphologically and biologically heterogeneous neoplasms. Well-differentiated endocrine tumors (benign or of uncertain behavior) can be distinguished from well-differentiated and poorly differentiated endocrine carcinomas. Although many well-differentiated endocrine carcinomas show rather low rates of tumor growth, more than two-thirds of pancreatic endocrine carcinomas display distant metastases at the time of diagnosis. As the currently applied therapies beyond

  14. Changes in the Activation and Reconstitution of Lymphocytes Resulting from Total-Body Irradiation Correlate with Slowed Tumor Growth

    Microsoft Academic Search

    Glen M. Miller; Dong W. Kim; Melba L. Andres; Lora M. Green; Daila S. Gridley

    2003-01-01

    Alterations in cytokine secretion, activation marker expression, and immune cell concentrations were investigated at sequential time points following delivery of total-body irradiation (TBI) to C57BL\\/6 mice (n = 64) in the Lewis lung tumor model. Significantly slower tumor growth was observed when a 3-Gy dose of TBI was administered 2 h prior to tumor implantation (p < 0.05). The antitumor

  15. Tumor

    MedlinePLUS

    ... environmental substance. Other risk factors for cancer include: Benzene and other chemicals and toxins Drinking too much ... a tumor is found, a piece of the tissue is removed and examined under a microscope. This ...

  16. Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

    PubMed Central

    Mishra, Siddhartha Kumar; Kang, Ju-Hee; Lee, Chang Woo; Oh, Seung Hyun; Ryu, Jun Sun; Bae, Yun Soo; Kim, Hwan Mook

    2013-01-01

    Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosis-inducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties. PMID:24008365

  17. Rosemary (Rosmarinus officinalis) Extract Modulates CHOP/GADD153 to Promote Androgen Receptor Degradation and Decreases Xenograft Tumor Growth

    PubMed Central

    Petiwala, Sakina M.; Berhe, Saba; Li, Gongbo; Puthenveetil, Angela G.; Rahman, Ozair; Nonn, Larisa; Johnson, Jeremy J.

    2014-01-01

    The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease, diabetes and various solid organ cancers. In this particular study, a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry, MTT, BrdU, Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells as opposed to “normal” cells. Furthermore, we observed standardized rosemary extract to decrease androgen receptor expression that appears to be regulated by the expression of CHOP/GADD153. Using a xenograft tumor model we observed standardized rosemary extract when given orally to significantly suppress tumor growth by 46% compared to mice not receiving standardized rosemary extract. In the last several years regulatory governing bodies (e.g. European Union) have approved standardized rosemary extracts as food preservatives. These results are especially significant as it is becoming more likely that individuals will be receiving standardized rosemary extracts that are a part of a natural preservative system in various food preparations. Taken a step further, it is possible that the potential benefits that are often associated with a “Mediterranean Diet” in the future may begin to extend beyond the Mediterranean diet as more of the population is consuming standardized rosemary extracts. PMID:24598693

  18. NIH study finds low-dose nicotine does not promote tumor growth in mouse models of lung cancer:

    Cancer.gov

    Experiments in mice show that low levels of exposure to nicotine, equivalent to those in humans who use nicotine replacement therapy (NRT) to help them quit smoking, did not promote lung tumor growth.

  19. Morphometric and Colorimetrie Analyses of Human Tumor Cell Line Growth and Drug Sensitivity in Soft Agar Culture1

    Microsoft Academic Search

    M. C. Alle; C. M. Pacula-Co; M. L. Hursey; L. R. Rubinstein; M. R. Boy

    1991-01-01

    Previous studies have demonstrated the suitability of image analysis of tetrazolium-stained colonies to assess growth and drug sensitivity of human tumor cells cultivated in soft agar culture. In the present study, the potential utility of colorimetrie analysis to expedite experimental drug evaluations using human tumor cell lines was investigated. The same culture dishes were assessed by image analysis and by

  20. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

    SciTech Connect

    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  1. Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth.

    PubMed

    Shukla, Sudhanshu; Patric, Irene Rosita Pia; Patil, Vikas; Shwetha, Shivayogi D; Hegde, Alangar S; Chandramouli, Bangalore A; Arivazhagan, Arimappamagan; Santosh, Vani; Somasundaram, Kumaravel

    2014-08-01

    Glioblastoma (GBM) is the most aggressive type of brain tumor and shows very poor prognosis. Here, using genome-wide methylation analysis, we show that G-CIMP+ and G-CIMP-subtypes enrich distinct classes of biological processes. One of the hypermethylated genes in GBM, ULK2, an upstream autophagy inducer, was found to be down-regulated in GBM. Promoter hypermethylation of ULK2 was confirmed by bisulfite sequencing. GBM and glioma cell lines had low levels of ULK2 transcripts, which could be reversed upon methylation inhibitor treatment. ULK2 promoter methylation and transcript levels showed significant negative correlation. Ectopic overexpression of ULK2-induced autophagy, which further enhanced upon nutrient starvation or temozolomide chemotherapy. ULK2 also inhibited the growth of glioma cells, which required autophagy induction as kinase mutant of ULK2 failed to induce autophagy and inhibit growth. Furthermore, ULK2 induced autophagy and inhibited growth in Ras-transformed immortalized Baby Mouse Kidney (iBMK) ATG5(+/+) but not in autophagy-deficient ATG5(-/-) cells. Growth inhibition due to ULK2 induced high levels of autophagy under starvation or chemotherapy utilized apoptotic cell death but not at low levels of autophagy. Growth inhibition by ULK2 also appears to involve catalase degradation and reactive oxygen species generation. ULK2 overexpression inhibited anchorage independent growth, inhibited astrocyte transformation in vitro and tumor growth in vivo. Of all autophagy genes, we found ULK2 and its homologue ULK1 were only down-regulated in all grades of glioma. Thus these results altogether suggest that inhibition of autophagy by ULK1/2 down-regulation is essential for glioma development. PMID:24923441

  2. Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis

    PubMed Central

    Li, Bin; Yang, Yang; Cao, Liu; Ye, Yuxiang; Li, Jiangchao; Ding, Yi; Wang, Huiping; Wang, Jintao; He, Xiaodong; Zhang, Qianqian; Lan, Tian; Kenneth Ka Ho, Lee; Li, Weidong; Song, Xiaoyu; Zhou, Jia; Yang, Xuesong; Wang, Lijing

    2014-01-01

    Angiogenesis is involved in the development, progression and metastasis of various human cancers. Herein, we report the discovery of glipizide, a widely used drug for type 2 diabetes mellitus, as a promising anticancer agent through the inhibition of tumor angiogenesis. By high-throughput screening (HTS) of an FDA approved drug library utilizing our in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, glipizide has been identified to significantly inhibit blood vessel formation and development. Moreover, glipizide was found to suppress tumor angiogenesis, tumor growth and metastasis using xenograft tumor and MMTV-PyMT transgenic mouse models. We further revealed that the anticancer capability of glipizide is not attributed to its antiproliferative effects, which are not significant against various human cancer cell lines. To investigate whether its anticancer efficacy is associated with the glucose level alteration induced by glipizide application, glimepiride, another medium to long-acting sulfonylurea antidiabetic drug in the same class, was employed for the comparison studies in the same fashion. Interestingly, glimepiride has demonstrated no significant impact on the tumor growth and metastasis, indicating that the anticancer effects of glipizide is not ascribed to its antidiabetic properties. Furthermore, glipizide suppresses endothelial cell migration and the formation of tubular structures, thereby inhibiting angiogenesis by up-regulating the expression of natriuretic peptide receptor A. These findings uncover a novel mechanism of glipizide as a potential cancer therapy, and also for the first time, provide direct evidence to support that treatment with glipizide may reduce the cancer risk for diabetic patients. PMID:25294818

  3. Selenized milk casein in the diet of BALB/c nude mice reduces growth of intramammary MCF-7 tumors

    PubMed Central

    2013-01-01

    Background Dietary selenium has the potential to reduce growth of mammary tumors. Increasing the Se content of cows’ milk proteins is a potentially effective means to increase Se intake in humans. We investigate the effects of selenized milk protein on human mammary tumor progression in immunodeficient BALB/c nude mice. Methods Four isonitrogenous diets with selenium levels of 0.16, 0.51, 0.85 and 1.15 ppm were formulated by mixing low- and high-selenium milk casein isolates with a rodent premix. MCF-7 cells were inoculated into the mammary fat pad of female BALB/c nude mice implanted with slow-release 17 ?-estradiol pellets. Mice with palpable tumors were randomly assigned to one of the four diets for 10 weeks, during which time weekly tumor caliper measurements were conducted. Individual growth curves were fit with the Gompertz equation. Apoptotic cells and Bcl-2, Bax, and Cyclin D1 protein levels in tumors were determined. Results There was a linear decrease in mean tumor volume at 70 days with increasing Se intake (P < 0.05), where final tumor volume decreased 35% between 0.16 and 1.15 ppm Se. There was a linear decrease in mean predicted tumor volume at 56, 63 and 70 days, and the number of tumors with a final volume above 500 mm3, with increasing Se intake (P < 0.05). This tumor volume effect was associated with a decrease in the proportion of tumors with a maximum growth rate above 0.03 day-1. The predicted maximum volume of tumors (Vmax) and the number of tumors with a large Vmax, were not affected by Se-casein. Final tumor mass, Bcl-2, Bax, and Cyclin D1 protein levels in tumors were not significantly affected by Se-casein. There was a significantly higher number of apoptotic cells in high-Se tumors as compared to low-Se tumors. Conclusions Taken together, these results suggest that turnover of cells in the tumor, but not its nutrient supply, were affected by dairy Se. We have shown that 1.1 ppm dietary Se from selenized casein can effectively reduce tumor progression in an MCF-7 xenograft breast cancer model. These results show promise for selenized milk protein as an effective supplement during chemotherapy. PMID:24152862

  4. Enhanced Tumor Formation in Cyclin D1 Transforming Growth Factor 1 Double Transgenic Mice with Characterization by Magnetic Resonance Imaging

    Microsoft Academic Search

    Natasha G. Deane; Haakil Lee; Jalal Hamaamen; Anna Ruley; M. Kay Washington; Bonnie LaFleur; Snorri S. Thorgeirsson; Ronald Price; R. Daniel Beauchamp

    2004-01-01

    Transgenic mice that overexpress cyclin D1 protein in the liver develop liver carcinomas with high penetrance. Transforming growth factor (TGF-) serves as either an epithelial cell growth inhibitor or a tumor promoter, depending on the cellular context. We interbred LFABP-cyclin D1 and Alb-TGF-1 transgenic mice to produce cyclin D1\\/TGF-1 double transgenic mice and followed the development of liver tumors over

  5. Humanization of an Anti-Vascular Endothelial Growth Factor Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders

    Microsoft Academic Search

    Leonard G. Presta; Helen Chen; Shane J. O'Connor; Vanessa Chisholm; Y. Gloria Meng; Lynne Krummen; Marjorie Winkler; Napoleone Ferrara

    1997-01-01

    Vascular endothelial growth factor (VE(ìF) is a major mediator of angiogenesis associated with tumors and other pathological conditions, including proliferative diahetic retinopathy and age-related macular degeneration. The murine anti-human \\\\ I (.1 monoclonal antibody imiiM \\\\l> \\\\ I.di i A.4.6.1 has heen shown to potently suppress angio- genesis and growth in a variety of human tumor cells lines transplanted in

  6. Inhibition of cell growth and intracellular Ca 2+ mobilization in human brain tumor cells by Ca 2+ channel antagonists

    Microsoft Academic Search

    Yong Soo Lee; Mohammed M. Sayeed; Robert D. Wurster

    1994-01-01

    The effects of various Ca2+ channel agonists and antagonists on tumor cell growth were investigated using U-373 MG human astrocytoma and SK-N-MC human\\u000a neuroblastoma cell lines. Classical Ca2+ channel antagonists, verapamil, nifedipine, and diltiazem, and inorganic Ca2+ channel antagonists, Ni2+ and Co2+, inhibited growth of these tumor cells in a dose-dependent manner. Except Ni2+, these Ca2+ channel antagonists did not

  7. WT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells.

    PubMed

    Nichols, K E; Re, G G; Yan, Y X; Garvin, A J; Haber, D A

    1995-10-15

    The Wilms' tumor suppressor gene WT1 encodes a zinc finger transcription factor, whose expression inhibits the growth of the RM1 Wilms' tumor cell line. Transient transfection of WT1 constructs into 3T3 or 293 cells results in transcriptional repression of a number of cotransfected promoters containing the early growth response gene 1 consensus sequence. We now show that WT1 has properties of a transcriptional activator in RM1 cells, an effect that may be associated with the presence of a mutated p53 gene in these cells. Stable transfection of wild-type WT1 into RM1 cells results in induction of endogenous insulin-like growth factor 2 (IGF2) but not of other previously postulated WT1-target genes. The induction of IGF2 is dramatically enhanced by WT1 mutants encoding an altered transactivation domain. We conclude that IGF2 is a potentially physiological target gene for WT1 and that its induction may contribute to the growth-stimulating effects of WT1 variants. PMID:7553624

  8. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.

    PubMed

    Friel, Anne M; Zhang, Ling; Pru, Cindy A; Clark, Nicole C; McCallum, Melissa L; Blok, Leen J; Shioda, Toshi; Peluso, John J; Rueda, Bo R; Pru, James K

    2015-01-28

    Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A lentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4. To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1?µM), doxorubicin (Dox, 2?µg/ml), or P4?+?Dox for 48?h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dox-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitoneal inoculation of immunocompromised NOD/SCID and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol?+?0.9% saline) or chemotherapy [Paclitaxel (15?mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (50?mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1-intact control tumors, suggesting that PGRMC1 promotes tumor cell viability during chemotherapeutic stress. In sum, these in vitro and in vivo findings demonstrate that PGRMC1 plays a prominent role in the growth and chemoresistance of human endometrial tumors. PMID:25304370

  9. Biodegradable polymeric micelle-encapsulated quercetin suppresses tumor growth and metastasis in both transgenic zebrafish and mouse models

    NASA Astrophysics Data System (ADS)

    Wu, Qinjie; Deng, Senyi; Li, Ling; Sun, Lu; Yang, Xi; Liu, Xinyu; Liu, Lei; Qian, Zhiyong; Wei, Yuquan; Gong, Changyang

    2013-11-01

    Quercetin (Que) loaded polymeric micelles were prepared to obtain an aqueous formulation of Que with enhanced anti-tumor and anti-metastasis activities. A simple solid dispersion method was used, and the obtained Que micelles had a small particle size (about 31 nm), high drug loading, and high encapsulation efficiency. Que micelles showed improved cellular uptake, an enhanced apoptosis induction effect, and stronger inhibitory effects on proliferation, migration, and invasion of 4T1 cells than free Que. The enhanced in vitro antiangiogenesis effects of Que micelles were proved by the results that Que micelles significantly suppressed proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, transgenic zebrafish models were employed to investigate anti-tumor and anti-metastasis effects of Que micelles, in which stronger inhibitory effects of Que micelles were observed on embryonic angiogenesis, tumor-induced angiogenesis, tumor growth, and tumor metastasis. Furthermore, in a subcutaneous 4T1 tumor model, Que micelles were more effective in suppressing tumor growth and spontaneous pulmonary metastasis, and prolonging the survival of tumor-bearing mice. Besides, immunohistochemical and immunofluorescent assays suggested that tumors in the Que micelle-treated group showed more apoptosis, fewer microvessels, and fewer proliferation-positive cells. In conclusion, Que micelles, which are synthesized as an aqueous formulation of Que, possess enhanced anti-tumor and anti-metastasis activity, which can serve as potential candidates for cancer therapy.

  10. Tight junction protein claudin-1 is differentially expressed in craniopharyngioma subtypes and indicates invasive tumor growth

    PubMed Central

    Stache, Christina; Hölsken, Annett; Fahlbusch, Rudolf; Flitsch, Jörg; Schlaffer, Sven-Martin; Buchfelder, Michael; Buslei, Rolf

    2014-01-01

    Background Claudins are tight junction proteins expressed in epithelial tissues that play important roles in cell polarity and adhesion. Altered distribution of claudin-1(CLDN1) affects cell mobility and tumor invasiveness. Craniopharyngiomas (CPs) represent epithelial tumors of the sellar region, consisting of adamantinomatous (adaCP) and papillary (papCP) variants. Their tendency to infiltrate surrounding brain structures complicates successful surgery. Reliable markers are required to predict tumor behavior and to establish individualized treatment protocols. Methods We describe the distribution pattern of CLDN1 in a large cohort of 66 adaCPs, 21 papCPs, and 24 Rathke`s cleft cyst (RCC) cases using immunohistochemistry. CLDN1 mRNA levels were analyzed with qRT-PCR in 33 CP samples. The impact on the migration potential was studied in primary adaCP cell cultures (n = 11) treated with small interfering RNA (siRNA) for CLDN1. Furthermore, CLDN1 distribution patterns and expression levels were compared between invasive (n = 16) and noninvasive (n = 17) tumor groups. Results PapCPs and RCCs exhibited a distinct homogenous and membranous expression pattern, whereas CLDN1 immunoreactivity appeared weaker and more heterogeneous in adaCPs. In the latter cases, whirl-like cell clusters showed complete absence of CLDN1. mRNA analysis confirmed reduced CLDN1 levels in adaCPs versus papCPs. Interestingly, invasive tumors exhibited significantly lower CLDN1 expression compared with noninvasive counterparts regardless of CP subtype. Accordingly, siRNA treatment for CLDN1 altered tumor cell migration in vitro. Conclusion CLDN1 represents a novel marker in the differential diagnosis of CP variants and RCCs. Low CLDN1 expression levels correlate with an invasive CP growth pattern and may serve as a prognostic marker. PMID:24305709

  11. Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development

    Microsoft Academic Search

    Beate M. Lichtenberger; Poi Kiang Tan; Heide Niederleithner; Napoleone Ferrara; Peter Petzelbauer; Maria Sibilia

    2010-01-01

    SUMMARY It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth. Here, we demonstrate that in K5-SOS- dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autono- mous and angiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis

  12. [Utility of bolus dynamic CT for the detection of hypervascular malignant hepatic tumors: mainly referring to the comparison with delayed phase contrast-enhanced CT].

    PubMed

    Matsuda, H; Abe, K; Freeny, P C

    1996-03-01

    In order to analyze the usefulness of dynamic contrast-enhanced CT, 84 patients who had hepatocellular carcinoma or suspected hypervascular metastases were studied with conventional incremental dynamic CT (CID-CT) or double helical CT (DH-CT). Delayed phase contrast-enhanced CT studies were consecutively performed in all patients. Thirty-six of 84 patients had malignant hepatic neoplasms; six had hepatocellular carcinoma and 30 had metastatic tumors. At first, the detectability of hepatic lesions was evaluated with bolus dynamic CT and delayed phase CT. Dynamic CT has detected more lesions than delayed CT. Some hepatic lesions described as isodensity were missed on CID-CT. Therefore, delayed phase CT cannot be eliminated when CID-CT is performed. Secondly, hepatic lesion detectability with CID-CT was compared with that of DH-CT. DH-CT did not miss the hepatic lesions picked up by delayed phase CT and was expected to provide excellent detectability of hypervascular hepatic neoplasms. In addition, first helical CT showed most hepatic lesions as areas of obvious hyperdensity, while CID-CT did not show their correct vascularities. So-called hypervascular hepatic tumors, however, were not always hypervascular and were demonstrated as areas of iso-hypodensity even on initial helical scanning. Second helical CT was useful to detect these so-called hypervascular, but actually hypovascular lesions. In conclusion, dynamic CT was helpful in detecting hypervascular hepatic malignant neoplasms, and DH-CT was more accurate than CID-CT for the detection of hepatic lesions and the evaluation of vascular lesion. PMID:8992451

  13. Soil salinity delays germination and limits growth of hyphae from propagules of arbuscular mycorrhizal fungi.

    PubMed

    Juniper, S; Abbott, L K

    2006-07-01

    Colonisation of plant roots by some arbuscular mycorrhizal (AM) fungi is reduced in the presence of sodium chloride (NaCl), probably due to a direct effect of NaCl on the fungi. However, there appear to be differences between the fungi in their ability to colonise plants in the presence of NaCl. This experiment tested the hypothesis that propagules of different isolates and species of AM fungi from saline and nonsaline soils would differ in their ability to germinate and grow in the presence of NaCl in the soil solution. Spores or pieces of root colonised by a range of AM fungi were incubated between filters buried in soil to which NaCl had been added at concentrations of 0, 150 or 300 mM in the soil solution. At regular intervals, filters were removed from the soil and both the percentage of propagules which had germinated and the length of proliferating hyphae were determined. Germination of spores of AM fungi studied was delayed in the presence of NaCl, but the fungi differed in the extent to which germination was inhibited. Two isolates of Scutellospora calospora reached maximum germination in 300 mM NaCl, but neither of two isolates of Acaulospora laevis germinated in the presence of NaCl. Germination of spores of the other fungi, including some isolated from saline soil, fell between these extremes. For some fungi, the specific rate of hyphal extension was reduced by NaCl. For others, the specific rate of growth was similar in the presence of NaCl to that in the control treatment, but overall production of hyphae was reduced in the NaCl treatments because germination was reduced. PMID:16525784

  14. Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD.

    PubMed

    Zhou, Xia; Fan, Lucy X; Peters, Dorien J M; Trudel, Marie; Bradner, James E; Li, Xiaogang

    2015-07-15

    In this study, we identified a BET bromodomain (BRD) protein, Brd4, not only as a novel epigenetic regulator of autosomal dominant polycystic kidney disease (ADPKD) but also as a novel client protein of Hsp90. We found that Brd4 was upregulated in Pkd1 mutant mouse renal epithelial cells and tissues. This upregulation of Brd4 appears to result from the chaperone activity of Hsp90 and escape proteasomal degradation. We further identify that Brd4 is an upstream regulator of the expression of c-Myc which has been upregulated in all rodent models of PKD and ADPKD patients with unknown mechanism. Inhibition of Brd4 in Pkd1 mutant renal epithelial cells with JQ1, a selective small-molecular inhibitor of BET BRD protein(s), (1) decreased the levels of c-Myc mRNA and protein; (2) increased the levels of p21 mRNA and protein, which was transcriptionally repressed by c-Myc; (3) decreased the phosphorylation of Rb; and (4) decreased cystic epithelial cell proliferation as shown by inhibition of S-phase entry. Most importantly, treatment with JQ1 strikingly delayed cyst growth and kidney enlargement, and preserved renal function in two early stage genetic mouse strains with Pkd1 mutations. This study not only provides one of the mechanisms of how c-Myc is upregulated in PKD but also suggests that targeting Brd4 with JQ1 may function as a novel epigenetic approach in ADPKD. The unraveled link between Brd4 and Hsp90 in ADPKD may also be a general mechanism for the upregulation of Brd4 in cancer cells and opens up avenues for combination therapies against ADPKD and cancer. PMID:25877301

  15. Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma

    PubMed Central

    Jiang, Xingming; Ma, Ning; Wang, Dayong; Li, Fuyuan; He, Rongzhang; Li, Dongliang; Zhao, Ruiqi; Zhou, Qingxin; Wang, Yimin; Zhang, Fumin; Wan, Ming; Kang, Pengcheng; Gao, Xu; Cui, Yunfu

    2015-01-01

    The antidiabetic drug metformin exerts antineoplastic effects in many types of malignancies, however the effect of metformin on cholangiocarcinoma (CCA) still remains unclear. In the present study, we investigated that metformin treatment was closely associated with the clinicopathologic characteristics and improved postoperative survival of CCA patients. Metformin inhibited CCA tumor growth by cell cycle arrest in vitro and in vivo. We explored that the expression of six miRNAs (mir124, 182, 27b, let7b, 221 and 181a), which could directly target cell-cycle-regulatory genes, was altered by metformin in vitro and in vivo. These miRNAs were dysregulated in cholangiocarcinoma and promoted the CCA genesis and metformin exactly modulated these carcinogenic miRNAs expression to arrest the cell cycle and inhibit the proliferation. Meanwhile, these miRNAs expression changes correlated with the tumor volume and postoperative survival of CCA patients and could be used to predict the prognosis. Further we confirmed that metformin upregulated Drosha to modulate these miRNAs expression. Our results elucidated that metformin inhibited CCA tumor growth via the regulation of Drosha-mediated multiple carcinogenic miRNAs expression and comprehensive evaluation of these miRNAs expression could be more efficient to predict the prognosis. Moreover, metformin might be a quite promising strategy for CCA prevention and treatment. PMID:25605008

  16. PCTAIRE1 regulates p27 stability, apoptosis and tumor growth in malignant melanoma

    PubMed Central

    Yanagi, Teruki; Reed, John C.; Matsuzawa, Shu-ichi

    2014-01-01

    PCTAIRE1 is a cyclin-dependent kinase family protein that has been implicated in spermatogenesis. Although we recently revealed the function of PCTAIRE1 in tumorigenesis of epithelial carcinoma cells, its tumorigenic function in melanoma remains unclear. Interrogation of the Oncomine database revealed that malignant melanoma showed up-regulation of PCTAIRE1 mRNA compared to normal skin and benign melanocytic nevus tissues. In the melanoma cell lines A2058 and SK-MEL-28, PCTAIRE1 gene knockdown using siRNA or shRNA diminished melanoma cell proliferation as assessed by cellular ATP levels, cell counting and clonogenic assays. Moreover, FACS analyses of annexin V-PI staining and DNA content showed that PCTAIRE1 knockdown caused apoptosis in A2058 cells. In contrast, PCTAIRE1 does not appear to be involved in the proliferation of immortalized human keratinocyte HaCaT cells. Depletion of PCTAIRE1 by siRNA/shRNA led to p27 accumulation in melanoma cells but not HaCaT cells. In tumor xenografts of melanoma A2058 cells, conditional knockdown of PCTAIRE1 restored p27 protein expression and suppressed tumor growth. Our findings reveal a crucial role for PCTAIRE1 in regulating p27 protein levels and tumor growth in melanoma cells, suggesting that PCTAIRE1 could provide a target for melanoma treatment. PMID:25593992

  17. Effect of microRNA-203 on tumor growth in human hypopharyngeal squamous cell carcinoma.

    PubMed

    Wang, Ru; Fang, Jugao; Ma, Hongzhi; Feng, Lin; Lian, Meng; Yang, Fan; Wang, Haizhou; Wang, Qi; Chen, Xiaohong

    2015-07-01

    MicroRNAs (MiRNAs) have been recognized to regulate cancer initiation and progression in carcinogenesis as either oncogenes or tumor suppressor genes, but their role in hypopharyngeal cancer development is not clearly defined. To determine whether miRNA-203 can promote tumor growth in human hypopharyngeal squamous cell carcinoma, we conducted experiments on the functional study of miRNA-203 and identification of miRNA-203 regulated target genes in hypopharyngeal cancer cells. We found that cell proliferation and cell colony-forming increased more in the miRNA-203 up-regulated cancer cells than in the negative control cancer cells. Up-regulation of miRNA-203 accelerated cell cycle progression in hypopharyngeal cancer cells. TP63 and B3GNT5 mRNAs were identified and validated as targets of miRNA-203. However, transwell assay and wound scratch assay showed that miRNA-203 did not involve in invasion and metastasis in hypopharyngeal cancer cells. According to the results, we conclude that miRNA-203 can promote tumor growth in human hypopharyngeal squamous cell carcinoma. These results provide the convincing evidence for the first time that up-regulation of miRNA-203 contributes to the malignancy of hypopharyngeal squamous cell carcinoma, possibly through down-regulating TP63 and B3GNT5. PMID:25840888

  18. Inhibition of Angiogenesis and Vascular Tumor Growth by Interferon-Producing Cells

    PubMed Central

    Albini, Adriana; Marchisone, Chiara; Del Grosso, Federica; Benelli, Roberto; Masiello, Luciana; Tacchetti, Carlo; Bono, Maria; Ferrantini, Maria; Rozera, Carmela; Truini, Mauro; Belardelli, Filippo; Santi, Leonardo; Noonan, Douglas M.

    2000-01-01

    We developed an in vivo gene therapy approach to characterize and optimize the anti-angiogenic activity of class I interferons (IFNs), using packaging cell lines producing an amphotropic LXSN-based retrovirus expressing either IFN-?1 (?1Am12), IFN-? (?Am12) murine cDNAs, or the vector alone (neoAm12). Pretreatment of endothelial-like Eahy926 cells in vitro with conditioned media (CM) from ?1Am12 or ?Am12 cells for 48 hours significantly inhibited their migration and invasion as compared to neoAm12-CM-treated cells. ?Am12-CM also inhibited the formation of capillary-like structures on Matrigel by EAhy926 cells. In vivo, inclusion of the ?Am12 cells strongly inhibited, and ?1Am12 partially inhibited, the angiogenic response in the Matrigel sponge model in both immune-competent and athymic nude mice. Electron microscopy showed a reduction of host cell infiltration in ?1Am12- and ?Am12-containing sponges and reduction of invading tubular clefts of host cells as compared to controls. Finally, inoculation of either ?1Am12 or ?Am12 cells (10%) along with a highly angiogenic Kaposi’s sarcoma cell line (90%) resulted in a powerful reduction of tumor growth in nude mice in vivo, as did infection with the interferon-?-producing retroviruses. These data suggest that a gene therapy approach using class I interferons can effectively inhibit tumor angiogenesis and growth of vascular tumors. PMID:10751362

  19. Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.

    PubMed Central

    Zhang, Y; Weiler-Guettler, H; Chen, J; Wilhelm, O; Deng, Y; Qiu, F; Nakagawa, K; Klevesath, M; Wilhelm, S; Böhrer, H; Nakagawa, M; Graeff, H; Martin, E; Stern, D M; Rosenberg, R D; Ziegler, R; Nawroth, P P

    1998-01-01

    Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain. PMID:9525972

  20. Discrete functions of GSK3? and GSK3? isoforms in prostate tumor growth and micrometastasis

    PubMed Central

    Gao, Fei; Al-Azayzih, Ahmad; Somanath, Payaningal R.

    2015-01-01

    Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3?, but not GSK3? expression inhibited proliferation, survival and colony formation by the PC3, DU145 and LNCaP prostate cancer cells, and the growth of PC3 tumor xenografts in athymic nude mice. Silencing of GSK3?, but not GSK3? resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3? and GSK3? equally inhibited the ability of prostate cancer cells to migrate and invade the endothelial-barrier in vitro, and PC3 cell micrometastasis to lungs in vivo. Mechanistically, whereas silencing GSK3? resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3? resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of ?-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3? in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3? and GSK3? in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms. PMID:25714023

  1. Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea.

    PubMed

    Wang, Piwen; Vadgama, Jaydutt V; Said, Jonathan W; Magyar, Clara E; Doan, Ngan; Heber, David; Henning, Susanne M

    2014-01-01

    The chemopreventive activity of green tea (GT) is limited by the low bioavailability and extensive methylation of GT polyphenols (GTPs) in vivo. We determined whether a methylation inhibitor quercetin (Q) will enhance the chemoprevention of prostate cancer in vivo. Androgen-sensitive LAPC-4 prostate cancer cells were injected subcutaneously into severe combined immunodeficiency (SCID) mice one week before the intervention. The concentration of GTPs in brewed tea administered as drinking water was 0.07% and Q was supplemented in diet at 0.2% or 0.4%. After 6-weeks of intervention tumor growth was inhibited by 3% (0.2% Q), 15% (0.4% Q), 21% (GT), 28% (GT+0.2% Q) and 45% (GT+0.4% Q) compared to control. The concentration of non-methylated GTPs was significantly increased in tumor tissue with GT+0.4% Q treatment compared to GT alone, and was associated with a decreased protein expression of catechol-O-methyltransferase and multidrug resistance-associated protein (MRP)-1. The combination treatment was also associated with a significant increase in the inhibition of proliferation, androgen receptor and phosphatidylinositol 3-kinase/Akt signaling, and stimulation of apoptosis. The combined effect of GT+0.4% Q on tumor inhibition was further confirmed in another experiment where the intervention started prior to tumor inoculation. These results provide a novel regimen by combining GT and Q to improve chemoprevention in a non-toxic manner and warrant future studies in humans. PMID:24314868

  2. Semaphorin 3A Suppresses Tumor Growth and Metastasis in Mice Melanoma Model

    PubMed Central

    Chakraborty, Goutam; Patil, Tushar V.; Kundu, Gopal C.

    2012-01-01

    Background Recent understanding on cancer therapy indicated that targeting metastatic signature or angiogenic switch could be a promising and rational approach to combat cancer. Advancement in cancer research has demonstrated the potential role of various tumor suppressor proteins in inhibition of cancer progression. Current studies have shown that axonal sprouting inhibitor, semaphorin 3A (Sema 3A) acts as a potent suppressor of tumor angiogenesis in various cancer models. However, the function of Sema 3A in regulation of melanoma progression is not well studied, and yet to be the subject of intense investigation. Methodology/Principal Findings In this study, using multiple in vitro and in vivo approaches we have demonstrated that Sema 3A acts as a potent tumor suppressor in vitro and in vivo mice (C57BL/6) models. Mouse melanoma (B16F10) cells overexpressed with Sema 3A resulted in significant inhibition of cell motility, invasiveness and proliferation as well as suppression of in vivo tumor growth, angiogenesis and metastasis in mice models. Moreover, we have observed that Sema 3A overexpressed melanoma clone showed increased sensitivity towards curcumin and Dacarbazine, anti-cancer agents. Conclusions Our results demonstrate, at least in part, the functional approach underlying Sema 3A mediated inhibition of tumorigenesis and angiogenesis and a clear understanding of such a process may facilitate the development of novel therapeutic strategy for the treatment of cancer. PMID:22448259

  3. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo.

    PubMed

    Guan, Siao-Syun; Chang, Jungshan; Cheng, Chun-Chia; Luo, Tsai-Yueh; Ho, Ai-Sheng; Wang, Chia-Chi; Wu, Cheng-Tien; Liu, Shing-Hwa

    2014-07-15

    Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo. PMID:24947902

  4. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo

    PubMed Central

    Guan, Siao-Syun; Chang, Jungshan; Cheng, Chun-Chia; Luo, Tsai-Yueh; Ho, Ai-Sheng; Wang, Chia-Chi; Wu, Cheng-Tien; Liu, Shing-Hwa

    2014-01-01

    Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo. PMID:24947902

  5. The Cancer Growth Suppressor Gene mda-7 Selectively Induces Apoptosis in Human Breast Cancer Cells and Inhibits Tumor Growth in Nude Mice

    Microsoft Academic Search

    Zao-Zhong Su; Malavi T. Madireddi; Jiao Jiao Lin; Charles S. H. Young; Shinichi Kitada; John C. Reed; Neil I. Goldstein; Paul B. Fisher

    1998-01-01

    A differentiation induction subtraction hybridization strategy is being used to identify and clone genes involved in growth control and terminal differentiation in human cancer cells. This scheme identified melanoma differentiation associated gene-7 (mda-7), whose expression is upregulated as a consequence of terminal differentiation in human melanoma cells. Forced expression of mda-7 is growth inhibitory toward diverse human tumor cells. The

  6. Brain Tumor Tropism of Transplanted Human Neural Stem Cells Is Induced by Vascular Endothelial Growth Factor1*

    PubMed Central

    Schmidt, Nils Ole; Przylecki, Wojciech; Yang, Wendy; Ziu, Mateo; Teng, Yang; Kim, Seung U; Black, Peter Mcl; Aboody, Karen S; Carroll, Rona S

    2005-01-01

    Abstract The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors. PMID:16036113

  7. Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect.

    PubMed

    Renaud, Stéphanie; Corcé, Vincent; Cannie, Isabelle; Ropert, Martine; Lepage, Sylvie; Loréal, Olivier; Deniaud, David; Gaboriau, François

    2015-08-01

    Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer. PMID:26070250

  8. Cytohesin-3 is upregulated in hepatocellular carcinoma and contributes to tumor growth and vascular invasion

    PubMed Central

    Fu, Ying; Li, Jun; Feng, Ming-Xuan; Yang, Xiao-Mei; Wang, Ya-Hui; Zhang, Yan-Li; Qin, Wenxin; Xia, Qiang; Zhang, Zhi-Gang

    2014-01-01

    Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality, and is characterized by high potential for metastasis and recurrence. The outcome of it is still poor due to lacking of targeted therapeutic strategies. There is an urgent need to find new therapeutic targets for interventions against HCC metastasis and recurrence. In the present study, we found cytohesin-3, a member of the cytohesin family, was upregulated in HCC tissues, and its expression was negatively correlated with the overall survival and relapse-free survival of HCC patients. Further clinicopathological correlation analysis revealed that cytohesin-3 expression was related with tumor size and vascular invasion. And in vitro studies revealed that knock-down of cytohesin-3 suppressed HCC cells proliferation and migration. These results suggest that cytohesin-3 may act as a novel prognostic factor of HCC, and it might also be useful to exploit targeted therapeutic drugs against HCC growth and metastasis. PMID:24966920

  9. Cancer cachexia and tumor growth reduction in Walker 256 tumor-bearing rats supplemented with N-3 polyunsaturated fatty acids for one generation.

    PubMed

    Togni, Valéria; Ota, Claudia C C; Folador, Alessandra; Júnior, O Tchaikovski; Aikawa, Júlia; Yamazaki, Ricardo K; Freitas, Fábio A; Longo, Rita; Martins, Edgair F; Calder, Philip C; Curi, Rui; Fernandes, Luiz C

    2003-01-01

    In this study we investigated the effect of lifelong supplementation of the diet with coconut oil (CO, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids, PUFAs) on tumor growth, animal survival, and metabolic indicators of cachexia in adult rats. Female Wistar rats were supplemented with CO or FO prior to mating and then throughout pregnancy and gestation, and then the male offspring were supplemented from weaning until 90 days of age. Then they were inoculated subcutaneously with Walker 256 tumor cells. Tumor weight at 14 days in control rats (those fed standard chow) was approximately 20 g. These animals displayed cancer cachexia, which was characterized by loss of weight, hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, and depletion of glycogen stores. Supplementation of the diet with CO did not change these parameters, except that there was a smaller decrease in serum triacylglycerol concentration. Supplementation of the diet with FO significantly decreased tumor growth (by approximately 60%), increased survival (50% at 30 days postinoculation vs. 30% in the controls and 13.5% in the CO group), and prevented the fall in body weight. Furthermore, FO supplementation partly abolished the fall in serum glucose, totally prevented the elevation in serum lactate concentrations, partly prevented the hypertriacylgylcerolemia, and preserved tissue glycogen stores. Lifelong consumption of FO, rich in n-3 PUFAs, protects against tumor growth and cancer cachexia and improves survival. PMID:12925304

  10. Neovascularization and tumor growth in the rabbit brain. A model for experimental studies of angiogenesis and the blood-brain barrier.

    PubMed Central

    Zagzag, D.; Brem, S.; Robert, F.

    1988-01-01

    A model for the study of tumor angiogenesis within the rabbit brain is presented. Implantation of the VX2 carcinoma provides a reproducible tumor accompanied by angiogenesis. The authors report the sequential growth, histology, tumor neovascularization, and vascular permeability of this tumor following its intracerebral implantation. Tumor angiogenesis correlates with the rapid and logarithmic intracerebral tumor growth. The proliferation of blood vessels in the tumor and the organization of tumor cells around tumor vessels are described. Breakdown of the blood-brain barrier (detected by Evans blue leakage) starts in the early stages of tumor development and becomes prominent as the tumor vasculature and size increase. This model is useful for experimental studies of angiogenesis. Images Figure 2 Figure 3 Figure 6 Figure 4 Figure 5 Figure 7 Figure 8 Figure 10 Figure 12 Figure 13 Figure 15 PMID:2451889

  11. An In Vitro One-Dimensional Assay to Study Growth Factor-Regulated Tumor Cell–Macrophage Interaction

    PubMed Central

    Sharma, Ved P.; Beaty, Brian T.; Cox, Dianne; Condeelis, John S.; Eddy, Robert J.

    2014-01-01

    Growth factor-dependent pairing and motility between tumor cells and tumor-associated macrophages on extracellular matrix (ECM) fibers of the tumor microenvironment have been shown to enhance intravasation and metastatic spread of breast carcinomas. We describe an in vitro motility assay that combines time- lapse wide-field microscopy and micro-patterned linear adhesive substrates to reconstitute the in vivo behavior between macrophages, tumor cells, and ECM fibers in orthotopic rodent tumor models observed by intravital imaging. Commercially available linear stripes of 650 nm dye-labeled fibronectin microlithographed onto glass cover slips are sequentially plated with fluorescently labeled MTLn3 tumor cells and bone marrow-derived macrophages and time-lapse imaged for up to 8 h. Incubation with pharmacological inhibitors during the assay can identify important paracrine or autocrine signaling pathways involved in the macrophage–tumor cell interaction. This high-resolution motility assay will lead to a more detailed description of immune cell–tumor cell behavior as well as interrogating additional cell types within the tumor microenvironment which use cytokine/growth factor paracrine signaling interactions to facilitate intravasation and metastasis. PMID:24908299

  12. Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases.

    PubMed

    Lamora, Audrey; Mullard, Mathilde; Amiaud, Jérôme; Brion, Régis; Heymann, Dominique; Redini, Françoise; Verrecchia, Franck

    2015-06-10

    Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-?/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-?/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-?/Smad3 cascade and the response of TGF-? key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination. PMID:26015407

  13. Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo

    PubMed Central

    Joshi, Shweta; Singh, Alok R.; Zulcic, Muamera; Bao, Lei; Messer, Karen; Ideker, Trey; Dutkowski, Janusz; Durden, Donald L.

    2014-01-01

    Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the ?4?1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the ?4?1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis. PMID:24770346

  14. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.

    PubMed

    Joshi, Shweta; Singh, Alok R; Zulcic, Muamera; Bao, Lei; Messer, Karen; Ideker, Trey; Dutkowski, Janusz; Durden, Donald L

    2014-01-01

    Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the ?4?1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the ?4?1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis. PMID:24770346

  15. Vascular endothelial growth factor immunoexpression is increased in malignant salivary gland tumors.

    PubMed

    Fonseca, Felipe Paiva; Basso, Marcos Paulo Montanhana; Mariano, Fernanda Viviane; Kowalski, Luiz Paulo; Lopes, Márcio Ajudarte; Martins, Manoela Domingues; Rangel, Ana Lúcia Carrinho Ayroza; Santos-Silva, Alan Roger; Vargas, Pablo Agustin

    2015-06-01

    Salivary gland tumors (SGTs) consist of a heterogeneous group of lesions accounting for 3% to 10% of all head and neck neoplasms. Little is known about their angiogenic properties, and despite vascular endothelial growth factor (VEGF) has been previously studied in these lesions, further investigations are warranted to better determine its clinical and prognostic significance. In the current study, a total of 132 formalin-fixed, paraffin-embedded SGTs were organized in tissue microarray blocks and submitted to immunohistochemistry against VEGF protein. Slides were scanned and immunoreactions analyzed using Pixelcount V9 algorithm (Aperio Technologies Inc, Vista, CA, USA). Clinical and follow-up data were retrieved from patients' medical charts. Tumors included 50 cases of pleomorphic adenoma, 32 mucoepidermoid carcinomas, 30 adenocarcinomas not otherwise specified, and 20 adenoid cystic carcinomas. A slight male preponderance was found (1.1:1.0), with a mean age of 47.5 years. Parotid gland was the most affected location. Vascular endothelial growth factor expression was found in the cytoplasm of all cases analyzed with variable intensity, proving to be overexpressed in malignant tumors if compared with pleomorphic adenoma. A significant correlation of VEGF reactivity was found only with age, showing no further significant associations. Age and presence of paresthesia were the only features that predicted a lower specific survival rate under univariate and multivariate analyses. Log-rank test evidenced VEGF high expression as a potential determinant of reduced survival, although a statistical significance could not be reached. Hence, considering VEGF overexpression in malignant tumors and its potential association with a lower survival rate, this protein might be associated with SGTs pathogenesis and aggressiveness. PMID:25900273

  16. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    SciTech Connect

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States)] [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States); Bosland, Maarten C.; Kajdacsy-Balla, Andre [Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612 (United States)] [Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Gnanasekar, Munirathinam, E-mail: mgnanas@uic.edu [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States)] [Department of Biomedical Sciences, University of Illinois, College of Medicine, Rockford, IL 61107 (United States)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. Black-Right-Pointing-Pointer Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. Black-Right-Pointing-Pointer Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. Black-Right-Pointing-Pointer Knock down of RAGE abrogates prostate tumor growth in vivo. Black-Right-Pointing-Pointer Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  17. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila.

    PubMed

    Wei, Xiaomu; Shimizu, Takeshi; Lai, Zhi-Chun

    2007-04-01

    Tissue growth and organ size are determined by coordinated cell proliferation and apoptosis in development. Recent studies have demonstrated that Hippo (Hpo) signaling plays a crucial role in coordinating these processes by restricting cell proliferation and promoting apoptosis. Here we provide evidence that the Mob as tumor suppressor protein, Mats, functions as a key component of the Hpo signaling pathway. We found that Mats associates with Hpo in a protein complex and is a target of the Hpo serine/threonine protein kinase. Mats phosphorylation by Hpo increases its affinity with Warts (Wts)/large tumor suppressor (Lats) serine/threonine protein kinase and ability to upregulate Wts catalytic activity to target downstream molecules such as Yorkie (Yki). Consistently, our epistatic analysis suggests that mats acts downstream of hpo. Coexpression analysis indicated that Mats can indeed potentiate Hpo-mediated growth inhibition in vivo. Our results support a model in which Mats is activated by Hpo through phosphorylation for growth inhibition, and this regulatory mechanism is conserved from flies to mammals. PMID:17347649

  18. Challenge to the suppression of tumor growth by the ?4-galactosyltransferase genes

    PubMed Central

    FURUKAWA, Kiyoshi

    2015-01-01

    It has been well established that structural changes in glycans attached to proteins and lipids are associated with malignant transformation of cells. We focused on galactose residues among the sugars since they are involved in the galectin-mediated biology, and many carbohydrate antigens are frequently expressed on this sugar. We found changes in the expression of the ?4-galactosyltransferase (?4GalT) 2 and 5 genes in cancer cells: decreased expression of the ?4GalT2 gene and increased expression of the ?4GalT5 gene. The growth of mouse melanoma cells showing enhanced expression of the ?4GalT2 gene or reduced expression of the ?4GalT5 gene is inhibited remarkably in syngeneic mice. Tumor growth inhibition is probably caused by the induction of apoptosis, inhibition of angiogenesis, and/or reduced MAPK signals. Direct transduction of human ?4GalT2 cDNA together with the adenovirus vector into human hepatocellular carcinoma cells grown in SCID mice results in marked growth retardation of the tumors. ?4GalT gene-transfer appears to be a potential tool for cancer therapy. PMID:25743061

  19. Does delay in diagnosing colorectal cancer in symptomatic patients affect tumor stage and survival? A population-based observational study

    Microsoft Academic Search

    Jochim S Terhaar sive Droste; Frank A Oort; René WM van der Hulst; Veerle MH Coupé; Mike E Craanen; Gerrit A Meijer; Linde M Morsink; Otto Visser; Roy LJ van Wanrooij; Chris JJ Mulder

    2010-01-01

    BACKGROUND: Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear. Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC. METHODS: Prospective population-based observational study evaluating daily clinical practice in Northern Holland.

  20. Dietary fat modulation of mammary tumor growth and metabolism demonstrated by /sup 31/P-nuclear magnetic resonance

    SciTech Connect

    Erickson, K.L.; Buckman, D.K.; Hubbard, N.E.; Ross, B.

    1986-03-05

    The relationship of dietary fat concentration and saturation on the growth and metabolic activity of line 168 was studied using syngeneic mice fed 6 experimental diets before and during tumor growth. Tumor latency was significantly greater for mice fed a diet containing the minimum of essential fatty acids (EFA, 0.5% corn oil) or 8% coconut oil (SF) than for mice fed 8 or 20% safflower oil (PUF) or 20% SF. Changes in dietary fat resulted in alterations of tumor cell and serum fatty acid composition but not the number of inflammatory cells infiltrating the tumor. /sup 31/P-surface coil NMR was used to measure possible changes in tumor metabolism in vivo. Although pH decreased from 7.2 to 6.6 as the tumor volume increased, there was no difference in pH among dietary groups. There was an inverse relationship between both sugar phosphate (SP)/Pi and ATP/Pi ratios and tumor volume; those ratios for mice fed an EFA deficient or minimal EFA diet decreased at a different rate than ratios for mice fed diets with additional fat. Tumors of mice fed diets containing no or a low level (0.3%) of 18:2 had higher SP/ATP ratios than mice fed diets containing a moderate level (approx. 4%) of 18:2. Thus, high levels of dietary fat had a significant effect on promotion of mammary tumors during early stages of tumor growth. Differences in tumor volume associated with dietary fat may be related to changes in the levels of high energy phosphate metabolites.

  1. Fluorescence imaging of vascular endothelial growth factor in mice tumors using targeted liposome ICG probe

    NASA Astrophysics Data System (ADS)

    Zanganeh, Saeid; Xu, Yan; Backer, Marina V.; Backer, Joseph M.; Zhu, Quing

    2013-03-01

    Indocyanine Green encapsulating liposomes (Lip/ICG) and scVEGF-Lip/ICG liposomes, decorated with site-specifically lipidated engineered single-chain vascular endothelial growth factor (scVEGF) for targeting VEGF receptors were tested as potential tracers for fluorescent tomography. Two groups of experiments were conducted with tumor-bearing mice (n=4 to 6 per group) with tumors placed in a scattering medium at the imaging depths of 1.5 and 2.0 cm. Lip/ICG and scVEGF-Lip/ICG were injected intravenously in the amounts corresponding to 5 nmol of ICG/mouse. We detected kinetics of increase and decline in fluorescent signals in tumors for both imaging depths and for both targeted and untargeted Lip/ICG. Maximum fluorescent signals were approximately 2-fold higher at 1.5 cm vs. 2.0 cm imaging. A signal from untargeted Lip/ICG reached maximum at 15 min post-injection and then rapidly declined with t1/2 ~15 min. In contrast, a signal from targeted scVEGF-Lip/ICG reached maximum at 30 min post-injection and then slow declined with t1/2 ~60-90 min. Preferential retention of scVEGF-Lip(ICG) vs. Lip(ICG) was confirmed by the analysis of fluorescence in cryosections of corresponding tumors, harvested at 400 min post-injection. Our results suggest that targeted scVEGF-Lip/ICG can provide for significantly better post-injection time window for detection of relatively deeply seated tumors.

  2. Alendronate liposomes for antitumor therapy: activation of ?? T cells and inhibition of tumor growth.

    PubMed

    Gutman, Dikla; Epstein-Barash, Hila; Tsuriel, Moshe; Golomb, Gershon

    2012-01-01

    Circulating ?? T cells are cytotoxic lymphocytes that are unique to primates. Recent -studies have shown that amino-bisphosphonates (nBP) activate ?? T cells to kill tumor cells in an indirect mechanism, which requires antigen presenting cells (APC). We hypothesized that selective targeting of nBP to monocytes would result in a more potent ?? T cells activation in circulation, and in tissue associated macrophages (TAM) following monocytes-laden drug extravasation and liposomes accumulation at the tumor site. In addition, inhibition of TAM by alendronate liposomes (ALN-L) is expected. ALN was targeted exclusively to monocytes, but not to lymphocytes, by encapsulating it in negatively-charged liposomes. The proportion of human ?d-T cells in the CD3(+) population following treatment with ALN-L or the free drug was increased, from 5.6 ± 0.4% to 50.9 ;± 12.2% and 49.5 ± 12.9%, respectively. ALN solution and liposomes treatments resulted in an increased, and in a dose dependent manner, TNF? secretion from h-PBMC. Preliminary results showed that ALN-L inhibited tumor growth in a nude mouse breast tumor model. It is suggested that enhanced activation of ?? T cells could be obtained due to interaction with circulating monocytes as well as by TAM endocytosing liposomal nBP leading to a potentiated anti-tumor effect of nBP. It should be noted that this could be validated only in primates/humans since ?? T cells are unique in these species. PMID:22101722

  3. Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide.

    PubMed

    Golubovskaya, Vita M; Huang, Grace; Ho, Baotran; Yemma, Michael; Morrison, Carl D; Lee, Jisook; Eliceiri, Brian P; Cance, William G

    2013-02-01

    Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15 to 18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report, we tested the FAK autophosphorylation inhibitor, Y15, in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose- and time-dependent manner, caused apoptosis, and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small-molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide. PMID:23243059

  4. tRNAPhe and tRNAPro are the near-ultraviolet molecular targets triggering the growth delay effect

    SciTech Connect

    Blondel, M.O.; Favre, A.

    1988-02-15

    The illumination of Escherichia coli cells with UVA light, 320 nm less than or equal to lambda less than or equal to 380 nm, triggers a transient growth and division delay. The built-in 4-thiouridine chromophore which absorbs light at 340 nm leads to the quantitative 8-13 crosslinking of a number of tRNA species corresponding to 50% of the bulk tRNA molecules. Determination of the tRNA acylation level by the various aminoacids shows that only the tRNA species acylated by Phe and Pro are strikingly affected in vivo. Both acylation levels decrease to less than 10% of their initial value during the illumination period, remain stable all along the growth lag and increase concomitantly with cell mass when growth resumes. Hence tRNA(Phe) and tRNA(Pro) are the UVA light molecular targets triggering growth delay and related effects of biological significance such as cell volume reduction, photoprotection and protection against UV mutagenesis (antiphotomutagenesis).

  5. Dihydroartemisinin shift the immune response towards Th1, inhibit the tumor growth in vitro and in vivo

    Microsoft Academic Search

    Shokoofe Noori; Zuhair M. Hassan

    2011-01-01

    Some investigators have been found that Artemisinin and its derivates have inhibitory effect on growth of cancer cells. Among these derivatives, Dihydroartemisinin (DHA) is well known as a semi-synthetic one. In addition, T cells are proved to be essential for the destruction of cancer cells. In this research, we assessed the effects of DHA on tumor cell growth inhibition in

  6. Role of growth factors, steroid and peptide hormones in the regulation of human prostatic tumor growth

    Microsoft Academic Search

    M. Motta; D. Dondi; R. M. Moretti; M. Montagnani Marelli; F. Pimpinelli; R. Maggi; P. Limonta

    1996-01-01

    Previous work carried out in the authors' laboratory has shown that LHRH agonists directly inhibit the proliferation of hormone-responsive and hormone-independent human prostatic cancer cell lines (respectively LNCaP and DU145). In addition, the hormone-dependent LNCaP cells respond to a challenge with testosterone with an increase in growth rate. The following experiments have been performed to investigate whether the LHRH agonists

  7. Osteopontin contributes to hepatocyte growth factor-induced tumor growth and metastasis formation

    Microsoft Academic Search

    E. V Ariztia; V Subbarao; D. B Solt; A. W Rademaker; A. P Iyer; Z. N Oltvai

    2003-01-01

    The cytokine hepatocyte growth factor (HGF)\\/scatter factor-1 and its cognate receptor, Met, are involved in the etiology and progression of many types of cancer. Despite recent advances in understanding the signal transduction pathways activated by HGF, the mechanism by which HGF exerts its tumorigenic effect is not well understood. To identify proteins that may be involved in mediating HGF-induced cell

  8. The Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor Cediranib (Recentin; AZD2171) Inhibits Endothelial Cell Function and Growth of Human Renal Tumor Xenografts

    SciTech Connect

    Siemann, Dietmar W. [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States)], E-mail: siemadw@ufl.edu; Brazelle, W.D. [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States); Juergensmeier, Juliane M. [Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom)

    2009-03-01

    Purpose: The goal of this study was to examine the therapeutic potential of the vascular endothelial growth factor (VEGF) signaling inhibitor cediranib in a human model of renal cell carcinoma (Caki-1). Methods and Materials: The effects of cediranib treatment on in vitro endothelial cell function (proliferation, migration, and tube formation), as well as in vivo angiogenesis and tumor growth, were determined. Results: In vitro, cediranib significantly impaired the proliferation and migration of endothelial cells and their ability to form tubes, but had no effect on the proliferation of Caki-1 tumor cells. In vivo, cediranib significantly reduced Caki-1 tumor cell-induced angiogenesis, reduced tumor perfusion, and inhibited the growth of Caki-1 tumor xenografts. Conclusions: The present results are consistent with the notion that inhibition of VEGF signaling leads to an indirect (i.e., antiangiogenic) antitumor effect, rather than a direct effect on tumor cells. These results further suggest that inhibition of VEGF signaling with cediranib may impair the growth of renal cell carcinoma.

  9. MicroRNA-510 promotes cell and tumor growth by targeting peroxiredoxin1 in breast cancer

    PubMed Central

    2013-01-01

    Introduction MicroRNAs are small non-coding RNAs that are involved in the post-transcriptional negative regulation of mRNAs. MicroRNA 510 (miR-510) was initially shown to have a potential oncogenic role in breast cancer by the observation of its elevated levels in human breast tumor samples when compared to matched non-tumor samples. Few targets have been identified for miR-510. However, as microRNAs function through the negative regulation of their direct targets, the identification of those targets is critical for the understanding of their functional role in breast cancer. Methods Breast cancer cell lines were transfected with pre-miR-510 or antisense miR-510 and western blotting and quantitative real time PCR were performed. Functional assays performed included cell growth, migration, invasion, colony formation, cytotoxicity and in vivo tumor growth. We performed a PCR assay to identify novel direct targets of miR-510. The study focused on peroxiredoxin 1 (PRDX1) as it was identified through our screen and was bioinformatically predicted to contain a miR-510 seed site in its 3' untranslated region (3'UTR). Luciferase reporter assays and site-directed mutagenesis were performed to confirm PRDX1 as a direct target. The Student's two-sided, paired t-test was used and a P-value less than 0.05 was considered significant. Results We show that miR-510 overexpression in non-transformed and breast cancer cells can increase their cell growth, migration, invasion and colony formation in vitro. We also observed increased tumor growth when miR-510 was overexpressed in vivo. We identified PRDX1 through a novel PCR screen and confirmed it as a direct target using luciferase reporter assays. The reintroduction of PRDX1 into breast cancer cell lines without its regulatory 3'UTR confirmed that miR-510 was mediating its migratory phenotype at least in part through the negative regulation of PRDX1. Furthermore, the PI3K/Akt pathway was identified as a positive regulator of miR-510 both in vitro and in vivo. Conclusions In this study, we provide evidence to support a role for miR-510 as a novel oncomir. We show that miR-510 directly binds to the 3'UTR of PRDX1 and blocks its protein expression, thereby suppressing migration of human breast cancer cells. Taken together, these data support a pivotal role for miR-510 in breast cancer progression and suggest it as a potential therapeutic target in breast cancer patients. PMID:23971998

  10. Fluorescence imaging of vascular endothelial growth factor in tumors for mice embedded in a turbid medium

    NASA Astrophysics Data System (ADS)

    Biswal, Nrusingh C.; Gamelin, John K.; Yuan, Baohong; Backer, Marina V.; Backer, Joseph M.; Zhu, Quing

    2010-01-01

    We demonstrate the feasibility of fluorescence imaging of deeply seated tumors using mice injected with an angiogenesis tracer, a vascular endothelial