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1

Radiation-guided drug delivery to tumor blood vessels results in improved tumor growth delay.  

PubMed

Tumor blood vessels are biological targets for cancer therapy. In this study, a tumor vasculature targeting system that consisted of liposomes and lectin (WGA) was built. Liposomes were used to carry a number of liposome-friendly anti-tumoral agents along with WGA, a lectin which posseses a specific affinity for binding to inflamed endothelial cells. In order to target tumor vasculature, inflammation of endothelial cells was induced by radiation. Because ionizing radiation induces an inflammatory response in tumor vasculature, lectin-conjugates were utilized to determine whether radiation can be used to target drug delivery to tumor vessels. Wheat germ agglutinin (WGA) is one such lectin that binds to inflamed microvasculature. WGA was conjugated to liposomes containing cisplatin and administered to tumor bearing mice. Tumor growth delay was used to analyze the efficacy of cytotoxicity. FITC-conjugated WGA accumulated within irradiated tumor microvasculature. WGA was conjugated to liposomes and labeled with 111In. This demonstrated radiation-inducible tumor-selective binding. WGA-liposome-conjugates were loaded with Cisplatin and administered to mice bearing irradiated tumors. Tumors treated with a combination of liposome encapsulated cisplatin together with radiation showed a significant increase in tumor growth delay as compared to radiation alone. These findings demonstrate that ionizing radiation can be used to guide drug delivery to tumor microvasculature. PMID:15451595

Geng, Ling; Osusky, Katherine; Konjeti, Sekhar; Fu, Allie; Hallahan, Dennis

2004-10-19

2

Effects of Lévy noise and immune delay on the extinction behavior in a tumor growth model  

NASA Astrophysics Data System (ADS)

The combined effects of Lévy noise and immune delay on the extinction behavior in a tumor growth model are explored. The extinction probability of tumor with certain density is measured by exit probability. The expression of the exit probability is obtained using the Taylor expansion and the infinitesimal generator theory. Based on numerical calculations, it is found that the immune delay facilitates tumor extinction when the stability index ? < 1, but inhibits tumor extinction when the stability index ? > 1. Moreover, larger stability index and smaller noise intensity are in favor of the extinction for tumor with low density. While for tumor with high density, the stability index and the noise intensity should be reduced to promote tumor extinction.

Hao, Meng-Li; Xu, Wei; Gu, Xu-Dong; Qi, Lu-Yuan

2014-09-01

3

Analysis of mathematical models for the growth of tumors with time delays in cell proliferation  

NASA Astrophysics Data System (ADS)

We study two mathematical models for the growth of tumors with time delays in cell proliferation, one for nonnecrotic tumors in the presence of inhibitors, and the other for necrotic tumors. Mathematical formulations of these models are retarded differential equations. By using a comparison method, we make rigorous analysis of these models. The results show that dynamical behavior of solutions of these models are similar to that of solutions for corresponding nonretarded problems, and the tumor will tend to a dormant state as time goes to infinity in favorable conditions (nutrient sufficient, inhibitor less), while it will finally disappear in unfavorable conditions (nutrient insufficient, inhibitor much).

Cui, Shangbin; Xu, Shihe

2007-12-01

4

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

SciTech Connect

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.

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

5

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

SciTech Connect

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.

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

6

Delayed growth  

MedlinePLUS

Growth - slow (child 0 - 5 years); Weight gain - slow (child 0 - 5 years); Slow rate of growth; Retarded growth and development; ... A child should have regular, well-baby check-ups with a health care provider. These checkups are usually scheduled ...

7

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

PubMed Central

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

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

2014-01-01

8

Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.  

PubMed

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer. PMID:24599971

Benesch, Matthew G K; Tang, Xiaoyun; Maeda, Tatsuo; Ohhata, Akira; Zhao, Yuan Y; Kok, Bernard P C; Dewald, Jay; Hitt, Mary; Curtis, Jonathan M; McMullen, Todd P W; Brindley, David N

2014-06-01

9

Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice  

PubMed Central

Background Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis. Methods Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1?/? or Akt2?/? mice. Tumor onset, growth rate, and metastasis were determined. Results Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors. Conclusions Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer. PMID:23919516

2013-01-01

10

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

PubMed Central

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

2014-01-01

11

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

Microsoft Academic Search

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

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

12

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

PubMed

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

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

13

Small Interfering RNA Targeted to IGF-IR Delays Tumor Growth and Induces Proinflammatory Cytokines in a Mouse Breast Cancer Model  

PubMed Central

Insulin-like growth factor I (IGF-I) and its type I receptor (IGF-IR) play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs) for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2?-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD). Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- ? and IFN-?. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2?-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines. PMID:22235273

Durfort, Tiphanie; Tkach, Mercedes; Meschaninova, Mariya I.; Rivas, Martín A.; Elizalde, Patricia V.; Venyaminova, Alya G.; Schillaci, Roxana; François, Jean-Christophe

2012-01-01

14

Curcumin induces apoptosis in breast cancer cell lines and delays the growth of mammary tumors in neu transgenic mice.  

PubMed

Breast cancer is a leading cancer in women and despite the benefits of the current therapies a significant number of patients with this tumor is at risk of relapse. Some of the alterations taking place in breast cancer cells are currently exploited by molecularly targeted drugs. Different drugs have been developed which target a single molecule but, given that the tumor originates from the dysregulation of many genes, there is the need to find new drugs that have more than one molecular target. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] (CUR), a polyphenolic compound found in the spice turmeric, is a pleiotropic molecule able to interact with a variety of molecular targets and has antitumor, anti-inflammatory, antioxidant, immunomodulatory and antimicrobial activities. Here we demonstrate that CUR inhibits the growth of breast cancer cell lines in a dose dependent manner, with IC50 values in the micromolar range, and induces an increase in the percentage of cells in sub-G0 phase, representing the apoptotic cell population. The activation of apoptosis was confirmed by PARP-1 cleavage and by the increased ratio between the pro-apoptotic Bax and the anti-apoptotic Bcl-2 protein. In addition, in CUR-treated cells the activity of ERK1/ERK2 MAP kinases was down-regulated. The cytotoxic effects of CUR were observed in breast cancer cells expressing either high or low levels of ErbB2/neu. The in vivo antitumor activity of CUR was tested in BALB-neuT mice transgenic for the neu oncogene, which develop atypical hyperplasia of the mammary gland at 6 weeks of age and invasive carcinoma at 16 weeks of age. CUR, administered to mice both early and in an advanced stage of mammary carcinogenesis, induced a significant prolongation of tumor-free survival and a reduction of tumor multiplicity. In addition, CUR administration was safe, since no modification of hematological and clinical chemistry parameters could be observed in BALB-neuT and BALB/c mice treated with this compound for several weeks. These findings support further studies on the therapeutic potential of CUR in combination with standard therapies in breast cancer patients. PMID:23489691

Masuelli, L; Benvenuto, M; Fantini, M; Marzocchella, L; Sacchetti, P; Di Stefano, E; Tresoldi, I; Izzi, V; Bernardini, R; Palumbo, C; Mattei, M; Lista, F; Galvano, F; Modesti, A; Bei, R

2013-01-01

15

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

PubMed Central

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

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

2015-01-01

16

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

PubMed

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

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

2015-02-01

17

Mechanics in Tumor Growth 1 Mechanics in Tumor Growth  

E-print Network

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

Preziosi, Luigi

18

Strange Attractor in Immunology of Tumor Growth  

E-print Network

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.

Margarita Voitikova

1997-08-21

19

Monoclonal Antibodies Targeting Tumor Growth  

Cancer.gov

The type 1 insulin-like growth factor (IGF) receptor (IGF1R) is over-expressed by many tumors and mediates proliferation, motility, and protection from apoptosis. Agents that inhibit IGF1R expression or function can potentially block tumor growth and metastasis. Its major ligands, IGF-I, and IGF-II are over-expressed by multiple tumor types.

20

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

SciTech Connect

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.

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

21

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

NASA Astrophysics Data System (ADS)

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.

Bi, Ping; Ruan, Shigui; Zhang, Xinan

2014-06-01

22

Steady-state analysis of necrotic core formation for solid avascular tumors with time delays in regulatory apoptosis.  

PubMed

A mathematical model for the growth of solid avascular tumor with time delays in regulatory apoptosis is studied. The existence of stationary solutions and the mechanism of formation of necrotic cores in the growth of the tumors are studied. The results show that if the natural death rate of the tumor cell exceeds a fixed positive constant, then the dormant tumor is nonnecrotic; otherwise, the dormant tumor is necrotic. PMID:25667597

Zhang, Fangwei; Xu, Shihe

2014-01-01

23

Steady-State Analysis of Necrotic Core Formation for Solid Avascular Tumors with Time Delays in Regulatory Apoptosis  

PubMed Central

A mathematical model for the growth of solid avascular tumor with time delays in regulatory apoptosis is studied. The existence of stationary solutions and the mechanism of formation of necrotic cores in the growth of the tumors are studied. The results show that if the natural death rate of the tumor cell exceeds a fixed positive constant, then the dormant tumor is nonnecrotic; otherwise, the dormant tumor is necrotic. PMID:25667597

2014-01-01

24

How Growth Abnormalities Delay "Puberty" in Drosophila  

NSDL National Science Digital Library

In various organisms, including flies, amphibians, and mammals, major developmental transitions such as metamorphosis and puberty are triggered by specific hormones. The requirement for a hormone to proceed to the next stage allows the organism to reestablish the temporal coordination of development between multiple organs that might develop at slightly different rates. Additionally, organisms appear to have evolved mechanisms for delaying these transitions in situations where growth in an organ is abnormal or delayed. New evidence in the fruit fly Drosophila melanogaster indicates that DILP8, a protein of the insulin and relaxin family, delays the onset of metamorphosis under several conditions that alter growth in imaginal discs. Similar mechanisms might operate in disease states in humans where alterations in growth or tissue inflammation can delay puberty.

Iswar K. Hariharan (University of California Berkeley; Department of Molecular and Cell Biology REV)

2012-06-19

25

Biologic Determinants of Tumor Growth in Healing Wounds  

PubMed Central

The morphologic characteristics of a scar may render it an “immunologically privileged site” providing fertile ground for tumor occurrence and growth. We sought to extend this concept and to determine the effect of different stages of wound healing on tumor occurrence. Syngeneic strain-2 guinea pigs and a methylcholanthrene-induced liposarcoma (MCA-2) were used. Incisional flank wounds were created at appropriate intervals such that at the time of tumor inoculation each group of animals had a sequentially aged wound which was a) acute, b) three weeks old, c) nine weeks old, d) 11 weeks old, e) created one week after tumor injection, or f) no wound. Wounds which were three, nine, or 11 weeks old consistently caused a significant increase in tumor growth rate following inoculation of a single cell tumor suspension (<.001). The delayed wounds, or those created following after tumor injection, and the acute wounds did not promote increased tumor growth. This study demonstrates that the ability of a wound to amplify or retard tumor growth may vary with its age. As a postulate we suggest that the relative paucity of lymphatic regeneration within scar tissue may render it an “immunologically privileged site” such that early recognition and destruction of tumor cells within the scar may be delayed long enough for the tumor to grow to a “critical size.” Subsequent to this regardless of the host's immunocompetence the tumor can no longer be destroyed by an immune mechanism. The general lack of progressive growth of tumor cells placed in acute wounds suggests that they were not protected from immunocompetent cells and were destroyed by the ongoing inflammatory response to injury. Therefore, different biologic characteristics of a surgical scar are important in potentiating or retarding tumor growth. Variations in such factors may account for the local recurrence of cancer in operative wounds. PMID:426550

Pendergrast, W. Jefferson; Futrell, J. William

1979-01-01

26

Delayed menopause due to granulosa cell tumor of the ovary  

PubMed Central

A 52-year-old patient presented with complaints of menorrhagia. Endometrial biopsy revealed simple hyperplasia of the endometrium. Total abdominal hysterectomy with bilateral oophorectomy was carried out. The ovaries looked grossly normal, but histopathology reported granulosa cell tumor of the right ovary. Granulosa cell tumors belong to the sexcord stromal category and account for approximately 2% of all ovarian tumors. We review the features and treatment of granulosa cell tumors and the importance of screening for ovarian tumors in a case of endometrial hyperplasia and delayed menopause. PMID:22408338

Murkey, Bhushan; Nadkarni, Trupti; Bhalerao, Sarita; Jassawalla, M. J.

2011-01-01

27

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

NASA Astrophysics Data System (ADS)

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.

Guo, Wei; Mei, Dong-Cheng

2014-12-01

28

Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression  

PubMed Central

Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1? promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)–deficient mice which have a reduced potential for inflammation, and IL-1R antagonist–deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1?–induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonist–deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which down-regulate tumor immunity is one of the mechanisms linking inflammation and cancer. PMID:17942936

Bunt, Stephanie K.; Yang, Linglin; Sinha, Pratima; Clements, Virginia K.; Leips, Jeff; Ostrand-Rosenberg, Suzanne

2015-01-01

29

Delayed fluorescence in algal growth inhibition tests  

Microsoft Academic Search

A series of 72-hour growth inhibition tests with green alga Desmodesmus (Scenedesmus) subspicatus (ISO 8692) has been performed to test the delayed fluorescence (DF) parameters as possible endpoint measurements. Sensitivity\\u000a to five toxicants with direct and indirect effects on photosynthesis was tested, and the median effective concentration (EC50) values derived from the cell concentration, absorbance and DF were compared. The

Maja Berden-Zrimec; Luka Drinovec; Alexis Zrimec; Tatjana Tišler

2007-01-01

30

Delay-induced state transition and resonance in periodically driven tumor model with immune surveillance  

NASA Astrophysics Data System (ADS)

The phenomenon of stochastic resonance (SR) in a tumor growth model under the presence of immune surveillance is investigated. Time delay and cross-correlation between multiplicative and additive noises are considered in the system. The signal-to-noise ratio (SNR) is calculated when periodic signal is introduced multiplicatively. Our results show that: (i) the time delay can accelerate the transition from the state of stable tumor to that of extinction, however the correlation between two noises can accelerate the transition from the state of extinction to that of stable tumor; (ii) the time delay and correlation between two noises can lead to a transition between SR and double SR in the curve of SNR as a function of additive noise intensity, however for the curve of SNR as a function of multiplicative noise intensity, the time delay can cause the SR phenomenon to disappear, and the cross-correlation between two noises can lead to a transition from SR to stochastic reverse-resonance. Finally, we compare the SR phenomenon for the multiplicative periodic signal with that for additive periodic signal in the tumor growth model with immune surveillance.

Yang, Tao; Han, Qinglin; Zeng, Chunhua; Wang, Hua; Fu, Yunchang; Zhang, Chun

2014-06-01

31

The Role of Fibroblast Growth Factors in Tumor Growth  

PubMed Central

Biological processes that drive cell growth are exciting targets for cancer therapy. The fibroblast growth factor (FGF) signaling network plays a ubiquitous role in normal cell growth, survival, differentiation, and angiogenesis, but has also been implicated in tumor development. Elucidation of the roles and relationships within the diverse FGF family and of their links to tumor growth and progression will be critical in designing new drug therapies to target FGF receptor (FGFR) pathways. Recent studies have shown that FGF can act synergistically with vascular endothelial growth factor (VEGF) to amplify tumor angiogenesis, highlighting that targeting of both the FGF and VEGF pathways may be more efficient in suppressing tumor growth and angiogenesis than targeting either factor alone. In addition, through inducing tumor cell survival, FGF has the potential to overcome chemotherapy resistance highlighting that chemotherapy may be more effective when used in combination with FGF inhibitor therapy. Furthermore, FGFRs have variable activity in promoting angiogenesis, with the FGFR-1 subgroup being associated with tumor progression and the FGFR-2 subgroup being associated with either early tumor development or decreased tumor progression. This review highlights the growing knowledge of FGFs in tumor cell growth and survival, including an overview of FGF intracellular signaling pathways, the role of FGFs in angiogenesis, patterns of FGF and FGFR expression in various tumor types, and the role of FGFs in tumor progression. PMID:19508171

Korc, Murray; Friesel, Robert E.

2013-01-01

32

Sunscreens for delay of ultraviolet induction of skin tumors  

SciTech Connect

Sunscreens with different sun protection factors (SPFs) have been tested for their capability of delaying or preventing actinic damage and skin cancer development in groups of hairless, pigmented mice exposed to artificial ultraviolet (UV) light of increasing intensity. The dose delivered was less than or equal to 1 minimal erythema dose (MED) in the group of untreated mice, so that the mice to which sunscreens were applied never obtained a sunburn after UV exposure. The quality of UV light was similar to bright midday sun at a latitude of 56 degrees (city of Copenhagen). Tumorigenesis was demonstrated to be delayed corresponding to the SPF claimed by the manufacturer, but almost all of the UV-irradiated mice developed skin tumors. Histologic examination revealed actinic degeneration and tumors of squamous cell type with marked variation in differentiation. Metastases to lymph nodes and lungs were found in only 10%. Toxic reactions, such as eczematous-like skin reactions, dark coloring, and amyloidosis, were observed predominantly in the group treated with the sunscreen of highest SPF value. Long-term investigations seem to be necessary to unveil these problems--in particular, the specific SPF value, in sunscreens, that should be recommended to the public for prevention or delay of actinic damage and/or cancer development.

Wulf, H.C.; Poulsen, T.; Brodthagen, H.; Hou-Jensen, K.

1982-08-01

33

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

E-print Network

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

Ruan, Shigui

34

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

E-print Network

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

Grether, Gregory

35

Growth factors, tumor promoters, and cancer genes  

SciTech Connect

This book contains over 30 selections. Some of the titles are: Growth-regulated genes and human leukemias; Tyrosyl and phosphatidylinositol kinases of human erythrocyte membranes; Growth factors, oncogenes, and multistage carcinogenesis; Tumorigenic transformation of human teratocarcinoma cells by activated ras oncogene but not the homologous photo-oncogene; and Genes that cooperate with tumor promoters in transformation.

Colburn, N.H.; Moses, H.L.; Stanbridge, E.J.

1988-01-01

36

In vitro repolarized tumor macrophages inhibit gastric tumor growth.  

PubMed

Gastric cancer is the second most frequent cause of cancer-related death worldwide. Combined surgery and chemo/radiotherapy give only a limited 5-year survival rate. Alternative therapeutic strategies such as immunotherapy are needed to improve this survival rate. Macrophages are functionally plastic cells. Type 1 macrophages (M1) inhibit, whereas type 2 macrophages (M2) promote, tumor growth. In this study, we examined the effects of in vitro repolarized tumor macrophages on gastric tumor growth in vivo. We demonstrated that peritoneal macrophages isolated from mouse forestomach carcinoma (MFC) tumor-bearing mice (TPM) displayed a M2 functional phenotype as indicated by a characteristic cytokine production profile and expression pattern of inducible nitric oxide synthase (iNOS) and arginase (Arg) of M2 macrophages. Treatment of TPM with type 1 cytokine IL-12 and IFN-gamma repolarized TPM toward the M1 phenotype as confirmed by a cytokine production profile and expression pattern of iNOS and Arg of typical M1 macrophages. Repolarized TPM significantly inhibits the growth of MFC tumors implanted subcutaneously compared to peritoneal macrophage (PM) isolated from normal animals, TPM, or M2 macrophages. Our study supports in vitro repolarization of macrophages as a potential immunotherapeutic strategy for gastric cancer. PMID:23879167

Liu, Hao; Wu, Xiaolin; Wang, Shanmei; Deng, Wei; Zan, Lipin; Yu, Shuangjiang

2013-01-01

37

An approach to constitutional delay of growth and puberty.  

PubMed

Constitutional delay of growth and puberty is a transient state of hypogonadotropic hypogonadism associated with prolongation of childhood phase of growth, delayed skeletal maturation, delayed and attenuated pubertal growth spurt, and relatively low insulin-like growth factor-1 secretion. In a considerable number of cases, the final adult height (Ht) does not reach the mid-parental or the predicted adult Ht for the individual, with some degree of disproportionately short trunk. In the pre-pubertal male, testosterone (T) replacement therapy can be used to induce pubertal development, accelerate growth and relieve the psychosocial complaints of the adolescents. However, some issues in the management are still unresolved. These include type, optimal timing, dose and duration of sex steroid treatment and the possible use of adjunctive or alternate therapy including: oxandrolone, aromatase inhibitors and human growth hormone. PMID:23087852

Soliman, Ashraf T; De Sanctis, Vincenzo

2012-09-01

38

A tumor growth model with deformable ECM  

NASA Astrophysics Data System (ADS)

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

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

2014-12-01

39

A validated mathematical model of tumor growth including tumor-host interaction, cell-mediated immune  

E-print Network

A validated mathematical model of tumor growth including tumor-host interaction, cell of tumor cells to such cytotoxic substances (Lavi et al., 2012). Mathematical modelling of tumor growth/n, 28933 M´ostoles, Madrid, Spain Abstract We consider a dynamical model of cancer growth including three

Rey Juan Carlos, Universidad

40

Necrotic tumor growth: an analytic approach  

E-print Network

The present paper deals with a free boundary problem modeling the growth process of necrotic multi-layer tumors. We prove the existence of flat stationary solutions and determine the linearization of our model at such an equilibrium. Finally, we compute the solutions of the stationary linearized problem.

Kohlmann, Martin

2011-01-01

41

Gompertzian stochastic model with delay effect to cervical cancer growth  

NASA Astrophysics Data System (ADS)

In this paper, a Gompertzian stochastic model with time delay is introduced to describe the cervical cancer growth. The parameters values of the mathematical model are estimated via Levenberg-Marquardt optimization method of non-linear least squares. We apply Milstein scheme for solving the stochastic model numerically. The efficiency of mathematical model is measured by comparing the simulated result and the clinical data of cervical cancer growth. Low values of Mean-Square Error (MSE) of Gompertzian stochastic model with delay effect indicate good fits.

Mazlan, Mazma Syahidatul Ayuni binti; Rosli, Norhayati binti; Bahar, Arifah

2015-02-01

42

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

PubMed Central

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

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

2013-01-01

43

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

PubMed

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 over-express 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

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

2012-09-01

44

Nonlinear simulation of the effect of microenvironment on tumor growth  

Microsoft Academic Search

In this paper, we present and investigate a model for solid tumor growth that incorporates features of the tumor microenvironment. Using analysis and nonlinear numerical simulations, we explore the effects of the interaction between the genetic characteristics of the tumor and the tumor microenvironment on the resulting tumor progression and morphology. We find that the range of morphological responses can

Paul Macklin; John Lowengrub

2007-01-01

45

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARb-deficient mice  

E-print Network

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARb-deficient mice Sabine Mu Peters5 and Rolf Mu¨ ller1, * 1 Institute of Molecular Biology and Tumor Research (IMT), Philipps show that the growth of syn- geneic Pparb wild-type tumors is impaired in Pparb�/� mice, concomitant

Omiecinski, Curtis

46

Catch-Up Growth after Hypothyroidism Is Caused by Delayed Growth Plate Senescence  

PubMed Central

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth. PMID:18174286

Marino, Rose; Hegde, Anita; Barnes, Kevin M.; Schrier, Lenneke; Emons, Joyce A.; Nilsson, Ola; Baron, Jeffrey

2008-01-01

47

Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression  

Microsoft Academic Search

Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1B promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity.

Stephanie K. Bunt; Linglin Yang; Pratima Sinha; Virginia K. Clements; Jeff Leips; Suzanne Ostrand-Rosenberg

2007-01-01

48

TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo  

PubMed Central

We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p. PMID:23776618

Shan, Zhihong; Shakoori, Abbas; Bodaghi, Sohrab; Goldsmith, Paul; Jin, Jen; Wiest, Jonathan S.

2013-01-01

49

Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression  

PubMed Central

SUMMARY 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 lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors. PMID:21251614

DuPage, Michel; Cheung, Ann; Mazumdar, Claire; Winslow, Monte M.; Bronson, Roderick; Schmidt, Leah M.; Crowley, Denise; Chen, Jianzhu; Jacks, Tyler

2010-01-01

50

Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.  

PubMed

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 lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors. PMID:21251614

DuPage, Michel; Cheung, Ann F; Mazumdar, Claire; Winslow, Monte M; Bronson, Roderick; Schmidt, Leah M; Crowley, Denise; Chen, Jianzhu; Jacks, Tyler

2011-01-18

51

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

Microsoft Academic Search

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

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

2006-01-01

52

The early antitumor immune response is necessary for tumor growth  

PubMed Central

Early events responsible of tumor growth in patients with a normal immune system are poorly understood. Here, we discuss, in the context of human melanoma, the Prehn hypothesis according to which a weak antitumor immune response may be required for tumor growth before weakly or non-immunogenic tumor cell subpopulations are selected by the immune system. PMID:23162761

Parmiani, Giorgio; Maccalli, Cristina

2012-01-01

53

Properties of Tumor Spheroid Growth Exhibited by Simple Mathematical Models  

PubMed Central

Solid tumors, whether in vitro or in vivo, are not an undifferentiated mass of cells. They include necrotic regions, regions of cells that are in a quiescent state (either slowly growing or not growing at all), and regions where cells proliferate rapidly. The decision of a cell to become quiescent or proliferating is thought to depend on both nutrient and oxygen availability and on the presence of tumor necrosis factor, a substance produced by necrotic cells that somehow inhibits the further growth of the tumor. Several different models have been suggested for the basic growth rate of in vitro tumor spheroids, and several different mechanisms are possible by which tumor necrosis factor might halt growth. The models predict the trajectory of growth for a virtual tumor, including proportions of the various components during its time evolution. In this paper we look at a range of hypotheses about basic rates tumor growth and the role of tumor necrotic factor, and determine what possible tumor growth patterns follow from each of twenty-five reasonable models. Proliferating, quiescent and necrotic cells are included, along with tumor necrosis factor as a potential inhibitor of growth in the proliferating pool and two way exchange between the quiescent and proliferating pools. We show that a range of observed qualitative properties of in vitro tumor spheroids at equilibrium are exhibited by one particular simple mathematical model, and discuss implications of this model for tumor growth. PMID:23508803

Wallace, Dorothy I.; Guo, Xinyue

2013-01-01

54

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.

55

The growth of a primary tumor (sarcoma M-1) during the training of rats to hypoxia in the low pressure chamber  

Microsoft Academic Search

The effect of hypoxic training of rats on the growth of transplantable tumors (sarcoma M-1) was studied in experiments involving 161 animals. In training the rats at an “altitude” of 6,000 m, the tumor growth was delayed by 18.6 per cent. With the rise of the training “altitude” there is a progressively increasing development of the tumor growth-inhibiting mechanisms. At

G. N. Arkhipov; S. I. Lebedinskaya; V. V. Parin

1961-01-01

56

The Role of Complement in Tumor Growth  

PubMed Central

Complement is a central part of the immune system that has developed as a first defense against non-self cells. Neoplastic transformation is accompanied by an increased capacity of the malignant cells to activate complement. In fact, clinical data demonstrate complement activation in cancer patients. On the basis of the use of protective mechanisms by malignant cells, complement activation has traditionally been considered part of the body's immunosurveillance against cancer. Inhibitory mechanisms of complement activation allow cancer cells to escape from complement-mediated elimination and hamper the clinical efficacy of monoclonal antibody–based cancer immunotherapies. To overcome this limitation, many strategies have been developed with the goal of improving complement-mediated effector mechanisms. However, significant work in recent years has identified new and surprising roles for complement activation within the tumor microenvironment. Recent reports suggest that complement elements can promote tumor growth in the context of chronic inflammation. This chapter reviews the data describing the role of complement activation in cancer immunity, which offers insights that may aid the development of more effective therapeutic approaches to control cancer. PMID:24272362

Pio, Ruben; Corrales, Leticia; Lambris, John D.

2015-01-01

57

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

PubMed Central

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

2010-01-01

58

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.

59

Reproducible growth in tissue culture of retinoblastoma tumor specimens  

Microsoft Academic Search

Retinoblastoma is a unique embryonic tumor which fre quently arises because of an autosomal dominantly inherited mutation. Study of the genetic changes associated with reti- noblastomas requires techniques that allow proliferation of fresh tumor specimens in tissue culture. However, until the present study, there were no reported methods for routinely obtaining in vitro growth of fresh retinoblastoma tumor cells. When

B L Gallie; Wendy Holmes; Robert A. Phillips

1982-01-01

60

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

PubMed

Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-?B ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These findings revealed that OGCs in the tumor environment promoted tumor growth and lymphangiogenesis, at least in part, by secreting VEGF-C. PMID:24607909

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

2014-03-28

61

Fibroblast Growth Factors Are Required for Efficient Tumor Angiogenesis1  

Microsoft Academic Search

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF re- ceptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and

Amelia Compagni; Petra Wilgenbus; Maria-Antonietta Impagnatiello; Matt Cotten; Gerhard Christofori

62

Altered tumor cell growth and tumorigenicity in models of microgravity  

Microsoft Academic Search

Spaceflight environment and microgravity (MG) causes immune dysfunction and is a major health risk to humans, especially during long-term space missions. The effects of microgravity environment on tumor growth and carcinogenesis are yet unknown. Hence, we investigated the effects of simulated MG (SMG) on tumor growth and tumorigenicity using in vivo and in vitro models. B16 melanoma cells were cultured

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

2002-01-01

63

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

PubMed Central

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

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

2015-01-01

64

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

PubMed

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

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

2015-01-01

65

Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models.  

PubMed

Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA-DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4(+) and CD8(+) T-cells, FOXP3(+) T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p < 0.05). MPA-DMBA-induced tumors contained a higher percentage of FOXP3(+) CD4(+) T-cells (p < 0.01) and MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer. PMID:25395320

Gad, Ekram; Rastetter, Lauren; Slota, Meredith; Koehnlein, Marlese; Treuting, Piper M; Dang, Yushe; Stanton, Sasha; Disis, Mary L

2014-12-01

66

A multiphase model for three-dimensional tumor growth  

PubMed Central

Several mathematical formulations have analyzed the time-dependent behaviour of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) for the transport of nutrients. The equations are solved by a Finite Element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTS) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behaviour: initially, the rapidly growing tumor cells tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 ?m, surrounded by a shell of viable tumor cells whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case – mostly due to the relative adhesion of the tumor and healthy cells to the ECM, and the less favourable transport of nutrients. In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas tumor cell 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 3D geometry. It is shown that tumor cells tend to migrate among adjacent vessels seeking new oxygen and nutrient. 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 tumor cell proliferation. PMID:24554920

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

2014-01-01

67

A multiphase model for three-dimensional tumor growth.  

PubMed

Several mathematical formulations have analyzed the time-dependent behaviour of a tumor mass. However, most of these propose simplifications that compromise the physical soundness of the model. Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) for the transport of nutrients. The equations are solved by a Finite Element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry. Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTS) and tumor cords. First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium. The tumor growth pattern follows a biphasic behaviour: initially, the rapidly growing tumor cells tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time. A core with necrotic cells appears for tumor sizes larger than 150 ?m, surrounded by a shell of viable tumor cells whose thickness stays almost constant with time. A formula to estimate the size of the necrotic core is proposed. In the second case, the MTS is confined within a healthy tissue. The growth rate is reduced, as compared to the first case - mostly due to the relative adhesion of the tumor and healthy cells to the ECM, and the less favourable transport of nutrients. In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas tumor cell 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 3D geometry. It is shown that tumor cells tend to migrate among adjacent vessels seeking new oxygen and nutrient. 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 tumor cell proliferation. PMID:24554920

Sciumè, G; Shelton, S; Gray, Wg; Miller, Ct; Hussain, F; Ferrari, M; Decuzzi, P; Schrefler, Ba

2013-01-01

68

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

PubMed Central

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

2014-01-01

69

Assessment of Tumor Growth in Pancreatic Neuroendocrine Tumors in von Hippel Lindau Syndrome  

PubMed Central

Background The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing but only a subset of these heterogeneous tumors will progress to malignant disease which is associated with a poor prognosis. Currently, there is limited data on the natural history of these tumors and it is difficult to determine which patients require surgical intervention because the risk of metastatic disease cannot be accurately determined. Study Design We conducted a prospective study of 87 patients with von Hippel Lindau syndrome-associate solid pancreatic lesions to determine the natural history of these tumors with biochemical testing, follow up anatomic and functional imaging, and advanced imaging analysis with a median follow up of 4 years. Results Approximately 20% of consecutive tumor measurements during follow up were decreased in size and 20% showed no change. This included 2 of 4 surgically-proven malignant tumors which had a net decrease in tumor size over time. Tumor volume, as derived from greatest diameter and volumetric measurement, showed good correlation to pathology tumor measurement of surgically resected tumors (Spearman rank correlation ?=0.72, p=0.0011, and ?=0.83, p<0.0001; respectively). Tumor density measurement had an inverse relationship with tumor size (Spearman rank correlation ?0.22, p=0.0047). A tumor density cutoff of 200 was 75% specific for malignant tumors. Conclusions PNETs demonstrate a non-linear growth pattern, which includes periods of no growth and apparent decrease in size by imaging. These growth patterns are variable and not associated with tumor grade and malignancy. Tumor density, as measured in this cohort, may offer a specific diagnostic tool for malignant disease. PMID:24440063

Weisbrod, Allison B.; Kitano, Mio; Thomas, Francine; Williams, David; Gulati, Neelam; Gesuwan, Krisana; Liu, Yixun; Venzon, David; Turkbey, Ismail; Choyke, Peter; Yao, Jack; Libutti, Steven K.; Nilubol, Naris; Linehan, William M.; Kebebew, Electron

2013-01-01

70

FEM-Based 3-D Tumor Growth Prediction for Kidney Tumor  

Microsoft Academic Search

It is important to predict the tumor growth so that appropriate treatment can be planned in the early stage. In this letter, we propose a finite-element method (FEM)-based 3-D tu- mor growth prediction system using longitudinal kidney tumor images. To the best of our knowledge, this is the first kidney tu- mor growth prediction system. The kidney tissues are classified

Xinjian Chen; Ronald Summers; Jianhua Yao

2011-01-01

71

BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors.  

PubMed

Bone morphogenetic protein 4 (BMP4) has potential as an anticancer agent. Recent studies have suggested that BMP4 inhibits the survival of cancer stem cells (CSCs) of neural and colon cancers. Here, we showed that BMP4 paracrinically inhibited tumor angiogenesis via the induction of Thrombospondin-1 (TSP1), and consequently suppressed tumor growth in vivo. Although HeLa (human cervical cancer), HCI-H460-LNM35 (highly metastatic human lung cancer) and B16 (murine melanoma) cells did not respond to the BMP4 treatment in vitro, the growth of xeno- and allografts of these cells was suppressed via reductions in tumor angiogenesis after intraperitoneal treatment with BMP4. When we assessed the mRNA expression of major angiogenesis-related factors in grafted tumors, we found that the expression of TSP1 was significantly upregulated by BMP4 administration. We then confirmed that BMP4 was less effective in suppressing the tumor growth of TSP1-knockdown cancer cells. Furthermore, we found that BMP4 reduced vascular endothelial growth factor (VEGF) expression in vivo in a TSP1-dependent manner, which indicates that BMP4 interfered with the stabilization of tumor angiogenesis. In conclusion, the BMP4/TSP1 loop paracrinically suppressed tumor angiogenesis in the tumor microenvironment, which subsequently reduced the growth of tumors. BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy. PMID:24013228

Tsuchida, R; Osawa, T; Wang, F; Nishii, R; Das, B; Tsuchida, S; Muramatsu, M; Takahashi, T; Inoue, T; Wada, Y; Minami, T; Yuasa, Y; Shibuya, M

2014-07-17

72

Delayed Frost Growth on Jumping-Drop Superhydrophobic Surfaces  

SciTech Connect

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.

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

2013-01-01

73

Tumor growth modeling based on cell and tumor lifespans  

E-print Network

is that the mean value of the tumor lifespan can be approached by a logarithmic function of the initial cancer cell by clinicians of the appropriate treat- ment planning. Keywords: Markov chain; cancer cells; radiotherapy 1 the Target Theory and assumes there exists a number of radio-sensitive sites within the cell, called targets

Paris-Sud XI, Université de

74

Tumor growth inhibitory effect of juglone and its radiation sensitizing potential: in vivo and in vitro studies.  

PubMed

The present study aimed at evaluating the anticancer and radiosensitizing potential of juglone against a chemoresistant and radioresistant tumor (B16F1 melanoma) growing on C57BL/6J mice. Volume doubling time, growth delay, and median survival were used to assess the in vivo anticancer and radiosensitizing potential of juglone. In vitro radiosensitizing potential of juglone was studied using clonogenic, comet, and reactive oxygen species induction assays. Treatment of tumor-bearing mice with sublethal doses of juglone caused a dose-dependent inhibition of tumor growth as evident from the growth delay and median survival values. Comet assay using tumor tissue and blood showed differential toxicity of juglone, where higher levels of DNA damage was seen in tumor tissue compared with blood cells. Pretreatment of tumor-bearing mice with optimum dose of juglone before radiation resulted in significant tumor growth inhibition compared with radiation alone. From the clonogenic assay, the authors observed a sensitization enhancement ratio of 1.37 for the combination treatment compared with radiation alone. Furthermore, comet assay studies revealed the potential of juglone to enhance the radiation-induced DNA damage and cause a delay in its repair. Juglone pretreatment before radiation also resulted in a significant elevation in the intracellular reactive oxygen species levels compared with radiation alone. In conclusion, the results of this study show the potential of juglone to inhibit the growth of melanoma in vivo. The study also revealed the potential of juglone to augment the radiation-induced cell death of melanoma cells, which may be attributed to oxidative stress-mediated DNA damage and its delayed repair. PMID:21498474

Aithal, Kiran B; Kumar, Sunil; Rao, B Nageshwar; Udupa, Nayanabhirama; Rao, Satish Bola Sadashiva

2012-03-01

75

VEGF-integrin interplay controls tumor growth and vascularization  

NASA Astrophysics Data System (ADS)

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

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

2005-05-01

76

Retroviral gene transfer of dominant negative raf-1 mutants suppresses ha-ras-induced transformation and delays tumor formation.  

PubMed

Activating mutants of ras are among the most frequently found genetic alterations in human cancers. Therefore, Ras appears to be an attractive target for therapeutic intervention using gene transfer. The protein kinase Raf-1 acts as a direct downstream effector of Ras and is involved in Ras-induced cellular transformation. Using the NIH3T3 fibroblast-derived tumor cell line PEJ, which expresses oncogenic Ha-rasG12V, we analyzed whether dominant negative mutants of Raf-1 can inhibit Ras-mediated transformation. Retroviral gene transfer was used to stably transduce PEJ cells with three different dominant negative mutants of Raf-1. This resulted in reversion of the transformed phenotype in vitro as evidenced by an increase in contact inhibition and reduced anchorage-independent growth. However, tumor formation in nude mice was significantly delayed only by one of these mutants. Therefore, dominant negative mutants of the oncoprotein Myc, which is known to synergize with Raf-1 in tumor formation, were transduced into PEJ cells expressing a dominant negative Raf mutant. This leads to killing of the cells. These results indicate that although interference with Ras-induced transformation using dominant negative mutants of Raf is feasible and effective in vitro using retroviral vectors, an additional block (e.g., that of Myc) is necessary to kill PEJ cells. These results also indicate that interference with Ras-dependent signaling is not sufficient for inhibition of tumor formation of PEJ cells in vivo. PMID:10830717

Heinicke, T; Radziwill, G; Nawrath, M; Rommel, C; Pavlovic, J; Moelling, K

2000-05-01

77

IL18-producing Salmonella inhibit tumor growth  

Microsoft Academic Search

Previous studies have shown that intravenously applied bacteria can accumulate in tumors and lead to sporadic tumor regression. Recently, systemic administration of attenuated Salmonella typhimurium was demonstrated to generate no significant side effects in humans, but also no antitumor responses. We report the enhanced antitumor activity in preclinical mouse cancer models of nonvirulent S. typhimurium engineered to synthesize the cytokine

M Loeffler; G Le'Negrate; M Krajewska; J C Reed

2008-01-01

78

Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis  

PubMed Central

Alcohol consumption has been recognized as a risk factor for breast cancer. Experimental studies demonstrate that alcohol exposure promotes the progression of existing mammary tumors. However, the mechanisms underlying this effect remain unclear. In the present study, the role of vascular endothelial growth factor (VEGF) in alcohol promotion of breast cancer development was investigated using a mouse xenograft model of mammary tumors and a three-dimensional (3D) tumor/endothelial cell co-culture system. For the mouse xenograft model, mouse E0771 breast cancer cells were implanted into the mammary fat pad of C57BL6 mice. These mice were exposed to alcohol in their drinking water. For the 3D co-culture system, E0771 cells and MDA-MB231 breast cancer cells were co-cultured with SVEC4-10EE2 and human umbilical vein endothelial cells, respectively. The results demonstrated that alcohol increased tumor angiogenesis and accelerated tumor growth. Furthermore, it appeared that alcohol induced VEGF expression in breast cancer cells in vitro and in vivo. Blocking VEGF signaling by SU5416 inhibited tumor angiogenesis in the 3D tumor/endothelial cell co-culture system. Furthermore, injection of SU5416 into mice inhibited alcohol-promoted mammary tumor growth in vivo. These results indicate that alcohol may promote mammary tumor growth by stimulating VEGF-dependent angiogenesis. PMID:25009649

LU, YANMIN; NI, FANG; XU, MEI; YANG, JINLIAN; CHEN, JI; CHEN, ZHUO; WANG, XINYI; LUO, JIA; WANG, SIYING

2014-01-01

79

Understanding the Mechanisms of Tumor Growth | Physical Sciences in Oncology  

Cancer.gov

Though cancer is certainly a disease caused by changes in a cell's genes, it has become clear over the past few years that cancer is also a disease of biomechanical malfunctions. Indeed, research has shown that interactions between the mechanical properties of tumors and the tissues that surround them play a critical role in the development and growth of tumors.

80

Multiphase modeling of tumor growth with matrix remodeling and fibrosis  

E-print Network

We present a multiphase mathematical model for tumor growth which incorporates the remodeling of the extracellular matrix and describes the formation of fibrotic tissue by tumor cells. We also detail a full qualitative analysis of the spatially homogeneous problem, and study the equilibria of the system in order to characterize the conditions under which fibrosis may occur.

Andrea Tosin; Luigi Preziosi

2009-10-26

81

Multiphase modeling of tumor growth with matrix remodeling and fibrosis  

E-print Network

We present a multiphase mathematical model for tumor growth which incorporates the remodeling of the extracellular matrix and describes the formation of fibrotic tissue by tumor cells. We also detail a full qualitative analysis of the spatially homogeneous problem, and study the equilibria of the system in order to characterize the conditions under which fibrosis may occur.

Tosin, Andrea

2009-01-01

82

Taurolidine Inhibits Tumor Cell Growth In Vitro and In Vivo  

Microsoft Academic Search

Background: Taurolidine, a derivative of the amino acid taurine, exhibits antiendotoxin, antibacterial, and antiadherence activity. We hypothesized that Taurolidine may inhibit tumor cell growth, both in an in vitro and in vivo setting. Our aim was to examine the effect of Taurolidine on the growth of a rat metastatic colorectal tumor cell line (DHD\\/K12\\/TRb) in vitro and in vivo.Methods: In

Morgan McCourt; Jiang Huai Wang; Shastri Sookhai; H. Paul Redmond

2000-01-01

83

Phase transition in tumor growth: I avascular development  

NASA Astrophysics Data System (ADS)

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.

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

2013-12-01

84

Bioavailable copper modulates oxidative phosphorylation and growth of tumors  

PubMed Central

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

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

2013-01-01

85

Patient specific tumor growth prediction using multimodal images.  

PubMed

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±0.5mm, the RMSD was 4.3±0.4%, the AICVFD was 2.6±0.6%, and the RVD was 7.7±1.3%. PMID:24607911

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

2014-04-01

86

Mirtazapine Inhibits Tumor Growth via Immune Response and Serotonergic System  

PubMed Central

To study the tumor inhibition effect of mirtazapine, a drug for patients with depression, CT26/luc colon carcinoma-bearing animal model was used. BALB/c mice were randomly divided into six groups: two groups without tumors, i.e. wild-type (no drug) and drug (mirtazapine), and four groups with tumors, i.e. never (no drug), always (pre-drug, i.e. drug treatment before tumor inoculation and throughout the experiment), concurrent (simultaneously tumor inoculation and drug treatment throughout the experiment), and after (post-drug, i.e. drug treatment after tumor inoculation and throughout the experiment). The “psychiatric” conditions of mice were observed from the immobility time with tail suspension and spontaneous motor activity post tumor inoculation. Significant increase of serum interlukin-12 (sIL-12) and the inhibition of tumor growth were found in mirtazapine-treated mice (always, concurrent, and after) as compared with that of never. In addition, interferon-? level and immunocompetent infiltrating CD4+/CD8+ T cells in the tumors of mirtazapine-treated, tumor-bearing mice were significantly higher as compared with that of never. Tumor necrosis factor-? (TNF-?) expressions, on the contrary, are decreased in the mirtazapine-treated, tumor-bearing mice as compared with that of never. Ex vivo autoradiography with [123I]ADAM, a radiopharmaceutical for serotonin transporter, also confirms the similar results. Notably, better survival rates and intervals were also found in mirtazapine-treated mice. These findings, however, were not observed in the immunodeficient mice. Our results suggest that tumor growth inhibition by mirtazapine in CT26/luc colon carcinoma-bearing mice may be due to the alteration of the tumor microenvironment, which involves the activation of the immune response and the recovery of serotonin level. PMID:22808019

Fang, Chun-Kai; Chen, Hong-Wen; Chiang, I-Tsang; Chen, Chia-Chieh; Liao, Jyh-Fei; Su, Ton-Ping; Tung, Chieh-Yin; Uchitomi, Yosuke; Hwang, Jeng-Jong

2012-01-01

87

Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors  

SciTech Connect

Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Wu Shengjie [Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Chemaitilly, Wassim [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee (United States); Lukose, Renin C.; Merchant, Thomas E. [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)] [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)

2012-11-15

88

Role of thrombin as a tumor growth factor.  

PubMed

The clinical observation that thrombosis in some patients heralds the onset of malignancy has been recognized for over a century. Thrombin the key terminal enzyme of coagulation also promotes angiogenesis and stimulates tumor-platelet adhesion, adhesion to endothelium, tumor implantation, tumor cell growth and metastasis. The thrombin receptor, a member of the protease-activated receptor family, is expressed on many tumor cell lines and on breast tumor biopsy specimens. In addition to mitogenic effects on fibroblast, smooth muscle cells and endothelial cells, thrombin also exerts direct effects on cancer cells by activation of the cell cycle through downregulation of p27(Kip1) and induction of Skp2, and cyclins D and A. MicroRNA 222, which inhibits p27(Kip1), is upregulated by thrombin. In the transgenic TRAMP mouse model of prostate cancer inhibition of endogenous thrombin by hirudin retards spontaneous tumor growth. Inhibition of thrombin may lead to tumor dormancy and could explain inhibition of tumor growth and metastasis by anticoagulants observed in animal models and a beneficial effect on survival observed in some clinical trials of anticoagulants in cancer patients. PMID:20190559

Green, David; Karpatkin, Simon

2010-02-15

89

Host STAT2/type I interferon axis controls tumor growth.  

PubMed

The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2(-/-) mice formed larger tumors compared to wild type (WT) mice. IFN-? treatment of Stat2(-/-) mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2(-/-) mice. Additionally, we found tumor antigen cross-presentation by Stat2(-/-) dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8(+) T cells primed by Stat2(-/-) dendritic cells into tumor-bearing Stat2(-/-) mice did not induce tumor regression with IFN-? intervention. We observed that an increase in the number of CD4(+) and CD8(+) T cells in the draining lymph nodes of IFN-?-treated tumor-bearing WT mice was absent in IFN-? treated Stat2(-/-) mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy. PMID:24895110

Yue, Chanyu; Xu, Jun; Tan Estioko, Marc Daryl; Kotredes, Kevin P; Lopez-Otalora, Yolanda; Hilliard, Brendan A; Baker, Darren P; Gallucci, Stefania; Gamero, Ana M

2015-01-01

90

A Big Bang model of human colorectal tumor growth.  

PubMed

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

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

91

Estimating the growth kinetics of experimental tumors from as few as two determinations of tumor size: implications for clinical oncology  

Microsoft Academic Search

Clinical information on tumor growth is often limited to a few determinations of the size of the tumor burden taken at variable time. As a consequence, fitting of growth equations to clinical data is hampered by the small number of available data. On the other hand, characterising the tumor growth kinetics in terms of clinically relevant parameters, such as the

Roberto Chignola; Roberto Israel Foroni

2005-01-01

92

Epidermal growth factor effect on serum-free growth of primary and metastatic human tumors.  

PubMed

The effect of epidermal growth factor (EGF) on the in vitro growth of human malignant tumors was compared in serum-supplemented (n = 54) and serum-free (N = 41) media at clonal density to determine the true EGF dependency of tumors. In the complete absence of serum at a 1,000 cells/cm2 seeding inoculation (approximately 100-200 adherent cells), EGF increased growth by greater than 50% in 27 of 41 specimens (66%), and growth increased by 100% or more in 18 of these EGF-sensitive tumors. In 12 serum-free cultures (29%), in vitro growth failed to occur without EGF. With 10% serum supplementation and a lower cell density (250 cells/cm2), EGF increased growth by greater than 50% in 34 of 54 specimens (63%), of which 25 had more than a 100% increase. The maximum growth induced by EGF in serum was usually seen in those tumors already capable of moderate in vitro growth. No difference in response to EGF was detected between specimens from primary tumors (n = 24) and those from metastases (n = 30). Under the stringent culture conditions of complete absence of serum and with tumors seeded at a low cell number, EGF stimulated most primary or metastatic human tumors to establish and sustain short-term in vitro growth successfully. PMID:2783955

Singletary, S E; Frappaz, D; Tucker, S L; Larry, L; Brock, W A; Spitzer, G

1989-01-01

93

Thymidine Phosphorylase is Angiogenic and Promotes Tumor Growth  

NASA Astrophysics Data System (ADS)

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-^3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.

Moghaddam, Amir; Zhang, Hua-Tang; Fan, Tai-Ping D.; Hu, De-En; Lees, Vivien C.; Turley, Helen; Fox, Stephen B.; Gatter, Kevin C.; Harris, Adrian L.; Bicknell, Roy

1995-02-01

94

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

PubMed

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

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

2010-01-01

95

Paradoxical Inhibition of Solid Tumor Cell Growth by bcl2  

Microsoft Academic Search

The BCL2 gene product has been demonstratedto prevent apoptosis and provide a selective growth advantage to many cell types. We report an unexpected effect ofbcl2 expression on the in vitro growth of several solid tumor cell lines. Expressionof bcl2 in these cell lines resulted in growth inhibition similar to that seen with p53. In contrast, a COOH-terminal deletion mutant of

Jennifer A. Pietenpol; Nickolas Papadopoulos; Sanford Markowitz; James K. V. Willson; Kenneth W. Kinzler; Bert Vogelstein

96

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

PubMed Central

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

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

1995-01-01

97

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

PubMed

Defining tumor stage at diagnosis is a pivotal point for clinical decisions about patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by a transport equation describing metastatic growth and endowed with a boundary condition for metastatic emission. Model predictions were compared with experimental results from orthotopic breast tumor xenograft experiments conducted in Nod/Scid? mice. Primary tumor growth, metastatic spread and growth were monitored by 3D bioluminescence tomography. A tailored computational approach allowed the use of Monolix software for mixed-effects modeling with a partial differential equation model. Primary tumor growth was described best by Bertalanffy, West, and Gompertz models, which involve an initial exponential growth phase. All other tested models were rejected. The best metastatic model involved two parameters describing metastatic spreading and growth, respectively. Visual predictive check, analysis of residuals, and a bootstrap study validated the model. Coefficients of determination were [Formula: see text] for primary tumor growth and [Formula: see text] for metastatic growth. The data-based model development revealed several biologically significant findings. First, information on both growth and spreading can be obtained from measures of total metastatic burden. Second, the postulated link between primary tumor size and emission rate is validated. Finally, fast growing peritoneal metastases can only be described by such a complex partial differential equation model and not by ordinary differential equation models. This work advances efforts to predict metastatic spreading during the earliest stages of cancer. PMID:25217520

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

2014-11-15

98

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

SciTech Connect

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.

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

99

Immunosuppressive drugs and their effect on experimental tumor growth  

Microsoft Academic Search

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

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

1995-01-01

100

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

NASA Astrophysics Data System (ADS)

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.

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

2015-02-01

101

Tumor  

MedlinePLUS

... excessively in the body. Normally, the body controls cell growth and division. New cells are created to replace ... room for healthy replacements. If the balance of cell growth and death is disturbed, a tumor may form. ...

102

Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma  

PubMed Central

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

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

103

Histone Methylase MLL1 plays critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo  

PubMed Central

Mixed lineage leukemias (MLL) are human histone H3 lysine-4 specific methyl transferases that play critical roles in gene expression, epigenetics, and cancer. Herein, we demonstrated that antisense-mediated knockdown of MLL1 induced cell cycle arrest and apoptosis in cultured cells. Intriguingly, application of MLL1-antisense specifically knocked down MLL1 in vivo and suppressed the growth of xenografted cervical tumor implanted in nude mouse. MLL1-knockdown downregulated various growth and angiogenic factors such as HIF1?, VEGF and CD31 in tumor tissue affecting tumor growth. MLL1 is overexpressed along the line of vascular network and localized adjacent to endothelial cell layer expressing CD31, indicating potential roles of MLL1 in vasculogenesis. MLL1 is also overexpressed in the hypoxic regions along with HIF1?. Overall, our studies demonstrated that MLL1 is a key player in hypoxia signaling, vasculogenesis, and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy. PMID:22926525

Ansari, Khairul I.; Kasiri, Sahba; Mandal, Subhrangsu S.

2012-01-01

104

Embelin suppresses pancreatic cancer growth by modulating tumor immune microenvironment.  

PubMed

Since pancreatic carcinoma is largely refractory to conventional therapies, development of novel agents is required for the effective treatment of pancreatic cancer. The objective of this paper was to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer growth in mice by modulating tumor immune microenvironment. Embelin inhibited PANC-1 tumor growth, angiogenesis, and metastasis which were associated with suppression of Akt and Sonic Hedgehog (Shh) pathways. Embelin inhibited the expression of Bcl-2, cyclin D1, CDK2 and CDK6, IL-6 and IL-8, and induced the expression of Bax in tumor tissues. Embelin also reversed epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, Slug and Zeb1. Embelin inhibited pancreatic cancer growth in Kras(G12D) mice by modulating tumor immune microenvironment where CTL, NKT, ??T, NK, and IFN? (Th1 type) cells were up-regulated, and Th17, PMN-MDSC, IL-6 and IL-8 (Th2 type) immune cells were inhibited. These data suggest that embelin can inhibit pancreatic cancer growth by modulating tumor immune microenvironment and Akt and Shh pathways, and inhibiting inflammation. Embelin may offer therapeutic benefits for the treatment and/or prevention of pancreatic cancer. PMID:24389175

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

2014-01-01

105

Soluble syndecan-1 promotes growth of myeloma tumors in vivo  

Microsoft Academic Search

Syndecan-1 (CD138) is a transmembrane heparan sulfate-bearing proteoglycan ex- pressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed syndecan-1 accumulates in the bone marrow, and high levels of syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble syndecan-1 on tumor cell growth and

Yang Yang; Shmuel Yaccoby; Wei Liu; J. Kevin Langford; Carla Y. Pumphrey; Allison Theus; Joshua Epstein; Ralph D. Sanderson

2002-01-01

106

Molecular mechanisms of TRP regulation in tumor growth and metastasis.  

PubMed

Transient Receptor Potential (TRP) channels modulate intracellular Ca2+ concentrations, consequently affecting both cell death and proliferation. It is not, therefore, surprising that the membrane expression of some TRP channels is altered during tumor growth and metastasis. These variations in channel abundance are due to TRP regulation on the transcriptional, translational, and targeting levels. This article mainly reviews the transcriptional mechanisms modulating TRP expression during tumorigenesis, involving hormones, growth factors, and alternative splicing. PMID:19103233

Gkika, Dimitra; Prevarskaya, Natalia

2009-06-01

107

Phase transitions in tumor growth: II prostate cancer cell lines  

NASA Astrophysics Data System (ADS)

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

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

2015-05-01

108

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN-?.  

PubMed

The importance of neutrophils in tumor immune surveillance, invasive growth and angiogenesis becomes increasingly clear. Many of neutrophil activities are controlled by endogenous IFN-?. Here, we provide evidence that endogenous IFN-? is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1(-/-) mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival, in the absence of endogenous IFN-?, a strong enhancement of G-CSF expression and PI3 Kinase phosphorylation is detected. These data explain the increased longevity of tumor infiltrating neutrophils and the accumulation of such cells in tumors. Taken together, our findings add to the important role of Type I IFN in immune surveillance against cancer. PMID:24806531

Andzinski, Lisa; Wu, Ching-Fang; Lienenklaus, Stefan; Kröger, Andrea; Weiss, Siegfried; Jablonska, Jadwiga

2015-02-01

109

Logistic Growth: Quadratic, No Time Delay, K Constant b = [K -N(0)]/N(0)  

E-print Network

Logistic Growth: Quadratic, No Time Delay, K Constant #12;b = [K - N(0)]/N(0) Logistic Population-Cummings Protozoan, small metazoan & large mammal: Logistic growth (app.), Increasing time to max dN/dt #12;Gause, sociology, technology How might logistic growth's assumptions fail biologically? #12;Density

Caraco, Thomas

110

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

PubMed

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

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

111

Joint fitting reveals hidden interactions in tumor growth.  

PubMed

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

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

2015-01-21

112

Joint fitting reveals hidden interactions in tumor growth  

E-print Network

Tumor growth is often the result of the simultaneous development of two or more cancer cell populations. Their interaction between them characterizes the system evolution. 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, 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.

Barberis, Lucas; Condat, Carlos Alberto

2014-01-01

113

Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-?  

Microsoft Academic Search

The transforming growth factor (TGF)-?s are potent growth inhibitors of normal epithelial cells. In established tumor cell systems, however, the preponderant experimental evidence suggests that TGF-?s can foster tumor-host interactions that indirectly support the viability and\\/or progression of cancer cells. The timing of this 'TGF-? switch' during the progressive transformation of epithelial cells is not clear. More recent evidence also

Nancy Dumont; Carlos L Arteaga

2000-01-01

114

Prevention of local tumor growth with paclitaxel-loaded microspheres  

E-print Network

Prevention of local tumor growth with paclitaxel- loaded microspheres Solomon M. Azouz, MS,a Joseph. The primary aim of this study was to assess the feasibility of a microsphere drug delivery system to locally resection margin. Methods: Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded

115

Altered tumor cell growth and tumorigenicity in models of microgravity  

NASA Astrophysics Data System (ADS)

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

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

116

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

PubMed

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

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

117

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

SciTech Connect

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.

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

118

Liposomal simvastatin inhibits tumor growth via targeting tumor-associated macrophages-mediated oxidative stress.  

PubMed

Statins possess antitumor actions at doses 100- to 500-fold higher than those needed to lower cholesterol levels. Thus, the antitumor efficacy of statins could be improved greatly by using tumor-targeted delivery systems. Therefore the present work aims to investigate the antitumor activity of long-circulating liposome-encapsulated simvastatin (LCL-SIM) versus free SIM in B16.F10 murine melanoma-bearing mice. Our results showed that LCL-SIM inhibits strongly the B16.F10 melanoma growth (by 85%) whereas free SIM was ineffective. Moreover, the antitumor activity of LCL-SIM depends on the presence of functional tumor-associated macrophages (TAM) in tumor tissue and is mainly based on the reduction of the TAM-mediated oxidative stress as well as of the production of the hypoxia-inducible factor 1 ? (HIF-1 ?) in tumors. In conclusion, our findings suggest that the antitumor activity of LCL-SIM on B16.F10 melanoma growth is a result of the tumor-targeting property of the liposome formulation and is tightly dependent on the presence of TAM in tumor tissue. PMID:25444912

Alupei, Marius Costel; Licarete, Emilia; Patras, Laura; Banciu, Manuela

2015-01-28

119

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

120

Effect of intermittent fasting on prostate cancer tumor growth in a mouse model.  

PubMed

Caloric restriction (CR) has been shown to have anti-cancer properties. However, CR may be difficult to apply in humans secondary to compliance and potentially deleterious effects. An alternative is intermittent CR, or in the extreme case intermittent fasting (IF). In a previous small pilot study, we found 2 days per week of IF with ad libitum feeding on the other days resulted in trends toward prolonged survival of mice bearing prostate cancer xenografts. We sought to confirm these findings in a larger study. A total of 100 (7- to 8-week-old) male severe combined immunodeficiency mice were injected subcutaneously with 1 × 10(5) LAPC-4 prostate cancer cells. Mice were randomized to either ad libitum Western Diet (44% carbohydrates, 40% fat and 16% protein) or ad libitum Western Diet with twice-weekly 24 h fasts (IF). Tumor volumes and mouse bodyweights were measured twice weekly. Mice were killed when tumor volumes reached 1000 mm(3). Serum and tumor were collected for analysis of the insulin/insulin-like growth factor 1 (IGF-1) hormonal axis. Overall, there was no difference in mouse survival (P=0.37) or tumor volumes (P ? 0.10) between groups. Mouse body weights were similar between arms (P=0.84). IF mice had significantly higher serum IGF-1 levels and IGF-1/IGFBP-3 ratios at killing (P<0.001). However, no difference was observed in serum insulin, IGFBP-3 or tumor phospho-Akt levels (P ? 0.39). IF did not improve mouse survival nor did it delay prostate tumor growth. This may be secondary to metabolic adaptations to the 24 h fasting periods. Future studies are required to optimize CR for application in humans. PMID:20733612

Thomas, J A; Antonelli, J A; Lloyd, J C; Masko, E M; Poulton, S H; Phillips, T E; Pollak, M; Freedland, S J

2010-12-01

121

Human STEAP3 maintains tumor growth under hypoferric condition  

SciTech Connect

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

Isobe, Taichi, E-mail: tisobe@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Baba, Eishi, E-mail: e-baba@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Arita, Shuji, E-mail: arita.s@nk-cc.go.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Komoda, Masato, E-mail: komoda@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Tamura, Shingo, E-mail: tamshin@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Shirakawa, Tsuyoshi, E-mail: t-w-r@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Ariyama, Hiroshi, E-mail: hariyama@kyumed.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Takaishi, Shigeo, E-mail: takaishi@med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Kusaba, Hitoshi, E-mail: hkusaba@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); and others

2011-11-01

122

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

PubMed Central

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 perform group analyses. Additionally, transfer of structural and functional information from neuroanatomical brain atlases into the individual patient's space can be achieved via the inverse mapping, for the purpose of segmenting brains and facilitating surgical or radiotherapy treatment planning. A method that estimates the brain tissue loss and replacement by tumor is applied for achieving equivalent image content between an atlas and a patient's scan, based on a biomechanical model of tumor growth. Automated estimation of the parameters modeling brain tissue loss and displacement is performed via optimization of an objective function reflecting feature-based similarity and elastic stretching energy, which is optimized in parallel via APPSPACK (Asynchronous Parallel Pattern Search). The results of the method, applied to 21 brain tumor patients, indicate that the registration accuracy is relatively high in areas around the tumor, as well as in the healthy portion of the brain. Also, the calculated deformation in the vicinity of the tumor is shown to correlate highly with expert-defined visual scores indicating the tumor mass effect, thereby potentially leading to an objective approach to quantification of mass effect, which is commonly used in diagnosis. PMID:19408350

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

2009-01-01

123

Delayed adolescent growth in homozygous sickle cell disease  

Microsoft Academic Search

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).

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

1994-01-01

124

Mathematical Modeling of Interleukin-35 Promoting Tumor Growth and Angiogenesis  

PubMed Central

Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8 T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased. PMID:25356878

Liao, Kang-Ling; Bai, Xue-Feng; Friedman, Avner

2014-01-01

125

Low Levels of Tumor Necrosis Factor ? Increase Tumor Growth by Inducing an Endothelial Phenotype of Monocytes Recruited to the Tumor Site  

PubMed Central

Microenvironmental cues instruct infiltrating tumor-associated myeloid cells to drive malignant progression. A subpopulation of tumor-associated myeloid cells coexpressing endothelial and myeloid markers, although rare in peripheral blood, are primarily associated with tumors where they enhance tumor growth and angiogenesis. These biphenotypic vascular leukocytes result from the endothelial differentiation of myeloid progenitors, a process regulated by tumor necrosis factor (TNF)? in vitro. An in vivo increase in tumor-derived TNF? expression promoted tumor growth and vascularity of mouse melanoma, lung cancer, and mammary tumors. Notably, tumor growth was accompanied by a significant increase in myeloid/endothelial biphenotypic populations. TNF?-associated tumor growth, vascularity, and generation of tumor vascular leukocytes in mouse melanoma tumors were dependent on intact host TNF? receptors. Importantly, TNFA-expressing tumors did not exhibit increased inflammation over control tumors, suggesting a unique action related to myeloid to endothelial differentiation. Our studies suggest that TNF? constitutes a tumor microenvironment signal that biases recruited monocytes toward a proangiogenic/provasculogenic myeloid/endothelial phenotype. PMID:19118019

Li, Bin; Vincent, Alicia; Cates, Justin; Brantley-Sieders, Dana M.; Polk, D. Brent; Young, Pampee P.

2009-01-01

126

Netrin-4 regulates angiogenic responses and tumor cell growth  

SciTech Connect

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

Nacht, Mariana; St Martin, Thia B.; Byrne, Ann; Klinger, Katherine W.; Teicher, Beverly A. [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States); Madden, Stephen L. [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)], E-mail: steve.madden@genzyme.com; Jiang, Yide [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)], E-mail: yide.jiang@genzyme.com

2009-03-10

127

The role of mechanical forces in tumor growth and therapy  

PubMed Central

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

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

2014-01-01

128

Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN depleted head and neck cancer tumor cells  

PubMed Central

Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were co-cultured with fibroblasts or inoculated with fibroblasts into SCID mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Co-culture experiments demonstrated fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN silenced cells compared to control vector transfected cells, while inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast co-culture, suggesting the importance of FGFR2 signaling in fibroblast mediated tumor growth. Analysis of xenografted tumors revealed EMMPRIN silenced tumors had a larger stromal compartment compared to control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast independent tumor growth. PMID:21665938

Liu, Zhiyong; Hartman, Yolanda E.; Warram, Jason M.; Knowles, Joseph A.; Sweeny, Larrisa; Zhou, Tong; Rosenthal, Eben L.

2011-01-01

129

3D Multi-Cell Simulation of Tumor Growth and Angiogenesis  

PubMed Central

We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors. PMID:19834621

Shirinifard, Abbas; Gens, J. Scott; Zaitlen, Benjamin L.; Pop?awski, Nikodem J.; Swat, Maciej; Glazier, James A.

2009-01-01

130

The role of the microenvironment in tumor growth and invasion  

PubMed Central

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

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

2011-01-01

131

Integrative models of vascular remodeling during tumor growth  

PubMed Central

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

Rieger, Heiko; Welter, Michael

2015-01-01

132

Caveolin-1 is down-regulated in alveolar rhabdomyosarcomas and negatively regulates tumor growth  

PubMed Central

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with histological variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of less than 30%. Caveolin-1 (CAV1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signaling. In the present study we report that compared to other forms of rhabdomyosarcoma (RMS) CAV1 expression is either undetectable or very low in ARMS cell lines and tumor samples. DNA methylation analysis of the promoter region and azacytidine-induced re-expression suggest the involvement of epigenetic mechanisms in the silencing of CAV1. Reintroduction of CAV1 in three of these cell lines impairs their clonogenic capacity and promotes features of muscular differentiation. In vitro, CAV1-expressing cells show high expression of Caveolin-3 (CAV3), a muscular differentiation marker. Blockade of MAPK signaling is also observed. In vivo, CAV1-expressing xenografts show growth delay, features of muscular differentiation and increased cell death. In summary, our results suggest that CAV1 could function as a potent tumor suppressor in ARMS tumors. Inhibition of CAV1 function therefore, could contribute to aberrant cell proliferation, leading to ARMS development. PMID:25313138

Huertas-Martínez, Juan; Rello-Varona, Santiago; Herrero-Martín, David; Barrau, Ignasi; García-Monclús, Silvia; Sáinz-Jaspeado, Miguel; Lagares-Tena, Laura; Núñez-Álvarez, Yaiza; Mateo-Lozano, Silvia; Mora, Jaume; Roma, Josep; Toran, Nuria; Moran, Sebastian; López-Alemany, Roser; Gallego, Soledad; Esteller, Manel; Peinado, Miguel A.; Xavier García del, Muro; Tirado, Oscar M.

2014-01-01

133

Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth  

Microsoft Academic Search

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.

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

134

Numerical simulation of hypoxic cell regulation in avascular tumor growth  

NASA Astrophysics Data System (ADS)

Avascular tumor is an early stage of tumor which does not have the blood vessels themselves and depends entirely on the cells around them to get the supply of nutrients such as oxygen and glucose. Hypoxia is a condition in which living cells are deprived of oxygen needed to maintain metabolism and growth. In avascular tumor, the hypoxic environment inhibits the cells proliferation and distinguishes the cellular dynamics into proliferative, quiescent and necrotic cells. In this paper, we present a numerical simulation of mathematical model describing these cellular dynamics using Matlab software with R2009a version. The model formulated in the form of one-dimensional parabolic partial differential equations depending on time and space. The discretization is based on forward differential respect to time and central differential respect to space of finite difference approximation. The results of simulation show that the distribution of proliferating, quiescent and necrotic cells within a tumor spheroid with respect to time and the cells regulation under different rates of nutrients consumptions in one-dimensional computational domain. In conclusion, in the hypoxic environment, the proliferative and quiescent cells grow slowly dependent on some parameter changes and the necrotic cells emerged at the tumor core.

Mohd Said, Norfarizan; Ibrahim, Arsmah; Alias, Norma

2013-04-01

135

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

PubMed

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

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

136

Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.  

PubMed

Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis. PMID:19887554

Qamri, Zahida; Preet, Anju; Nasser, Mohd W; Bass, Caroline E; Leone, Gustavo; Barsky, Sanford H; Ganju, Ramesh K

2009-11-01

137

Distinct Role of Fibroblast Growth Factor-2 and Vascular Endothelial Growth Factor on Tumor Growth and Angiogenesis  

PubMed Central

Tumors express more than a single angiogenic growth factor. To investigate the relative impact of fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) on tumor growth and neovascularization, we generated tumor cell transfectants differing for VEGF and/or FGF-2 expression. Human endometrial adenocarcinoma HEC-1-B-derived Tet-FGF-2 cells that express FGF-2 under the control of the tetracycline-responsive promoter (Tet-off system) were further transfected with a VEGF121 anti-sense (AS-VEGF) cDNA. Next, Tet-FGF-2 and AS-VEGF/Tet-FGF-2 cells were transplanted subcutaneously in nude mice that received tetracycline or not in the drinking water. Simultaneous expression of FGF-2 and VEGF in Tet-FGF-2 cells resulted in fast-growing lesions characterized by high blood vessel density, patency and permeability, and limited necrosis. Blood vessels were highly heterogeneous in size and frequently associated with pericytes. Inhibition of FGF-2 production by tetracycline caused a significant decrease in tumor burden paralleled by a decrease in blood vessel density and size. AS-VEGF expression resulted in a similar reduction in blood vessel density associated with a significant decrease in pericyte organization, vascular patency, and permeability. The consequent decrease in tumor burden was paralleled by increased tumor hypoxia and necrosis. A limited additional inhibitory effect was exerted by simultaneous down-regulation of FGF-2 and VEGF expression. These findings demonstrate that FGF-2 and VEGF stimulate vascularization synergistically but with distinctive effects on vessel functionality and tumor survival. Blockade of either one of the two growth factors results in a decrease in blood vessel density and, consequently, in tumor burden. However, inhibition of the expression of VEGF, but not of FGF-2, affects also vessel maturation and functionality, leading to tumor hypoxia and necrosis. Our experimental model represents an unique tool to investigate anti-neoplastic therapies in different angiogenic environments. PMID:12759248

Giavazzi, Raffaella; Sennino, Barbara; Coltrini, Daniela; Garofalo, Angela; Dossi, Romina; Ronca, Roberto; Tosatti, Maria Pia Molinari; Presta, Marco

2003-01-01

138

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

NASA Astrophysics Data System (ADS)

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.

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

2012-11-01

139

Polyploidization delay in rat hepatocytes under liver growth inhibition by hypokinesia  

NASA Technical Reports Server (NTRS)

A study of young rats, weighing 55 to 59 g, after being for 10 days in conditions of limited mobility, shows a retardation of body growth as well as that of liver growth. The decrease in the rate of growth is accompanied by a reduction of cell proliferation and by delay polyploidization of hepatocytes in the liver of experimental rats. The materials, methods, and results of research are discussed.

Faktor, V. M.; Malyutin, V. F.; Li, S. Y.; Brodskiy, V. Y.

1981-01-01

140

Tumor suppressor TSLC1 inhibits growth, proliferation, invasiveness and angiogenesis in nude mice xenografted tumor of Eca109 cells  

PubMed Central

Tumor suppressor in lung cancer 1 (TSLC1) is a novel tumor suppressor gene whose inactivation is implicated in the occurrence, invasion, metastasis and prognosis of esophageal cancer. TSLC1 was studied by comparing the tumor formation of TSLC1 transfectant and control cells in nude mice. Compared with blank group and mock group, tumor size and infiltrating range of transfected group was less, differentiation of tumor tissue was slightly better, and differences of tumor angiogenesis was worse. There was no obvious difference between blank group and mock group. We have shown TSLC1 gene inhibited the growth proliferation, infiltration and angiogenesis of Eca109 cells. PMID:25035773

Liang, Qi-Lian; Chen, Guo-Qiang; Liu, Qiu-Long; Li, Zhou-Yu; Zhang, Xiang-Ning; Zhou, Yuan; Ou, Wen-Ting; Wang, Bi-Rong; Hu, Li-Ren

2014-01-01

141

Environmental enrichment does not impact on tumor growth in mice  

PubMed Central

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

Kershaw, Michael H

2013-01-01

142

Lifespan Based Pharmacokinetic-Pharmacodynamic Model of Tumor Growth Inhibition by Anticancer Therapeutics  

PubMed Central

Accurate prediction of tumor growth is critical in modeling the effects of anti-tumor agents. Popular models of tumor growth inhibition (TGI) generally offer empirical description of tumor growth. We propose a lifespan-based tumor growth inhibition (LS TGI) model that describes tumor growth in a xenograft mouse model, on the basis of cellular lifespan T. At the end of the lifespan, cells divide, and to account for tumor burden on growth, we introduce a cell division efficiency function that is negatively affected by tumor size. The LS TGI model capability to describe dynamic growth characteristics is similar to many empirical TGI models. Our model describes anti-cancer drug effect as a dose-dependent shift of proliferating tumor cells into a non-proliferating population that die after an altered lifespan TA. Sensitivity analysis indicated that all model parameters are identifiable. The model was validated through case studies of xenograft mouse tumor growth. Data from paclitaxel mediated tumor inhibition was well described by the LS TGI model, and model parameters were estimated with high precision. A study involving a protein casein kinase 2 inhibitor, AZ968, contained tumor growth data that only exhibited linear growth kinetics. The LS TGI model accurately described the linear growth data and estimated the potency of AZ968 that was very similar to the estimate from an established TGI model. In the case study of AZD1208, a pan-Pim inhibitor, the doubling time was not estimable from the control data. By fixing the parameter to the reported in vitro value of the tumor cell doubling time, the model was still able to fit the data well and estimated the remaining parameters with high precision. We have developed a mechanistic model that describes tumor growth based on cell division and has the flexibility to describe tumor data with diverse growth kinetics. PMID:25333487

Mo, Gary; Gibbons, Frank; Schroeder, Patricia; Krzyzanski, Wojciech

2014-01-01

143

Mo polyoxometalate nanoparticles inhibit tumor growth and vascular endothelial growth factor induced angiogenesis  

NASA Astrophysics Data System (ADS)

Tumor growth depends on angiogenesis, which can furnish the oxygen and nutrients that proliferate tumor cells. Thus, blocking angiogenesis can be an effective strategy to inhibit tumor growth. In this work, three typical nanoparticles based on polyoxometalates (POMs) have been prepared; we investigated their capability as antitumor and anti-angiogenesis agents. We found that Mo POM nanoparticles, especially complex 3, inhibited the growth of human hepatocellular liver carcinoma cells (HepG2) through cellular reactive oxygen species levels’ elevation and mitochondrial membrane potential damage. Complex 3 also suppressed the proliferation, migration, and tube formation of endothelial cells in vitro and chicken chorioallantoic membrane development ex vivo. Furthermore, western blot analysis of cell signaling molecules indicated that Mo POMs blocked the vascular endothelial growth factor receptor 2-mediated ERK1/2 and AKT signaling pathways in endothelial cells. Using transmission electron microscopy, we demonstrated their cellular uptake and localization within the cytoplasm of HepG2 cells. These results indicate that, owing to the extraordinary physical and chemical properties, Mo POM nanoparticles can significantly inhibit tumor growth and angiogenesis, which makes them potential drug candidates in anticancer and anti-angiogenesis therapies.

Zheng, Wenjing; Yang, Licong; Liu, Ying; Qin, Xiuying; Zhou, Yanhui; Zhou, Yunshan; Liu, Jie

2014-06-01

144

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth  

PubMed Central

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

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

145

Twist promotes tumor cell growth through YB-1 expression.  

PubMed

YB-1 controls gene expression through both transcriptional and translational mechanisms and is involved in various biological activities such as brain development, chemoresistance, and tumor progression. We have previously shown that YB-1 is overexpressed in cisplatin-resistant cells and is involved in resistance against DNA-damaging agents. Structural analysis of the YB-1 promoter reveals that several E-boxes may participate in the regulation of YB-1 expression. Here, we show that the E-box-binding transcription factor Twist is overexpressed in cisplatin-resistant cells and that YB-1 is a target gene of Twist. Silencing of either Twist or YB-1 expression induces G(1) phase cell cycle arrest of tumor cell growth. Significantly, reexpression of YB-1 led to increase colony formation when Twist expression was down-regulated by small interfering RNA. However, cotransfection of Twist expression plasmid could not increase colony formation when YB-1 expression was down-regulated. Collectively, these data suggest that YB-1 is a major downstream target of Twist. Both YB-1 and Twist expression could induce tumor progression, promoting cell growth and driving oncogenesis in various cancers. Thus, both YB-1 and Twist may represent promising molecular targets for cancer therapy. PMID:18172301

Shiota, Masaki; Izumi, Hiroto; Onitsuka, Takamitsu; Miyamoto, Naoya; Kashiwagi, Eiji; Kidani, Akihiko; Yokomizo, Akira; Naito, Seiji; Kohno, Kimitoshi

2008-01-01

146

Hybrid Cellular Continuum Simulations of Heterogeneity in Tumor Growth  

NASA Astrophysics Data System (ADS)

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.

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

2010-03-01

147

Transforming growth factor-alpha secretion by epidermal growth factor-dependent human tumor cell lines.  

PubMed

Pairs of cell lines from spontaneous human tumors (cervical adenocarcinoma, melanoma, and synovial sarcoma) were established using serum-free culture conditions with and without exogenous epidermal growth factor (EGF). EGF-adapted cultures of melanoma and cervical adenocarcinoma origin secreted higher levels of bioactive transforming growth factor alpha (TGF-alpha) when compared to cultures maintained in the absence of EGF. Depletion of EGF for these EGF-adapted cultures resulted in growth arrest. In contrast, the sarcoma cell lines did not secrete TGF-alpha regardless of the culture conditions but EGF significantly stimulated proliferation of these cells in short-term assays. We show that exogenous EGF induces TGF-alpha production and supports proliferation of tumor cells of various tissue origin but is not essential for in vitro growth factor-deprived conditions. PMID:2285223

Singletary, S E; Williams, N N; Rodeck, U; Larry, L; Tucker, S; Spitzer, G; Herlyn, M

1990-01-01

148

Impact of body mass index on growth in boys with delayed puberty.  

PubMed

It is unclear whether overweight but otherwise healthy boys with delayed puberty have a variation of constitutional delay of growth and maturation (CDGM) or a different etiology for their pubertal delay. To characterize better this group of boys and investigate whether their growth pattern distinguishes them from boys with typical CDGM, growth data were analyzed in eight overweight (BMI SDS > or = 85th percentile) and 37 non-overweight (BMI SDS <85th percentile) boys with delayed puberty. Primary outcome measures included predicted height (PH) and adult height (AH). At diagnosis of delayed puberty, the overweight boys had less delayed bone ages (chronological age [CA] - bone age [BA] = 1.2 +/- 1.0 vs 2.5 +/- 1.1 years, p <0.01), greater height SDS for CA (-0.5 +/- 0.7 vs -2.4 +/- 0.8, p <0.001), and greater height SDS for BA (0.6 +/- 0.9 vs -0.4 +/- 1.1, p <0.05). PH for the overweight boys exceeded their mid-parental height (MPH) by 5.0 +/- 7.2 cm while non-overweight boys were predicted to fall below their MPH by 2.8 +/- 6.3 cm (p <0.01). Available AH data corroborated the differences in PH, with a trend for overweight boys to have greater height relative to their MPH than the non-overweight boys. These observations suggest that in the context of delayed puberty, being overweight may modulate adult height and/or that the etiology of delayed puberty in overweight boys may differ from typical CDGM. PMID:16995581

Nathan, Brandon M; Sedlmeyer, Ines L; Palmert, Mark R

2006-08-01

149

Antivascular Endothelial Growth Factor Receptor (Fetal Liver Kinase 1) Monoclonal Antibody Inhibits Tumor Angiogenesis and Growth of Several Mouse and Human Tumors  

Microsoft Academic Search

Tumor angiogenesis is mediated by tumor-secreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor (fetal liver kinase 1 (Flk-1)\\/kinase insert domain-containing receptor) play an important role in vascular permeability and tumor angiogenesis. Previ- ously, we reported on the development of anti-Flk-1 and antikinase insert domain-containing receptor monoclonal

Marie Prewett; James Huber; Yiwen Li; Angel Santiago; William O'Connor; Karen King; Jay Overholser; Andrea Hooper; Bronislaw Pytowski; Larry Witte; Peter Bohlen; Daniel J. Hicklin

1999-01-01

150

Liposome-encapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice.  

PubMed

We hypothesize that liposome-encapsulated hemoglobin with high O? affinity (P??0? = 12 mm Hg, h-LEH) may increase O? delivery to hypoxic tumors and enhance radiation therapy synergistically to suppress tumor growth. First, h-LEH (5, 10, and 20 mL/kg) was intravenously infused 30 min before radiation (20 Gy) of SCCVII tumor grown in C3H/HeN mice. Second, 10 mL/kg of h-LEH was administered 30, 60, 90, and 120 min prior to radiation to determine optimal timing. Tumor size was monitored thereafter to titrate tumor growth suppression. Third, additional mice with SCCVII tumor were infused with h-LEH or empty liposome (EL), and tumors were excised at various time points for immunohistochemical examination of h-LEH and hypoxia-inducible factor-1? (HIF-1?). h-LEH was most effective at 10 mL/kg in comparison to 5 or 20 mL/kg of h-LEH or EL. Tumor growth was most suppressed when the interval between h-LEH infusion and radiation was shortest, 30 min. As a result, 10 mL/kg of h-LEH infusion 30 min prior to radiation prolonged 5-fold tumor-growth time from 20.0 days (radiation and EL) to 26.5 days, P<0.01, synergy ratio 1.42. While human hemoglobin (h-LEH) was detected in tumors 0.5 to 24 h after administration, HIF-1? accumulation was sparse and became significantly reduced compared to controls 48 and 72 h after h-LEH infusion. h-LEH (10 mL/kg) was highly effective in enhancing radiation therapy synergistically under ambient respiration against tumor growth in mice. Decreased accumulation of HIF-1? in h-LEH-treated tumor may suggest targeted tumor oxygenation as a potential mechanism. PMID:22339726

Murayama, Chieko; Kawaguchi, Akira T; Ishikawa, Kenji; Kamijo, Akemi; Kato, Nobusuke; Ohizumi, Yukio; Sadahiro, Sotaro; Haida, Munetaka

2012-02-01

151

Triparanol suppresses human tumor growth in vitro and in vivo  

SciTech Connect

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

Bi, Xinyu [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)] [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China); Han, Xingpeng [Department of Pathology, Tianjin Chest Hospital, Tianjin 300051 (China)] [Department of Pathology, Tianjin Chest Hospital, Tianjin 300051 (China); Zhang, Fang [Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang (China)] [Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang (China); He, Miao [Life Sciences School, Sun Yat-sen University, Guangzhou 510275 (China)] [Life Sciences School, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Yi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)] [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhi, Xiu-Yi, E-mail: xiuyizhi@yahoo.com.cn [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)] [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)] [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)

2012-08-31

152

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

E-print Network

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

Paris-Sud XI, Université de

153

Nerve Growth Factor from Cobra Venom Inhibits the Growth of Ehrlich Tumor in Mice  

PubMed Central

The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved. PMID:24577582

Osipov, Alexey V.; Terpinskaya, Tatiana I.; Kryukova, Elena V.; Ulaschik, Vladimir S.; Paulovets, Lubov V.; Petrova, Elena A.; Blagun, Ekaterina V.; Starkov, Vladislav G.; Utkin, Yuri N.

2014-01-01

154

Dispersal, survival and delayed growth of benthic foraminiferal propagules  

NASA Astrophysics Data System (ADS)

New data support our previously published propagule dispersal hypothesis and show that propagules of some benthic foraminiferal species can survive for two years before growth commences. Following exposure to simulated shallow-water conditions, shallow-water species of benthic foraminifera appeared and grew in large numbers (commonly >100 ind/12 ml sediment) in the <32 µm-size sediment fraction collected from 320 m water depth in the Skagerrak basin (North Sea). None of the shallow-water species that grew abundantly ( Planorbulina mediterranensis, Morulaeplecta bulbosa, Bolivina pseudoplicata, Cuneata arctica, Eggerelloides scaber, Gavelinopsis praegeri) seem to grow or reproduce at or in the vicinity of the sampling site. Consequently, they must have been transported there as <32 µm-sized individuals. Their sudden appearance when exposed to shallow-water conditions suggests that they had been transported to the sampling site as propagules and that they could survive in the sediments until conditions became suitable for growth and, for some, reproduction. The lack of agglutination on the proloculi of the agglutinated taxa that appeared in the growth-chambers may enhance their passive transport via currents and, thereby, dispersal. Of all the indigenous foraminiferal species that occur at the sampling site, only Textularia earlandi and Bolivinellina pseudopunctata continued to grow and reproduce when transferred from bathyal (320 m) to simulated shallow-water (0 m) conditions. The former is considered a highly opportunistic species. According to the literature, most of the morphospecies which grew in the experiments are cosmopolitan. Our results indicate substantial inter-specific differences in dispersal potential and support previous suggestions that among free-living species, some serial forms have the potential for long-distance dispersal. Still, oceanographic, physical and ecological boundaries and barriers constrain the distribution of most species. In addition to benthic foraminifera, Gromia spp. (rhizarian protists related to the foraminifera) grew in >60% of the experimental growth-chambers.

Alve, Elisabeth; Goldstein, Susan T.

2010-01-01

155

Effects of delayed settlement on post-settlement growth and survival of scleractinian coral larvae.  

PubMed

Demographic connectivity requires both the dispersal of individuals between sub-populations, and their subsequent contribution to population dynamics. For planktonic, non-feeding marine larvae, the capacity to delay settlement enables greater dispersal distances, but the energetic cost of delayed settlement has been shown to adversely impact post-settlement fitness in several taxa. Here, we assess whether delayed settlement influences mortality rates or growth rates for the first 6 weeks following settlement of the scleractinian coral, Acropora tenuis. Coral larvae that were settled at 2, 4, and 6 weeks after spawning, and then deployed in the field, showed negligible effects of delayed settlement on post-settlement survival and time to initial budding for colony formation. Between-cohort differences in budding rate appeared to be explained by temporal variation in the post-settlement acquisition of zooxanthellae. The potential for coral larvae to remain in the pelagic zone for increased periods of time with little to no effect on post-settlement survival and growth suggests that the capacity for delayed settlement is likely to have meaningful demographic consequences for broadcast-spawning reef-building corals, and that the predicted trade-off between delayed settlement and post-settlement fitness is less applicable to reef-building scleractinian corals than other taxa with non-feeding larvae. PMID:23525803

Graham, Erin M; Baird, Andrew H; Willis, Bette L; Connolly, Sean R

2013-10-01

156

The Motor Protein KIF14 Inhibits Tumor Growth and Cancer Metastasis in Lung Adenocarcinoma  

PubMed Central

The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P?=?0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas. PMID:23626713

Hung, Pei-Fang; Hong, Tse-Ming; Hsu, Yi-Chiung; Chen, Hsuan-Yu; Chang, Yih-Leong; Wu, Chen-Tu; Chang, Gee-Chen; Jou, Yuh-Shan

2013-01-01

157

Maternal MDMA administration in mice leads to neonatal growth delay.  

PubMed

The psychoactive recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is widely abused. The fact that MDMA induces neurotoxic damage in serotonergic nerve endings is well known. However, the effects of MDMA on pregnant and neonatal animals remain unknown. Therefore, we studied the effects of gestational exposure to MDMA on birth, growth, and behavior of pups. Female BALB/c mice were orally administered either water (10 ml/kg) or MDMA (20 mg/10 ml/kg) from gestational day 1 to postnatal day (P) 21. MDMA did not affect the birth rate, but the survival rate of the pups significantly decreased. A significant reduction in body weight gain was observed in pups from MDMA-administered dams during P3-P21. Maternal MDMA treatment caused an attenuated cliff avoidance reaction and decreased motor function in the pups, as determined by the wire hanging test. These results suggest that MDMA treatment during pregnancy and lactation causes growth retardation and dysfunction of motor neurons in mouse pups. PMID:24418707

Kaizaki, Asuka; Tanaka, Sachiko; Yoshida, Takemi; Numazawa, Satoshi

2014-02-01

158

Interleukin 10 transfected into Chinese hamster ovary cells prevents tumor growth and macrophage infiltration.  

PubMed

Expression of cytokines in tumor cells provides a sensitive modality to analyze the consequences of local cytokines in vivo on tumor infiltrating cells and tumorigenicity. We have transfected Chinese hamster ovary (CHO) cells with an interleukin 10 (IL-10) expression vector. CHO-IL10 cells although unaltered with respect to their in vitro growth lost tumorigenicity, both in nude and in SCID mice and in an IL-10 dose dependent manner. In addition, CHO-IL10 cells suppressed the growth of equal numbers of coinjected but not of contralaterally injected CHO cells. Immunohistology with anti-CR3/Mac-1 and anti-Mac-3 monoclonal antibodies revealed that CHO tumors were substantially infiltrated by macrophages. However, in CHO-IL10 tumors macrophages were virtually absent within the tumor tissue. Our results suggest that IL-10 indirectly suppresses tumor growth of certain tumors by inhibiting infiltration of macrophages which may provide tumor growth promoting activity. PMID:8364905

Richter, G; Krüger-Krasagakes, S; Hein, G; Hüls, C; Schmitt, E; Diamantstein, T; Blankenstein, T

1993-09-15

159

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

E-print Network

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

Breedlove, Marc

160

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

Microsoft Academic Search

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

Mervat M El-Eshmawy; Ibrahim A Abdel Aal; Amany K El hawary

2010-01-01

161

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

PubMed Central

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

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

162

Composite waves for a cell population system modelling tumor growth and invasion  

E-print Network

Composite waves for a cell population system modelling tumor growth and invasion Min Tang Nicolas coefficient . The right hand side (, ) is the growth term; it expresses that cells divide freely, thus The recent biomechanical theory of cancer growth considers solid tumors as liquid-like materials comprising

Paris-Sud XI, Université de

163

Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency.  

PubMed

The growth of Lewis lung carcinoma (LLC) was sustained in plasminogen-deficient mice when transplanted into the dorsal skin but was dramatically suppressed in another anatomic location, the footpad. This unanticipated negative effect of plasminogen deficiency on footpad tumor growth was entirely relieved by superimposing a deficit in fibrinogen. This finding was not simply an unusual feature of LLC tumors--T241 fibrosarcoma growth in the footpad was also restricted by plasminogen deficiency in a fibrinogen-dependent manner. The probable mechanistic basis for suppression of tumor growth was revealed through transmission electron microscopy studies of tumor tissues. Occlusive microvascular thrombi were commonplace within footpad tumors from plasminogen-deficient mice, whereas no such lesions were observed within either dorsal skin tumors from plasminogen-deficient mice or footpad tumors from mice that also lacked fibrinogen. The data infer that tumor growth in the footpad of plasminogen-deficient mice is compromised as a function of the formation and persistence of vaso-occlusive thrombi that limit tumor blood supply. These studies indicate that plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their relative importance is dependent on the tumor microenvironment. Furthermore, these studies suggest that one target of plasmin(ogen) relevant to tumor progression in vivo is intravascular fibrin. PMID:12829586

Palumbo, Joseph S; Talmage, Kathryn E; Liu, Hong; La Jeunesse, Christine M; Witte, David P; Degen, Jay L

2003-10-15

164

Perfluorochemical emulsions can increase tumor radiosensitivity  

Microsoft Academic Search

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.

B. A. Teicher; C. M. Rose

1984-01-01

165

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

SciTech Connect

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

Sun, Qingwen [Shanghai Chest Hospital, Shanghai 200433 (China) [Shanghai Chest Hospital, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Jiang, Songmin [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China)] [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Han, Baohui [Shanghai Chest Hospital, Shanghai 200433 (China)] [Shanghai Chest Hospital, Shanghai 200433 (China); Sun, Tongwen [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)] [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China); Li, Zhengnan; Zhao, Lina; Gao, Qiang [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China)] [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China); Sun, Jialin, E-mail: jialin_sun@126.com [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)] [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)

2012-11-02

166

Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model  

PubMed Central

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

2014-01-01

167

Expression of the Type-1 Repeats of Thrombospondin-1 Inhibits Tumor Growth Through Activation of Transforming Growth Factor-?  

PubMed Central

In the present study, the type-1 repeats of thrombospondin-1 (TSP-1) were transfected into A431 cells. Expression of all three type-1 repeats (3TSR) and expression of just the second type-1 repeat containing the transforming growth factor (TGF)-? activating sequence KRFK (TSR2 + KRFK) significantly inhibited in vivo tumor angiogenesis and growth in nude mice. These tumors expressed increased levels of both active and total TGF-?. A431 cells expressing the second type-1 repeat without the KRFK sequence (TSR2 ? KRFK) produced tumors that were slightly larger than the 3TSR and TSR2 + KRFK tumors. These tumors expressed elevated levels of active TGF-? but levels of total TGF-? were not different from control tumors. Injection of the peptide, LSKL, which blocks TSP-1 activation of TGF-?, reversed the growth inhibition observed with cells expressing TSR2 + KRFK to a level comparable to controls. Various residues in the WSHWSPW region and the VTCG sequence of both TSR2+/? KRFK were mutated. Although mutation of the VTCG sequence had no significant effect on tumor growth, mutation of the WSHWSPW sequence reduced inhibition of tumor growth. These findings suggest that the inhibition of tumor angiogenesis and growth by endogenous TSP-1 involves regulation of both active and total TGF-? and the sequences KRFK and WSHWSPW in the second type-1 repeat. PMID:15277228

Yee, Karen O.; Streit, Michael; Hawighorst, Thomas; Detmar, Michael; Lawler, Jack

2004-01-01

168

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

NASA Astrophysics Data System (ADS)

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

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

2013-03-01

169

Tumor-secreted Hsp90 Subverts Polycomb Function to Drive Prostate Tumor Growth and Invasion.  

PubMed

Prostate cancer remains the second highest contributor to male cancer-related lethality. The transition of a subset of tumors from indolent to invasive disease is associated with a poor clinical outcome. Activation of the epithelial to mesenchymal transition (EMT) genetic program is a major risk factor for cancer progression. We recently reported that secreted extracellular Hsp90 (eHsp90) initiates EMT in prostate cancer cells, coincident with its enhanced expression in mesenchymal models. Our current work substantially extended these findings in defining a pathway linking eHsp90 signaling to EZH2 function, a methyltransferase of the Polycomb repressor complex. EZH2 is also implicated in EMT activation, and its up-regulation represents one of the most frequent epigenetic alterations during prostate cancer progression. We have now highlighted a novel epigenetic function for eHsp90 via its modulation of EZH2 expression and activity. Mechanistically, eHsp90 initiated sustained activation of MEK/ERK, a signal critical for facilitating EZH2 transcriptional up-regulation and recruitment to the E-cadherin promoter. We further demonstrated that an eHsp90-EZH2 pathway orchestrates an expanded repertoire of EMT-related events including Snail and Twist expression, tumor cell motility, and anoikis resistance. To evaluate the role of eHsp90 in vivo, eHsp90 secretion was stably enforced in a prostate cancer cell line resembling indolent disease. Remarkably, eHsp90 was sufficient to induce tumor growth, suppress E-cadherin, and initiate localized invasion, events that are exquisitely dependent upon EZH2 function. In summary, our findings illuminate a hitherto unknown epigenetic function for eHsp90 and support a model wherein tumor eHsp90 functions as a rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior. PMID:25670862

Nolan, Krystal D; Franco, Omar E; Hance, Michael W; Hayward, Simon W; Isaacs, Jennifer S

2015-03-27

170

A FACTOR FROM NORMAL TISSUES INHIBITING TUMOR GROWTH  

PubMed Central

Extracts of desiccated embryo skin and placenta have been found to exert a definite retarding action on the growth of two transplantable carcinomas of mice, but they were without effect on sarcomas. In tests involving some 828 inoculations of the tumor cells and the extracts, complete suppression of growth occurred in from 55 to 71 per cent of instances, as compared with 21 to 27 per cent in the controls, and where growth was not completely suppressed some retardation was found in practically every instance. To judge from findings in rabbits the inhibitor is not demonstrable in the placenta until the beginning of the second third of pregnancy, reaches its maximum by the last third, but disappears about 2 or 3 days before term. Extracts of fresh placenta are without effect, and no very definite inhibition was noted in extracts of a variety of other desiccated or fresh tissues. The conclusions here reported are based on the results of over 3800 inoculations. PMID:19870301

Murphy, James B.; Sturm, Ernest

1934-01-01

171

Simulation of the effect of plasma species on tumor growth and apoptosis  

NASA Astrophysics Data System (ADS)

Tumor modeling is a technique that entails using mathematical and physical equations to describe the biological disease, most importantly uncontrolled cell growth and the tumor life cycle. The model utilized in this paper makes use of a three-dimensional hybrid discrete–continuum model to show the apoptotic effect a tumor volume undergoes when treated with reactive oxygen and nitrogen species from the cold atmospheric plasma. The results compare untreated and treated tumors of varying sizes by measuring spatiotemporal data to predict trends of tumor evolution. The simulation results show that the treated tumor death, irrespective of tumor volume, follows an exponential decay and that the untreated tumor follows an expected growth pattern. Future experiments and applications can lead to a predictive tumor model allowing for individualized treatment planning for the cold atmospheric plasma therapy.

Murphy, William; Carroll, Caitlin; Keidar, Michael

2014-11-01

172

Ski Promotes Tumor Growth Through Abrogation of Transforming Growth Factor-? Signaling in Pancreatic Cancer  

PubMed Central

Objective: We hypothesized that human pancreatic cancer resists TGF-? signaling and cell death through increased Ski expression. Summary Background Data: Ski is an oncogenic protein that acts as a TGF-? repressor and prevents related gene transcription. Previous work suggests that Ski acts as an oncoprotein in melanoma and esophageal cancer. Ski expression and function have not been determined in human pancreatic cancer. Methods: Immunohistochemistry and immunoblots assessed Ski expression in human pancreatic cancer. Panc-1 cells were treated with or without Ski siRNA, and Ski and Smad protein expression, transcriptional reporter activation, and growth assays were determined. Panc-1 cells were inoculated in the flank of nude mice and tumor volume and histology assessed after administration of Ski siRNA or control vector. Results: Ski was abundantly expressed in human pancreatic cancer specimens assessed by immunohistochemistry (91%) and immunoblot analysis (67%). Panc-1 cells exhibited nascent Ski expression that was maximally inhibited 48 hours after transfection with Ski siRNA. TGF-? transcriptional activity was increased 2.5-fold in Ski siRNA-treated cells compared with control (P < 0.05). Ski siRNA increased TGF-?-induced Smad2 phosphorylation and p21 expression. Panc-1 growth in culture was decreased 2-fold at 72 hours. A Ski siRNA expression vector injected into nude mice resulted in a 5-fold decrease in growth. Conclusion: Inhibition of Ski through RNA interference restored TGF-? signaling and growth inhibition in vitro, and decreased tumor growth in vivo. PMID:17592292

Heider, T Ryan; Lyman, Suzanne; Schoonhoven, Robert; Behrns, Kevin E.

2007-01-01

173

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

Microsoft Academic Search

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

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

174

Delayed union of the clavicle treated with plasma rich in growth factors.  

PubMed

Nonunion is an uncommon complication of fracture of the clavicle; it is usually treated surgically. The use of biological treatments in this type of condition is increasingly more common because of their ease of application. Plasma rich in growth factors (PRGF) has been used in delayed healing and in nonunion of fractures. We report a case of delayed union fracture of the clavicle in which biological treatment was chosen before considering surgery. Three percutaneous injections of PRGF, one every 2 weeks, were delivered into the delayed union site. The autologous PGRF used was obtained through the patented PRGF system. Three months after the final dose, computed tomography study showed healing of the bone. The patient regained complete mobility of the shoulder without pain. Currently she is able to carry out all the normal life activities and experiences no pain. PMID:21138228

Seijas, Roberto; Santana-Suarez, Romen Y; Garcia-Balletbo, Montserrat; Cuscó, Xavier; Ares, Oscar; Cugat, Ramón

2010-10-01

175

Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth  

PubMed Central

An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. PMID:25223704

Yin, Yuan; Cai, Xing; Chen, Xi; Liang, Hongwei; Zhang, Yujing; Li, Jing; Wang, Zuoyun; Chen, Xiulan; Zhang, Wen; Yokoyama, Seiji; Wang, Cheng; Li, Liang; Li, Limin; Hou, Dongxia; Dong, Lei; Xu, Tao; Hiroi, Takachika; Yang, Fuquan; Ji, Hongbin; Zhang, Junfeng; Zen, Ke; Zhang, Chen-Yu

2014-01-01

176

Carbon Monoxide Expedites Metabolic Exhaustion to Inhibit Tumor Growth  

PubMed Central

One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. PMID:24121491

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

2013-01-01

177

An RGD motif present in cadherin 17 induces integrin activation and tumor growth.  

PubMed

Little is known about the mechanism of integrin activation by cadherin 17 (CDH17). Here we observed the presence of a tri-peptide motif, RGD, in domain 6 of the human CDH17 sequence and other cadherins such as cadherin 5 and cadherin 6. The use of CDH17 RAD mutants demonstrated a considerable decrease of proliferation and adhesion in RKO and KM12SM colon cancer cells. Furthermore, RGD peptides inhibited the adhesion of both cell lines to recombinant CDH17 domain 6. The RGD motif added exogenously to the cells provoked a change in ?1 integrin to an active, high-affinity conformation and an increase in focal adhesion kinase and ERK1/2 activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. CDH17 RGD effects were also active in pancreatic cancer cells. Our results suggest that ?2?1 integrin interacts with two different ligands, collagen IV and CDH17, using two different binding sites. In summary, the RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins. PMID:25336636

Bartolomé, Rubén A; Peláez-García, Alberto; Gomez, Inmaculada; Torres, Sofía; Fernandez-Aceñero, María Jesús; Escudero-Paniagua, Beatriz; Imbaud, J Ignacio; Casal, J Ignacio

2014-12-12

178

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

SciTech Connect

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.

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

1993-06-01

179

Knockout of Mitochondrial Thioredoxin Reductase Stabilizes Prolyl Hydroxylase 2 and Inhibits Tumor Growth and Tumor-Derived Angiogenesis  

PubMed Central

Abstract Aims: Mitochondrial thioredoxin reductase (Txnrd2) is a central player in the control of mitochondrial hydrogen peroxide (H2O2) abundance by serving as a direct electron donor to the thioredoxin-peroxiredoxin axis. In this study, we investigated the impact of targeted disruption of Txnrd2 on tumor growth. Results: Tumor cells with a Txnrd2 deficiency failed to activate hypoxia-inducible factor-1? (Hif-1?) signaling; it rather caused PHD2 accumulation, Hif-1? degradation and decreased vascular endothelial growth factor (VEGF) levels, ultimately leading to reduced tumor growth and tumor vascularization. Increased c-Jun NH2-terminal Kinase (JNK) activation proved to be the molecular link between the loss of Txnrd2, an altered mitochondrial redox balance with compensatory upregulation of glutaredoxin-2, and elevated PHD2 expression. Innovation: Our data provide compelling evidence for a yet-unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular Hif-1? accumulation. In addition, simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems was used as an efficient therapeutic approach in hindering tumor growth. Conclusion: This work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-Hif-1? axis, which highlights how the loss of Txnrd2 and the resulting altered mitochondrial redox balance impairs tumor growth as well as tumor-related angiogenesis. Furthermore, it opens a new avenue for a therapeutic approach to hinder tumor growth by the simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems. Antioxid. Redox Signal. 22, 938–950. PMID:25647640

Hellfritsch, Juliane; Kirsch, Julian; Schneider, Manuela; Fluege, Tamara; Wortmann, Markus; Frijhoff, Jeroen; Dagnell, Markus; Fey, Theres; Esposito, Irene; Kölle, Pirkko; Pogoda, Kristin; Angeli, José Pedro Friedmann; Ingold, Irina; Kuhlencordt, Peter; Östman, Arne; Pohl, Ulrich

2015-01-01

180

Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules  

E-print Network

Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules Samuel the best timing of treatments. However, the influence of variations in tumor kinetics has not been kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate

Paris-Sud XI, Université de

181

Preventing Growth of Brain Tumors by Creating a Zone of Resistance  

Microsoft Academic Search

Glioblastoma multiforme (GBM) is a devastating form of brain cancer for which there is no effective treatment. Here, we report a novel approach to brain tumor therapy through genetic modification of normal brain cells to block tumor growth and effect tumor regression. Previous studies have focused on the use of vector-based gene therapy for GBM by direct intratumoral injection with

Casey A Maguire; Dimphna H Meijer; Stanley G LeRoy; Laryssa A Tierney; Marike LD Broekman; Fabricio F Costa; Xandra O Breakefield; Anat Stemmer-Rachamimov; Miguel Sena-Esteves

2008-01-01

182

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

PubMed Central

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

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

2014-01-01

183

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

PubMed Central

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

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

184

Impact of metabolic heterogeneity on tumor growth, invasion, and treatment outcomes.  

PubMed

Histopathologic knowledge that extensive heterogeneity exists between and within tumors has been confirmed and deepened recently by molecular studies. However, the impact of tumor heterogeneity on prognosis and treatment remains as poorly understood as ever. Using a hybrid multiscale mathematical model of tumor growth in vascularized tissue, we investigated the selection pressures exerted by spatial and temporal variations in tumor microenvironment and the resulting phenotypic adaptations. A key component of this model is normal and tumor metabolism and its interaction with microenvironmental factors. The metabolic phenotype of tumor cells is plastic, and microenvironmental selection leads to increased tumor glycolysis and decreased pH. Once this phenotype emerges, the tumor dramatically changes its behavior due to acid-mediated invasion, an effect that depends on both variations in the tumor cell phenotypes and their spatial distribution within the tumor. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the interior of the tumor. These cells then grow to the edge of the tumor and invade into the normal tissue using acidosis. Simulations suggest that diffusible cytotoxic treatments, such as chemotherapy, may increase the metabolic aggressiveness of a tumor due to drug-mediated selection. Chemotherapy removes the metabolic stratification of the tumor and allows more aggressive cells to grow toward blood vessels and normal tissue. Antiangiogenic therapy also selects for aggressive phenotypes due to degradation of the tumor microenvironment, ultimately resulting in a more invasive tumor. In contrast, pH buffer therapy slows down the development of aggressive tumors, but only if administered when the tumor is still stratified. Overall, findings from this model highlight the risks of cytotoxic and antiangiogenic treatments in the context of tumor heterogeneity resulting from a selection for more aggressive behaviors. Cancer Res; 75(8); 1567-79. ©2015 AACR. PMID:25878146

Robertson-Tessi, Mark; Gillies, Robert J; Gatenby, Robert A; Anderson, Alexander R A

2015-04-15

185

Tumor STAT1 Transcription Factor Activity Enhances Breast Tumor Growth and Immune Suppression Mediated by Myeloid-derived Suppressor Cells*  

PubMed Central

Previous studies had implicated the IFN-? transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33+ myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach. PMID:23486482

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

2013-01-01

186

Molecular mechanism of interferon alfa–Mediated growth inhibition in human neuroendocrine tumor cells  

Microsoft Academic Search

Background & Aims: Although human neuroendocrine tumors respond to interferon (IFN)-? treatment in vivo, the underlying mechanisms of growth inhibition are poorly understood. To characterize the antiproliferative effects at a molecular level, we explored the growth-regulatory action of IFN-? in the human neuroendocrine tumor cell lines BON and QGP1. Methods: IFN-? receptor expression and signal transduction were examined by reverse-transcription

Katharina M. Detjen; Martina Welzel; Katrin Farwig; Felix H. Brembeck; Astrid Kaiser; Ernst-Otto Riecken; Bertram Wiedenmann; Stefan Rosewicz

2000-01-01

187

Brachmann-de Lange syndrome: a cause of early symmetric fetal growth delay.  

PubMed

Brachmann-de Lange syndrome is characterized by pre- and postnatal growth retardation, microbrachycephaly, hirsutism, various visceral and limb anomalies and a typical face. A sonographic prenatal diagnosis at mid-trimester is reported in a case of severe, symmetrical fetal growth delay at 20 weeks gestation, with a thickened skin on the forehead, a small nose and a marked depressed nasal bridge, a long philtrum, micrognathia and a persistently flexed right forearm, with a single bone associated to oligodactyly. Due to the severe mental impairment with a commonly estimated intelligence quotient under 60, the pregnancy was terminated after parental consent. PMID:10584631

Boog, G; Sagot, F; Winer, N; David, A; Nomballais, M F

1999-08-01

188

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression  

PubMed Central

Neuroblastoma (NB) is a common childhood malignant tumor of the neural crest-derived sympathetic nervous system. In NB the frequent loss of heterozygosity (LOH) on chromosome 1p raises the possibility that this region contains tumor-suppressor genes whose inactivation contributes to tumorigenesis. The human homolog of the Drosophila neural fate determination gene CASZ1, a zinc-finger transcription factor, maps to chromosome 1p36.22, a region implicated in NB tumorigenesis. Quantitative real-time PCR analysis showed that low-CASZ1 expression is significantly correlated with increased age (?18 months), Children's Oncology Group high-risk classification, 1p LOH and MYCN amplification (all P<0.0002) and decreased survival probability (P=0.0009). CASZ1 was more highly expressed in NB with a differentiated histopathology (P<0.0001). Retinoids and epigenetic modification agents associated with regulation of differentiation induced CASZ1 expression. Expression profiling analysis revealed that CASZ1 regulates the expression of genes involved in regulation of cell growth and developmental processes. Specific restoration of CASZ1 in NB cells induced cell differentiation, enhanced cell adhesion, inhibited migration and suppressed tumorigenicity. These data are consistent with CASZ1 being a critical modulator of neural cell development, and that somatically acquired disruption of normal CASZ1 expression contributes to the malignant phenotype of human NB. PMID:21252912

Liu, Z; Yang, X; Li, Z; McMahon, C; Sizer, C; Barenboim-Stapleton, L; Bliskovsky, V; Mock, B; Ried, T; London, W B; Maris, J; Khan, J; Thiele, C J

2011-01-01

189

Ohio State study shows how normal cells can fuel tumor growth:  

Cancer.gov

A new study published in the journal Nature Cell Biology has discovered how normal cells in mouse tumors can fuel tumor growth. Led by researchers at the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, the study examines what happens when normal cells called fibroblasts in mouse mammary tumors lose an important tumor-suppressor gene called Pten.

190

Key Molecule Reprograms Microenvironment to Support Tumor Growth | Physical Sciences in Oncology  

Cancer.gov

A team of investigators from the Ohio State University Comprehensive Cancer Center has identified two key molecules that cause normal cells in the tissue surrounding a tumor, the stroma, to produce nutrients that fuel tumor growth. The results of this study, which were published in the journal Nature Cell Biology, demonstrate what happens when normal cells called fibroblasts in mouse mammary tumors lose an important tumor-suppressor gene called Pten.

191

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

PubMed

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6?mg/kg bodyweight of enalapril i.p., 20?mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs. PMID:25121552

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

2014-10-01

192

Sca1-positive murine pituitary adenoma cells show tumor growth advantage  

PubMed Central

The role of tumor stem cells in benign tumors such as pituitary adenomas remains unclear. We investigated whether cells within pituitary adenomas that spontaneously develop in Rb+/? mice are hierarchically distributed with a subset being responsible for tumor growth. Cells derived directly from such tumors grew as spheres in serum-free culture medium supplemented with EGF and bFGF. Some cells within growing pituitary tumor spheres (PTS) expressed common stem cell markers (Sca1, Sox2, Nestin, CD133), but were devoid of hormone-positive differentiated cells. Under subsequent differentiating conditions (matrigel-coated growth surface), PTS expressed all six pituitary hormones. We next searched for specific markers of the stem cell population and isolated a Sca1+ cell population that showed increased sphere formation potential, lower hormone mRNA expression, higher expression of stem cell markers (Notch1, Sox2, Nestin), and increased proliferation rates. When transplanted into NOD scid gamma mice brains, Sca1+ pituitary tumor cells exhibited higher rates of tumor formation (brain tumors observed in 11/11 [100%] vs. 7/12 [54%] of mice transplanted with Sca1+ and Sca1? cells, respectively). Magnetic resonance imaging and histological analysis of brain tumors showed that those derived from Sca1+ pituitary tumor cells were also larger and plurihormonal. Our findings show that Sca1+ cells derived from benign pituitary tumors exhibit an undifferentiated expression profile and tumor proliferative advantages, and we propose that they could represent putative pituitary tumor stem/progenitor cells. PMID:24481638

Donangelo, Ines; Ren, Song-Guang; Eigler, Tamar; Svendsen, Clive; Melmed, Shlomo

2014-01-01

193

Anaerobic exercise reduces tumor growth, cancer cachexia and increases macrophage and lymphocyte response in Walker 256 tumor-bearing rats  

Microsoft Academic Search

Here, we investigated the effect of jump exercise on tumor growth, cancer cachexia, lymphocyte proliferation and macrophage\\u000a function in Walker 256 tumor-bearing rats. Male Wistar rats (60 days) were divided into sedentary (C) and exercised (E) groups.\\u000a Jump training consisted of six sets of 10 jumps in water with overload of 50% of body mass with 1 min of resting, four times

Carina de Lima; Luciana E. Alves; Fabíola Iagher; Andressa Franzoi Machado; Sandro J. Bonatto; Diogo Kuczera; Carine Ferreira de Souza; Daniele Cristina Pequito; Ana Lúcia Muritiba; Everson Araújo Nunes; Luiz Cláudio Fernandes

2008-01-01

194

Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis.  

PubMed

Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice. Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelial-barrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis. PMID:24990940

Alhusban, Ahmed; Al-Azayzih, Ahmad; Goc, Anna; Gao, Fei; Fagan, Susan C; Somanath, Payaningal R

2014-09-01

195

[Double esophageal carcinosarcomas showing rapid growth of a new polypoid tumor after sloughing of another polypoid tumor].  

PubMed

A 55-year-old man presented at our hospital with a large polypoid esophageal tumor. Initial upper gastrointestinal endoscopy revealed that this tumor had sloughed off to be replaced with ulceration in the thoracic esophagus. However, after the tumor at the thoracic esophagus sloughed off, a semi-circular, superficial, flat squamous cell carcinoma was observed adjacent to the ulceration. In addition, a separate carcinosarcoma, 2cm in diameter, was found at the esophagogastric junction. Approximately one month later, endoscopic re-examination revealed a new polypoid tumor approximately 4cm in diameter that was growing rapidly in the center of the superficial thoracic esophageal carcinoma lesion. Standard subtotal esophagectomy was performed. Histopathological examination revealed that both lesions were esophageal carcinosarcomas. This is a rare case of double esophageal carcinosarcoma associated with rapid polypoid tumor growth from a superficial squamous cell carcinoma lesion. PMID:23912005

Yamashita, Yukimasa; Fukushima, Masashi; Sumitomo, Yasuhiko; Son, Yongi; Maruo, Masayuki; Itai, Ryosuke; Ono, Hiroshi; Kimura, Yoshito; Ikeda, Eiji; Takada, Mariko; Mikami, Sakae; Nishigami, Takayuki

2013-08-01

196

Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

PubMed Central

Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1?, IL-6, IL-8, and TNF-? level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PMID:23300633

Pratheeshkumar, Poyil; Son, Young-Ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-Chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

2012-01-01

197

Protein tyrosine phosphatase receptor type O expression in the tumor niche correlates with reduced tumor growth, angiogenesis, circulating tumor cells and metastasis of breast cancer.  

PubMed

Protein tyrosine phosphatase receptor type O (PTPRO) has been recognized as a tumor suppressor in various types of cancer cells. However, little attention has been given to the role of PTPRO expression in the tumor microenvironment. We aimed to reveal the role of PTPRO in the breast cancer niche. Py8119 mouse breast cancer cells were implanted orthotopically into female wild-type or ptpro-/- C57Bl/6 mice. We observed that the loss of PTPRO in the tumor niche was correlated with larger tumor volume, more metastases, increased number of circulating tumor cells (CTCs), less apoptosis and reduced necrosis rates in the orthotopic mouse model of breast cancer. The tumor microenvironment in the ptpro-/- mice also showed increased microvessel density. Moreover, an intracardiac injection mouse model was used to determine the role of PTPRO in the pre-metastatic niche. Notably, more metastases were observed in the mice of the ptpro-/- group. Taken together, PTPRO expression in the tumor niche prevents tumor growth and the formation of metastases of breast cancer, in part by attenuating tumor-associated angiogenesis and inducing the apoptosis and necrosis of tumor cells. PMID:25646811

Liu, Zhao; Hou, Jiajie; Ren, Lidong; He, Jing; Sun, Beicheng; Sun, Lu-Zhe; Wang, Shui

2015-04-01

198

Delayed soil thawing affects root and shoot functioning and growth in Scots pine.  

PubMed

In boreal regions, soil can remain frozen after the start of the growing season. We compared relationships between root characteristics and water relations in Scots pine (Pinus sylvestris L.) saplings subjected to soil frost treatments before and during the first week of the growing period in a controlled environment experiment. Delayed soil thawing delayed the onset of sap flow or totally blocked it if soil thawing lagged the start of the growing period by 7 days. This effect was reflected in the electrical impedance of needles and trunks and in the relative electrolyte leakage of needles. Prolonged soil frost reduced or completely inhibited root growth. In unfrozen soil, limited trunk sap flow was observed despite unfavorable aboveground growing conditions (low temperature, low irradiance, short photoperiod). Following the earliest soil thaw, sap flow varied during the growing season, depending on light and temperature conditions, phenological stage of the plant and the amount of live needles in the canopy. The results suggest that delayed soil thawing can reduce tree growth, and if prolonged, it can be lethal. PMID:18708340

Repo, Tapani; Lehto, Tarja; Finér, Leena

2008-10-01

199

Trichinella spiralis infection reduces tumor growth and metastasis of B16-F10 melanoma cells.  

PubMed

Recently, attempts have been made to use parasites as novel candidates for live vaccine vectors against solid tumors. In this study, we examined the effects of Trichinella spiralis (T. spiralis) infection on solid tumor growth and metastasis. After oral infection with T. spiralis larvae, B16-F10 cells were injected subcutaneously and intravenously into C57BL/6 mice to evaluate tumor growth and metastatic potential, respectively. Tumor growth and lung metastases in T. spiralis infected mice were significantly reduced compared with control mice. To elucidate the mechanism of tumor reduction by parasitic infection, we conducted cytokine arrays using mouse serum. CXCL9 and CXCL10 were increased in the infection group and decreased in the infection-tumor group. However, the expression level was not changed in the infection-metastasis group compared to the infection or control-metastasis groups. Although SDF-1 and IL-4 were increased in the infection group, there was no significant change in expression in the infection-tumor group or the infection-metastasis group. Additionally, IL-4 and KC were increased in the infection-tumor group compared to the control-tumor group, but there was no difference in expression between the control-metastasis group and the infection-metastasis group. CXCL13 was significantly increased in the infection-metastasis group only. These results suggest that T. spiralis infection reduced tumor growth and metastasis through a complex transition in cytokine regulation profiles including CXCL9, CXCL10, and CXCL13. PMID:23499484

Kang, Yun-Jeong; Jo, Jin-Ok; Cho, Min-Kyoung; Yu, Hak-Sun; Leem, Sun-Hee; Song, Kyoung Seob; Ock, Mee Sun; Cha, Hee-Jae

2013-09-01

200

A theoretical and empirical investigation of delayed growth response in the continuous culture of bacteria.  

PubMed

When the growth of bacteria in a chemostat is controlled by limiting the supply of a single essential nutrient, the growth rate is affected both by the concentration of this nutrient in the culture medium and by the amount of time that it takes for the chemical and physiological processes that result in the production of new biomass. Thus, although the uptake of nutrient by cells is an essentially instantaneous process, the addition of new biomass is delayed by the amount of time that it takes to metabolize the nutrient. Mathematical models that incorporate this "delayed growth response" (DGR) phenomenon have been developed and analysed. However, because they are formulated in terms of parameters that are difficult to measure directly, these models are of limited value to experimentalists. In this paper, we introduce a DGR model that is formulated in terms of measurable parameters. In addition, we provide for this model a complete set of criteria for determining persistence versus extinction of the bacterial culture in the chemostat. Specifically, we show that DGR plays a role in determining persistence versus extinction only under certain ranges of chemostat operating parameters. It is also shown, however, that DGR plays a role in determining the steady-state nutrient and bacteria concentrations in all instances of persistence. The steady state and transient behavior of solutions of our model is found to be in agreement with data that we obtained in growing Escherichia coli 23716 in a chemostat with glucose as a limiting nutrient. One of the theoretical predictions of our model that does not occur in other DGR models is that under certain conditions a large delay in growth response might actually have a positive effect on the bacteria's ability to persist. PMID:12781747

Ellermeyer, Sean; Hendrix, Jerald; Ghoochan, Nariman

2003-06-21

201

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma  

PubMed Central

Background Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach. Methods We studied in vitro cell models, cohorts of mice allografted with Nf2?/? Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2. Results We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest. Conclusions Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors. PMID:24414536

Giovannini, Marco; Bonne, Nicolas-Xavier; Vitte, Jeremie; Chareyre, Fabrice; Tanaka, Karo; Adams, Rocky; Fisher, Laurel M.; Valeyrie-Allanore, Laurence; Wolkenstein, Pierre; Goutagny, Stephane; Kalamarides, Michel

2014-01-01

202

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

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.

Iliakis, G.; Nusse, M.

1982-09-01

203

RPA Inhibition increases Replication Stress and Suppresses Tumor Growth  

PubMed Central

The ATR/Chk1 pathway is a critical surveillance network that maintains genomic integrity during DNA replication by stabilizing the replication forks during normal replication to avoid replication stress. One of the many differences between normal cells and cancer cells is the amount of replication stress that occurs during replication. Cancer cells with activated oncogenes generate increased levels of replication stress. This creates an increased dependency on the ATR/Chk1 pathway in cancer cells and opens up an opportunity to preferentially kill cancer cells by inhibiting this pathway. In support of this idea, we have identified a small molecule termed HAMNO ((1Z)-1-[(2-hydroxyanilino)methylidene]naphthalen-2-one), a novel protein interaction inhibitor of replication protein A (RPA), a protein involved in the ATR/Chk1 pathway. HAMNO selectively binds the N-terminal domain of RPA70, effectively inhibiting critical RPA protein interactions which rely on this domain. HAMNO inhibits both ATR autophosphorylation and phosphorylation of RPA32 Ser33 by ATR. By itself, HAMNO treatment creates DNA replication stress in cancer cells that are already experiencing replication stress, but not in normal cells, and it acts synergistically with etoposide to kill cancer cells in vitro and slow tumor growth in vivo. Thus, HAMNO illustrates how RPA inhibitors represent candidate therapeutics for cancer treatment, providing disease selectivity in cancer cells by targeting their differential response to replication stress. PMID:25070753

Glanzer, Jason G.; Liu, Shengqin; Wang, Ling; Mosel, Adam; Peng, Aimin; Oakley, Greg G.

2014-01-01

204

Changes in lipid metabolism during Walker 256 tumor growth and the therapeutic effect of hyperthermia.  

PubMed

The dynamics of lipoprotein content during Walker 256 tumor growth in rats was studied. Moderate changes in HDL and LDL were paralleled by significant changes in VLDL level. A 2-fold increase of VLDL in comparison with the intact control was recorded on day 10 of tumor growth. Exposure to total hyperthermia additionally stimulated VLDL synthesis and this parameter increased by 4 times and more in rats with tumors in comparison with controls. This effect of hyperthermia correlated with significant subsequent decrease of rat mortality caused by the lethal effect of the tumor. PMID:24824711

Efremov, A V; Khegai, I I; Molokov, K V; Pakhomova, Yu V

2014-04-01

205

Exploring Cancer with Gapminder: Modeling Tumor Growth with Excel - BioQUEST Summer Workshop  

NSDL National Science Digital Library

This session explores global health data from Gapminder and WHO. Participants will look at social, economic, and environmental development at local, national and global levels and interpret log transformations for graphical display. We will build a data driven phenomenological model of tumor growth with a minimal number of parameters in order to make predictions about tumor growth. By relating the volume of the tumor to time measured in days we will predict when a tumor started to grow and when it will reach a size that is lethal to the patient.

Claudia Neuhauser (University of Minnesota-Rochester; Health Sciences)

2010-06-18

206

Vaccination with OVA-bound nanoparticles encapsulating IL-7 inhibits the growth of OVA-expressing E.G7 tumor cells in vivo.  

PubMed

Immunotherapy has gained special attention due to its specific effects on tumor cells and systemic action to block metastasis. We recently demonstrated that ovalbumin (OVA) conjugated to the surface of nanoparticles (NPs) (OVA?NPs) can manipulate humoral immune responses. In the present study, we aimed to ascertain whether vaccination with OVA-NPs entrapping IL-7 (OVA-NPs-IL-7) are able to induce antitumor immune responses in vivo. Pretreatment with a subcutaneous inoculation of OVA-NPs delayed the growth of thymic lymphoma cells expressing a model tumor antigen OVA (E.G7-OVA), and OVA-NPs-IL-7 substantially blocked the growth of E.G7-OVA tumor cells, although NPs-IL-7 alone had a meager effect, as assessed by the mean tumor size and the percentage of tumor-free mice. However, pretreatment with OVA-NPs-IL-7 failed to reduce the growth of parental thymic tumor cells, suggesting that the antitumor effect was antigen-specific. A tetramer assay revealed that vaccination with OVA-NPs-IL-7 tended to enhance the proportion of cytotoxic T cells (CTLs) specific for OVA. When the tumor-free mice inoculated with OVA-NPs-IL-7 plus EG.7 cells were rechallenged with E.G7-OVA cells, they demonstrated reduced growth compared with that in the control mice. Thus, a single subcutaneous injection of OVA-NPs-IL-7 into mice induced tumor-specific and also memory-like immune responses, resulting in regression of tumor cells. Antigens on NPs entrapping IL-7 would be a promising carrier to develop and enhance immune responses, including humoral and cellular immunity as well as a method of drug delivery to a specific target of interest. PMID:25394516

Toyota, Hiroko; Yanase, Noriko; Yoshimoto, Takayuki; Harada, Mitsunori; Kato, Yasuki; Mizuguchi, Junichiro

2015-01-01

207

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

PubMed

Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity. PMID:22421704

Novosyadlyy, Ruslan; Leroith, Derek

2012-06-01

208

The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation  

PubMed Central

The occurrence of acute graft-versus-host disease (GVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid CDDO can inhibit murine early acute GVHD but anti-tumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from acute lethal GVHD compared to CDDO. This correlated with reduced TNF-? production, reduced donor T cell proliferation and decreased adhesion molecule (?4?7 integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying acute GVHD while preserving or possibly even augmenting GVT effects. PMID:20338256

Li, Minghui; Sun, Kai; Redelman, Doug; Welniak, Lisbeth A.; Murphy, William J.

2010-01-01

209

Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation  

PubMed Central

The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L+ DCs are found in primary breast tumor infiltrates. OX40L+ DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell–derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs. PMID:21339324

Pedroza-Gonzalez, Alexander; Xu, Kangling; Wu, Te-Chia; Aspord, Caroline; Tindle, Sasha; Marches, Florentina; Gallegos, Michael; Burton, Elizabeth C.; Savino, Daniel; Hori, Toshiyuki; Tanaka, Yuetsu; Zurawski, Sandra; Zurawski, Gerard; Bover, Laura; Liu, Yong-Jun; Banchereau, Jacques

2011-01-01

210

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

Question 2.7: Logistic growth of a tumor. Zobl et al. [1] have studied the growth functions be described by a logistic growth function, dN/dt = rN(1 - N/K), where r defines the initial growth rate, and K Tumorvolume Data Logistic growth N'=rN(1-[N/K] 5 ) 0 10 20 30 40 50 Time after virus inoculation (in days) 0

Utrecht, Universiteit

211

Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling  

SciTech Connect

Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and {beta}-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States)] [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Oakley, Gregory G.; Wahl, James K. [Department of Oral Biology, University of Nebraska College of Dentistry, Lincoln, NE 68588 (United States)] [Department of Oral Biology, University of Nebraska College of Dentistry, Lincoln, NE 68588 (United States); Simpson, Melanie A., E-mail: msimpson2@unl.edu [Department of Biochemistry, University of Nebraska, Lincoln, NE 68588 (United States); Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

2011-05-01

212

Effect of hyperthermia in combination with TRAIL on the JNK-Bim signal transduction pathway and growth of xenograft tumors  

PubMed Central

Approximately 25% of patients with colorectal cancer develop metastases to the liver, and surgery is currently the best treatment available. But there are several patients who are unresectable, and isolated hepatic perfusion (IHP) offers a different approach in helping to treat these patients. IHP is a method used for isolating the liver and delivering high doses of chemotherapeutic agents. The efficacy of IHP has been improved by combining hyperthermia not only with chemotherapeutics but with other deliverable agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we used human colorectal cancer CX-1 cells and treated them with hyperthermia and TRAIL, causing cytotoxicity. We were able to demonstrate that the numbers of live cells were significantly reduced with hyperthermia and 10 ng/ml of TRAIL combined. We also showed that the effect of hyperthermia on TRAIL in our studies was enhancement of the apoptotic pathway by the promotion of JNK and BimEL activity as well as PARP cleavage. We have also used our CX-1 cells to generate tumors in Balb/c nude mice. With intra-tumoral injections of TRAIL combined with hyperthermia at 42°C, we were able to show a delayed onset of tumor growth in our xenograft model. PMID:20544795

Alcala, Marco A.; Park, Kyungsoo; Yoo, Jinsang; Lee, Dae-Hee; Park, Bae-hang; Lee, Byeong-Chel; Bartlett, David L.; Lee, Yong J.

2010-01-01

213

Methionine Enkephalin (MENK) Inhibits tumor growth through regulating CD4+Foxp3+ Regulatory T cells (Tregs) in mice.  

PubMed

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

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

2015-03-01

214

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

E-print Network

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 ...

DuPage, Michel

215

Loss of stromal JUNB does not affect tumor growth and angiogenesis.  

PubMed

The transcription factor AP-1 subunit JUNB has been shown to play a pivotal role in angiogenesis. It positively controls angiogenesis by regulating Vegfa as well as the transcriptional regulator Cbfb and its target Mmp13. In line with these findings, it has been demonstrated that tumor cell-derived JUNB promotes tumor growth and angiogenesis. In contrast to JUNB's function in tumor cells, the role of host-derived stromal JUNB has not been elucidated so far. Here, we show that ablation of Junb in stromal cells including endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts does not affect tumor growth in two different syngeneic mouse models, the B16-F1 melanoma and the Lewis lung carcinoma model. In-depth analyses of the tumors revealed that tumor angiogenesis remains unaffected as assessed by measurements of the microvascular density and relative blood volume in the tumor. Furthermore, we could show that the maturation status of the tumor vasculature, analyzed by the SMC marker expression, ?-smooth muscle actin and Desmin, as well as the attachment of pericytes to the endothelium, is not changed upon ablation of Junb. Taken together, these results indicate that the pro-angiogenic functions of stromal JUNB are well compensated with regard to tumor angiogenesis and tumor growth. PMID:24027048

Braun, Jennifer; Strittmatter, Karin; Nübel, Tobias; Komljenovic, Dorde; Sator-Schmitt, Melanie; Bäuerle, Tobias; Angel, Peter; Schorpp-Kistner, Marina

2014-03-15

216

Salmonella typhimurium engineered to produce CCL21 inhibit tumor growth  

Microsoft Academic Search

Intravenously-applied bacteria tend to accumulate in tumors and can sporadically lead to tumor regression. Systemic administration\\u000a of attenuated Salmonella typhimurium is safe and has shown no significant adverse effects in humans. The purpose of this study was to test the hypothesis that\\u000a engineering S. typhimurium to express a chemokine, CCL21, would increase anti-tumor activity. We engineered an attenuated strain of

Markus Loeffler; Gaelle Le’Negrate; Maryla Krajewska; John C. Reed

2009-01-01

217

Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth  

Microsoft Academic Search

Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb+\\/ mice. Pttg\\/ pituitary glands exhibit ARF\\/p53\\/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary

Vera Chesnokova; Svetlana Zonis; Tami Rubinek; Kalman Kovacs; Kolja Wawrowsky; Shlomo Melmed

2007-01-01

218

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

NASA Astrophysics Data System (ADS)

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.

Donatelli, Donatella; Trivisa, Konstantina

2014-07-01

219

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

PubMed Central

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

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

2013-01-01

220

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

Microsoft Academic Search

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

Jill M. Manske; Summer E. Hanson

2005-01-01

221

Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL.  

PubMed

Many of the current antitumor therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Antimitotic drugs trigger mitotic checkpoint activation, mitotic arrest and eventually cell death. However, mitotic slippage represents a major mechanism of resistance to these treatments. In an attempt to circumvent the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. In this study, we show that treatments that induce mitotic checkpoint activation and mitotic arrest downregulate FLICE-like inhibitory protein (FLIP) levels and sensitize several tumor cell lines to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. Interestingly, we also demonstrate that in absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or overexpression of nondegradable cyclin B is sufficient to induce both FLIP downregulation and sensitivity to TRAIL. In summary, our data suggest that a combination of antimitotic drugs targeting cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, thereby facilitating tumor suppression. PMID:24488010

Sánchez-Pérez, T; Medema, R H; López-Rivas, A

2015-01-29

222

Antigen-processing machinery breakdown and tumor growth  

Microsoft Academic Search

Defects in the major histocompatibility complex (MHC) class I antigen-processing machinery (APM) have been described in tumors of different histology. Murine data suggest that defects in the MHC class II APM might also be associated with malignant transformation of human cells. This article describes the pathophysiology of the MHC class I and II APM, reviews APM abnormalities in tumor cells

Barbara Seliger; Markus J Maeurer; Soldano Ferrone

2000-01-01

223

Estrogen receptor ? polymorphism in boys with constitutional delay of growth and puberty  

PubMed Central

Purpose There were a lot of reports regarding associations of polymorphisms in the estrogen receptor ? (ESR1). with many disorders. But, those with constitutional delay of growth and puberty (CDGP) are not known. Our aim is to find out any association between CDGP and ESR1. Methods In a total of 27 subjects, we compared 7 CDGP patients with 20 healthy controls with their heights and sexual maturity rates were within normal range. We selected three single nucleotide polymorphisms from intron 1 of ESR1 (rs3778609, rs12665044, and rs827421) as candidates, respectively. Results In genotype analyses, the frequency of G/G genotype at rs827421 in intron 1 of ESR1 was increased in CDGP boys (P=0.03). Conclusion The genetic variation of ESR1 can be a contributing factor of tempo of growth and puberty. PMID:24904855

Kang, Byung Ho; Kim, So Youn; Park, Mun Suk; Yoon, Kyung Lim

2013-01-01

224

Mass General study identifies growth factor essential to the most common malignant pediatric brain tumor  

Cancer.gov

A multi-institutional team led by Massachusetts General Hospital researchers has identified a molecular pathway that appears to be essential for the growth and spread of medulloblastoma, the most common malignant brain tumor in children.

225

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

E-print Network

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 ...

Martin, John D.

226

Polysialic Acid Directs Tumor Cell Growth by Controlling Heterophilic Neural Cell Adhesion Molecule Interactions  

Microsoft Academic Search

Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), pro- motes neural plasticity and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression profiles were initiated by

Ralph Seidenfaden; Andrea Krauter; Frank Schertzinger; Rita Gerardy-Schahn; H. Hildebrandt

2003-01-01

227

Formal asymptotic limit of a diffuse-interface tumor-growth  

E-print Network

Eindhoven, Multiscale Engineering Fluid Dynamics, Gem-Z 3.136, PO Box 513, 5600 MB Eindhoven, Netherlands (k.g.v is referred to as avas- cular growth, as the tumor has not yet acquired its own blood supply to nurture itself) and has a natural four- constituent interpretation: a tumorous phase u 1, a healthy cell phase u -1

Paris-Sud XI, Université de

228

Pitt team finds protein that keeps balance between tumor cell growth and suppression  

Cancer.gov

Using an approach that combines molecular biology, genetics, cell biology and physiology, and pathology, researchers at the University of Pittsburgh Cancer Institute (UPCI) and the University of Pittsburgh School of Medicine have identified a protein that governs a key molecule involved in orchestrating the balance between tumor growth and tumor suppression.

229

Mast Cells in Tumor Growth: Angiogenesis, Tissue Remodeling and Immune-modulation  

PubMed Central

Summary There is a growing acceptance that tumor-infiltrating myeloid cells play an active role in tumor growth and mast cells are one of the earliest cell types to infiltrate developing tumors. Mast cells accumulate at the boundary between healthy tissues and malignancies and are often found in close association with blood vessels within the tumor microenvironment. They express many pro-angiogenic compounds, and may play an early role in angiogenesis within developing tumors. Mast cells also remodel extracellular matrix during wound healing, and this function is subverted in tumor growth, promoting tumor spread and metastasis. In addition, mast cells modulate immune responses by dampening immune rejection or directing immune cell recruitment, depending on local stimuli. In this review, we focus on key roles for mast cells in angiogenesis, tissue remodeling and immune modulation and highlight recent findings on the integral role that mast cells play in tumor growth. New findings suggest that mast cells may serve as a novel therapeutic target for cancer treatment and that inhibiting mast cell function may lead to tumor regression. PMID:19233249

Maltby, Steven; Khazaie, Khashayarsha; McNagny, Kelly M.

2009-01-01

230

The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C.  

PubMed

In clear-cell renal cell carcinoma (ccRCC), inactivation of the tumor suppressor von Hippel-Lindau (VHL) occurs in the majority of the tumors and is causal for the pathogenesis of ccRCC. Recently, a large-scale genomic sequencing study of ccRCC tumors revealed that enzymes that regulate histone H3 lysine 4 trimethylation (H3K4Me3), such as JARID1C/KDM5C/SMCX and MLL2, were mutated in ccRCC tumors, suggesting that H3K4Me3 might have an important role in regulating gene expression and tumorigenesis. In this study we report that in VHL-deficient ccRCC cells, the overall H3K4Me3 levels were significantly lower than that of VHL+/+ counterparts. Furthermore, this was hypoxia-inducible factor (HIF) dependent, as depletion of HIF subunits by small hairpin RNA in VHL-deficient ccRCC cells restored H3K4Me3 levels. In addition, we demonstrated that only loss of JARID1C, not JARID1A or JARID1B, abolished the difference of H3K4Me3 levels between VHL-/- and VHL+/+ cells, and JARID1C displayed HIF-dependent expression pattern. JARID1C in VHL-/- cells was responsible for the suppression of HIF-responsive genes insulin-like growth factor-binding protein 3 (IGFBP3), DNAJC12, COL6A1, growth and differentiation factor 15 (GDF15) and density-enhanced phosphatase 1. Consistent with these findings, the H3K4Me3 levels at the promoters of IGFBP3, DNAJC12, COL6A1 and GDF15 were lower in VHL-/- cells than in VHL+/+ cells, and the differences disappeared after JARID1C depletion. Although HIF2? is an oncogene in ccRCC, some of its targets might have tumor suppressive activity. Consistent with this, knockdown of JARID1C in 786-O VHL-/- ccRCC cells significantly enhanced tumor growth in a xenograft model, suggesting that JARID1C is tumor suppressive and its mutations are tumor promoting in ccRCC. Thus, VHL inactivation decreases H3K4Me3 levels through JARID1C, which alters gene expression and suppresses tumor growth. PMID:21725364

Niu, X; Zhang, T; Liao, L; Zhou, L; Lindner, D J; Zhou, M; Rini, B; Yan, Q; Yang, H

2012-02-01

231

[The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis].  

PubMed

Extracellular matrix metalloproteinases (MMPs) are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs) are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN). MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs) and endothelial cells (ECs). MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT). MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM.  PMID:23001203

Fink, Krzysztof; Boraty?ski, Janusz

2012-01-01

232

Platelet-Derived Growth Factor-BB Controls Epithelial Tumor Phenotype by Differential Growth Factor Regulation in Stromal Cells  

PubMed Central

Platelet-derived growth factor (PDGF) stimulates tumor growth and progression by affecting tumor and stromal cells. In the HaCaT skin carcinogenesis model, transfection of immortal nontumorigenic and PDGF-receptor-negative HaCaT keratinocytes with PDGF-B induced formation of benign tumors. Here, we present potential mechanisms underlying this tumorigenic conversion. In vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation. In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation. Accordingly, in HaCaT/PDGF-B transplants, initially enhanced VEGF expression by stromal fibroblasts was subsequently reduced, followed by down-regulation of angiogenesis, myofibroblast accumulation, and vessel maturation. The PDGF-induced, persistently increased expression of the hepatocyte growth factor by fibroblasts in vitro and in vivo was most probably responsible for enhanced epithelial cell proliferation and benign tumor formation. Thus, by paracrine stimulation of the stroma, PDGF-BB induced epithelial hyperproliferation, thereby promoting tumorigenicity, whereas the time-limited activation of the stroma followed by stromal maturation provides a possible explanation for the benign tumor phenotype. PMID:17071599

Lederle, Wiltrud; Stark, Hans-Jürgen; Skobe, Mihaela; Fusenig, Norbert E.; Mueller, Margareta M.

2006-01-01

233

A proposed simulation system for modeling cell growth and assessing the effect of drug treatment on tumors  

Microsoft Academic Search

The use of simulation techniques to develop schedules for chemotherapy of solid tumors is discussed. In recent years the Gompertz model has been verified as an accurate model of tumor cell growth. Interest in describing the growth of cell systems has resulted in the development of generalized cell growth simulation systems, enabling models of cell growth, cell kills and reaction

V. K. Ghanta; C. D. Atnip; M. White; R. N. Hiramoto

1976-01-01

234

Ethanol Promotes Mammary Tumor Growth and Angiogenesis: the Involvement of Chemoattractant Factor MCP-1  

PubMed Central

Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors. However, the underlying cellular and molecular mechanisms remain unclear. Alcohol induces a pro-inflammatory response by modulating the expression of cytokines and chemokines. Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine (C-C motif) ligand 2 (CCL2), is a pro-inflammatory chemokine implicated in breast cancer development/malignancy. We investigated the role of MCP-1 in alcohol-promoted mammary tumor progression. Using a xenograft model, we demonstrated that alcohol increased tumor angiogenesis and promoted growth/metastasis of breast cancer cells in C57BL/6 mice. Alcohol up-regulated the expression of MCP-1 and its receptor CCR2 in breast cancer cells in vitro and in vivo. Using a three-dimensional (3-D) tumor/endothelial cell co-culture system, we demonstrated MCP-1 regulated tumor/endothelial cell interaction and promoted tumor angiogenesis. More importantly, MCP-1 mediated alcohol-promoted angiogenesis; an antagonist of the MCP-1 receptor CCR2 significantly inhibited alcohol-stimulated tumor angiogenesis. The CCR2 antagonist abolished ethanol-stimulated growth of mammary tumors in mice. We further demonstrated that MCP-1 enhanced the migration, but not the proliferation of endothelial cells as well as breast cancer cells. These results suggest that MCP-1 plays an important role in ethanol-stimulated tumor angiogenesis and tumor progression. PMID:22160640

Wang, Siying; Xu, Mei; Li, Feifei; Wang, Xin; Bower, Kimberly A.; Frank, Jacqueline A.; Lu, Yanmin; Chen, Gang; Zhang, Zhuo; Ke, Zunji; Shi, Xianglin; Luo, Jia

2011-01-01

235

Protein Arginine Methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor Programmed Cell Death 4  

PubMed Central

Programmed Cell Death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify Protein Arginine Methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that co-expression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy. PMID:21700716

Powers, Matthew A.; Fay, Marta M.; Factor, Rachel E.; Welm, Alana L.; Ullman, Katharine S.

2011-01-01

236

Antisense oligonucleotides directed against insulin-like growth factor-II messenger ribonucleic acids delay the progress of rat hepatocarcinogenesis  

PubMed Central

Background: Hepatocellular carcinoma (HCC) is a multistep complex process, caused by many of genetic alteration. Insulin-like growth factors and their receptor have been widely implicated to HCC. Insulin-like growth factor-II (IGF-II) is a mitogenic polypeptide, found in various fetal and neonatal tissues of humans and rats and expresses in HCC. Here we investigated anticancer potential of phosphorothioate antisense oligonucleotides (ASOs) against three coding exons (exon-1/exon-2/exon-3) of IGF-II messenger ribonucleic acid in rat hepatocarcinogenesis model. Materials and Methods: During diethylnitrosamine and 2-acetylaminofluorene induced hepatocarcinogenesis, rats were treated with ASOs. Various biochemical and histological studies were conducted. Results: About 40% of carcinogen treated rats, which received two oligomers (against exon-1 or-3) did not show any hepatic lesion, hyperplastic nodule or tumor and remaining 60% of those rats showed lesion incidence and had about 59% and 55% reductions in the numbers of hepatic altered foci, respectively. Reductions in the total lesion-area when compared with carcinogen control rats were 64% and 53%, respectively for the animals treated with carcinogen and received the ASOs against exon-1/-3. Fluorescein isothiocyanate-labeled ASO reached in the hepatocytes in 2 h. No predominant IGF-II overexpression was observed in case of rats treated with the two ASOs. Treatment of the antisense IGF-II oligomers in carcinogen treated rats show better hepatocellular integrity along with several preneoplastic/neoplastic marker isoenzyme/enzyme modulations. Conclusions: Two of the three antisense oligomer-types effectively controlled IGF-II overexpression, causing the delay of the development and/or progress of hepatic cancer in rats. PMID:24737950

Ghosh, Miltu Kumar; Patra, Falguni; Ghosh, Shampa; Hossain, Chowdhury Mobaswar; Mukherjee, Biswajit

2014-01-01

237

Growth Hormone-Releasing Factor from a Human Pancreatic Tumor that Caused Acromegaly  

Microsoft Academic Search

A 44 amino acid peptide with growth hormone-releasing activity has been isolated from a human tumor of the pancreas that had caused acromegaly. The primary structure of the tumor-derived peptide is H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn- Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2. The synthetic replicate has full biological activity in vitro and in vivo specifically to stimulate the secretion of immunoreactive growth hormone. The tumor-derived peptide is identical

Roger Guillemin; Paul Brazeau; Peter Bohlen; Frederick Esch; Nicholas Ling; William B. Wehrenberg

1982-01-01

238

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

PubMed

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

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

2013-04-01

239

Computational Modeling of 3D Tumor Growth and Angiogenesis for Chemotherapy Evaluation  

PubMed Central

Solid tumors develop abnormally at spatial and temporal scales, giving rise to biophysical barriers that impact anti-tumor chemotherapy. This may increase the expenditure and time for conventional drug pharmacokinetic and pharmacodynamic studies. In order to facilitate drug discovery, we propose a mathematical model that couples three-dimensional tumor growth and angiogenesis to simulate tumor progression for chemotherapy evaluation. This application-oriented model incorporates complex dynamical processes including cell- and vascular-mediated interstitial pressure, mass transport, angiogenesis, cell proliferation, and vessel maturation to model tumor progression through multiple stages including tumor initiation, avascular growth, and transition from avascular to vascular growth. Compared to pure mechanistic models, the proposed empirical methods are not only easy to conduct but can provide realistic predictions and calculations. A series of computational simulations were conducted to demonstrate the advantages of the proposed comprehensive model. The computational simulation results suggest that solid tumor geometry is related to the interstitial pressure, such that tumors with high interstitial pressure are more likely to develop dendritic structures than those with low interstitial pressure. PMID:24404145

Tang, Lei; van de Ven, Anne L.; Guo, Dongmin; Andasari, Vivi; Cristini, Vittorio; Li, King C.; Zhou, Xiaobo

2014-01-01

240

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

PubMed

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

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

2012-01-01

241

A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member APRIL, Inhibits Tumor Cell Growth  

Microsoft Academic Search

A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregu- lated in many tumors including colon and prostate carcinomas. Here we identify B cell matura- tion antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI),

Paul Rennert; Pascal Schneider; Teresa G. Cachero; Jeffrey Thompson; Luciana Trabach; Sylvie Hertig; Nils Holler; Fang Qian; Colleen Mullen; Kathy Strauch; Jeffrey L. Browning; Christine Ambrose; Jürg Tschopp

242

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

NASA Astrophysics Data System (ADS)

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.

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

243

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

PubMed

The objective of this study is to observe the adult growth hormone level in postoperative pituitary tumor patients of multi-centers, and explore the change of hypophyseal hormones in postoperative pituitary tumor patients. Sixty patients with pituitary tumor admitted during March, 2011-March, 2012 were selected. Postoperative hypophyseal hormone deficiency and the change of preoperative, intraoperative, and postoperative growth hormone levels were recorded. Growth hormone hypofunction was the most common hormonal hypofunction, which took up to 85.0 %. Adrenocortical hormone hypofunction was next to it and accounted for 58.33 %. GH + ACTH + TSH + Gn deficiency was the most common in postoperative hormone deficiency, which took up to 40.00 %, and GH + ACTH + TSH + Gn + AVP and GH deficiencies were next to it and accounted for 23.33 and 16.67 %, respectively. The hormone levels in patients after total pituitary tumor resection were significantly lower than those after partial pituitary tumor resection, and the difference was statistically significant; growth hormone and serum prolactin levels after surgery in two groups were decreased, and the difference was statistically significant. The incidence rate of growth hormone deficiency in postoperative pituitary tumor patients is high, which is usually complicated with deficiency of various hypophyseal hormones. In clinical, we should pay attention to the levels of the hypopnyseal hormones, and take timely measures to avoid postoperative complications. PMID:25403160

Cheng, Jing-Min; Gu, Jian-Wen; Kuang, Yong-Qin; Ma, Yuan; Xia, Xun; Yang, Tao; Lu, Min; He, Wei-Qi; Sun, Zhi-Yong; Zhang, Yan-Chao

2015-03-01

244

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

PubMed

Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-?B pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1? release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance. PMID:25429070

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

2015-01-01

245

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

PubMed Central

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

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

246

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

PubMed Central

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

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

247

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.  

PubMed

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

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

248

Some mathematical aspects of tumor growth and therapy Beno^it Perthame  

E-print Network

and secondly, models of resistance to therapy and cell adaptation again using asymptotic analysis. Key wordsSome mathematical aspects of tumor growth and therapy Beno^it Perthame§ September 1, 2014 Abstract to understand the biological and mechanical effects that are involved in the tissue growth, the optimal therapy

249

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

Microsoft Academic Search

BACKGROUND: Electrotherapy effectiveness at different doses has been demonstrated in preclinical and clinical studies; however, several aspects that occur in the tumor growth kinetics before and after treatment have not yet been revealed. Mathematical modeling is a useful instrument that can reveal some of these aspects. The aim of this paper is to describe the complete growth kinetics of unperturbed

Luis E Bergues Cabrales; J Godina Juan Nava; Andrés Ramírez Aguilera; Javier A González Joa; Héctor M Camué Ciria; Maraelys Morales González; Miriam Fariñas Salas; Manuel Verdecia Jarque; Tamara Rubio González; Miguel A O'Farril Mateus; Soraida C Acosta Brooks; Fabiola Suárez Palencia; Lisset Ortiz Zamora; María Quevedo; Sarah Edward Seringe; Vladimir Crombet Cuitié; Idelisa Bergues Cabrales; Gustavo Sierra González

2010-01-01

250

Delayed Complications after Anterior Craniofacial Resection of Malignant Skull Base Tumors  

PubMed Central

Objective?To report complications occurring at least 6 months after completion of treatment for patients with anterior skull base malignancy undergoing anterior craniofacial resection (CFR). Design?Retrospective review of medical records of all patients undergoing traditional CFR for treatment of anterior skull base malignancy from 2002 through 2011. Setting?Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary Cranial Base Center. Participants?Thirty-one consecutive patients who had at least 18 months of follow-up for analysis were reviewed. All patients underwent traditional CFR. A total of 28 patients received postoperative proton beam radiation therapy. Eleven patients received adjuvant chemotherapy. Main Outcome Measures?A delayed complication was any complication occurring at least 6 months after the completion of treatment. Results?Seventeen patients had delayed complications. Orbital complications were the most common type (13 patients) followed by issues with wound healing (6 patients). The most common orbital complication was epiphora (7 patients). The most common wound complication was a nasocutaneous fistula (5 patients). Conclusions?Patients with anterior skull malignancy can develop complications months to years after the completion of treatment. Therefore, it is important to continue to follow and report complications for several years when deciding on the optimal approach for treatment of these patients. PMID:24719797

Gray, Stacey T.; Lin, Alice; Curry, William T.; Barker, Fred G.; Busse, Paul; Sanan, Akshay; Deschler, Daniel G.; Lin, Derrick T.

2013-01-01

251

Delayed complications after anterior craniofacial resection of malignant skull base tumors.  

PubMed

Objective?To report complications occurring at least 6 months after completion of treatment for patients with anterior skull base malignancy undergoing anterior craniofacial resection (CFR). Design?Retrospective review of medical records of all patients undergoing traditional CFR for treatment of anterior skull base malignancy from 2002 through 2011. Setting?Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary Cranial Base Center. Participants?Thirty-one consecutive patients who had at least 18 months of follow-up for analysis were reviewed. All patients underwent traditional CFR. A total of 28 patients received postoperative proton beam radiation therapy. Eleven patients received adjuvant chemotherapy. Main Outcome Measures?A delayed complication was any complication occurring at least 6 months after the completion of treatment. Results?Seventeen patients had delayed complications. Orbital complications were the most common type (13 patients) followed by issues with wound healing (6 patients). The most common orbital complication was epiphora (7 patients). The most common wound complication was a nasocutaneous fistula (5 patients). Conclusions?Patients with anterior skull malignancy can develop complications months to years after the completion of treatment. Therefore, it is important to continue to follow and report complications for several years when deciding on the optimal approach for treatment of these patients. PMID:24719797

Gray, Stacey T; Lin, Alice; Curry, William T; Barker, Fred G; Busse, Paul; Sanan, Akshay; Deschler, Daniel G; Lin, Derrick T

2014-04-01

252

Interleukin10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth  

Microsoft Academic Search

BACKGROUND: Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like,

Aline Bolpetti; João S Silva; Luisa L Villa; Ana Paula Lepique

2010-01-01

253

Effects of photodynamic hyperthermal therapy with indocyanine green on tumor growth in a colon 26 tumor-bearing mouse model  

PubMed Central

The present study used indocyanine green (ICG) and a broadband light source apparatus [photodynamic hyperthermal therapy (PHT) group] in order to treat a colon 26 tumor-bearing mouse model. The other groups were administered either ICG alone (ICG group), light alone (light group) or no treatment (control group). Following the treatment, tumor growth was measured. Nine days after the treatment, the tumors were resected and histological and immunohistological examinations were performed. In the PHT group, the growth rates of the tumor tissues were significantly decreased compared with those observed in the other groups (P<0.05). The proportion of necrotic areas in the PHT and light groups were increased significantly compared with those observed in the ICG and control groups. However, there were no significant differences between the PHT and light groups. The proportion of Ki-67 in the PHT and light groups was less than that observed in the ICG and control groups. The number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in the PHT group was significantly increased compared with that observed in the other groups. These data indicate that PHT is effective in vivo and in vitro. PMID:24944683

ONOYAMA, MASAKI; AZUMA, KAZUO; TSUKA, TAKESHI; IMAGAWA, TOMOHIRO; OSAKI, TOMOHIRO; MINAMI, SABURO; OGAWA, NOBUHIKO; OKAMOTO, YOSHIHARU

2014-01-01

254

Basic fibroblast growth factor for treatment of onychomadesis with delayed regrowth of the nail.  

PubMed

Onychomadesis usually arises from an inflammation of the paronychium or as a result of blisters and hemorrhaging under a nail that has been struck or compressed. No documented interactions between basic fibroblast growth factor (bFGF) and onychomadesis have hitherto been reported. This case report describes a 25-year-old woman with onychomadesis following infection of the ingrown nail of her left thumb. After ten months of observation with no treatment showed no regrowth of her left thumbnail, the external use of bFGF and antibiotic ointment was started. One month later, nail regrowth was observed up to the halfway point of the nail bed, and after treatment for three months, the regrown nail reached the top of the nail bed. Both thumbnails now looked identical. This case suggests that external use of bFGF can promote nail regrowth in cases of onychomadesis with delayed regrowth of the nail. PMID:23864965

Oji, Tomito; Yazawa, Masaki; Kishi, Kazuo

2013-01-01

255

Basic Fibroblast Growth Factor for Treatment of Onychomadesis with Delayed Regrowth of the Nail  

PubMed Central

Onychomadesis usually arises from an inflammation of the paronychium or as a result of blisters and hemorrhaging under a nail that has been struck or compressed. No documented interactions between basic fibroblast growth factor (bFGF) and onychomadesis have hitherto been reported. This case report describes a 25-year-old woman with onychomadesis following infection of the ingrown nail of her left thumb. After ten months of observation with no treatment showed no regrowth of her left thumbnail, the external use of bFGF and antibiotic ointment was started. One month later, nail regrowth was observed up to the halfway point of the nail bed, and after treatment for three months, the regrown nail reached the top of the nail bed. Both thumbnails now looked identical. This case suggests that external use of bFGF can promote nail regrowth in cases of onychomadesis with delayed regrowth of the nail. PMID:23864965

Oji, Tomito; Yazawa, Masaki; Kishi, Kazuo

2013-01-01

256

Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats.  

PubMed

In this study we have examined whether the slower rate of CNS remyelination that occurs with age is associated with a change in growth factor expression patterns, an association that would provide further support for a causal relationship between growth factors and remyelination. Using quantitative in situ hybridization we have shown that there are differences in IGF-I, TGF-beta 1, and PDGF-A mRNA expression during remyelination of lysolecithin-induced demyelination in the spinal cord of young adult and old adult rats. IGF-I and TGF-beta1 mRNA expression in old rats had a delayed and lower peak expression compared to young rats. The initial increase in PDGF-A mRNA expression was delayed in old rats compared to young rats, but after 5 days both age groups had similar patterns of expression, as was the expression pattern of FGF-2 mRNA at all survival times. In neither age group were increases in CNTF, NT-3, or GGF-2 mRNA expression detected. An analysis of the macrophage response using oligonucleotide probes for scavenger receptor-B mRNA indicated that differences in the macrophage response in young and old animals was the likely cause of the age related change in IGF-I and TGF-beta 1 mRNA expression patterns. On the basis of these data we suggest a model of remyelination in which PDGF is involved in the initial phase of oligodendrocyte progenitor recruitment, while IGF-I and TGF-beta 1 trigger the differentiation of the recruited cells into myelinating oligodendrocytes. PMID:11083917

Hinks, G L; Franklin, R J

2000-11-01

257

Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy  

PubMed Central

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

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

258

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

PubMed

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

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

2014-04-01

259

Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies  

PubMed Central

Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches toward cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that although experimental tumor growth is enhanced by low levels of circulating antibodies directed against the nonhuman sialic acid N-glycolyl-neuraminic acid (Neu5Gc), which accumulates in human tumors, growth could be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. However, it remains generally unclear whether the immune responses that mediate cancer immunosurveillance vs. those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens, such as Neu5Gc, can alter tumor progression. We found that although growth was stimulated at low antibody doses, it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC; i.e., inverse hormesis). Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance vs. inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. Similar findings were made in a human tumor xenograft model using a narrow range of doses of a monoclonal antibody currently in clinical use. These findings may have implications for the etiology, prevention, and treatment of cancer. PMID:24711415

Pearce, Oliver M. T.; Läubli, Heinz; Verhagen, Andrea; Secrest, Patrick; Zhang, Jiquan; Varki, Nissi M.; Crocker, Paul R.; Bui, Jack D.; Varki, Ajit

2014-01-01

260

Non-invasive optical imaging of tumor growth in intact animals  

NASA Astrophysics Data System (ADS)

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

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

2003-12-01

261

Characterization of tumors produced by signal peptide-basic fibroblast growth factor-transformed cells.  

PubMed

Basic fibroblast growth factor (bFGF) is found in a variety of cells and tissues. We have previously shown that bFGF is a transforming growth factor, but only when fused to a signal peptide (sp-bFGF). Cells expressing the native bFGF are tumorigenic in nude mice only, where the tumors form at a low frequency and grow very slowly as compared to sp-bFGF tumors. The cells transformed by the sp-bFGF growth factor gene cause rapidly growing tumors within 10 days in 100% of syngeneic and nude mice. In nude mice, the tumors are highly vascularized, while the vascularization in immunocompetent syngeneic mice is not as prominent. The syngeneic mice have a characteristic humoral immune response to sp-bFGF tumors, which differs from that mounted against ras-induced tumors. The ability of bFGF to induce tumorigenicity is significant in view of the recent discoveries of three new oncogenes: hst, int-2, and an oncogene from a human colon cancer. In addition to homology with FGF, the proteins encoded by these oncogenes all have a potential signal peptide at the protein's amino terminus, suggesting a mode of action analogous to that of our artificial signal peptide-bFGF (sp-bFGF) transforming growth factor model system. PMID:2469690

Rogelj, S; Weinberg, R A; Fanning, P; Klagsbrun, M

1989-01-01

262

Surface-Modified HK:siRNA Nanoplexes with Enhanced Pharmacokinetics and Tumor Growth Inhibition  

PubMed Central

We characterized in this study the pharmacokinetics and antitumor efficacy of histidine-lysine (HK):siRNA nanoplexes modified with PEG and a cyclic RGD (cRGD) ligand targeting ?v?3 and ?v?5 integrins. With noninvasive imaging, systemically administered surface-modified HK:siRNA nanoplexes showed nearly 4-fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HK:siRNA nanoplexes. We then determined whether the surface-modified HK:siRNA nanoplex carrier was more effective in reducing MDA-MB-435 tumor growth with an siRNA targeting Raf-1. Repeated systemic administration of the selected surface modified HK:siRNA nanoplexes targeting Raf-1 showed 35% greater inhibition of tumor growth than unmodified HK:siRNA nanoplexes and 60% greater inhibition of tumor growth than untreated mice. The improved blood pharmacokinetic results and tumor localization observed with the integrin-targeting surface modification of HK:siRNA nanoplexes correlated with greater tumor growth inhibition. This investigation reveals that through control of targeting ligand surface display in association with a steric PEG layer, modified HK: siRNA nanoplexes show promise to advance RNAi therapeutics in oncology and potentially other critical diseases. PMID:23360232

2013-01-01

263

Heparin Affinity: Purification of a Tumor-Derived Capillary Endothelial Cell Growth Factor  

Microsoft Academic Search

A tumor-derived growth factor that stimulates the proliferation of capillary endothelial cells has a very strong affinity for heparin. This heparin affinity makes it possible to purify the growth factor to a single-band preparation in a rapid two-step procedure. The purified growth factor is a cationic polypeptide, has a molecular weight of about 18,000, and stimulates capillary endothelial cell proliferation

Y. Shing; J. Folkman; R. Sullivan; C. Butterfield; M. Klagsbrun

1984-01-01

264

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

PubMed Central

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

2014-01-01

265

Radiotherapy planning for glioblastoma based on a tumor growth model  

E-print Network

, the benefit of radiotherapy to prolong survival is undoubted [1, 2, 3]. Conse- quently, we hypothesize common primary brain tumors. For glioblastoma, the most ag- gressive form, median survival is a little radiotherapy, and chemotherapy. The clinical experience suggests that improvements in radiotherapy alone

Paris-Sud XI, Université de

266

Adenosine A2B receptor blockade slows growth of bladder and breast tumors1  

PubMed Central

The accumulation of high levels of adenosine in tumors activates A2A and A2B receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of A2AARs has been reported to activate anti-tumor T cells, stimulates DC function and inhibits angiogenesis. Here we evaluated the effects of intermittent intratumor injection of a non-selective adenosine receptor antagonist, aminophylline (AMO, theophylline ethylenediamine) and, for the first time, a selective A2BAR antagonist, ATL801. AMO and ATL801 slowed the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice, and reduced by 85% metastasizes of breast cancer cells from mammary fat to lung. Based on experiments with A2AAR?/? or A2BAR?/? mice, the effect of AMO injection was unexpectedly attributed to A2BAR and not to A2AAR blockade. AMO and ATL801 significantly increased tumor levels of IFN? and the interferon-inducible chemokine CXCL10, which is a ligand for CXCR3. This was associated with an increase in activated tumor-infiltrating CXCR3+ T cells and a decrease in endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3?/? mice and in RAG1?/? mice that lack mature T cells. In RAG1?/? mice A2BAR deletion enhanced CD86 expression on CD11b- DCs. Bone marrow chimera experiments demonstrated that CXCR3 and A2BAR expression on bone marrow cells are required for the anti-tumor effects of AMO. The data suggest that blockade of A2BARs enhances DC activation and CXCR3-dependent anti-tumor responses. PMID:22116822

Cekic, Caglar; Sag, Duygu; Li, Yuesheng; Theodorescu, Dan; Strieter, Robert M.; Linden, Joel

2011-01-01

267

Depletion of Tumor-Associated Macrophages Slows the Growth of Chemically Induced Mouse Lung Adenocarcinomas  

PubMed Central

Chronic inflammation is a risk factor for lung cancer, and low-dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programing changes within 2?weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ?50% of control levels after 4–6?weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of insulin-like growth factor-I, CXCL1, IL-6, and CCL2 diminished with clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and clodronate liposome-treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression. PMID:25505466

Fritz, Jason M.; Tennis, Meredith A.; Orlicky, David J.; Yin, Hao; Ju, Cynthia; Redente, Elizabeth F.; Choo, Kevin S.; Staab, Taylor A.; Bouchard, Ronald J.; Merrick, Daniel T.; Malkinson, Alvin M.; Dwyer-Nield, Lori D.

2014-01-01

268

Immunosurveillance by anti-angiogenesis: tumor growth arrest by T cell-derived thrombospondin-1  

PubMed Central

Recent advances in cancer immunotherapy suggest that manipulation of the immune system to enhance the anti-tumor response may be a highly effective treatment modality. One understudied aspect of immune surveillance is anti-angiogenic surveillance, the regulation of tumor angiogenesis by the immune system, independent of tumor cell lysis. CD4+ T cells can negatively regulate angiogenesis by secreting anti-angiogenic factors such as thrombospondin-1 (TSP-1). In tumor-bearing mice, we show that a Th1-directed viral infection that triggers upregulation of TSP-1 in CD4+ and CD8+ T cells can inhibit tumor angiogenesis and suppress tumor growth. Using bone marrow chimeras and adoptive T cell transfers, we demonstrated that TSP-1 expression in the T cell compartment was necessary and sufficient to inhibit tumor growth by suppressing tumor angiogenesis after the viral infection. Our results establish that tumorigenesis can be stanched by anti-angiogenic surveillance triggered by an acute viral infection, suggesting novel immunological approaches to achieve anti-angiogenic therapy. PMID:24590059

Schadler, Keri L.; Crosby, Erika J.; Zhou, Alice Yao; Bhang, Dong Ha; Braunstein, Lior; Baek, Kwan Hyuck; Crawford, Danielle; Crawford, Alison; Angelosanto, Jill; Wherry, E. John; Ryeom, Sandra

2014-01-01

269

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

NASA Astrophysics Data System (ADS)

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.

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

2007-07-01

270

Production of Insulin-like Growth Factor-binding Proteins by Human Central Nervous System Tumors1  

Microsoft Academic Search

Central nervous system (CNS) tumor cells possess specific receptors for insulin-like growth factors (IGFs) and respond to the growth-pro moting effects of IGFs in cell culture. In the present study, we asked whether CNS tumors also produce IGF-binding proteins (BPs) which may modulate the effects of IGFs on CNS tumor cells. Primary cell cultures were established from 20 CNS tumors.

Terry G. Unterman; Roberta P. Click; Gillian T. Waites; Stephen C. Bell

271

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

PubMed

Immunization with xenogeneic DNA is a promising cancer treatment to overcome tolerance to self-antigens. Heat shock protein 70 (HSP70) is over-expressed in various kinds of tumors and is believed to be involved in tumor progression. This study tested a xenogeneic chicken HSP70 (chHSP70) DNA vaccine in an experimental canine transmissible venereal tumor (CTVT) model. Three vaccination strategies were compared: the first (PE) was designed to evaluate the prophylactic efficacy of chHSP70 DNA vaccination by delivering the vaccine before tumor inoculation in a prime boost setting, the second (T) was designed to evaluate the therapeutic efficacy of the same prime boost vaccine by vaccinating the dogs after tumor inoculation; the third (PT) was similar to the first strategy (PE), with the exception that the electroporation booster injection was replaced with a transdermal needle-free injection. Tumor growth was notably inhibited only in the PE dogs, in which the vaccination program triggered tumor regression significantly sooner than in control dogs (NT). The CD4(+) subpopulation of tumor-infiltrating lymphocytes and canine HSP70 (caHSP70)-specific IFN-?-secreting lymphocytes were significantly increased during tumor regression in the PE dogs as compared to control dogs, demonstrating that specific tolerance to caHSP70 has been overcome. In contrast, no benefit of the therapeutic strategy (T) could be noticed and the (PT) strategy only led to partial control of tumor growth. In summary, antitumor prophylactic activity was demonstrated using the chHSP70 DNA vaccine including a boost via electroporation. Our data stressed the importance of DNA electroporation as a booster to get the full benefit of DNA vaccination but also of cancer immunotherapy initiation as early as possible. Xenogeneic chHSP70 DNA vaccination including an electroporation boost is a potential vaccine to HSP70-expressing tumors, although further research is still required to better understand true clinical potential. PMID:21392590

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

2011-04-18

272

Accelerated Tumor Growth Mediated by Sub-lytic Levels of Antibody-Induced Complement Activation is Associated with Activation of the PI3K/AKT Survival Pathway  

PubMed Central

Purpose We addressed the possibility that low levels of tumor cell bound antibodies targeting gangliosides might accelerate tumor growth. Experimental Design To test this hypothesis, we treated mice with a range of mAb doses against GM2, GD2, GD3 and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in-vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it. Results Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2-expressing cell lines both in-vitro and in a SCID mouse model, while very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM antibodies targeting GM2 but consistent against IgG-mAb targeting GD3 as well. These findings were mirrored by in-vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the PI3K/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K-activation and accelerated tumor growth in-vitro and in-vivo are eliminated by PI3K-inhibitors NVP-BEZ235 and Wortmannin. These PI3K-inhibitors also significantly increased efficacy of high doses of these 4 mAbs. Conclusion Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced-antibodies targeting a variety of tumor-cell-surface-antigens. PMID:23833306

Wu, Xiaohong; Ragupathi, Govind; Panageas, Katherine; Hong, Feng; Livingston, Philip O.

2013-01-01

273

Combined blockade of integrin-?4?1 plus cytokines SDF-1? or IL-1? potently inhibits tumor inflammation and growth.  

PubMed

Tumor-associated macrophages promote tumor growth by stimulating angiogenesis and suppressing antitumor immunity. Thus, therapeutics that inhibit macrophage recruitment to tumors may provide new avenues for cancer therapy. In this study, we showed how chemoattractants stromal cell-derived growth factor 1 alpha (SDF-1?) and interleukin 1 beta (IL-1?) collaborate with myeloid cell integrin-?4?1 to promote tumor inflammation and growth. We found that SDF-1? and IL-1? are highly expressed in the microenvironments of murine lung, pancreatic, and breast tumors; surprisingly, SDF-1? was expressed only by tumor cells, whereas IL-1? was produced only by tumor-derived granulocytes and macrophages. In vivo, both factors directly recruited proangiogenic macrophages to tissues, whereas antagonists of both factors suppressed tumor inflammation, angiogenesis, and growth. Signals induced by IL-1? and SDF-1? promoted the interaction of talin and paxillin with the cytoplasmic tails of integrin-?4?1, thereby stimulating myeloid cell adhesion to endothelium in vitro and in vivo. Inhibition of integrin-?4?1, SDF-1?, or IL-1? was sufficient to block tumor inflammation and growth, and the combined blockade of these molecules greatly accentuated these effects. Furthermore, antagonists of integrin-?4?1 inhibited chemotherapy-induced tumor inflammation and acted synergistically with chemotherapeutic agents to suppress tumor inflammation and growth. These results show that targeting myeloid cell recruitment mechanisms can be an effective approach to suppress tumor progression. PMID:21948958

Schmid, Michael C; Avraamides, Christie J; Foubert, Philippe; Shaked, Yuval; Kang, Sang Won; Kerbel, Robert S; Varner, Judith A

2011-11-15

274

Combined blockade of integrin ?4?1 plus cytokines SDF-1? or IL-1? potently inhibits tumor inflammation and growth  

PubMed Central

Tumor-associated macrophages promote tumor growth by stimulating angiogenesis and suppressing anti-tumor immunity. Thus, therapeutics that inhibit macrophage recruitment to tumors may provide new avenues for cancer therapy. Here we show how the chemoattractants SDF-1? and IL-1? collaborate with myeloid cell integrin ?4?1 to promote tumor inflammation and growth. We found that SDF-1? and IL-1? are highly expressed in the microenvironments of murine lung, pancreatic and breast tumors; surprisingly, SDF-1? was expressed only by tumor cells, while IL-1? was produced only by tumor-derived granulocytes and macrophages. In vivo, both factors directly recruited pro-angiogenic macrophages to tissues, while antagonists of both factors suppressed tumor inflammation, angiogenesis and growth. Signals induced by IL-1? and SDF-1? promoted the interaction of talin and paxillin with the cytoplasmic tails of integrin ?4?1, thereby stimulating myeloid cell adhesion to endothelium in vitro and in vivo. While inhibiting integrin ?4?1, SDF-1? or IL-1? was sufficient to block tumor inflammation and growth, the combined blockade of these molecules greatly accentuated these effects. Furthermore, antagonists of integrin ?4?1 inhibited chemotherapy-induced tumor inflammation and synergized with chemotherapeutic agents to suppress tumor inflammation and growth. These results demonstrate that targeting myeloid cell recruitment mechanisms can be an effective approach to suppress tumor progression. PMID:21948958

Schmid, Michael C.; Avraamides, Christie J.; Foubert, Philippe; Shaked, Yuval; Kang, Sang-Won; Kerbel, Robert S.; Varner, Judith A.

2011-01-01

275

The antiparasitic drug, potassium antimony tartrate, inhibits tumor angiogenesis and tumor growth in nonsmall-cell lung cancer.  

PubMed

Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening US Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various nonsmall-cell lung cancer (NSCLC) cells with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dosage of 40 mg/kg (i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo antiangiogenesis property of PAT, which was well correlated with its tumor growth inhibition in NSCLC cells. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration, and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC cells. Further study of PAT in anticancer clinical trials may be warranted. PMID:25352499

Wang, Beibei; Yu, Weiwei; Guo, Jiawei; Jiang, Xingwu; Lu, Weiqiang; Liu, Mingyao; Pang, Xiufeng

2015-01-01

276

Transplantation of human renal cell carcinoma into NMRI nu/nu mice. III. Effect of irradiation on tumor acceptance and tumor growth  

SciTech Connect

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.

Otto, U.; Huland, H.; Baisch, H.; Kloeppel, G.

1985-07-01

277

Growth-inhibitory activity and downregulation of the class II tumor-suppressor gene H-rev107 in tumor cell lines and experimental tumors.  

PubMed

The H-rev107 gene is a new class II tumor suppressor, as defined by its reversible downregulation and growth-inhibiting capacity in HRAS transformed cell lines. Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation. Cell populations of H-rev107 transfectants showed an attenuated tumor formation in nude mice. Cells explanted from tumors or maintained in cell culture for an extended period of time no longer exhibited detectable levels of the H-rev107 protein, suggesting strong selection against H-rev107 expression in vitro and in vivo. Expression of the truncated form of H-rev107 lacking the COOH-terminal membrane associated domain of 25 amino acids, had a weaker inhibitory effect on proliferation in vitro and was unable to attenuate tumor growth in nude mice. The H-rev107 mRNA is expressed in most adult rat tissues, and immunohistochemical analysis showed expression of the protein in differentiated epithelial cells of stomach, of colon and small intestine, in kidney, bladder, esophagus, and in tracheal and bronchial epithelium. H-rev107 gene transcription is downregulated in rat cell lines derived from liver, kidney, and pancreatic tumors and also in experimental mammary tumors expressing a RAS transgene. In colon carcinoma cell lines only minute amounts of protein were detectable. Thus, downregulation of H-rev107 expression may occur at the level of mRNA or protein. PMID:9049257

Sers, C; Emmenegger, U; Husmann, K; Bucher, K; Andres, A C; Schäfer, R

1997-02-24

278

Growth-inhibitory Activity and Downregulation of the Class II Tumor-suppressor Gene H-rev107 in Tumor Cell Lines and Experimental Tumors  

PubMed Central

The H-rev107 gene is a new class II tumor suppressor, as defined by its reversible downregulation and growth-inhibiting capacity in HRAS transformed cell lines. Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation. Cell populations of H-rev107 transfectants showed an attenuated tumor formation in nude mice. Cells explanted from tumors or maintained in cell culture for an extended period of time no longer exhibited detectable levels of the H-rev107 protein, suggesting strong selection against H-rev107 expression in vitro and in vivo. Expression of the truncated form of H-rev107 lacking the COOH-terminal membrane associated domain of 25 amino acids, had a weaker inhibitory effect on proliferation in vitro and was unable to attenuate tumor growth in nude mice. The H-rev107 mRNA is expressed in most adult rat tissues, and immunohistochemical analysis showed expression of the protein in differentiated epithelial cells of stomach, of colon and small intestine, in kidney, bladder, esophagus, and in tracheal and bronchial epithelium. H-rev107 gene transcription is downregulated in rat cell lines derived from liver, kidney, and pancreatic tumors and also in experimental mammary tumors expressing a RAS transgene. In colon carcinoma cell lines only minute amounts of protein were detectable. Thus, downregulation of H-rev107 expression may occur at the level of mRNA or protein. PMID:9049257

Sers, Christine; Emmenegger, Urban; Husmann, Knut; Bucher, Katharina; Andres, Ann-Catherine; Schäfer, Reinhold

1997-01-01

279

Astroglial growth factors in normal human brain and brain tumors: comparison with embryonic brain  

Microsoft Academic Search

Aqueous extracts of 18-day embryonic chicken brains, 15-day embryonic and adult rat brains and human brain tumors, as well as control histologically-normal adult human brain taken from around brain tumors or around arteriovenous malformations each stimulated the growth of cultured chick astrocytes. Eight mitogenic fractions were separated reproducibly by Bio-Gel P-10 molecular seive chromatography. They had apparent molecular weights (M.W.)

Michel P. Rathbone; Galina K. Szlapetis; Rocco de Villiers; Rolando F. Del Maestro; Joseph Gilbert; John Groves; Kelly Erola; Jae-Kyoung Kim

1992-01-01

280

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

Microsoft Academic Search

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

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

281

Effect of fibrin sealant on perianastomotic tumor growth in an experimental model of colorectal cancer surgery  

Microsoft Academic Search

Viable intraluminal tumor cells can penetrate a clinically intact rodent colonic anastomosis and give rise to perianastomotic tumor growth. The aim of this study was to determine whether transanastomotic cell migration can be prevented by fibrin-based tissue sealant. Following distal colonic transection and reanastomosis with 5\\/0 silk sutures, Fischer F344 rats were randomly allocated to three experimental groups. In Group

J. R. McGregor; D. H. Reinbach; S. W. Dahill; P. J. O'Dwyer

1993-01-01

282

Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis  

Microsoft Academic Search

Bioluminescent imaging (BLI) permits sensitive in vivo detection and quantification of cells specifically engineered to emit visible light. Three stable human tumor cell lines\\u000a engineered to express luciferase were assessed for their tumorigenicity in subcutaneous, intravenous and spontaneous metastasis\\u000a models. Bioluminescent PC-3M-luc-C6 human prostate cancer cells were implanted subcutaneously into SCID-beige mice and were\\u000a monitored for tumor growth and response

Darlene E. Jenkins; Yoko Oei; Yvette S. Hornig; Shang-Fan Yu; Joan Dusich; Tony Purchio; Pamela R. Contag

2003-01-01

283

The role of glucose in the growth of 9L multicell tumor spheroids  

SciTech Connect

Monolayer-cultured 9L rat brain tumor cells grew optimally in culture media containing glucose concentrations greater than 0.07 mg/ml, but growth ceased at concentrations lower than this value. Assuming that this glucose concentration defines the proliferating fraction of cells in 9L multicell tumor spheroids, it is possible to simulate spheroid growth based on the intraspheroid glucose distribution derived by the author earlier. An excellent fit to experimental growth data was obtained by assigning the proliferating fraction a growth rate constant equal to 40% of that of monolayer-cultured cells. This definition is in accord with our observation that the colony-forming efficiency (CFE) of spheroid-derived cells is 40% of the CFE of cells maintained in monolayer. This suggests that the role of glucose in 9L cell growth is similar in spheroids and in monolayer culture.

Li, C.K.N.

1982-11-15

284

A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.  

PubMed

Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules. PMID:23982260

Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

2014-10-01

285

Silencing Met receptor tyrosine kinase signaling decreased oral tumor growth and increased survival of nude mice  

PubMed Central

SUMMARY Objectives The hepatocyte growth factor receptor (Met) is frequently overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC), correlating positively with high-grade tumors and shortened patient survival. As such, Met may represent an important therapeutic target. The purpose of this study was to explore the role of Met signaling for HNSCC growth and locoregional dissemination. Materials and methods Using a lentiviral system for RNA interference, we knocked down Met in established HNSCC cell lines that express high levels of the endogenous receptor. The effect of Met silencing on in vitro proliferation, cell survival and migration was examined using western analysis, immunohisto-chemistry and live cell imaging. In vivo tumor growth, dissemination and mouse survival was assessed using an orthotopic tongue mouse model for HNSCC. Results We show that Met knockdown (1) impaired activation of downstream MAPK signaling; (2) reduced cell viability and anchorage independent growth; (3) abrogated HGF-induced cell motility on laminin; (4) reduced In vivo tumor growth by increased cell apoptosis; (5) caused reduced incidence of tumor dissemination to regional lymph nodes and (6) increased the survival of nude mice with orthotopic xenografts. Conclusion Met signaling is important for HNSCC growth and locoregional dissemination In vivo and that targeting Met may be an important strategy for therapy. PMID:24268630

Tao, X.; Hill, K.S.; Gaziova, I.; Sastry, S.K.; Qui, S.; Szaniszlo, P.; Fennewald, S.; Resto, V.A.; Elferink, L.A.

2013-01-01

286

Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity  

PubMed Central

SUMMARY Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits. PMID:25079331

Marusyk, Andriy; Tabassum, Doris P.; Altrock, Philipp M.; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia

2014-01-01

287

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

PubMed

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

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

288

Plant Growth Hormone Kinetin Delays Aging, Prolongs the Lifespan, and Slows Down Development of the Fruitfly Zaprionus paravittiger  

Microsoft Academic Search

A cytokinin plant growth hormone kinetin (Kn) retards senescence in plants and delays ageing in human cells in culture. We have now observed that Kn also slows down ageing and prolongs the lifespan of the fruitfly Zaprionus paravittiger when these insects are fed with 25-125 ppm Kn added in their diet medium. In addition, 25 ppm Kn also slows down

S. P. Sharma; P. Kaur; S. I. S. Rattan

1995-01-01

289

Protection of Xenopus laevis Embryos Against Alcohol-induced Delayed Gut Maturation and Growth Retardation by Peroxiredoxin 5 and Catalase  

Microsoft Academic Search

Accumulated evidence indicates that maternal alcohol consumption causes fetal enteric damage and growth retardation. In this study, we investigated the underlying molecular mechanisms in a Xenopus model of fetal alcohol exposure. We established a condition of transient alcohol exposure that produces tadpoles with delayed gut maturation and decreased body length. We then investigated the roles of reactive oxygen species (ROS)

Ying Peng; Pai-Hao Yang; Samuel S. M. Ng; Ching Tung Lum; Hsiang-Fu Kung; Marie C. Lin

2004-01-01

290

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms  

PubMed Central

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

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

291

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

PubMed Central

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

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

2013-01-01

292

Model of avascular tumor growth and response to low dose exposure  

NASA Astrophysics Data System (ADS)

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.

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

2011-12-01

293

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

PubMed Central

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.

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

2014-01-01

294

Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed I?B Kinase Activation  

PubMed Central

Tumor necrosis factor alpha (TNF-?)-induced NF-?B activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-?B activation. Here, by assessing the kinetics and amplitude of I?B kinase (IKK) activation, we report that TNF-?-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-? activates NF-?B through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC. PMID:23459942

Blackwell, Ken; Zhang, Laiqun; Workman, Lauren M.; Ting, Adrian T.; Iwai, Kazuhiro

2013-01-01

295

Neutrophil Elastase-Mediated Degradation of IRS-1 Accelerates Lung Tumor Growth  

PubMed Central

Summary Lung cancer is the leading cause of cancer death worldwide1. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness2-3. To determine the role of neutrophil elastase (NE or Elane) on tumor progression, we utilized the LSL-K-ras model of murine lung adenocarcinoma4 to generate LSL-K-ras/Elane?/? mice. Tumor burden was markedly reduced in LSL-K-ras/Elane?/? mice at all time points following induction of mutant K-ras expression. Kaplan-Meier life survival analysis demonstrated that while 100% of LSL-K-ras/Elane+/+ mice died, none of the mice lacking NE died. NE directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells where it degraded insulin receptor substrate-1 (IRS1). Co-immunoprecipitation studies showed that as NE degraded IRS1, there was increased interaction between PI3K and the potent mitogen platelet derived growth factor receptor (PDGFR) thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between NE and IRS1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS1 as a key regulator of PI3K within malignant cells. Additionally, this is the first description of a secreted proteinase gaining access to a cell beyond its plasma membrane and altering intracellular signaling. PMID:20081861

Houghton, A. McGarry; Rzymkiewicz, Danuta M.; Ji, Hongbin; Gregory, Alyssa D.; Egea, Eduardo E.; Metz, Heather E.; Stolz, Donna B.; Land, Stephanie R.; Marconcini, Luiz A.; Kliment, Corrine R.; Jenkins, Kimberly M.; Beaulieu, Keith A.; Mouded, Majd; Frank, Stuart J.; Wong, Kwok K.; Shapiro, Steven D.

2010-01-01

296

Tie2-dependent deletion of ?6 integrin subunit in mice reduces tumor growth and angiogenesis.  

PubMed

The ?6 integrin subunit (?6) has been implicated in cancer cell migration and in the progression of several malignancies, but its role in tumor angiogenesis is unclear. In mice, anti-?6 blocking antibodies reduce tumor angiogenesis, whereas Tie1-dependent ?6 gene deletion enhances neovessel formation in melanoma and lung carcinoma. To clarify the discrepancy in these results we used the cre-lox system to generate a mouse line, ?6fl/fl?Tie2Cre(+), with ?6 gene deletion specifically in Tie2-lineage cells: endothelial cells, pericytes, subsets of hematopoietic stem cells, and Tie2-expressing monocytes/macrophages (TEMs), known for their proangiogenic properties. Loss of ?6 expression in ?6fl/fl?Tie2Cre(+) mice reduced tumor growth in a murine B16F10 melanoma model. Immunohistological analysis of the tumors showed that Tie2-dependent ?6 gene deletion was associated with reduced tumor vascularization and with reduced infiltration of proangiogenic Tie2-expressing macrophages. These findings demonstrate that ?6 integrin subunit plays a major role in tumor angiogenesis and TEM infiltration. Targeting ?6 could be used as a strategy to reduce tumor growth. PMID:25176420

Bouvard, Claire; Segaoula, Zacharie; De Arcangelis, Adèle; Galy-Fauroux, Isabelle; Mauge, Laetitia; Fischer, Anne-Marie; Georges-Labouesse, Elisabeth; Helley, Dominique

2014-11-01

297

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria  

PubMed Central

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

Bird, Lina J.; Coleman, Maureen L.

2013-01-01

298

Novel monoclonal antibody inhibits tumor growth in breast cancer and angiosarcoma  

Cancer.gov

A monoclonal antibody targeting a protein known as SFPR2 has been shown by researchers at the University of North Carolina and its Lineberger Comprehensive Cancer Center to inhibit tumor growth in pre-clinical models of breast cancer and angiosarcoma. In a paper published in the April 19 issue of Molecular Cancer Therapeutics, a team used a monoclonal antibody to target SFRP2 expressed in cells from triple-negative breast cancer and the aggressive blood-vessel malignancy angiosarcoma, reducing the rate of tumor growth.

299

Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo  

PubMed Central

The endothelial cell receptor-tyrosine kinases, VEGF receptor 2 (VEGF-R2) and Tie-2, and their ligands, vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2, respectively, play key roles in tumor angiogenesis. Several studies suggest that the VEGF receptor pathway and the Tie-2 pathway are independent and essential mediators of angiogenesis, leading to the hypothesis that simultaneous interference with both pathways should result in additive effects on tumor growth. In this study, a human melanoma xenograft model (M21) was used to analyze the effects of simultaneous intradiabody depletion of vascular endothelial growth receptor-R2 and Tie-2 on tumor angiogenesis and tumor xenograft growth. The intradiabodies were expressed from recombinant adenovirus delivered through subtumoral injection. Blockade of both VEGF-R2 and Tie-2 pathways simultaneously or the VEGF receptor pathway alone resulted in a significant inhibition of tumor growth and tumor angiogenesis (92.2% and 74.4%, respectively). In addition, immunohistochemical staining of intradiabody-treated tumors demonstrated a decreased number of tumor-associated blood vessels versus control treatment. Previous studies with intrabodies had demonstrated that the Tie-2 receptor pathway was essential for tumor growth. The simultaneous blockade of the VEGF and Tie-2 pathways resulted in effective inhibition of tumor growth and demonstrated the potential of simultaneous targeting of multiple pathways as a therapeutic strategy. PMID:15928093

Jendreyko, Nina; Popkov, Mikhail; Rader, Christoph; Barbas, Carlos F.

2005-01-01

300

Vav1 promotes lung cancer growth by instigating tumor-microenvironment cross-talk via growth factor secretion.  

PubMed

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

Sebban, Shulamit; Farago, Marganit; Rabinovich, Shiran; Lazer, Galit; Idelchuck, Yulia; Ilan, Lena; Pikarsky, Eli; Katzav, Shulamit

2014-10-15

301

Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.  

PubMed Central

Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8105469

Kalthoff, H; Roeder, C; Gieseking, J; Humburg, I; Schmiegel, W

1993-01-01

302

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

PubMed Central

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

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

2012-01-01

303

The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways  

PubMed Central

Background Human osteopontin (OPN), a known tumor associated protein, exists in different isoforms, whose function is unclear. It also possesses a RGD domain, which has been implicated in diverse function. Here, we use genetic approaches to systematically investigate the function of the RGD domain in different OPN isoforms on tumor progression and metastasis for 2 different solid tumor models. Methodology/Principal Findings Using isoform-specific qRT-PCR, we found that OPN-A and B were the main isoforms overexpressed in evaluated human tumors, which included 4 soft tissue sarcomas, 24 lung and 30 head and neck carcinomas. Overexpression of either OPN-A or B in two different cell types promoted local tumor growth and lung metastasis in SCID mouse xenografts. However, expression of either isoform with the RGD domain either mutated or deleted decreased tumor growth and metastasis, and resulted in increased apoptosis by TUNEL staining. In vitro, whereas mutation of the RGD domain did not affect cell-cell adhesion, soft agar growth or cell migration, it increased apoptosis under hypoxia and serum starvation. This effect could be mitigated when the RGD mutant cells were treated with condition media containing WT OPN. Mechanistically, the RGD region of OPN inhibited apoptosis by inducing NF-?B activation and FAK phosphorylation. Inhibition of NF-?B (by siRNA to the p65 subunit) or FAK activation (by a inhibitor) significantly increased apoptosis under hypoxia in WT OPN cells, but not in RGD mutant cells. Conclusion/Significance Unlike prior reports, our data suggest that the RGD domain of both OPN-A and B promote tumor growth and metastasis mainly by protecting cells against apoptosis under stressed conditions and not via migration or invasion. Future inhibitors directed against OPN should target multiple isoforms and should inhibit cell survival mechanisms that involve the RGD domain, FAK phosphorylation and NF-?B activation. PMID:20224789

Kwok, Shirley; Kong, Christina; Banh, Alice; Kuo, Peiwen; Bouley, Donna M.; Vice, Carmen; Brustugun, Odd Terje; Denko, Nicholas C.; Koong, Albert C.; Giaccia, Amato; Le, Quynh-Thu

2010-01-01

304

Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies.  

PubMed

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

Kwon, Youngjoo

2014-11-01

305

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

NASA Astrophysics Data System (ADS)

Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose—the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm-1. It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm-1. The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a continuous fall-off of the density of infiltrating tumor cells. The approach can potentially be used to individualize the prescribed dose distribution if better methods to estimate radiosensitivity and infiltration length on a patient by patient basis become available.

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

2014-02-01

306

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

PubMed

Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose-the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm(-1). It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm(-1). The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a continuous fall-off of the density of infiltrating tumor cells. The approach can potentially be used to individualize the prescribed dose distribution if better methods to estimate radiosensitivity and infiltration length on a patient by patient basis become available. PMID:24440905

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

2014-02-01

307

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth  

Microsoft Academic Search

Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon\\/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to

Ilaria Sciamanna; Matteo Landriscina; Carmine Pittoggi; Michela Quirino; Cristina Mearelli; Rosanna Beraldi; Elisabetta Mattei; Annalucia Serafino; Alessandra Cassano; Paola Sinibaldi-Vallebona; Enrico Garaci; Carlo Barone; Corrado Spadafora

2005-01-01

308

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.

309

Cellular and Tumor Radiosensitivity is Correlated to Epidermal Growth Factor Receptor Protein Expression Level in Tumors Without EGFR Amplification;Epidermal growth factor receptor; Radiotherapy; Squamous cell carcinoma; Biomarker; Local tumor control  

SciTech Connect

Purpose: There is conflicting evidence for whether the expression of epidermal growth factor receptor in human tumors can be used as a marker of radioresponse. Therefore, this association was studied in a systematic manner using squamous cell carcinoma (SCC) cell lines grown as cell cultures and xenografts. Methods and Materials: The study was performed with 24 tumor cell lines of different tumor types, including 10 SCC lines, which were also investigated as xenografts on nude mice. Egfr gene dose and the length of CA-repeats in intron 1 were determined by polymerase chain reaction, protein expression in vitro by Western blot and in vivo by enzyme-linked immunosorbent assay, and radiosensitivity in vitro by colony formation. Data were correlated with previously published tumor control dose 50% data after fractionated irradiation of xenografts of the 10 SCC. Results: EGFR protein expression varies considerably, with most tumor cell lines showing moderate and only few showing pronounced upregulation. EGFR upregulation could only be attributed to massive gene amplification in the latter. In the case of little or no amplification, in vitro EGFR expression correlated with both cellular and tumor radioresponse. In vivo EGFR expression did not show this correlation. Conclusions: Local tumor control after the fractionated irradiation of tumors with little or no gene amplification seems to be dependent on in vitro EGFR via its effect on cellular radiosensitivity.

Kasten-Pisula, Ulla; Saker, Jarob [Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany); Eicheler, Wolfgang; Krause, Mechthild; Yaromina, Ala [Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technical University, Dresden (Germany); OncoRay Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technical University, Dresden (Germany); Meyer-Staeckling, Soenke [Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany); Scherkl, Benjamin; Kriegs, Malte [Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany); Brandt, Burkhard [Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany); Grenman, Reidar [Department of Otorhinolaryngology-Head and Neck Surgery and Department of Medical Biochemistry and Genetics, Turku University and University Hospital of Turku, Turku (Finland); Petersen, Cordula [Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany); Baumann, Michael [Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technical University, Dresden (Germany); OncoRay Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technical University, Dresden (Germany); Dikomey, Ekkehard, E-mail: dikomey@uke.uni-hamburg.de [Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hubertus Wald Tumor Center, Hamburg (Germany)

2011-07-15

310

Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits  

Microsoft Academic Search

Summary  Angiogenesis, the process by which new blood vessels form from existing vasculature, is critical for tumor growth and invasion.\\u000a Growth factors, such as VEGF, initiate signaling cascades resulting in the proliferation of resting endothelial cells. Blockade\\u000a of growth factor pathways has proven effective in inhibiting angiogenesis and tumor growth in vivo. Integrins, including the integrin ?5?1, are also important mediators

Vinay Bhaskar; Melvin Fox; Danna Breinberg; Melanie H-L Wong; Pauline E. Wales; Susan Rhodes; Robert B. DuBridge; Vanitha Ramakrishnan

2008-01-01

311

Insulin-like Growth Factor-I Is an Autocrine Regulator of Chromogranin A Secretion and Growth in Human Neuroendocrine Tumor Cells1  

Microsoft Academic Search

Carcinoid tumors are predominantly found in the gastrointestinal tract and are characterized by hypersecretion of various substances, including bioamines and neuropeptides, leading to functional tumor disease. Here, we demonstrate that human BON carcinoid tumor cells express function- ally active insulin-like growth factor-I (IGF-I) receptors and secrete IGF-I, suggesting an autocrine action of this growth factor. The IGF-I receptor was functionally

Gotz von Wichert; Peter M. Jehle; Andreas Hoeflich; Stefan Koschnick; Henning Dralle; Eckhard Wolf; Bertram Wiedenmann; Bernhard O. Boehm; Guido Adler; Thomas Seufferlein

2000-01-01

312

In vivo microCT quantification of lung tumor growth in SPC-raf transgenic mice.  

PubMed

Lung cancer is the most common cancer worldwide. Early detection might reduce morbidity. In this study we evaluate a microCT imaging algorithm to assess in-vivo tumour load and quantification of tumour growth in a transgenic disease model of lung adenocarcinomas. MicroCT was carried out with n=10 SPC-raf transgenic mice without gating in spontaneously breathing and isoflurane anaesthetised animals. Segmentation of the air-filled spaces was obtained using a region growing algorithm by 3 independent observers. Inter- and intra-observer variability of the algorithm was determined and compared against an alternative region growing algorithm. Due to the multiple very small tumor nodules that occur and the low signal-to-noise ratio direct volumetric measurement of solitary tumor nodules is not feasible. However, tumor growth can be assessed by measuring the decrease in the segmented volume of the aerated lung areas. The presented algorithm can thus be used to evaluate therapeutic efficacies of novel treatment strategies. The imaging algorithm allows in vivo quantification of lung tumor load and tumor growth in transgenic mice with an acceptable intra- and interobserver variability. PMID:19273175

Rodt, Thomas; von Falck, Christian; Halter, Roman; Ringe, Kristina; Shin, Hoen-Oh; Galanski, Michael; Borlak, Juergen

2009-01-01

313

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

PubMed Central

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

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

2013-01-01

314

An Adaptive Multigrid Algorithm for Simulating Solid Tumor Growth Using Mixture Models  

PubMed Central

In this paper we give the details of the numerical solution of a three-dimensional multispecies diffuse interface model of tumor growth, which was derived in (Wise et al., J. Theor. Biol. 253 (2008)) and used to study the development of glioma in (Frieboes et al., NeuroImage 37 (2007) and tumor invasion in (Bearer et al., Cancer Research, 69 (2009)) and (Frieboes et al., J. Theor. Biol. 264 (2010)). The model has a thermodynamic basis, is related to recently developed mixture models, and is capable of providing a detailed description of tumor progression. It utilizes a diffuse interface approach, whereby sharp tumor boundaries are replaced by narrow transition layers that arise due to differential adhesive forces among the cell-species. The model consists of fourth-order nonlinear advection-reaction-diffusion equations (of Cahn-Hilliard-type) for the cell-species coupled with reaction-diffusion equations for the substrate components. Numerical solution of the model is challenging because the equations are coupled, highly nonlinear, and numerically stiff. In this paper we describe a fully adaptive, nonlinear multigrid/finite difference method for efficiently solving the equations. We demonstrate the convergence of the algorithm and we present simulations of tumor growth in 2D and 3D that demonstrate the capabilities of the algorithm in accurately and efficiently simulating the progression of tumors with complex morphologies. PMID:21076663

Wise, S.M.; Lowengrub, J.S.; Cristini, V.

2010-01-01

315

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

PubMed

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

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

2013-07-01

316

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

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

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

317

Modeling of tumor growth and anticancer effects of combination therapy  

Microsoft Academic Search

Combination therapies are widely used in the treatment of patients with cancer. Selecting synergistic combination strategies\\u000a is a great challenge during early drug development. Here, we present a pharmacokinetic\\/pharmacodynamic (PK\\/PD) model with\\u000a a smooth nonlinear growth function to characterize and quantify anticancer effect of combination therapies using time-dependent\\u000a data. To describe the pharmacological effect of combination therapy, an interaction term

Gilbert Koch; Antje Walz; Gezim Lahu; Johannes Schropp

2009-01-01

318

PACAP inhibits tumor growth and interferes with clusterin in cervical carcinomas.  

PubMed

Secretory clusterin (sCLU), an anti-apoptotic protein, is overexpressed in many tumors and enhances tumorigenesis and chemo-resistance. However, the regulation mechanism controlling the sCLU maturation process or activity remains undetermined. In this study, we found PACAP as a negative regulator of CLU. Overexpression of the PACAP gene in cervical cancer cell lines lacking PACAP expression significantly inhibited cell growth and induced apoptosis. We further demonstrated that interaction of PACAP with CLU significantly downregulated CLU expression and secretion, inhibited the Akt-Raf-ERK pathway, and suppressed the growth of human tumor xenografts in nude mice. This novel inhibitory function of PACAP may be applicable for developing novel molecular therapies for tumors with increased sCLU expression. PMID:25451228

Lee, Ji-Hae; Lee, Ji-Yeon; Rho, Seung Bae; Choi, Jong-Soon; Lee, Dong-Gi; An, Sungwhan; Oh, Taejeong; Choi, Don-Chan; Lee, Seung-Hoon

2014-12-20

319

Luteolin and its inhibitory effect on tumor growth in systemic malignancies  

SciTech Connect

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.

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

2013-04-01

320

Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth  

Microsoft Academic Search

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

A Munguia; T Ota; T Miest; S J Russell

2008-01-01

321

On a Cahn-Hilliard type phase field system related to tumor growth  

E-print Network

of the viscous Cahn-Hilliard or Cahn-Hilliard equation depending on whether > 0 or = 0 (see [3, 9, 10On a Cahn-Hilliard type phase field system related to tumor growth Pierluigi Colli Dipartimento di with a phase field system of Cahn-Hilliard type. For positive viscosity coefficients, the authors prove

322

A Generative Approach for Image-Based Modeling of Tumor Growth  

PubMed Central

Extensive imaging is routinely used in brain tumor patients to monitor the state of the disease and to evaluate therapeutic options. A large number of multi-modal and multi-temporal image volumes is acquired in standard clinical cases, requiring new approaches for comprehensive integration of information from different image sources and different time points. In this work we propose a joint generative model of tumor growth and of image observation that naturally handles multimodal and longitudinal data. We use the model for analyzing imaging data in patients with glioma. The tumor growth model is based on a reaction-diffusion framework. Model personalization relies only on a forward model for the growth process and on image likelihood. We take advantage of an adaptive sparse grid approximation for efficient inference via Markov Chain Monte Carlo sampling. The approach can be used for integrating information from different multi-modal imaging protocols and can easily be adapted to other tumor growth models. PMID:21761700

Menze, Bjoern H.; Van Leemput, Koen; Honkela, Antti; Konukoglu, Ender; Weber, Marc-André; Ayache, Nicholas; Golland, Polina

2011-01-01

323

Tumor Cell Growth Arrest Caused by Subchromosomal Transferable DNA Fragments from Chromosome 11  

Microsoft Academic Search

A fundamental problem in the identification and isolation of tumor suppressor and other growth-inhibiting genes is the loss of power of genetic complementation at the subchromosomal level. A direct genetic strategy was developed to isolate subchromosomal transferable fragments (STFs) from any chromosome, each containing a selectable marker within the human DNA, that could be transferred to any mammalian cell. As

Minoru Koi; Laura A. Johnson; Linda M. Kalikin; Peter F. R. Little; Yusuke Nakamura; Andrew P. Feinberg

1993-01-01

324

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

PubMed Central

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

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

2014-01-01

325

Suppressing Activity of Common Intestinal Bacteria Reduces Tumor Growth | Physical Sciences in Oncology  

Cancer.gov

Over the past few years, cancer researchers have come to suspect that the bacteria living in our gastrointestinal system may play a role in the development of some types of cancer. Now, a team of investigators from the University of California, San Diego (UCSD) School of Medicine has discovered that common intestinal bacteria do promote tumor growth in genetically susceptible mice.

326

ture in vivo. So far, there is no evidence that tumors can stimulate the growth of  

E-print Network

ture in vivo. So far, there is no evidence that tumors can stimulate the growth of new lymphatic metastasis via the lymphatic vasculature as well as in various other disorders involving the lym- phatic system and their treatment. REFERENCES AND NOTES ___________________________ 1. N. Ferrara and T. Davis

Prentiss, Mara

327

Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth  

E-print Network

! 1! Classical Mathematical Models for Description and Forecast of Preclinical Tumor Growth. hal-00922553,version2-30Dec2013 #12;! 3! These results could be of value for preclinical cancer research by suggesting what model is best adapted when assessing anti-cancer drugs efficacies. They also

Boyer, Edmond

328

Selective Lymphocyte Activation and Inhibition of In Vitro Tumor Cell Growth by Novel Morphinans  

Microsoft Academic Search

Opioids can suppress immune functions and increase susceptibility to developing cancer and infectious diseases. Recently, novel opioid compounds have been synthesized that lack immunosuppressive effects. We evaluated the effects of morphinans with substituted pyrimidine (methyl, phenyl, hydroxy, and amino groups) and pyrazole groups on in vitro rat thymic lymphocyte and splenic macrophage functions, and tumor cell growth. We observed that

Ricardo Gomez-Flores; Kimberly R. Vietti; William J. Dunn III; Reyes Tamez-Guerra; Richard J. Weber

2006-01-01

329

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

SciTech Connect

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.

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

330

Effects of taurolidine and octreotide on tumor growth and lipid peroxidation after staging-laparoscopy in ductal pancreatic cancer  

Microsoft Academic Search

Irrigation with taurolidine after laparoscopy decreases tumor growth in colon carcinoma. In pancreatic cancer subcutaneous therapy with octreotide decreases oxidative stress and carcinogenesis as well. However, it is still unclear, whether irrigation with taurolidine or octreotide after laparoscopic pancreatic biopsy reduces tumor growth in pancreatic cancer as well.In 60 Syrian hamsters ductal pancreatic adenocarcinoma was induced by weekly injection of

M. Kilian; I. Mautsch; C. Braumann; I. Schimke; H. Guski; C. A. Jacobi; F. A. Wenger

2003-01-01

331

Regulation of Wilms' tumor gene expression by nerve growth factor and follicle-stimulating hormone in the  

E-print Network

Regulation of Wilms' tumor gene expression by nerve growth factor and follicle-stimulating hormone of the most important hormones for the growth and differentiation of secondary, antral, and preovulatory in the immature mouse ovary This study investigated the regulation of Wilms' tumor gene (WT1) in the ovary

Mayo, Kelly E.

332

Conditional quantile regression models of melanoma tumor growth curves for assessing treatment effect in small sample studies.  

PubMed

Tumor growth curves provide a simple way to understand how tumors change over time. The traditional approach to fitting such curves to empirical data has been to estimate conditional mean regression functions, which describe the average effect of covariates on growth. However, this method ignores the possibility that tumor growth dynamics are different for different quantiles of the possible distribution of growth patterns. Furthermore, typical individual preclinical cancer drug study designs have very small sample sizes and can have lower power to detect a statistically significant difference in tumor volume between treatment groups. In our work, we begin to address these issues by combining several independent small sample studies of an experimental cancer treatment with differing study designs to construct quantile tumor growth curves. For modeling, we use a Penalized Fixed Effects Quantile Regression with added study effects to control for study differences. We demonstrate this approach using data from a series of small sample studies that investigated the effect of a naturally derived biological peptide, P28, on tumor volumes in mice grafted with human melanoma cells. We find a statistically significant quantile treatment effect on tumor volume trajectories and baseline values. In particular, the experimental treatment and a corresponding conventional chemotherapy had different effects on tumor growth by quantile. The conventional treatment, Dacarbazine (DTIC), tended to inhibit growth for smaller quantiles, while the experimental treatment P28 produced slower rates of growth in the upper quantiles, especially in the 95th quantile. PMID:25231497

Revzin, Ella; Majumdar, Dibyen; Bassett, Gilbert W

2014-12-20

333

Introducing alpha(1,2)-linked fucose into hepatocarcinoma cells inhibits vasculogenesis and tumor growth.  

PubMed

The glycoantigen sialyl-Lewis x (sLex) and its isomer sialy-Lewis a (sLea) are frequently associated with advanced states of cancer and metastasis. In a previous work, we have shown that hepatocarcinoma cells (HCC) HepG2 interact with the endothelial E-selectin exclusively through sLe(x) oligosaccharides, the synthesis of which could be completely prevented by the alpha(1,2)-fucosyltransferase-I (FUT1), thus resulting in a strong inhibition of adhesion and rolling on activated endothelial cells. The purpose of the present study was to evaluate the impact of inhibiting sLex synthesis and the subsequent E-selectin adhesion, on HCC tumor growth in nude mice. Four weeks after subcutaneous transplantation of cells, no FUT1-derived tumor could be detected, whereas 75% of control animals developed large size tumor nodules. Between the 4th and the 8th week postinoculation, 33% tumors arose from FUT1-transduced cells but showed a slow growth (nodule volumes less than 500 mm(3)), while more than 50% of control tumors reached volumes between 1,500 and 3,000 mm(3). Several parameters were examined, including cell division and proliferation, apoptosis, adhesion to extracellular matrix components and angiogenesis/vasculogenesis. We provide evidence that among all, vasculogenesis was the most clearly affected by FUT1 expression, suggesting that tumor angiomorphogenesis may, at least partly, depend on E-selectin-mediated interaction between HCC and endothelial cells, the inhibition of which remarkably retards tumor growth. PMID:17583578

Mathieu, Sylvie; Gerolami, René; Luis, José; Carmona, Sylvie; Kol, Ossarath; Crescence, Lydie; Garcia, Stéphane; Borentain, Patrick; El-Battari, Assou

2007-10-15

334

Close Interactions between Mesenchymal Stem Cells and Neuroblastoma Cell Lines Lead to Tumor Growth Inhibition  

PubMed Central

Mesenchymal stem cells (MSCs) have attracted much interest in oncology since they exhibit marked tropism for the tumor microenvironment and support or suppress malignant cell growth depending on the tumor model tested. The aim of this study was to investigate the role of MSCs in the control of the growth of neuroblastoma (NB), which is the second most common solid tumor in children. In vivo experiments showed that systemically administered MSCs, under our experimental conditions, did not home to tumor sites and did not affect tumor growth or survival. However, MSCs injected intratumorally in an established subcutaneous NB model reduced tumor growth through inhibition of proliferation and induction of apoptosis of NB cells and prolonged the survival of hMSC-treated mice. The need for contact between MSCs and NB cells was further supported by in vitro experiments. In particular, MSCs were found to be attracted by NB cells, and to affect NB cell proliferation with different results depending on the cell line tested. Moreover, NB cells, after pre-incubation with hMSCs, acquired a more invasive behavior towards CXCL12 and the bone marrow, i.e., the primary site of NB metastases. In conclusion, this study demonstrates that functional cross-talk between MSCs and NB cell lines used in our experiments can occur only within short range interaction. Thus, this report does not support the clinical use of MSCs as vehicles for selective delivery of antitumor drugs at the NB site unless chemotherapy and/or radiotherapy create suitable local conditions for MSCs recruitment. PMID:23119082

Bianchi, Giovanna; Morandi, Fabio; Cilli, Michele; Daga, Antonio; Bocelli-Tyndall, Chiara; Gambini, Claudio

2012-01-01

335

SDF-1 Stimulates Vasculogenesis and Enhances Ewing’s Sarcoma Tumor Growth in the Absence of VEGF  

PubMed Central

Stromal cell-derived Factor-1? (SDF-1?) stimulates the migration of bone marrow (BM) cells, similar to Vascular Endothelial Growth Factor (VEGF). We previously demonstrated that inhibition of VEGF165 by small interfering RNA inhibited Ewing’s sarcoma tumor growth, tumor vessel formation and recruitment of BM cells to the tumor. To determine the importance of BM cells in tumor vessel development, we investigated the effects of SDF-1? on VEGF-inhibited TC/siVEGF7-1 Ewing’s tumor neovasculature formation and growth. The effect of SDF-1? on CD34+ progenitor cell chemotaxis was determined in vivo. Using a BM transplantation model with GFP+ transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1? on the recruitment of BM-derived cells to VEGF165-inhibited TC/siVEGF7-1 tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth. SDF-1? stimulated the migration of CD34+ progenitor cells to Matrigel plugs in vivo and promoted the retainment of BM-derived pericytes in close association with perfused, functional tumor vessels. Intratumor inoculation of Ad-SDF-1? into TC/siVEGF7-1 tumors resulted in increased SDF-1 and PDGF-BB expression, augmented tumor growth, an increase in the number of large, lumen-bearing vascular structures, and enhanced vessel pericyte coverage, with no change in VEGF165. SDF-1? stimulates BM cell chemotaxis and the association of these cells with functional tumor vessels. Furthermore, SDF-1? enhances tumor neovascularization and growth with no alteration in VEGF165. Our work suggests that SDF-1-mediated vasculogenesis may represent an alternate pathway that could potentially be utilized by tumors to sustain growth and neovasculature expansion after anti-VEGF therapy. PMID:18537159

Reddy, Krishna; Zhou, Zhichao; Jia, Shu-Fang; Lee, Tim H.; Morales-Arias, Jaime; Cao, Ying; Kleinerman, Eugenie S.

2008-01-01

336

Large solitary fibrous tumor with overexpression of insulin-like growth factor-2.  

PubMed

We present the case of a 66-year-old woman in whom a large solitary fibrous tumor (SFT) in the right thoracic cavity caused intermittent symptoms of hypoglycemia. A diagnosis was made of non-islet cell tumor hypoglycemia on the basis of the presence of hypoglycemia requiring continuous glucose infusion, elevated serum insulin-like growth factor-2 (IGF-2), and a large well-defined tumor in the right thoracic cavity. The patient underwent complete resection of the tumor. Histological examination revealed spindle tumor cells with a hemangiopericytoma-like vascular pattern. Mitotic figures and necrotic areas were rare, and cellular atypia and nuclear pleomorphism were mild. Under immunohistochemical examination, the tumor cells were positive for CD34. Overexpression of IGF-2 mRNA in the tumor was detected by reverse-transcription polymerase-chain reaction. The diagnosis of SFT with IGF-2 production was confirmed. Immediately after surgery, her serum glucose level was normalized (without the need for glucose infusion) and serum IGF-2 level was decreased. Two years after surgery, the patient remains alive and well, with no signs of recurrence or hypoglycemia. PMID:20709701

Okabe, Ryo; Sonobe, Makoto; Bando, Toru; Date, Hiroshi

2010-11-01

337

The B subunit of Escherichia coli enterotoxin helps control the in vivo growth of solid tumors expressing the Epstein–Barr virus latent membrane protein 2A  

PubMed Central

Latent membrane protein 2A (LMP2A) is expressed on almost all Epstein–Barr virus (EBV)-associated tumors and is a potential target for immunotherapeutic intervention and vaccination. However, LMP2A is not efficiently processed and presented on major histocompatibility antigens class I molecules to generate potent cytotoxic T-lymphocytes (CTL) responses capable of killing these tumors. The B subunit of Escherichia coli enterotoxin (EtxB), causes rapid internalization and processing of membrane-bound LMP2A on EBV-infected B cells, and facilitates loading of processed-LMP2A peptides onto MHC class I. This re-directed trafficking/delivery of LMP2A to the MHC class I machinery enhances recognition and killing by LMP2A-specific CTL in vitro. To test the potential of EtxB to enhance immune targeting of LMP2A expressed in solid tumors, we generated a murine tumor model (Renca-LMP2A), in which LMP2A is expressed as a transgenic neoantigen on a renal carcinoma (Renca) cell line and forms solid tumors when injected subcutaneously into BALB/c mice. The data show that in BALB/c mice which have only low levels of peripheral Kd-LMP2A-specific CD8+ T cells, merely a transient inhibition of tumor growth is achieved compared with naïve mice; suggesting that there is suboptimal LMP2A-specifc CTL recognition and poorly targeted tumor killing. However, importantly, treatment of these mice with EtxB led to a significant delay in the onset of tumor growth and significantly lower tumor volumes compared with similar mice that did not receive EtxB. Moreover, this remarkable effect of EtxB was achieved despite progressive reduction in tumor expression of LMP2A and MHC class I molecules. These data clearly demonstrate the potential efficacy of EtxB as a novel therapeutic agent that could render EBV-associated tumors susceptible to immune control. PMID:25641882

Ondondo, Beatrice; Faulkner, Lee; Williams, Neil A; Morgan, Andrew J; Morgan, David J

2015-01-01

338

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

Microsoft Academic Search

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

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

2010-01-01

339

Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling  

Microsoft Academic Search

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor

William Weidong Du; Burton B. Yang; Tatiana A. Shatseva; Bing L. Yang; Zhaoqun Deng; Sze Wan Shan; Daniel Y. Lee; Arun Seth; Albert J. Yee

2010-01-01

340

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

PubMed Central

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

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

2015-01-01

341

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

PubMed

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

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

2015-01-01

342

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

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

Otto, Christoph; Kaemmerer, Ulrike; Illert, Bertram; Muehling, Bettina; Pfetzer, Nadja; Wittig, Rainer; Voelker, Hans Ullrich; Thiede, Arnulf; Coy, Johannes F

2008-01-01

343

Human immunodeficiency virus (HIV)-infected tumor xenografts as an in vivo model for antiviral therapy: role of alpha/beta interferon in restriction of tumor growth in nude mice injected with HIV-infected U937 tumor cells.  

PubMed Central

The host factors involved in the restriction of tumor growth were studied in nude mice transplanted with a cloned line of chronically human immunodeficiency virus (HIV)-infected U937 cells. HIV-infected and uninfected U937 cells exhibited the same growth patterns in culture. However, HIV-infected cells were not tumorigenic when injected subcutaneously in nude mice, whereas large solid tumors were observed in mice injected with uninfected U937 cells. Injection of nude mice with antibody to alpha/beta interferon (IFN-alpha/beta) enabled HIV-infected U937 cells to grow progressively in approximately 90 to 100% of mice. HIV-infected U937 cells formed solid tumors in the majority (60 to 90%) of either immunosuppressed (splenectomized, irradiated, and anti-asialo-GM1-treated) or genetically immunodeficient (bg/nu/xid) nude mice. In mice treated with antibodies to IFN-alpha/beta with established HIV-positive tumors, a direct correlation was found between p24 antigenemia and tumor size. Treatment of established HIV-positive U937 cell tumors with human IFN-alpha or mouse IFN-alpha/beta resulted in a clear-cut inhibition of both tumor growth and p24 HIV antigenemia. In contrast, treatment with tumor necrosis factor alpha markedly inhibited tumor growth but did not significantly decrease serum p24 levels. 3'-Azido-3'-deoxythymidine treatment did not affect either tumor growth or the levels of serum p24 antigen. These data indicate that endogenous IFN-alpha/beta is a crucial factor in the restriction of both tumor growth and p24 antigenemia in mice injected with HIV-infected tumor cells. Moreover, the results suggest that the development of HIV-1 p24 antigenemia in athymic immunosuppressed mice may represent an interesting in vivo model for anti-HIV therapy. Images PMID:1901915

Puddu, P; Locardi, C; Sestili, P; Varano, F; Petrini, C; Modesti, A; Masuelli, L; Gresser, I; Belardelli, F

1991-01-01

344

Platelet-associated PF-4 as a biomarker of early tumor growth.  

PubMed

Early tumor detection and intervention are important determinants of survival in patients with cancer. We have recently reported that the "platelet angiogenesis proteome" may be used to detect microscopic tumors in mice. We now present evidence that changes in platelet-associated platelet factor-4 (PF-4) detect malignant growth across a spectrum of human cancers in mice. A deregulated expression of an 8206-Da protein was observed by surfaceenhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-ToF MS) proteomic comparison of platelets from normal and tumor-bearing mice. The differentially expressed protein was identified as PF-4 by tandem mass spectrometry and ProteinChip immunoassay using anti-PF-4 antibody. The platelet-associated PF-4 appeared to be up-regulated in early growth of human liposarcoma, mammary adenocarcinoma, and osteosarcoma. A 120-day follow-up study of liposarcoma revealed a sustained 2-fold or higher increase of platelet-associated PF-4 at 19, 30, and 120 days. In contrast, only an insignificant change of PF-4 was observed in the plasma of mice bearing the different human tumor xenografts, and throughout the 120 days of the liposarcoma study. We conclude that platelet-associated PF-4, but not its plasma counterpart, may represent a potential biomarker of early tumor presence. PMID:17914028

Cervi, David; Yip, Tai-Tung; Bhattacharya, Nandita; Podust, Vladimir N; Peterson, Jon; Abou-Slaybi, Abdo; Naumov, George N; Bender, Elise; Almog, Nava; Italiano, Joseph E; Folkman, Judah; Klement, Giannoula L

2008-02-01

345

Growth Rate Analysis and Efficient Experimental Design for Tumor Xenograft Studies  

PubMed Central

Human tumor xenograft studies are the primary means to evaluate the biological activity of anticancer agents in late-stage preclinical drug discovery. The variability in the growth rate of human tumors established in mice and the small sample sizes make rigorous statistical analysis critical. The most commonly used summary of antitumor activity for these studies is the T/C ratio. However, alternative methods based on growth rate modeling can be used. Here, we describe a summary metric called the rate-based T/C, derived by fitting each animal’s tumor growth to a simple exponential model. The rate-based T/C uses all of the data, in contrast with the traditional T/C, which only uses a single measurement. We compare the rate-based T/C with the traditional T/C and assess their performance through a bootstrap analysis of 219 tumor xenograft studies. We find that the rate-based T/C requires fewer animals to achieve the same power as the traditional T/C. We also compare 14-day studies with 21-day studies and find that 14-day studies are more cost efficient. Finally, we perform a power analysis to determine an appropriate sample size. PMID:25574127

Hather, Gregory; Liu, Ray; Bandi, Syamala; Mettetal, Jerome; Manfredi, Mark; Shyu, Wen-Chyi; Donelan, Jill; Chakravarty, Arijit

2014-01-01

346

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.  

PubMed

Lipid phosphate phosphatase-1 (LPP1) degrades lysophosphatidate (LPA) and attenuates receptor-mediated signaling. LPP1 expression is low in many cancer cells and tumors compared with normal tissues. It was hypothesized from studies with cultured cells that increasing LPP1 activity would decrease tumor growth and metastasis. This hypothesis has never been tested in vivo. To do this, we inducibly expressed LPP1 or a catalytically inactive mutant in cancer cells. Expressing active LPP1 increased extracellular LPA degradation by 5-fold. It also decreased the stimulation of Ca(2+) transients by LPA, a nondephosphorylatable LPA1/2 receptor agonist and a protease-activated receptor-1 peptide. The latter results demonstrate that LPP1 has effects downstream of receptor activation. Decreased Ca(2+) mobilization and Rho activation contributed to the effects of LPP1 in attenuating the LPA-induced migration of MDA-MB-231 breast cancer cells and their growth in 3D culture. Increasing LPP1 expression in breast and thyroid cancer cells decreased tumor growth and the metastasis by up to 80% compared with expression of inactive LPP1 or green fluorescent protein in syngeneic and xenograft mouse models. The present work demonstrates for the first time that increasing the LPP1 activity in three lines of aggressive cancer cells decreases their abilities to produce tumors and metastases in mice. PMID:25210149

Tang, Xiaoyun; Benesch, Matthew G K; Dewald, Jay; Zhao, Yuan Y; Patwardhan, Neeraj; Santos, Webster L; Curtis, Jonathan M; McMullen, Todd P W; Brindley, David N

2014-11-01

347

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis  

PubMed Central

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

XIAN, SHU-LIN; CAO, WEI; ZHANG, XIAO-DONG; LU, YUN-FEI

2015-01-01

348

Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity  

PubMed Central

Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis to ensure delivery of oxygen, nutrients, and growth factors to tumor cells and provide access to the systemic circulation. Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes that mediate many of the adaptive responses to decreased oxygen concentration, such as enhanced glucose uptake and formation of new blood vessels. Acting through Plexin-B1 on endothelial cells, Semaphorin 4D (Sema4D) has been shown to promote angiogenesis and enhance invasive growth and proliferation in some tumors. Here we show that the gene for Sema4D, the product of which is elevated in head and neck squamous cell carcinoma (HNSCC) cells, contains upstream hypoxia response elements (HRE) and is strongly induced in hypoxia in a HIF-1-dependent manner. Knocking down Sema4D expression with short hairpin (sh) RNA reduces in vitro endothelial cell migration and growth and vascularity of HNSCC xenografts expressing a degradation resistant HIF-1? subunit. We also demonstrate a correlation between HIF-1 activity and Sema4D expression in HNSCC specimens. These findings indicate that Sema4D is induced by hypoxia in a HIF-1-dependent manner and influences endothelial cell migration and tumor vascularity. Expression of Sema4D may be a strategy by which carcinomas promote angiogenesis and therefore could represent a therapeutic target for these malignancies. PMID:19762474

Sun, Qiangming; Zhou, Hua; Binmadi, Nada O.; Basile, John R.

2009-01-01

349

Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer  

PubMed Central

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment. PMID:24646915

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

2014-01-01

350

Over-expression of platelet-derived growth factor-D promotes tumor growth and invasion in endometrial cancer.  

PubMed

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment. PMID:24646915

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

2014-01-01

351

The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models  

PubMed Central

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. PMID:25256830

Bladt, Friedhelm; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree

2014-01-01

352

Functional Collaboration between Different Cyclin-Dependent Kinase Inhibitors Suppresses Tumor Growth with Distinct Tissue Specificity  

PubMed Central

The presence of two families of seven distinct mammalian cyclin-dependent kinase (CDK) inhibitor genes is thought to mediate the complexity of connecting a variety of cellular processes to the cell cycle control pathway. The distinct pattern of tissue expression of CDK inhibitor genes suggests that they may function as tumor suppressors with different tissue specificities. To test this hypothesis, we have characterized two strains of double mutant mice lacking either p18INK4c and p27KIP1 or p18INK4c and p21CIP1/WAF1. Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach. Six of these hyperplastic tissues and tumors were in endocrine organs, and several types of tumors routinely developed within the same animal, a phenotype reminiscent of that seen in combined human multiple endocrine neoplasia syndromes. The p18-p21 double null mice, on the other hand, developed pituitary adenomas, multifocal gastric neuroendocrine hyperplasia, and lung bronchioalveolar tumors later in life. G1 CDK2 and CDK4 kinase activities were increased in both normal and neoplastic tissues derived from mice lacking individual CDK inhibitors and were synergistically stimulated by the simultaneous loss of two CDK inhibitors. This indicates that an increase in G1 CDK kinase activity is a critical step during but is not sufficient for tumor growth. Our results suggest that functional collaborations between distinct CDK inhibitor genes are tissue specific and confer yet another level of regulation in cell growth control and tumor suppression. PMID:10913196

Franklin, David S.; Godfrey, Virginia L.; O'Brien, Deborah A.; Deng, Chuxia; Xiong, Yue

2000-01-01

353

The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models.  

PubMed

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. PMID:25256830

Bladt, Friedhelm; Friese-Hamim, Manja; Ihling, Christian; Wilm, Claudia; Blaukat, Andree

2014-01-01

354

Paracrine activation of WNT/?-catenin pathway in uterine leiomyoma stem cells promotes tumor growth  

PubMed Central

Uterine leiomyomas are extremely common estrogen and progesterone-dependent tumors of the myometrium and cause irregular uterine bleeding, severe anemia, and recurrent pregnancy loss in 15–30% of reproductive-age women. Each leiomyoma is thought to arise from a single mutated myometrial smooth muscle stem cell. Leiomyoma side-population (LMSP) cells comprising 1% of all tumor cells and displaying tumor-initiating stem cell characteristics are essential for estrogen- and progesterone-dependent in vivo growth of tumors, although they have remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells. However, how estrogen/progesterone regulates the growth of LMSP cells via mature neighboring cells is unknown. Here, we demonstrate a critical paracrine role of the wingless-type (WNT)/?-catenin pathway in estrogen/progesterone-dependent tumorigenesis, involving LMSP and differentiated myometrial or leiomyoma cells. Estrogen/progesterone treatment of mature myometrial cells induced expression of WNT11 and WNT16, which remained constitutively elevated in leiomyoma tissues. In LMSP cells cocultured with mature myometrial cells, estrogen-progesterone selectively induced nuclear translocation of ?-catenin and induced transcriptional activity of its heterodimeric partner T-cell factor and their target gene AXIN2, leading to the proliferation of LMSP cells. This effect could be blocked by a WNT antagonist. Ectopic expression of inhibitor of ?-catenin and T-cell factor 4 in LMSP cells, but not in mature leiomyoma cells, blocked the estrogen/progesterone-dependent growth of human tumors in vivo. We uncovered a paracrine role of the WNT/?-catenin pathway that enables mature myometrial or leiomyoma cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone, leading to the growth of uterine leiomyomas. PMID:24082114

Ono, Masanori; Yin, Ping; Navarro, Antonia; Moravek, Molly B.; Coon, John S.; Druschitz, Stacy A.; Serna, Vanida Ann; Qiang, Wenan; Brooks, David C.; Malpani, Saurabh S.; Ma, Jiajia; Ercan, Cihangir Mutlu; Mittal, Navdha; Monsivais, Diana; Dyson, Matthew T.; Yemelyanov, Alex; Maruyama, Tetsuo; Chakravarti, Debabrata; Kim, J. Julie; Kurita, Takeshi; Gottardi, Cara J.; Bulun, Serdar E.

2013-01-01

355

Paracrine activation of WNT/?-catenin pathway in uterine leiomyoma stem cells promotes tumor growth.  

PubMed

Uterine leiomyomas are extremely common estrogen and progesterone-dependent tumors of the myometrium and cause irregular uterine bleeding, severe anemia, and recurrent pregnancy loss in 15-30% of reproductive-age women. Each leiomyoma is thought to arise from a single mutated myometrial smooth muscle stem cell. Leiomyoma side-population (LMSP) cells comprising 1% of all tumor cells and displaying tumor-initiating stem cell characteristics are essential for estrogen- and progesterone-dependent in vivo growth of tumors, although they have remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells. However, how estrogen/progesterone regulates the growth of LMSP cells via mature neighboring cells is unknown. Here, we demonstrate a critical paracrine role of the wingless-type (WNT)/?-catenin pathway in estrogen/progesterone-dependent tumorigenesis, involving LMSP and differentiated myometrial or leiomyoma cells. Estrogen/progesterone treatment of mature myometrial cells induced expression of WNT11 and WNT16, which remained constitutively elevated in leiomyoma tissues. In LMSP cells cocultured with mature myometrial cells, estrogen-progesterone selectively induced nuclear translocation of ?-catenin and induced transcriptional activity of its heterodimeric partner T-cell factor and their target gene AXIN2, leading to the proliferation of LMSP cells. This effect could be blocked by a WNT antagonist. Ectopic expression of inhibitor of ?-catenin and T-cell factor 4 in LMSP cells, but not in mature leiomyoma cells, blocked the estrogen/progesterone-dependent growth of human tumors in vivo. We uncovered a paracrine role of the WNT/?-catenin pathway that enables mature myometrial or leiomyoma cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone, leading to the growth of uterine leiomyomas. PMID:24082114

Ono, Masanori; Yin, Ping; Navarro, Antonia; Moravek, Molly B; Coon, John S; Druschitz, Stacy A; Serna, Vanida Ann; Qiang, Wenan; Brooks, David C; Malpani, Saurabh S; Ma, Jiajia; Ercan, Cihangir Mutlu; Mittal, Navdha; Monsivais, Diana; Dyson, Matthew T; Yemelyanov, Alex; Maruyama, Tetsuo; Chakravarti, Debabrata; Kim, J Julie; Kurita, Takeshi; Gottardi, Cara J; Bulun, Serdar E

2013-10-15

356

Stanford researchers find antibody hinders growth of Gleevec-resistant gastrointestinal tumors in lab tests  

Cancer.gov

An antibody that binds to a molecule on the surface of a rare but deadly tumor of the gastrointestinal tract inhibits the growth of the cancer cells in mice, according to researchers at the Stanford University School of Medicine (home of the Stanford Cancer Institute). The effect remains even when the cancer cells have become resistant to other treatments, and the findings may one day provide a glimmer of hope for people with the cancer, known as gastrointestinal stromal tumor, or GIST. The scientists hope to move into human clinical trials of the antibody within two years.

357

Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram  

NASA Astrophysics Data System (ADS)

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.

Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

2014-03-01

358

Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of BRAFV600E–Driven Lung Tumors  

PubMed Central

Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BRAFV600E-induced lung cancer in the presence or absence of the tumor suppressor TRP53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect suggesting that both genes modulate tumorigenesis by regulating oxidative stress, revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse lifespan. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire, survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BRAFV600E-tumor growth and metabolism. PMID:23965987

Strohecker, Anne M.; Guo, Jessie Yanxiang; Karsli-Uzunbas, Gizem; Price, Sandy M.; Chen, Guanghua Jim; Mathew, Robin; McMahon, Martin; White, Eileen

2013-01-01

359

HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization.  

PubMed

The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor-1? (HIF1?) and activation of NF-?B in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1? and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-?B/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth. PMID:25297628

Azoitei, Ninel; Diepold, Kristina; Brunner, Cornelia; Rouhi, Arefeh; Genze, Felicitas; Becher, Alexander; Kestler, Hans; van Lint, Johan; Chiosis, Gabriela; Koren, John; Fröhling, Stefan; Scholl, Claudia; Seufferlein, Thomas

2014-12-01

360

Oncogenic KRAS desensitizes colorectal tumor cells to epidermal growth factor receptor inhibition and activation.  

PubMed

Epidermal growth factor receptor (EGFR)-targeting therapeutics have shown efficacy in the treatment of colorectal cancer patients. Clinical studies have revealed that activating mutations in the KRAS protooncogene predict resistance to EGFR-targeted therapy. However, the causality between mutant KRAS and resistance to EGFR inhibition has so far not been demonstrated. Here, we show that deletion of the oncogenic KRAS allele from colorectal tumor cells resensitizes those cells to EGFR inhibitors. Resensitization was accompanied by an acquired dependency on the EGFR for maintaining basal extracellular signal-regulated kinase (ERK) activity. Deletion of oncogenic KRAS not only resensitized tumor cells to EGFR inhibition but also promoted EGF-induced NRAS activation, ERK and AKT phosphorylation, and c-FOS transcription. The poor responsiveness of mutant KRAS tumor cells to EGFR inhibition and activation was accompanied by a reduced capacity of these cells to bind and internalize EGF and by a failure to retain EGFR at the plasma membrane. Of 16 human colorectal tumors with activating mutations in KRAS, 15 displayed loss of basolateral EGFR localization. Plasma membrane localization of the EGFR could be restored in vitro by suppressing receptor endocytosis through Rho kinase inhibition. This caused an EGFR-dependent increase in basal and EGF-stimulated ERK phosphorylation but failed to restore tumor cell sensitivity to EGFR inhibition. Our results demonstrate a causal role for oncogenic KRAS in desensitizing tumor cells not only to EGFR inhibitors but also to EGF itself. PMID:20563247

van Houdt, Winan J; Hoogwater, Frederik J H; de Bruijn, Menno T; Emmink, Benjamin L; Nijkamp, Maarten W; Raats, Danielle A E; van der Groep, Petra; van Diest, Paul; Borel Rinkes, Inne H M; Kranenburg, Onno

2010-06-01

361

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

SciTech Connect

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.

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

362

[Possibilities of cytostatic therapy in adenocarcinoma of the kidney. I. Influence of vinblastine on the growth of transplanted tumors].  

PubMed

The effect of vinblastine sulfate on the acceptance and growth of a very malignant, human adenocarcinoma of the kidney (RCCI) on nude mice was investigated. Without any treatment, this tumor has an acceptance rate of 100%. Subcutaneously transplanted pieces of tumor, measuring 3 X 3 X 1 mm, commence to grow rapidly 1 week after transplantation and reach a diameter of approximately 2 cm, 6 weeks thereafter. Tumors with a diameter of approximately 2 cm, treated during 6 weeks with vinblastine (0.6 mg/kg/week), continued to grow during treatment and thereafter. However, when these growing, pretreated tumors were transplanted on new experimental animals, they either were not accepted by them or grew very slowly. When animals with tumor transplants were treated for 6 weeks with vinblastine (same schedule as above), beginning on the 1st day after transplantation, tumor growth was markedly retarded in every case, but only very seldom the tumor was not accepted. PMID:7281370

Köllermann, M W; Otto, U; Dimigen, J

1981-01-01

363

tumors  

E-print Network

Background: To investigate the role of maspin expression in the progression of gastrointestinal stromal tumors, and its value as a prognostic indicator. Methods: In the study 54 patients with GIST diagnosis were included in Uludag University of Faculty of Medicine, Department of Pathology between 1997-2007. The expression of maspin in 54 cases of gastrointestinal stromal tumor was detected by immunohistochemistry and compared with the clinicopathologic tumor parameters. Results: The positive expression rates for maspin in the GISTs were 66,6 % (36 of 54 cases). Maspin overexpression was detected in 9 of 29 high risk tumors (31%) and was significantly higher in very low/low (78.6%) and intermediate-risk tumors (63.6%) than high-risk tumors. Conclusions: Maspin expression might be an important factor in tumor progression and patient prognosis in GIST. In the future, larger series may be studied to examine the prognostic significance of maspin in GISTs and, of course, maspin expression may be studied in different mesenchymal tumors. Background Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal

364

tumors  

E-print Network

Background: According to the scientific literature, less than 30 borderline ovarian tumors have been karyotyped and less than 100 analyzed for genomic imbalances by CGH. Methods: We report a series of borderline ovarian tumors (n = 23) analyzed by G-banding and karyotyping as well as high resolution CGH; in addition, the tumors were analyzed for microsatellite stability status and by FISH for possible 6q deletion. Results: All informative tumors were microsatellite stable and none had a deletion in 6q27. All cases with an abnormal karyotype had simple chromosomal aberrations with +7 and +12 as the most common. In three tumors with single structural rearrangements, a common breakpoint in 3q13 was detected. The major copy number changes detected in the borderline tumors were gains from chromosome arms 2q, 6q, 8q, 9p, and 13q and losses from 1p, 12q, 14q, 15q, 16p, 17p, 17q, 19p, 19q, and 22q. The series included five pairs of bilateral tumors and, in two of these pairs, informative data were obtained as to their clonal relationship. In both pairs, similarities were found between the tumors from the right and left side, strongly indicating that bilaterality had occurred via a metastatic process. The bilateral tumors as a group showed more aberrations than did the unilateral ones, consistent with the view that bilaterality is a sign of more advanced disease. Conclusion: Because some of the imbalances found in borderline ovarian tumors seem to be similar to imbalances already known from the more extensively studied overt ovarian carcinomas, we speculate that the subset of borderline tumors with detectable imbalances or karyotypic aberrations may contain a smaller subset of tumors with a tendency to develop a more malignant phenotype. The group of borderline tumors with no imbalances would, in this line of thinking, have less or no propensity for clonal evolution and development to full-blown carcinomas.

365

Inhibition of xenograft human glioma tumor growth by lentivirus-mediated gene transfer of alphastatin.  

PubMed

Angiogenesis is crucial for the development and metastasis of human brain glioma. Based on our previous successful construction of a lentivirus-mediated alphastatin (an endogenous angiogenesis inhibitor) gene transfer system and our findings that alphastatin exhibited potent inhibitory effects on the migration and differentiation of human umbilical vein endothelial cell lines (HUVECs) induced by vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in vitro, here, we investigated the effect of using lentiviral vectors to overexpress alphastatin in human glioma cells to show whether sustained long-term expression of alphastatin diminishes tumor growth in a xenograft glioma model. We found that the transduced glioma cells sustainedly secreted alphastatin, which did not affect the proliferative ability of the glioma cells. Furthermore, tumor xenografts treated with the recombinant lentivirus were significantly smaller compared to the control xenografts and vascularity within the treated tumors was evidently decreased. Our data suggest that stable expression of alphastatin inhibits human glioma growth by inhibiting angiogenesis, with a probable mechanism of suppressing the turnover of VE-cadherin membrane molecules. PMID:23242200

Che, Hongmin; Song, Jianrong; Guo, Shiwen; Wang, Weiwen; Gao, Guodong

2013-03-01

366

A New Ghost Cell/Level Set Method for Moving Boundary Problems: Application to Tumor Growth  

PubMed Central

In this paper, we present a ghost cell/level set method for the evolution of interfaces whose normal velocity depend upon the solutions of linear and nonlinear quasi-steady reaction-diffusion equations with curvature-dependent boundary conditions. Our technique includes a ghost cell method that accurately discretizes normal derivative jump boundary conditions without smearing jumps in the tangential derivative; a new iterative method for solving linear and nonlinear quasi-steady reaction-diffusion equations; an adaptive discretization to compute the curvature and normal vectors; and a new discrete approximation to the Heaviside function. We present numerical examples that demonstrate better than 1.5-order convergence for problems where traditional ghost cell methods either fail to converge or attain at best sub-linear accuracy. We apply our techniques to a model of tumor growth in complex, heterogeneous tissues that consists of a nonlinear nutrient equation and a pressure equation with geometry-dependent jump boundary conditions. We simulate the growth of glioblastoma (an aggressive brain tumor) into a large, 1 cm square of brain tissue that includes heterogeneous nutrient delivery and varied biomechanical characteristics (white matter, gray matter, cerebrospinal fluid, and bone), and we observe growth morphologies that are highly dependent upon the variations of the tissue characteristics—an effect observed in real tumor growth. PMID:21331304

Macklin, Paul

2011-01-01

367

Oridonin inhibits tumor growth in glioma by inducing cell cycle arrest and apoptosis.  

PubMed

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

Zhang, X-H; Liu, Y-X; Jia, M; Han, J-S; Zhao, M; Ji, S-P; Li, A-M

2014-01-01

368

Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing  

PubMed Central

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

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

369

Digital holographic microscopy for imaging growth and treatment response in 3D tumor models  

NASA Astrophysics Data System (ADS)

While three-dimensional tumor models have emerged as valuable tools in cancer research, the ability to longitudinally visualize the 3D tumor architecture restored by these systems is limited with microscopy techniques that provide only qualitative insight into sample depth, or which require terminal fixation for depth-resolved 3D imaging. Here we report the use of digital holographic microscopy (DHM) as a viable microscopy approach for quantitative, non-destructive longitudinal imaging of in vitro 3D tumor models. Following established methods we prepared 3D cultures of pancreatic cancer cells in overlay geometry on extracellular matrix beds and obtained digital holograms at multiple timepoints throughout the duration of growth. The holograms were digitally processed and the unwrapped phase images were obtained to quantify nodule thickness over time under normal growth, and in cultures subject to chemotherapy treatment. In this manner total nodule volumes are rapidly estimated and demonstrated here to show contrasting time dependent changes during growth and in response to treatment. This work suggests the utility of DHM to quantify changes in 3D structure over time and suggests the further development of this approach for time-lapse monitoring of 3D morphological changes during growth and in response to treatment that would otherwise be impractical to visualize.

Li, Yuyu; Petrovic, Ljubica; Celli, Jonathan P.; Yelleswarapu, Chandra S.

2014-03-01

370

The Epstein-Barr Virus Encoded BART miRNAs Potentiate Tumor Growth In Vivo  

PubMed Central

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

Qiu, Jin; Smith, Pamela; Leahy, Leah; Thorley-Lawson, David A.

2015-01-01

371

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

NASA Astrophysics Data System (ADS)

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

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

1981-02-01

372

Transduction of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand into Hematopoietic Cells Leads to Inhibition of Syngeneic Tumor Growth In vivo  

PubMed Central

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell death in many types of tumor and transformed cells but not in normal cells. This tumor-selective property has made TRAIL a promising candidate for the development of cancer therapy. However, safety issues are a concern because certain preparations of recombinant TRAIL protein were reported to induce toxicity in normal human hepatocytes in culture. In addition, previous studies on tumor selectivity of exogenous TRAIL protein were carried out in xenograft models, which do not directly address the tumor selectivity issue. It was not known whether exogenous or overexpression of TRAIL in a syngeneic system could induce tumor cell death while leaving normal tissue cells unharmed. Thus, the tumor selectivity of TRAIL-induced apoptosis remains to be further characterized. In our study, we established mice that overexpress TRAIL by retroviral-mediated gene transfer in bone marrowcells followed by bone marrow transplantation. Our results show that TRAIL overexpression is not toxic to normal tissues, as analyzed by hematologic and histologic analyses of tissue samples from TRAIL-transduced mice. We show for the first time that TRAIL overexpression in hematopoietic cells leads to significant inhibition of syngeneic tumor growth in certain tumor lines. This approach may be used further to identify important molecules that regulate the sensitivity of tumor cells to TRAIL-induced cell death in vivo. PMID:16778207

Song, Keli; Benhaga, Nordine; Anderson, Robin L.; Khosravi-Far, Roya

2010-01-01

373

Effects of increasing doses of a bolus injection and an intravenous long-term therapy of taurolidine on subcutaneous (metastatic) tumor growth in rats  

Microsoft Academic Search

Background experimental studies have shown that taurolidine suppresses intraperitoneal tumor growth following local application in rats. In opposite, a single intravenous therapy affected neither intraperitoneal nor subcutaneous growth of malignancies. Thus, an intravenous long-term therapy with taurolidine was investigated in rats after administration of a subcutaneous tumor load. VEGF and TNF? production and their effects on tumor growth have not

Chris Braumann; Marco Schoenbeck; Charalambos Menenakos; Maik Kilian; Christoph A. Jacobi

2005-01-01

374

Evaluation and Comparison of Vascular Endothelial Growth Factor Expression between Ameloblastoma and Keratocystic Odontogenic Tumor  

PubMed Central

Background: Odontogenic keratocyst (OKC) is a developmental odontogenic cyst with an aggressive clinical behavior suggesting a change in its terminology from a cyst to a tumor and has now been renamed as keratocystic odontogenic tumor (KCOT). The purpose of this study was to assess and compare angiogenesis in ameloblastoma and OKC. Materials and Methods: Angiogenesis was assessed by studying the immunohistochemical expression of vascular endothelial growth factor (VEGF). The study samples included 15 ameloblastomas and 15 KCOTs. The immunoreactivity was statistically evaluated using Mann–Whitney U-test. Results: VEGF expression was higher in ameloblastoma than KCOTs. However, a non-significant difference of VEGF expression was noted between ameloblastoma and KCOTs (P = 0.345). Conclusion: The results suggest that tumor angiogenesis may play a significant role in aggressive biologic behavior of KCOT. Thus, angiogenesis could be a potent target for developing anatiangiogenic therapeutic strategies. PMID:25709368

Dineshkumar, Thayalan; Priyadharsini, Nataraj; Gnanaselvi, U Punitha; Sathishkumar, Srinivasan; Srikanth, R P; Nagarathinam, A E

2015-01-01

375

Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth.  

PubMed

Antiangiogenic tumor therapy has failed in the adjuvant setting. Here we show that inhibition of the Tie2 ligand angiopoietin-2 (Ang2) effectively blocks metastatic growth in preclinical mouse models of postsurgical adjuvant therapy. Ang2 antibody treatment combines well with low-dose metronomic chemotherapy (LDMC) in settings in which maximum-dose chemotherapy does not prove effective. Mechanistically, Ang2 blockade could be linked to quenching the inflammatory and angiogenic response of endothelial cells (ECs) in the metastatic niche. Reduced EC adhesion molecule and chemokine expression inhibits the recruitment of tumor-promoting CCR2(+)Tie2(-) metastasis-associated macrophages. Moreover, LDMC contributes to therapeutic efficacy by inhibiting the recruitment of protumorigenic bone marrow-derived myeloid cells. Collectively, these data provide a rationale for mechanism-guided adjuvant tumor therapies. PMID:25490450

Srivastava, Kshitij; Hu, Junhao; Korn, Claudia; Savant, Soniya; Teichert, Martin; Kapel, Stephanie S; Jugold, Manfred; Besemfelder, Eva; Thomas, Markus; Pasparakis, Manolis; Augustin, Hellmut G

2014-12-01

376

A tissue-engineered therapeutic device inhibits tumor growth in vitro and in vivo.  

PubMed

Bone metastasis is one of the leading causes of death in breast cancer patients. The current treatment is performed as a palliative therapy and the adverse side effects can compromise the patients' quality of life. In order to both effectively treat bone metastasis and avoid the limitation of current strategies, we have invented a drug eluting scaffold with clay matrix release doxorubicin (DESCLAYMR_DOX) to mechanically support the structure after resecting the metastatic tissue while also releasing the anticancer drug doxorubicin which supplements growth inhibition and elimination of the remaining tumor cells. We have previously demonstrated that this device has the capacity to regenerate the bone and provide sustained release of the anticancer drug in vitro. In this study, we focus on the ability of the device to inhibit cancer cell growth in vitro as well as in vivo. Drug-release kinetics was investigated and the cell viability test showed that the tumor inhibitory effect is sustained for up to 4weeks in vitro. Subcutaneous implantation of DESCLAYMR_DOX in athymic mice resulted in significant growth inhibition of human tumor xenografts of breast origin and decelerated multi-organ metastasis formation. Fluorescence images, visualizing doxorubicin, showed a sustained drug release from the DESCLAYMR device in vivo. Furthermore, local use of DESCLAYMR_DOX implantation reduced the incidence of doxorubicin's cardio-toxicity. These results suggest that DESCLAYMR_DOX can be used in reconstructive surgery to support the structure after bone tumor resection and facilitate a sustained release of anticancer drugs in order to prevent tumor recurrence. PMID:25686557

Sun, Ming; Wang, Miao; Chen, Muwan; Dagnaes-Hansen, Frederik; Le, Dang Quang Svend; Baatrup, Anette; Horsman, Michael R; Kjems, Jørgen; Bünger, Cody Eric

2015-05-01

377

Copper Transporter 2 Regulates Endocytosis and Controls Tumor Growth and Sensitivity to Cisplatin In Vivo  

PubMed Central

Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using a short hairpin RNA interference. Robust expression of CTR2 was observed in parental tumors grown in vivo, whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells, and decreased the vascular density, but it did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cis-diamminedichloroplatinum(II) [cisplatin (cDDP)] by 9.1-fold and greatly increased its therapeutic efficacy. Because altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake 2.5-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by platelet-derived growth factor coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1 and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc42. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP. PMID:20930109

Blair, Brian G.; Larson, Christopher A.; Adams, Preston L.; Abada, Paolo B.; Pesce, Catherine E.; Safaei, Roohangiz

2011-01-01

378

LITAF and TNFSF15, two downstream targets of AMPK, exert inhibitory effects on tumor growth.  

PubMed

Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) ? factor (LITAF) is a multiple functional molecule whose sequence is identical to the small integral membrane protein of the lysosome/late endosome. LITAF was initially identified as a transcription factor that activates transcription of proinflammatory cytokine in macrophages in response to LPS. Mutations of the LITAF gene are associated with a genetic disease, called Charcot-Marie-Tooth syndrome. Recently, we have reported that mRNA levels of LITAF and TNF superfamily member 15 (TNFSF15) are upregulated by 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK). The present study further assesses their biological functions. Thus, we show that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator of AMPK, increases the abundance of LITAF and TNFSF15 in LNCaP and C4-2 prostate cancer cells, which is abrogated by small hairpin RNA (shRNA) or the dominant-negative mutant of AMPK ?1 subunit. Our data further demonstrate that AMPK activation upregulates the transcription of LITAF. Intriguingly, silencing LITAF by shRNA enhances proliferation, anchorage-independent growth of these cancer cells and tumor growth in the xenograft model. In addition, our study reveals that LITAF mediates the effect of AMPK by binding to a specific sequence in the promoter region. Furthermore, we show that TNFSF15 remarkably inhibits the growth of prostate cancer cells and bovine aortic endothelial cells in vitro, with a more potent effect toward the latter. In conjuncture, intratumoral injection of TNFSF15 significantly reduces the size of tumors and number of blood vessels and induces changes that are characteristic of tumor cell differentiation. Therefore, our studies for the first time establish the regulatory axis of AMPK-LITAF-TNFSF15 and also suggest that LITAF may function as a tumor suppressor. PMID:21217782

Zhou, J; Yang, Z; Tsuji, T; Gong, J; Xie, J; Chen, C; Li, W; Amar, S; Luo, Z

2011-04-21

379

Inhibition of Notch Signaling in Combination with Paclitaxel Reduces Platinum-Resistant Ovarian Tumor Growth  

PubMed Central

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

Groeneweg, Jolijn W.; DiGloria, Celeste M.; Yuan, Jing; Richardson, William S.; Growdon, Whitfield B.; Sathyanarayanan, Sriram; Foster, Rosemary; Rueda, Bo R.

2014-01-01

380

STAT3 silencing inhibits glioma single cell infiltration and tumor growth  

PubMed Central

Background Diffuse infiltration remains the fulcrum of glioblastoma's incurability, leading inevitably to recurrence. Therefore, uncovering the pathological mechanism is imperative. Because signal transducer and activator of transcription 3 (STAT3) correlates with glioma malignancy and predicts poor clinical outcome, we determined its role in glioma single cell infiltration and tumor growth. Methods STAT3 was silenced in Tu-2449 glioma cells via lentiviral gene transfer. Target gene expression was measured by real-time reverse transcription PCR, Western blotting, and immunohistochemistry. Microvilli were visualized by staining with wheat germ agglutinin. Migration and invasion were measured by Scratch and Matrigel chamber assays. Diffuse infiltration was studied in 350-?m-thick organotypic tissue cultures over 14 days using cells tagged with enhanced green fluorescent protein and live confocal laser scanning microscopy. Survival of tumor-bearing syngeneic, immunocompetent B6C3F1 mice was analyzed by Kaplan–Meier plots. Results STAT3 silencing reduced cell migration and invasion in vitro and stopped single cell infiltration ex vivo, while STAT3-expressing cells disseminated through the neuropil at ?100 µm/day. STAT3 silencing reduced transcription of several tumor progression genes. Mice with intracranial STAT3 knockdown tumors had a significant (P< .0007) survival advantage over controls, yielding 27% long-term survival. STAT3 knockdown reduced podoplanin expression 50-fold and inhibited concurrent microvilli formation. STAT3 knockdown tumors exhibited a weaker podoplanin immunoreactivity compared with controls. Podoplanin staining was diffuse, preferentially at tumor margins, and absent in normal brain. Conclusions Our results show compelling evidence that STAT3 is a key driver of diffuse infiltration and glioma growth and might therefore represent a promising target for an anti-invasive therapy. PMID:23486688

Priester, Maike; Copanaki, Ekaterini; Vafaizadeh, Vida; Hensel, Sandra; Bernreuther, Christian; Glatzel, Markus; Seifert, Volker; Groner, Bernd; Kögel, Donat; Weissenberger, Jakob