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1

Net growth delay: a novel parameter derived from tumor growth curves  

SciTech Connect

Growth delay does not only reflect the effect of treatment on the tumor parenchymal cells but also on the stroma. Due to tumor bed effect, the extent of growth delay determined from tumor growth curves is highly dependent on the end volume chosen. It was aimed to minimize the influence of the tumor bed effect on the growth delay calculated by choosing a smaller size and essentially an earlier time for regrowth. Net growth delay is a novel parameter derived from the tumor growth curves, allowing a better comparison of the results with colony assay and tumor control data.

Beck-Bornholdt, H.P.; Wuerschmidt, F.V.; Vogler, H.

1987-05-01

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

Short Hairpin RNA-Mediated Fibronectin Knockdown Delays Tumor Growth in a Mouse Glioma Model1  

PubMed Central

Glioblastoma multiforme is the most common and lethal primary brain tumor. Glioma progression depends on the rapid proliferation of tumor cells accompanied by an acute immunosuppressive environment, facilitated mainly by tumor infiltration of regulatory T cells (Tregs). In this study, we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and in mediating immunosuppression. Fibronectin binds to membrane-spanning integrin receptors and plays an important role in cell signaling, in defining cellular shape, in mobility, and in regulating the cell cycle. We found that inhibition of fibronectin expression in glioma cells, using short hairpin RNA-mediated silencing of gene expression, delayed cell proliferation in vitro. This delayed growth is explained, in part, by the observed reduced expression of integrin ?1 fibronectin receptor, which was restored by the inhibition of proteosomal activity. In our analysis of the downstream signaling targets of integrin ?1, we demonstrated reduced phosphorylation of Src kinase and STAT-3. We also observed reduced survivin expression that induced a three-fold increased accumulation of fibronectin-knockdown cells in the G2/M phase. In an experimental animal model, the fibronectin knockdown tumors had a mean survival advantage of 23 days over wild-type tumors. Moreover, brain samples of animals bearing fibronectin-knockdown tumors showed delayed Treg recruitment. Collectively, we propose that fibronectin is a key mediator of glioma progression because its inhibition delays both tumor progression and immunosuppression. PMID:20927322

Sengupta, Sadhak; Nandi, Suvobroto; Hindi, Enal S; Wainwright, Derek A; Han, Yu; Lesniak, Maciej S

2010-01-01

4

Silencing of Doublecortin-Like (DCL) Results in Decreased Mitochondrial Activity and Delayed Neuroblastoma Tumor Growth  

PubMed Central

Doublecortin-like (DCL) is a microtubule-binding protein crucial for neuroblastoma (NB) cell proliferation. We have investigated whether the anti-proliferative effect of DCL knockdown is linked to reduced mitochondrial activity. We found a delay in tumor development after DCL knockdown in vivo in doxycycline-inducible NB tumor xenografts. To understand the mechanisms underlying this tumor growth retardation we performed a series of in vitro experiments in NB cell lines. DCL colocalizes with mitochondria, interacts with the mitochondrial outer membrane protein OMP25/ SYNJ2BP and DCL knockdown results in decreased expression of genes involved in oxidative phosphorylation. Moreover, DCL knockdown decreases cytochrome c oxidase activity and ATP synthesis. We identified the C-terminal Serine/Proline-rich domain and the second microtubule-binding area as crucial DCL domains for the regulation of cytochrome c oxidase activity and ATP synthesis. Furthermore, DCL knockdown causes a significant reduction in the proliferation rate of NB cells under an energetic challenge induced by low glucose availability. Together with our previous studies, our results corroborate DCL as a key player in NB tumor growth in which DCL controls not only mitotic spindle formation and the stabilization of the microtubule cytoskeleton, but also regulates mitochondrial activity and energy availability, which makes DCL a promising molecular target for NB therapy. PMID:24086625

Verissimo, Carla S.; Elands, Rachel; Cheng, Sou; Saaltink, Dirk-Jan; ter Horst, Judith P.; Alme, Maria N.; Pont, Chantal; van de Water, Bob; Havik, Bjarte; Fitzsimons, Carlos P.; Vreugdenhil, Erno

2013-01-01

5

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

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

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

8

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

9

Secreted Protein Acidic and Rich in Cysteine Promotes Glioma Invasion and Delays Tumor Growth in Vivo1  

Microsoft Academic Search

Secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human astrocytomas, grades II-IV. We demonstrated previously that SPARC promotes invasion in vitro using the U87MG-derived clone U87T2 and U87T2-derived SPARC-transfected clones, A2b2, A2bi, and C2a4, in the spheroid confrontation assay. Additional in vitro studies demonstrated that SPARC delays growth, increases attachment, and modulates migration of tumor cells

Chad Schultz; Nancy Lemke; Shugang Ge; William A. Golembieski; Sandra A. Rempel

10

Antiangiogenesis therapy using a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay  

Microsoft Academic Search

Background  The present study investigated whether treatment with anginex, a novel antiangiogenic peptide, could block re-vascularization\\u000a after radiation treatment.\\u000a \\u000a \\u000a \\u000a Methods  A squamous cell (SCCVII) xenograft tumor mouse model was employed to assess the effects of anginex given post-radiation on\\u000a tumor growth, microvessel density (MVD), and oxygen levels. The oxygen status was determined by the partial pressure of O2.\\u000a \\u000a \\u000a \\u000a Results  Tumors in untreated mice

Morikazu Amano; Minoru Suzuki; Satoshi Andoh; Hajime Monzen; Kaoru Terai; Brent Williams; Chang W. Song; Kevin H. Mayo; Takeo Hasegawa; Ruud P. M. Dings; Robert J. Griffin

2007-01-01

11

Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling  

PubMed Central

Radiation-induced damage of normal tissues restricts the therapeutic doses of ionizing radiation that can be delivered to tumors and thereby limits the effectiveness of radiotherapy. Thrombospondin-1 signaling through its cell surface receptor CD47 limits recovery from several types of stress, and mice lacking either gene are profoundly resistant to radiation injury. We describe strategies to protect normal tissues from radiation damage using CD47 or thrombospondin-1 antibodies, a CD47-binding peptide, or antisense suppression of CD47. A morpholino oligonucleotide targeting CD47 confers radioresistance to human endothelial cells in vitro and protects soft tissue, bone marrow, and tumor-associated leukocytes in irradiated mice. In contrast, CD47 suppression in mice bearing melanoma or squamous lung tumors prior to irradiation result in 89% and 71% smaller tumors, respectively. Thus, inhibiting CD47 signaling maintains the viability of normal tissues following irradiation while increasing the radiosensitivity of tumors. PMID:20161613

Maxhimer, Justin B.; Soto-Pantoja, David R.; Ridnour, Lisa A; Shih, Hubert B.; DeGraff, William G.; Tsokos, Maria; Wink, David A.; Isenberg, Jeff S.; Roberts, David D.

2010-01-01

12

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

SciTech Connect

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

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

2008-11-01

13

Cordycepin-enriched Cordyceps militaris induces immunomodulation and tumor growth delay in mouse-derived breast cancer.  

PubMed

Cordyceps militaris (C. militaris) and its main functional component, cordycepin, has been shown to possess a number of pharmacological activities including immunological stimulation and antitumor effects. However, the pharmacological mechanisms of C. militaris on tumor immunity underlying its antitumor effect have yet to be elucidated. In the present study, we evaluated the antitumor and immunomodulatory effects of C. militaris on FM3A tumor-bearing C3H/He mice, comparing wild-type C. militaris and cordycepin-enriched C. militaris (JLM 0636). The concentration of cordycepin produced by crossbred JLM 0636 was 7.42 mg/g dry weight, which was 7-fold higher than that of wild-type C. militaris. Dietary administration of C. militaris revealed retardation of tumor growth as well as elongation of survival rates of tumor-bearing mice. This effect was more pronounced in JLM 0636. There was a cordycepin-dependent decrease in IL-2 and TGF-? secretion and an increase in IL-4 secretion without changes in the proliferative responses of concanavalin A-stimulated lymphocytes, which suggested that C. militaris feeding might induce changes in the subpopulations of tumor-derived T lymphocytes. CD4+CD25+ cell population was significantly reduced in the total splenocytes from JLM 0636-administered mice, while CD4+ T cell population remained unchanged. FoxP3+-expressing Treg cells among CD4+CD25+ population showed a similar pattern. On the contrary, CD8+ T cells as well as the IFN-? expressing CD8+ T cells from tumor-bearing mice were significantly upregulated by the administration of JLM 0636. These results demonstrated the suppressive role of JLM 0636 on the function of Treg cells contributing to tumor specific IFN-?-expressing CD8+ T cell responses in tumor-bearing mice, which explained the underlying mechanism of the antitumor immunity of cordycepin. Therefore, cordycepin-enriched C. militaris is a promising candidate for an adjuvant in cancer immunotherapy. PMID:23921598

Jeong, Min-Ho; Lee, Chang-Min; Lee, Sang-Wha; Seo, Su-Yeong; Seo, Min-Jeong; Kang, Byoung-Won; Jeong, Yong-Kee; Choi, Yoo-Jin; Yang, Kwang-Mo; Jo, Wol-Soon

2013-10-01

14

M867, a Novel Selective Inhibitor of Caspase-3 Enhances Cell Death and Extends Tumor Growth Delay in Irradiated Lung Cancer Models  

PubMed Central

Background Lung cancer remains the leading cause of cancer death worldwide. Radioresistance of lung cancer cells results in unacceptable rate of loco-regional failure. Although radiation is known to induce apoptosis, our recent study showed that knockdown of pro-apoptotic proteins Bak and Bax resulted in an increase in autophagic cell death and lung cancer radiosensitivity in vitro. To further explore the potential of apoptosis inhibition as a way to sensitize lung cancer for therapy, we tested M867, a novel chemical and reversible caspase-3 inhibitor, in combination with ionizing radiation in vivo and in vitro. Methods and Findings M867 reduced clonogenic survival in H460 lung cancer cells (DER?=?1.27, p?=?0.007) compared to the vehicle-treated treated cells. We found that administration of M867 with ionizing radiation in an in vivo mouse hind limb lung cancer model was well tolerated, and produced a significant tumor growth delay compared to radiation alone. A dramatic decrease in tumor vasculature was observed with M867 and radiation using von Willebrand factor staining. In addition, Ki67 index showed >5-fold reduction of tumor proliferation in the combination therapy group, despite the reduced levels of apoptosis observed with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Radiosensitizing effect of M867 through inhibiting caspases was validated using caspase-3/-7 double-knockout (DKO) mouse embryonic fibroblasts (MEF) cell model. Consistent with our previous study, autophagy contributed to the mechanism of increased cell death, following inhibition of apoptosis. In addition, matrigel assay showed a decrease in in vitro endothelial tubule formation during the M867/radiation combination treatment. Conclusions M867 enhances the cytotoxic effects of radiation on lung cancer and its vasculature both in vitro and in vivo. M867 has the potential to prolong tumor growth delay by inhibiting tumor proliferation. Clinical trials are needed to determine the potential of this combination therapy in patients with locally advanced lung cancer. PMID:18509530

Lu, Bo

2008-01-01

15

In vivo studies in NCT with a boronated porphyrin and tumor growth delay as an end point  

SciTech Connect

The robust carrying capacity of the porphyrin molecule and its propensity for localizing in tumor justified the synthesizing of a porphyrin labeled with boron for use in BNCT. However, problems associated with poor solubility impeded the utility of the molecule. Until BOPP was synthesized porphyrins were promising, but impractical. After in vitro experiments had demonstrated the biological efficacy of BOPP and had confirmed its intracellular localizing ability in vivo studies were carried out using mice. Irradiation of KHJJ murine mammary carcinoma to the TCD[sub 50] in a single fraction was precluded since this whole body dose is lethal. This problem was overcome by the use of radiation. BOPP was administered either as three 0.5 ml injections per day over two days or by continuous i.v. infusion, 2 ml per day over three days for a total dose of about 42 [mu]g [sup 10]B/gbw. Boron-10 distribution in the tumor at the time of irradiation was [approximately]20 [mu]g.

Laster, B.H. (Brookhaven National Lab., Upton, NY (United States) State Univ. of New York, Stony Brook, NY (United States). Dept. of Radiation Oncology); Kahl, S.B. (California Univ., San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry); Warkentien, L.; Bond, V.P. (Brookhaven National Lab., Upton, NY (United States))

1992-01-01

16

In vivo studies in NCT with a boronated porphyrin and tumor growth delay as an end point  

SciTech Connect

The robust carrying capacity of the porphyrin molecule and its propensity for localizing in tumor justified the synthesizing of a porphyrin labeled with boron for use in BNCT. However, problems associated with poor solubility impeded the utility of the molecule. Until BOPP was synthesized porphyrins were promising, but impractical. After in vitro experiments had demonstrated the biological efficacy of BOPP and had confirmed its intracellular localizing ability in vivo studies were carried out using mice. Irradiation of KHJJ murine mammary carcinoma to the TCD{sub 50} in a single fraction was precluded since this whole body dose is lethal. This problem was overcome by the use of radiation. BOPP was administered either as three 0.5 ml injections per day over two days or by continuous i.v. infusion, 2 ml per day over three days for a total dose of about 42 {mu}g {sup 10}B/gbw. Boron-10 distribution in the tumor at the time of irradiation was {approximately}20 {mu}g.

Laster, B.H. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States). Dept. of Radiation Oncology; Kahl, S.B. [California Univ., San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry; Warkentien, L.; Bond, V.P. [Brookhaven National Lab., Upton, NY (United States)

1992-12-31

17

Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer specific cytotoxicity and tumor growth delay  

PubMed Central

Purpose Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment and novel therapies are therefore in high demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug Experimental design The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter Insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the non-viral nanoparticle, DOTAP:Cholesterol for transgene delivery. Results INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the Herpes Simplex Virus Thymidine Kinase (HSVTK) gene and prodrug Ganciclovir (GCV). The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared to control treated xenografts. Conclusions The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to demonstrate an anti-tumor effect from the delivery of suicide gene therapeutics for SCLC in vivo. PMID:20371678

Christensen, Camilla L.; Gjetting, Torben; Poulsen, Thomas T.; Cramer, Frederik; Roth, Jack A.; Poulsen, Hans S.

2012-01-01

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  

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

21

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

PubMed

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. PMID:24985415

Bi, Ping; Ruan, Shigui; Zhang, Xinan

2014-06-01

22

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice  

PubMed Central

KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3?-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan–Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy. PMID:23471001

Cogoi, Susanna; Zorzet, Sonia; Rapozzi, Valentina; Geci, Imrich; Pedersen, Erik B.; Xodo, Luigi E.

2013-01-01

23

Mechanics in Tumor Growth 1 Mechanics in Tumor Growth  

E-print Network

the extracellular matrix. As will be described in the following this process is affected by the stress applied some of the main feature of tumor growth and in particular the phenomena involving stress description, one can say that the cells forming a compact tumor, like other cells in the body, live

Preziosi, Luigi

24

DEPLETION OF DENDRITIC CELLS DELAYS OVARIAN CANCER PROGRESSION BY BOOSTING ANTI-TUMOR IMMUNITY  

PubMed Central

Dendritic cells (DCs) and cytokines that expand myeloid progenitors are widely used to treat cancer. Here we demonstrate that CD11c+DEC205+ DCs co-expressing ?-Smooth Muscle Actin and VE-Cadherin home to perivascular areas in the ovarian cancer microenvironment and are required for the maintenance of tumor vasculature. Consequently, depletion of DCs in mice bearing established ovarian cancer by targeting different specific markers significantly delays tumor growth and enhances the effect of standard chemotherapies. Tumor growth restriction was associated with vascular apoptosis after DC ablation followed by necrosis, which triggered an anti-tumor immunogenic boost. Our findings provide a mechanistic rationale for selectively eliminating tumor-associated leukocytes to promote anti-tumor immunity while impeding tumor vascularization, and to develop more effective DC vaccines based on a better understanding of the tumor microenvironment. PMID:18768667

Huarte, Eduardo; Cubillos-Ruiz, Juan R.; Nesbeth, Yolanda C.; Scarlett, Uciane K.; Martinez, Diana G.; Buckanovich, Ronald J.; Benencia, Fabian; Stan, Radu V.; Keler, Tibor; Sarobe, Pablo; Sentman, Charles L.; Conejo-Garcia, Jose R.

2009-01-01

25

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

26

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

27

Tumor growth modeling based on cell and tumor lifespans  

E-print Network

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

Paris-Sud XI, Université de

28

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

29

Cancer Progression and Tumor Growth Kinetics  

NASA Astrophysics Data System (ADS)

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

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

2013-03-01

30

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

PubMed

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

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

2012-05-01

31

Intramuscular electroporation of a P1A-encoding plasmid vaccine delays P815 mastocytoma growth.  

PubMed

This study aimed to construct DNA vaccines encoding the mouse P1A tumor antigen and to generate a protective immune response against the P815 mastocytoma, as a model for vaccines against human MAGE-type tumor antigens. DNA vaccines were constructed and delivered to mice by intramuscular electroporation before tumor challenge. Immunization with a plasmid coding for the full-length P1A significantly delayed tumor growth and mice survived at least 10days longer than untreated controls. 10% of the mice completely rejected the P815 tumors while 50% of them showed a regression phase followed by tumor regrowth. Mice immunized by electroporation of a P1A35-43 minigene-encoding plasmid failed to reject tumor and even delay tumor growth. The P1A35-43-encoding plasmid was modified and helper epitope sequences were inserted. However, these modified plasmids were not able to improve the response against P815 mastocytoma. Consistent with these results, a 12-fold higher CTL activity was observed when the plasmid coding for full-length P1A was delivered as compared to the plasmid encoding the P1A35-43 epitope. Our results demonstrated that electroporation is an efficient method to deliver DNA vaccines against P815 and suggested the superiority of full-length as compared to minigene constructs for DNA vaccines. PMID:24342164

Vandermeulen, Gaëlle; Uyttenhove, Catherine; De Plaen, Etienne; Van den Eynde, Benoît J; Préat, Véronique

2014-12-01

32

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

33

Delayed Contrast Extravasation MRI for Depicting Tumor and Non-Tumoral Tissues in Primary and Metastatic Brain Tumors  

PubMed Central

The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases. PMID:23251672

Zach, Leor; Guez, David; Last, David; Daniels, Dianne; Grober, Yuval; Nissim, Ouzi; Hoffmann, Chen; Nass, Dvora; Talianski, Alisa; Spiegelmann, Roberto; Cohen, Zvi R.; Mardor, Yael

2012-01-01

34

Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth1  

Microsoft Academic Search

Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C

Terhi Karpanen; Mikala Egeblad; Marika J. Karkkainen; Hajime Kubo; Kari Alitalo

2001-01-01

35

Triggering CD40 on endothelial cells contributes to tumor growth  

PubMed Central

Inflammatory cells can either promote or inhibit tumor growth. Here we studied whether CD40, a key molecule for adaptive immune response, has any role in mammary carcinogenesis of BALB/NeuT transgenic tumor-prone mice. We transferred the HER2/neu oncogene into CD40-null background to obtain the CD40-KO/NeuT strain. CD40-KO/NeuT mice showed delayed tumor onset and reduced tumor multiplicity. BM (BM) transplantation experiments excluded a role of BM-derived cells in the reduced tumorigenicity associated with CD40 deficiency. Rather, CD40 expressed by endothelial cells (ECs) takes part to the angiogenic process. Accordingly, large vessels, well organized around the tumor lobular structures, characterize BALB/NeuT tumors, whereas tiny numerous vessels with scarce extracellular matrix are dispersed in the parenchyma of poorly organized CD40-KO/NeuT tumors. Activated platelets, which may interact with and activate ECs, are a possible source of CD40L. Their localization within tumor vessels prompted the idea of treating BALB/NeuT and CD40-KO/NeuT mice chronically with the anti-platelet drug clopidogrel, known to inhibit platelet CD40L expression. Treatment of BALB/NeuT mice reduced tumor growth to a level similar to CD40-deficient mice, whereas CD40-KO/NeuT mice treated or not showed the same attenuated tumor outgrowth, indicating that activated platelets are the likely source of CD40L in this model. Collectively, these data point to a participation of CD40/CD40L in the angiogenic processes associated with mammary carcinogenesis of BALB/NeuT mice. PMID:17043144

Chiodoni, Claudia; Iezzi, Manuela; Guiducci, Cristiana; Sangaletti, Sabina; Alessandrini, Isabella; Ratti, Chiara; Tiboni, Francesca; Musiani, Piero; Granger, D. Neil; Colombo, Mario P.

2006-01-01

36

Adult Height in Girls with Delayed Pubertal Growth  

Microsoft Academic Search

Background\\/Aims: Boys with constitutional delay of growth and puberty (CDGP) with early reduction in relative height before the onset of puberty will have adult height (AH) clearly below their target height (TH). Characteristics of growth in girls with CDGP are poorly known. We examined whether girls with CDGP attain their TH and whether early reduction in height SDS influences their

Karoliina Wehkalampi; Katarina Päkkilä; Tiina Laine; Leo Dunkel

2011-01-01

37

Slow crack growth and delayed failure of granite  

SciTech Connect

Delayed failure of granite was measured at 2 values of constant applied stress. An analysis was developed to determine from these data the rate of growth of pre-existing cracks. The results are expressed in terms of crack-growth velocity as a function of the stress intensity factor KI. The technique is capable of detecting crack-growth velocities as low as 10-12m/sec-1. 17 references.

Wilkins, B.J.S.

1980-12-01

38

Successful Mitigation of Delayed Intestinal Radiation Injury Using Pravastatin is not Associated with Acute Injury Improvement or Tumor Protection  

SciTech Connect

Purpose: To investigate whether pravastatin mitigates delayed radiation-induced enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition. Methods and Materials: Mitigation of delayed radiation-induced enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irradiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14 days, 15 weeks, and 26 weeks after irradiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments. Results: Pravastatin improved delayed radiation enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irradiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from radiation injury. Conclusion: Pravastatin provides effective protection against delayed radiation enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.

Haydont, Valerie [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France); 'Laboratoire de Radiopathologie. SRBE/DRPH', Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Gilliot, Olivier [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France); Rivera, Sofia [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France); Bourgier, Celine [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France); 'Laboratoire de Radiopathologie. SRBE/DRPH', Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Francois, Agnes [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France); 'Laboratoire de Radiopathologie. SRBE/DRPH', Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Aigueperse, Jocelyne [DRPH, Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France); Bourhis, Jean; Vozenin-Brotons, Marie-Catherine [UPRES EA 27-10, 'Radiosensibilite des tumeurs et tissus sains', Institut de Radioprotection et de Surete Nucleaire/Institut Gustave Roussy, Villejuif, Fontenay-aux-Roses (France)]|[Laboratoire de Radiopathologie. SRBE/DRPH, Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-Roses (France)]. E-mail: vozenin@igr.fr

2007-08-01

39

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

40

Reduced Tumor Growth and Angiogenesis in Endoglin-Haploinsufficient Mice  

Microsoft Academic Search

Endoglin is a transforming growth factor-?1 (TGF-?1) accessory receptor which is highly expressed in tumor vessels. To study the role of endoglin in tumor growth and angiogenesis we induced a highly vascularized tumor in mice heterozygous for endoglin (Eng+\\/–) and in their control littermates (Eng+\\/+) by injecting 106 Lewis lung carcinoma (3LL) cells subcutaneously. Nine days after injection, the tumor

Annette Düwel; Nélida Eleno; Mirjana Jerkic; Miguel Arevalo; Juan P. Bolańos; Carmelo Bernabeu; Jose M. López-Novoa

2007-01-01

41

THE EFFECTS OF DELAYED PUBERTY ON THE GROWTH PLATE  

PubMed Central

Background Many athletes are beginning intense training before puberty, a time of increased bone accrual when up to 25% of total bone mineral accrual occurs. Female athletes experiencing late or delayed pubertal onset may have open epiphyseal plates open that are vulnerable to injury. This investigation’s purpose was to determine whether a delay in puberty (primary amenorrhea) affects the growth plate immediately post-puberty and at maturity. Methods Forty-eight female Sprague–Dawley rats (23days-of-age) were randomly assigned to four groups (n=12); short-term control (C-ST), long-term control (C-LT), short-term GnRH antagonist (G-ST) and long-term GnRH antagonist (G-LT). At 25days-of-age, daily gonadotropin-releasing hormone antagonist (GnRH-a; Cetrotide™, Serono, Inc.) injections were administered delaying pubertal onset. Left tibias were analyzed. Stained frontal slices of proximal tibia (5 ?m thick) were analyzed in hypertrophic, proliferative and reserve zones for total height, zone height, and cell/ column counts. All procedures were approved by (IACUC) at Brooklyn College. Results Growth plate height was 19.7% wider in delayed puberty (G-ST) group and at maturity was 27.9% greater in G-LT group compared to control (C-LT) (p<0.05). No significant differences were found in short or long-term growth plate zone heights or cell/column counts between groups (p>0.05). Growth plate zone height normalized to total height resulted in 28.7 % larger reserve zone in the short term GnRH-a group (G-ST) but the proliferative zone was 8.5 % larger in the long-term group compared to the control group (p<0.05). Normalized to growth plate height a significant decrease was found in column counts in proliferative zones of the short and long-term GnRH-a groups. Conclusions Current data illustrates delayed puberty using GnRH-a injections results in significant growth plate height and decreases proliferative column counts and zone height\\potentially contributing to decreases in bone mass at maturity. PMID:23232387

Butler, Tiffiny A.; Yingling, Vanessa R.

2012-01-01

42

Chaperone-Mediated Autophagy Is Required for Tumor Growth  

PubMed Central

The cellular process of autophagy (literally “self-eating”) is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential. PMID:22089453

Kon, Maria; Kiffin, Roberta; Koga, Hiroshi; Chapochnick, Javier; Macian, Fernando; Varticovski, Lyuba; Cuervo, Ana Maria

2014-01-01

43

Chaperone-mediated autophagy is required for tumor growth.  

PubMed

The cellular process of autophagy (literally "self-eating") is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential. PMID:22089453

Kon, Maria; Kiffin, Roberta; Koga, Hiroshi; Chapochnick, Javier; Macian, Fernando; Varticovski, Lyuba; Cuervo, Ana Maria

2011-11-16

44

Self-Image in Adolescents with Delayed Puberty and Growth Retardation.  

ERIC Educational Resources Information Center

Adolescents with varying combinations of pubertal delay and growth retardation were given the Offer Self-Image Questionnaire. Delay in sexual maturation by itself had no deleterious effect on self-image but growth retardation did. (Author/GK)

Apter, Alan; And Others

1981-01-01

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 Muďż˝ 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 Pparbďż˝/ďż˝ mice, concomitant

Omiecinski, Curtis

46

Delayed transmission of a parasite is compensated by accelerated growth.  

PubMed

Compensatory or 'catch-up' growth following prolonged periods of food shortages is known to exist in many free-living animals. It is generally assumed that growth rates under normal circumstances are below maximum because elevated rates of growth are costly. The present paper gives experimental evidence that such compensatory growth mechanisms also exist in parasitic species. We explored the effect of periodic host unavailability on survival, infectivity and growth of the fish ectoparasite Argulus coregoni. Survival and infectivity of A. coregoni metanauplii deprived of a host for selected time periods were age dependent, which indicates that all metanauplii carry similar energy resources for host seeking. Following the periods off-host, metanauplii were allowed to settle on rainbow trout and were length measured until they reached gravidity. During early development on fish, body length of attached A. coregoni was negatively correlated with off-host period indicating a mechanism that creates size variance in an attached parasite cohort originally containing equal amounts of resources. However, over time the size differences between parasites became less pronounced and eventually parasites that were kept off-host for longest periods of time reached the length of those individuals that had been allowed to infect a host sooner. A. coregoni thus appears to compensate for delayed growth resulting from an extended host searching period by elevated growth rates, although we show that such accelerated growth incurred a cost, through decreased life-expectancy. PMID:16255823

Hakalahti, T; Bandilla, M; Valtonen, E T

2005-11-01

47

Delayed cerebrospinal fluid rhinorrhea after gamma knife surgery in a patient with a growth hormone-secreting adenoma.  

PubMed

We report a patient who developed delayed cerebrospinal fluid (CSF) rhinorrhea 11 years after gamma knife radiosurgery for a growth hormone (GH)-secreting adenoma. The treatment dose was 18 Gy for the tumor margin (50% isodose). One year later, an MRI of the head revealed that the tumor size had decreased. Eleven years later, the patient developed CSF rhinorrhea from the left nostril. Subsequent MRI examination revealed complete remission of the tumor in the sella turcica and the empty sella. The patient was admitted for direct endoscopic surgical repair of the skull base. We suggest that the cause of the CSF rhinorrhea is secondary empty sella. The other potential causes may be the original invasiveness of the tumor or delayed radiation damage to the mucous membranes of the skull. Long-term follow-up is required to monitor recurrence of CSF rhinorrhea. PMID:22349430

Hongmei, Yan; Zhe, Wang; Jing, Wang; Daokui, Wang; Peicheng, Cao; Yongjie, Li

2012-06-01

48

Influence of Correlated Noises on Growth of a Tumor  

E-print Network

We studied the effect of additive and multiplicative noises on the growth of a tumor based on a logistic growth model. The steady-state probability distribution and the average population of the tumor cells were given to explain the important roles of correlated noises in the tumor growth. We found that multiplicative noise induces a phase transition of the tumor growth from an uni-stable state to a bi-stable state; the relationship between the intensity of multiplicative noise and the population of the tumor cells showed a stochastic resonance-like characteristic. It was also confirmed that additive noise weakened rather than extinguish the tumor growth. Homologous noises, however, promote the growth of a tumor. We also discussed about the relationship between the tumor treatment and the model.

Zhong, W R; He, Z H; Zhong, Wei-Rong; Shao, Yuan-Zhi; He, Zhen-Hui

2005-01-01

49

A cellular automaton model for tumor growth in heterogeneous environment  

NASA Astrophysics Data System (ADS)

Cancer is not a single disease: it exhibits heterogeneity on different spatial and temporal scales and strongly interacts with its host environment. Most mathematical modeling of malignant tumor growth has assumed a homogeneous host environment. We have developed a cellular automaton model for tumor growth that explicitly incorporates the structural heterogeneity of the host environment such as tumor stroma. We show that these structural heterogeneities have non-trivial effects on the tumor growth dynamics and prognosis.

Jiao, Yang; Torquato, Sal

2011-03-01

50

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

51

Cellular potts modeling of tumor growth, tumor invasion, and tumor evolution.  

PubMed

Despite a growing wealth of available molecular data, the growth of tumors, invasion of tumors into healthy tissue, and response of tumors to therapies are still poorly understood. Although genetic mutations are in general the first step in the development of a cancer, for the mutated cell to persist in a tissue, it must compete against the other, healthy or diseased cells, for example by becoming more motile, adhesive, or multiplying faster. Thus, the cellular phenotype determines the success of a cancer cell in competition with its neighbors, irrespective of the genetic mutations or physiological alterations that gave rise to the altered phenotype. What phenotypes can make a cell "successful" in an environment of healthy and cancerous cells, and how? A widely used tool for getting more insight into that question is cell-based modeling. Cell-based models constitute a class of computational, agent-based models that mimic biophysical and molecular interactions between cells. One of the most widely used cell-based modeling formalisms is the cellular Potts model (CPM), a lattice-based, multi particle cell-based modeling approach. The CPM has become a popular and accessible method for modeling mechanisms of multicellular processes including cell sorting, gastrulation, or angiogenesis. The CPM accounts for biophysical cellular properties, including cell proliferation, cell motility, and cell adhesion, which play a key role in cancer. Multiscale models are constructed by extending the agents with intracellular processes including metabolism, growth, and signaling. Here we review the use of the CPM for modeling tumor growth, tumor invasion, and tumor progression. We argue that the accessibility and flexibility of the CPM, and its accurate, yet coarse-grained and computationally efficient representation of cell and tissue biophysics, make the CPM the method of choice for modeling cellular processes in tumor development. PMID:23596570

Szabó, András; Merks, Roeland M H

2013-01-01

52

Growth Failure After Treatment of Pediatric Brain Tumors  

Microsoft Academic Search

ABSTRACT. Objectives. Primary brain tumors are the most common solid tumors that occur in childhood. With improved management of these tumors, there are more survivors with long-term sequelae of radiation and che- motherapy including growth failure. The aim of this study was to assess growth prospectively in children with nonpituitary-related primary brain tumors. Methods. Forty-one children 3.1 to 13.8 years

Cheril L. Clarson; Rolando F. Del Maestro

53

Drug-Loaded Sickle Cells Programmed ex vivo for Delayed Hemolysis Target Hypoxic Tumor Microvessels and Augment Tumor Drug Delivery  

PubMed Central

Selective drug delivery to hypoxic tumor niches remains a significant therapeutic challenge that calls for new conceptual approaches. Sickle red blood cells (SSRBCs) have shown an ability to target such hypoxic niches and induce tumoricidal properties when used together with exogenous pro-oxidants. Here we determine whether the delivery of a model therapeutic encapsulated in murine SSRBCs can be enhanced by ex vivo photosensitization under conditions that delay autohemolysis to a time that coincides with maximal localization of SSRBCs in a hypoxic tumor. Hyperspectral imaging of 4T1 carcinomas shows oxygen saturation levels <10% in a large fraction (commonly 50% or more) of the tumor. Using video microscopy of dorsal skin window chambers implanted with 4T1 tumors, we demonstrate that allogeneic SSRBCs, but not normal RBCs (nRBCs), selectively accumulate in hypoxic 4T1 tumors between 12-24 hours after systemic administration. We further show that ex vivo photo-oxidation can program SSRBCs to postpone hemolysis/release of a model therapeutic to a point that coincides with their maximum sequestration in hypoxic tumor microvessels. Under these conditions, drug-loaded photosensitized SSRBCs show a 3-4 fold greater drug delivery to tumors compared to non-photosensitized SSRBCs, drug-loaded photosensitized nRBCs, and free drug. These results demonstrate that photo-oxidized SSRBCs, but not photo-oxidized nRBCs, sequester and hemolyze in hypoxic tumors and release substantially more drug than photo-oxidized nRBCs and non-photo-oxidized SSRBCs. Photo-oxidation of drug-loaded SSRBCs thus appears to exploit the unique tumor targeting and carrier properties of SSRBCs to optimize drug delivery to hypoxic tumors. Such programmed and drug-loaded SSRBCs therefore represent a novel and useful tool for augmenting drug delivery to hypoxic solid tumors. PMID:23871960

Choe, Se-woon; Terman, David S.; Rivers, Angela E.; Rivera, Jose; Lottenberg, Richard; Sorg, Brian S.

2014-01-01

54

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

PubMed Central

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

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

2007-01-01

55

Delayed frost growth on jumping-drop superhydrophobic surfaces.  

PubMed

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 interdrop frost wave. The growth of this interdrop frost front is shown to be up to 3 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 interdrop 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 interdrop phenomenon that is strongly coupled to the wettability and drop size distribution of the surface. A jumping-drop superhydrophobic condenser minimized frost formation relative to a conventional dropwise condenser in two respects: preventing heterogeneous ice nucleation by continuously removing subcooled condensate, and delaying frost growth by limiting the success of interdrop ice bridge formation. PMID:23286736

Boreyko, Jonathan B; Collier, C Patrick

2013-02-26

56

Combination therapy with gefitinib and doxorubicin inhibits tumor growth in transgenic mice with adrenal neuroblastoma  

PubMed Central

Highly relevant mouse models of human neuroblastoma (NB) are needed to evaluate new therapeutic strategies against NB. In this study, we characterized transgenic mice with bilateral adrenal tumors. On the basis of information from the tumoral gene expression profiles, we examined the antitumor effects of unencapsulated and liposomal doxorubicin (DXR), alone and in combination with gefitinib, on adrenal NB. We showed that intravenous injection of unencapsulated or liposomal DXR alone inhibited tumor growth in a dose-dependent manner, as assessed by magnetic resonance imaging (MRI). However, liposomal DXR did not exhibit greater antitumor effect than unencapsulated DXR. Immunohistochemical analysis revealed that the adrenal tumor vasculature with abundant pericyte coverage was a less leaky structure for liposomes. Combination therapy with unencapsulated or liposomal DXR plus gefitinib strongly suppressed tumor growth and delayed tumor regrowth than treatment with unencapsulated or liposomal DXR alone, even at a lower dose of DXR. Dynamic contrast-enhanced MRI analysis revealed that gefitinib treatment increased blood flow in the tumor, indicating that gefitinib treatment changes the tumor vascular environment in a manner that may increase the antitumor effect of DXR. In conclusion, the combination of gefitinib and DXR induces growth inhibition of adrenal NBs in transgenic mice. These findings will provide helpful insights into new treatments for NB. PMID:23930205

Kawano, Kumi; Hattori, Yoshiyuki; Iwakura, Hiroshi; Akamizu, Takashi; Maitani, Yoshie

2013-01-01

57

Inhibition of ehrlich mouse ascites tumor growth by cordycepin. Abstr  

Microsoft Academic Search

SUMMARY Cordycepin, a nucleoside isolated from cultures of the mold Cordycepsmilitaris, has been demonstrated to increase the survival time of mice bearing the Ehrlich mouse ascites tumor. In all these studies the drug was administered daily for a 7-day period. AVhendrug inoculations were started the same day as tumor inoculations, inhibition of tumor growth was noted at levels of from

N M Kredich; ARMAND J. GUARINO

1960-01-01

58

Resveratrol Treatment Delays Growth Plate Fusion and Improves Bone Growth in Female Rabbits  

PubMed Central

Trans-resveratrol (RES), naturally produced by many plants, has a structure similar to synthetic estrogen diethylstilbestrol, but any effect on bone growth has not yet been clarified. Pre-pubertal ovary-intact New Zealand white rabbits received daily oral administration of either vehicle (control) or RES (200 mg/kg) until growth plate fusion occurred. Bone growth and growth plate size were longitudinally monitored by X-ray imaging, while at the endpoint, bone length was assessed by a digital caliper. In addition, pubertal ovariectomized (OVX) rabbits were treated with vehicle, RES or estradiol cypionate (positive control) for 7 or 10 weeks and fetal rat metatarsal bones were cultured in vitro with RES (0.03 µM–50 µM) and followed for up to 19 days. In ovary-intact rabbits, sixteen-week treatment with RES increased tibiae and vertebrae bone growth and subsequently improved final length. In OVX rabbits, RES delayed fusion of the distal tibia, distal femur and proximal tibia epiphyses and femur length and vertebral bone growth increased when compared with controls. Histomorphometrical analysis showed that RES-treated OVX rabbits had a wider distal femur growth plate, enlarged resting zone, increased number/size of hypertrophic chondrocytes, increased height of the hypertrophic zone, and suppressed chondrocyte expression of VEGF and laminin. In cultured fetal rat metatarsal bones, RES stimulated growth at 0.3 µM while at higher concentrations (10 ?M and 50 ?M) growth was inhibited. We conclude that RES has the potential to improve longitudinal bone growth. The effect was associated with a delay of growth plate fusion resulting in increased final length. These effects were accompanied by a profound suppression of VEGF and laminin expression suggesting that impairment of growth plate vascularization might be an underlying mechanism. PMID:23840780

Karimian, Elham; Tamm, Chen; Chagin, Andrei S.; Samuelsson, Karin; Kjartansdottir, Kristin Ros; Ohlsson, Claes; Savendahl, Lars

2013-01-01

59

Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis  

PubMed Central

Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5?-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer. PMID:20080644

Stagg, John; Divisekera, Upulie; McLaughlin, Nicole; Sharkey, Janelle; Pommey, Sandra; Denoyer, Delphine; Dwyer, Karen M.; Smyth, Mark J.

2010-01-01

60

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

NASA Astrophysics Data System (ADS)

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

Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

2010-04-01

61

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

62

Host deficiency in caveolin-2 inhibits lung carcinoma tumor growth by impairing tumor angiogenesis.  

PubMed

Caveolin-2 (Cav-2), a member of caveolin protein family, is largely different from better known caveolin-1 (Cav-1) and thus might play distinct functions. Here, we provide the first genetic evidence suggesting that host-expressed Cav-2 promotes subcutaneous tumor growth and tumor-induced neovascularization using two independent syngeneic mouse models. Host deficiency in Cav-2 resulted in defective and reduced growth of subcutaneously implanted Lewis lung carcinoma (LLC) and B16-F10 melanoma tumors, respectively. Consistent with the defective growth, LLC and B16-F10 melanoma tumors implanted into Cav-2 KO mice displayed reduced microvascular density (MVD) determined by IHC with anti-CD31 antibodies, suggesting impaired pathologic angiogenesis. Additional studies involving LLC tumors extracted from Cav-2 KO mice just 10 days after implantation determined reduced cell proliferation, massive necrotic cell death, and fibrosis. In contrast with day 10, only MVD but not cell proliferation and survival was reduced in the earliest palpable LLC tumors extracted 6 days after implantation into Cav-2 KO mice, suggesting that impaired angiogenesis is the causative factor. Mechanistically, impaired LLC tumor growth and angiogenesis in Cav-2 KO mice was associated with increased expression levels of antiangiogenic thrombospondin-1 and inhibited S1177 phosphorylation of endothelial nitric oxide synthase. Taken together, our data suggest that host deficiency in Cav-2 impairs tumor-induced angiogenesis, leading to compromised tumor cell survival/proliferation manifested by the defective tumor growth. In conclusion, host-expressed Cav-2 may promote tumor growth via supporting tumor-induced angiogenesis. Thus, Cav-2 expressed in tumor microenvironment may potentially become a novel target for cancer therapy. Cancer Res; 74(22); 6452-62. ©2014 AACR. PMID:25269481

Liu, Yajun; Jang, Sungchan; Xie, Leike; Sowa, Grzegorz

2014-11-15

63

Brain tumor modeling: glioma growth and interaction with chemotherapy  

NASA Astrophysics Data System (ADS)

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

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

2011-10-01

64

[Adnexal torsion during puerperium as a complication of delayed surgical treatment of ovarian tumor in pregnancy].  

PubMed

Ovarian tumors in pregnancy represent a significant issue both in terms of diagnostics and therapy. Increased use of the ultrasound in pregnancy in the last several decades has contributed to the rise in the number of diagnosed asymptomatic adnexal tumors with pregnant women. We present a case of a patient treated in our clinic for asymptomatic ovarian tumor, which was diagnosed in pregnancy. The patient underwent check-ups every four weeks, comprising clinical and sonographical examinations and relevant laboratory and tumor marker tests. The course of pregnancy was normal, with no detected tumor growth and with the tumor marker levels within the reference range. Following an uneventful delivery, she developed abdominal pains during the puerperium, and the adnexal torsion was diagnosed intraoperatively. The attitudes to treating of adnexal tumors in pregnancy are controversial, and there exist no defined treatment protocols. It is, therefore, necessary to make an individual evaluation of each case, and the relevant decisions should be made with the pregnant woman's informed consent. The adnexal torsion in the presented case can be explained by the size of the tumor as well as the progressive reduction of the size of the uterus due to the physical involution during puerperium. PMID:22924317

Spari?, Radmila; Buzadzi?, Snezana; Argirovi?, Rajka; Opali?, Jasna

2012-01-01

65

A nonlinear structured population model of tumor growth with quiescence  

Microsoft Academic Search

A nonlinear structured cell population model of tumor growth is considered. The model distinguishes between two types of cells\\u000a within the tumor: proliferating and quiescent. Within each class the behavior of individual cells depends on cell size, whereas\\u000a the probabilities of becoming quiescent and returning to the proliferative cycle are in addition controlled by total tumor\\u000a size. The asymptotic behavior

M. Gyllenberg; G. F. Webb

1990-01-01

66

Second hand smoke stimulates tumor angiogenesis and growth  

Microsoft Academic Search

Exposure to second hand smoke (SHS) is believed to cause lung cancer. Pathological angiogenesis is a requisite for tumor growth. Lewis lung cancer cells were injected subcutaneously into mice, which were then exposed to sidestream smoke (SHS) or clean room air and administered vehicle, cerivastatin, or mecamylamine. SHS significantly increased tumor size, weight, capillary density, VEGF and MCP-1 levels, and

Bo-qing Zhu; Christopher Heeschen; Richard E. Sievers; Joel S. Karliner; William W. Parmley; John P. Cooke

2003-01-01

67

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

PubMed Central

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

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

2014-01-01

68

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

69

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

70

IL-12 Suppresses Vascular Endothelial Growth Factor Receptor 3 Expression on Tumor Vessels by Two Distinct IFN-?-Dependent Mechanisms  

PubMed Central

IL-12 has been shown to be effective in enhancing antitumor responses. However, how IL-12 exerts its antiangiogenic effect is largely unknown. In this study, we elucidate this mechanism using B16 transfected to express IL-12 (B16/IL-12), a system that provides constant, local production of IL-12 within the tumor microenvironment. Intratumoral IL-12 resulted in a significant delay in tumor growth and phenotypic changes in the vasculature. Vessels found within B16 tumors are chaotic and poorly formed and express vascular endothelial growth factor receptor 3 (VEGFR3), a growth factor receptor not expressed on normal adult vessels. However, the vessels within B16/IL-12 tumors have a more normal morphology and do not express VEGFR3. We have shown that IFN-? is required for IL-12 to suppress the aberrant expression of VEGFR3. Indeed, the presence of intratumoral IL-12 stimulates the immune system resulting in more IFN-?–producing tumor-infiltrating lymphocytes per tumor when compared with parental B16 tumors, which may have a marked effect on control of tumor growth. Interestingly, within B16/IL-12 tumors, T cells are necessary to suppress VEGFR3 expression on tumor vessels. Finally, using IFN-? receptor knockout mice in a bone marrow chimera system, we show that the IFN-? produced within the tumor suppresses VEGFR3 expression in two ways: 1) acting directly on tumor vessel endothelial cells, and 2) acting on the tumor-infiltrating lymphocytes to indirectly alter endothelial cells’ VEGFR3 expression. Our data indicate a mechanism in which tumor-infiltrating immune cells regulate tumor vessel phenotype. PMID:20061409

Sorensen, Elizabeth W.; Gerber, Scott A.; Frelinger, John G.; Lord, Edith M.

2011-01-01

71

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

72

Why does delay exist in the diagnosis of intradural spinal cord tumor despite the availability of MRI?  

Microsoft Academic Search

To elucidate the reasons for delay in the diagnosis of spinal cord tumors despite the availability of MRI in Japan, we reviewed the clinical records of 60 patients with tumors with reference to histological diagnosis, initial symptoms, time interval between onset of the initial symptoms and the first visit to a physician, and the subsequent interval to diagnosis using MRI.

Minori Kato; Hiroaki Nakamura; Hidetomi Terai; Sadahiko Konishi; Ryuichi Nagayama; Kunio Takaoka

2008-01-01

73

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

74

Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes  

Microsoft Academic Search

Development and preclinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts illustrate the diversity of human breast cancer

Yoko S DeRose; Guoying Wang; Yi-Chun Lin; Philip S Bernard; Saundra S Buys; Mark T W Ebbert; Rachel Factor; Cindy Matsen; Brett A Milash; Edward Nelson; Leigh Neumayer; R Lor Randall; Inge J Stijleman; Bryan E Welm; Alana L Welm

2011-01-01

75

Neutrophils responsive to endogenous IFN-? regulate tumor angiogenesis and growth in a mouse tumor model  

PubMed Central

Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-? inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-?–deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-? restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-?–deficient mice. We therefore suggest that constitutively produced endogenous IFN-? is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development. PMID:20237412

Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried

2010-01-01

76

Akt deficiency delays tumor progression, vascular invasion, and distant metastases in a murine model of thyroid cancer  

PubMed Central

Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induced primary cancer growth, but is reported to inhibit metastasis in vivo in several model systems. In contrast, clinical and in vitro studies suggest a metastasis-promoting role for Akt1 in thyroid cancer. The goal of this study was to determine the functional role of Akt1 in thyroid cancer growth and metastatic progression in vivo using thyroid hormone receptor ?PV/PV knock-in (PV) mice which develop metastatic thyroid cancer. We crossed Akt1-/- and PV mice and compared tumor development, local progression, metastasis, and histology in TR?PV/PV/Akt1+/+ (PVPV-Akt1WT) and TR?PV/PV/Akt1-/- (PVPV-Akt1KO) mice. Mice were sacrificed at 3, 6, 9, 12, and 15 months; necropsy was performed and serum TSH was measured. Thyroid hyperplasia occurred in both groups beginning at three months; the thyroid size was greater in the PVPV-Akt1WT mice (p<0.001). In comparison with PVPV-Akt1WT mice, thyroid cancer development was delayed in the PVPV-Akt1KO mice (P=0.003) and the degree of tumor invasion was reduced. The PVPV-Akt1WT mice displayed pulmonary metastases at 12 and 15 months of age, by contrast PVPV-Akt1KO mice did not develop distant metastases at 15 months of age. Despite continued expression of Akt2 or Akt3, pAkt levels were decreased, and there was evidence of reduced Akt effect on p27 in the PVPV-Akt1KO thyroids. TSH levels were similarly elevated in PV mice regardless of Akt1 expression. In conclusion, thyroid cancer development and progression in TR?PV/PV mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model. PMID:21532616

Saji, Motoyasu; Narahara, Katsunura; McCarty, Samantha K.; Vasko, Vasily V.; La Perle, Krista M.; Porter, Kyle; Jarjoura, David; Lu, Changxue; Cheng, Sheue-Yann; Ringel, Matthew D.

2011-01-01

77

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis  

PubMed Central

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

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

2013-01-01

78

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

2015-02-15

79

Final height in boys with untreated constitutional delay in growth and puberty  

Microsoft Academic Search

To determine the natural history and psychological impact of the growth pattern in boys with constitutional delay in growth and puberty (CDGP), 43 boys presenting with short stature due to CDGP were followed up to final height. At presentation mean (SD) chronological age was 14.0 (1.9) years, bone age delay 2.7 (1.0) years, standing height standard deviation score (SDS) -3.4

E C Crowne; S M Shalet; W H Wallace; D M Eminson; D A Price

1990-01-01

80

APRIL, a New Ligand of the Tumor Necrosis Factor Family, Stimulates Tumor Cell Growth  

PubMed Central

Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family designated APRIL (for a proliferation-inducing ligand). Although transcripts of APRIL are of low abundance in normal tissues, high levels of mRNA are detected in transformed cell lines, and in human cancers of colon, thyroid, and lymphoid tissues in vivo. The addition of recombinant APRIL to various tumor cells stimulates their proliferation. Moreover, APRIL-transfected NIH-3T3 cells show an increased rate of tumor growth in nude mice compared with the parental cell line. These findings suggest that APRIL may be implicated in the regulation of tumor cell growth. PMID:9743536

Hahne, Michael; Kataoka, Takao; Schröter, Michael; Hofmann, Kay; Irmler, Martin; Bodmer, Jean-Luc; Schneider, Pascal; Bornand, Tierry; Holler, Nils; French, Lars E.; Sordat, Bernard; Rimoldi, Donata; Tschopp, Jürg

1998-01-01

81

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

82

Effect of Magnetic Fields on Tumor Growth and Viability  

PubMed Central

Breast cancer is the most common nonskin cancer and is the second leading cause of cancer-related deaths in women. Most methods of intervention involve combinations of surgery, chemotherapy, and ionizing radiation. Both chemotherapy and ionizing radiation can be effective against many types of cancer, but they also harm normal tissues. The use of nonionizing, magnetic fields has shown early promise in a number of in vitro and animal studies. Our study tested the effect of varying durations of magnetic exposure on tumor growth and viability in mice injected with breast cancer cells. Cancer cells were labeled through stable expression of firefly luciferase for monitoring of tumor growth and progression by using an in vivo imaging system. We hypothesized that magnetic field exposure would influence tumor growth and progression. Our results showed that exposure of the mice to magnetic fields for 360 min daily for as long as 4 wk suppressed tumor growth. Our study is unique in that it uses an in vivo imaging system to monitor the growth and progression of tumors in real time in individual mice. Our findings support further exploration of the potential of magnetic fields in cancer therapeutics, either as adjunct or primary therapy. PMID:22330249

Tatarov, Ivan; Panda, Aruna; Petkov, Daniel; Kolappaswamy, Krishnan; Thompson, Keyata; Kavirayani, Anoop; Lipsky, Michael M; Elson, Edward; Davis, Christopher C; Martin, Stuart S; DeTolla, Louis J

2011-01-01

83

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

84

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. Cancer Res; 74(22); 6397-407. ©2014 AACR. 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

85

Inhibition of melanoma tumor growth in vivo by survivin targeting  

PubMed Central

A role of apoptosis (programmed cell death) in tumor formation and growth was investigated by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (Thr34?Ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of survivin Thr34?Ala in YUSAC2 melanoma cells prevented tumor formation upon s.c. injection into CB.17 severe combined immunodeficient-beige mice. When induced in established melanoma tumors, survivin Thr34?Ala inhibited tumor growth by 60–70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy. PMID:11149963

Grossman, Douglas; Kim, Paul J.; Schechner, Jeffrey S.; Altieri, Dario C.

2001-01-01

86

Improvements in Final Height Over 25 Years in Growth Hormone (GH)Deficient Childhood Survivors of Brain Tumors Receiving GH Replacement  

Microsoft Academic Search

Final height (FH) outcome is important in survivors of child- hood brain tumors. GH replacement is indicated in those found to be GH deficient (GHD). More recently, GnRH analogs (GnRHa) have been introduced to delay early or rapidly pro- gressing puberty to allow more time for linear growth. Studies to FH are important to determine the effectiveness of growth- promoting

HELENA K. GLEESON; RACHEL STOETER; AMANDA L. OGILVY-STUART; H. R. GATTAMANENI; BERNADETTE M. BRENNAN; STEPHEN M. SHALET

87

Pharmacological Inhibition of BMK1 Suppresses Tumor Growth Through PML  

PubMed Central

SUMMARY BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals. PMID:20832753

Yang, Qingkai; Deng, Xianming; Lu, Bingwen; Cameron, Michael; Fearns, Colleen; Patricelli, Matthew P.

2010-01-01

88

Requirement of the Na+/H+ exchanger for tumor growth.  

PubMed

The Na+/H+ exchanger is involved in a variety of cellular processes, including regulation of intracellular pH and possibly the control of cell growth and proliferation. To study the role of the Na+/H+ exchanger in tumor growth, human sodium proton exchanger-deficient (HSPD) mutants were derived from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 4833-4837, 1984). The HSPD cells were approximately 40% larger and contained approximately 70% more DNA than the parental cells. They were unable to grow in vitro in the absence of bicarbonate at pH less than 7.0, whereas the parental cells grew well at pH greater than or equal to 6.6. This difference in acid sensitivity was abolished in the presence of bicarbonate. In contrast to the parental MGH-U1 cells, the Na+/H+-deficient HSPD cells either failed to grow tumors, or showed severely retarded tumor growth when implanted into immune-deprived mice. This difference in tumor growth was not attributed to differences in cell size and DNA content, because Na+/H+ exchange-competent large cells (HLC), derived during the same proton suicide selection process as the HSPD cells, grew tumors at a rate close to that of the parental cells. Cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na+/H+ activity. HSPD cells also failed to form spheroids in culture, and the only spheroid formed consisted of revertant cells which had regained both Na+/H+ exchange activity and tumorigenic capacity. These results suggest that the Na+/H+ exchanger is important for tumor growth. PMID:2535690

Rotin, D; Steele-Norwood, D; Grinstein, S; Tannock, I

1989-01-01

89

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

90

Inhibition of IL-17A Suppresses Enhanced-Tumor Growth in Low Dose Pre-Irradiated Tumor Beds  

PubMed Central

Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL) levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-?1) in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A) was investigated as a possible target mechanism because IL-6 and TGF-? are key factors in Th17 cells differentiation from naďve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds. PMID:25181290

Lee, Eun-Jung; Park, Hyo Jin; Lee, Ik-Jae; Kim, Won Woo; Ha, Sang-Jun; Suh, Yang-Gun; Seong, Jinsil

2014-01-01

91

Molecular Cochaperones: Tumor Growth and Cancer Treatment  

PubMed Central

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

Calderwood, Stuart K.

2013-01-01

92

Growth of melanoma brain tumors monitored by photoacoustic microscopy  

NASA Astrophysics Data System (ADS)

Melanoma is a primary malignancy that is known to metastasize to the brain and often causes death. The ability to image the growth of brain melanoma in vivo can provide new insights into its evolution and response to therapies. In our study, we use a reflection mode photoacoustic microscopy (PAM) system to detect the growth of melanoma brain tumor in a small animal model. The melanoma tumor cells are implanted in the brain of a mouse at the beginning of the test. Then, PAM is used to scan the region of implantation in the mouse brain, and the growth of the melanoma is monitored until the death of the animal. It is demonstrated that PAM is capable of detecting and monitoring the brain melanoma growth noninvasively in vivo.

Staley, Jacob; Grogan, Patrick; Samadi, Abbas K.; Cui, Huizhong; Cohen, Mark S.; Yang, Xinmai

2010-07-01

93

Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis.  

PubMed

Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). These vaccines are all capable of inducing potent cell-mediated protective immunity against self-antigens, resulting in marked suppression of tumor growth and dissemination. Key mechanisms induced by these DNA vaccines include efficient suppression of angiogenesis in the tumor vasculature and marked activation of cytotoxic T cells, natural killer cells, and antigen-presenting dendritic cells. The vaccine targeting Legumain establishes the new paradigm whereby a reduction in the density of TAMs in the TME decreases the release of factors potentiating tumor growth and angiogenesis. This, in turn, remodels the TME and decreases its immunosuppressive milieu and thereby potentiates the DNA vaccine's ability to effectively suppress tumor cell proliferation, vascularization, and metastasis. It is anticipated that such research efforts will lead to novel DNA-based vaccines that will be effective for the treatment of cancer. PMID:18363997

Xiang, Rong; Luo, Yunping; Niethammer, Andreas G; Reisfeld, Ralph A

2008-04-01

94

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

PubMed

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

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

2014-12-01

95

Interleukin18 suppresses tumor growth and induces tumor cells apoptosis on implanted Lewis lung cancer  

Microsoft Academic Search

Objective  The aim of our study was to investigate the effects of interleukin-18 (IL-18) on implanted Lewis lung cancer in suppressing\\u000a tumor growth and inducing tumor cells apoptosis.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  One week after hypodermic inoculation of Lewis cells, sixteen tumor-bearing syngeneic mice were randomly divided into two\\u000a groups. The mice in the treatment group were intraperitoneal injected with the IL-18, in the control

Sheng Yang; Huishan Lu; Xiangqi Chen; Tingyan Lin; Zhiying Li; Mingqiang Kang

2010-01-01

96

Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape  

PubMed Central

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

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

2012-01-01

97

SUBVERSION OF HOST DEFENSE MECHANISMS BY MALIGNANT TUMORS: AN ESTABLISHED TUMOR AS A PRIVILEGED SITE FOR BACTERIAL GROWTH  

Microsoft Academic Search

There is ample evidence to support the proposal that most, if not all, tumors possess tumor-specific antigens and are immunogenic to varying degrees. This proposal rests on two main lines of evidence. First, that a state of specific immunity to growth of a tumor cell challenge can be generated in a host pre-exposed to various immunizing regimens with tumor cells

GEORGE L. SPITALNY; ROBERT J. NORTH

98

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

99

Radiotherapy planning for glioblastoma based on a tumor growth model  

E-print Network

Radiotherapy planning for glioblastoma based on a tumor growth model: Improving target volume Computer Vision Laboratory, ETH Z¨urich, Switzerland December 20, 2013 Abstract Glioblastoma differ from components. A retrospective study in- volving 10 glioblastoma patients treated at our institution has been

Paris-Sud XI, Université de

100

Prevention of local tumor growth with paclitaxel-loaded microspheres  

E-print Network

deliver chemotherapy and prevent the establishment and growth of lung cancer cells and establish proof. Colson, MD, PhDa Objectives: Lung cancer is associated with a significant rate of locoregional recur assay for tumor inhibition and induction of apoptosis. The in vivo prevention of Lewis lung carcinoma

101

Homeostatic competition drives tumor growth and metastasis nucleation  

E-print Network

point, subpopulations of cells may detach from the primary tumor and spread via the blood- stream preferential growth in differ- ent organs with a distribution that cannot be ex- plained by blood flow patterns in epithelial tissues from where they invade through the basal membrane into the connective tissue. At some

Turner, Matthew

102

Tumor growth instability and the onset of invasion  

E-print Network

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

Castro, M; Deisboeck, T; Castro, Mario; Molina-Paris, Carmen; Deisboeck, Thomas s.

2005-01-01

103

Stability and Hopf bifurcation for a regulated logistic growth model with discrete and distributed delays  

NASA Astrophysics Data System (ADS)

In this paper, we investigate the stability and Hopf bifurcation of a new regulated logistic growth with discrete and distributed delays. By choosing the discrete delay ? as a bifurcation parameter, we prove that the system is locally asymptotically stable in a range of the delay and Hopf bifurcation occurs as ? crosses a critical value. Furthermore, explicit algorithm for determining the direction of the Hopf bifurcation and the stability of the bifurcating periodic solutions is derived by normal form theorem and center manifold argument. Finally, an illustrative example is also given to support the theoretical results.

Fang, Shengle; Jiang, Minghui

2009-12-01

104

Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression or signaling  

PubMed Central

Mutations in PIK3CA, the gene encoding the p110? catalytic subunit of phosphatidylinositol-3 kinase (PI3K), have been shown to transform mammary epithelial cells (MECs). Studies suggest this transforming activity requires binding of mutant p110? via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTKs) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CAH1047R-expressing tumors. However, the p110?-specific inhibitor BYL719, in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Further, co-inhibition of p110? and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CAH1047R. These data suggest that PIK3CAH1047R-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110? and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations. PMID:23633485

Young, Christian D.; Pfefferle, Adam D.; Owens, Philip; Kuba, Maria G.; Rexer, Brent N.; Balko, Justin M.; Sanchez, Violeta; Cheng, Hailing; Perou, Charles M.; Zhao, Jean J.; Cook, Rebecca S.; Arteaga, Carlos L.

2013-01-01

105

TPX2 regulates tumor growth in human cervical carcinoma cells.  

PubMed

The targeting protein for the Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, has been utilized as a tool to evaluate, more precisely, the proliferative behavior of tumor cells. The abnormal expression of TPX2 in a variety of malignant tumor types has been reported, however less is known about its role in cervical cancer. In the present study, the association between TPX2 expression and the biological behavior of cervical cancer, was investigated. Immunohistochemistry and RT-PCR were used to detect the expression of TPX2 in cervical cancer tissues. The inhibitory effect of TPX2-siRNA on the growth of SiHa human cervical carcinoma cells was studied in vitro. TPX2 expression was identified as significantly higher in cervical carcinoma compared with the control, normal cervical tissues. TPX2 siRNA transfected into SiHa cells induced apoptosis and inhibited cell proliferation and invasion. Similar results were obtained by in vivo transplantation, as TPX2 siRNA transfection significantly reduced tumor growth of the xenograft in nude mice. The results demonstrated that TPX2 is important in the regulation of tumor growth in cervical cancer and therefore may be a potential therapeutic target as a novel treatment strategy. PMID:24718984

Jiang, Peiyue; Shen, Kexin; Wang, Xuerui; Song, Haiqin; Yue, Ying; Liu, Tongjun

2014-06-01

106

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

107

Noscapine inhibits tumor growth in TMZ-resistant gliomas.  

PubMed

Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas. PMID:21925789

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

2011-12-22

108

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

109

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

110

Vascular Endothelial Growth Factor as a Marker of Tumor Endothelium1  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that is a primary stimulant of the vascularization of solid tumors. VEGF production is induced by oncogenic gene mutations in the tumor cells and by hypoxic conditions inside the tumor mass. Hypoxia and the locally increased concentration of VEGF lead to an up-regulation of VEGF receptor expression on tumor endothelial

Rolf A. Brekken; Xianming Huang; Steven W. King; Philip E. Thorpe

1998-01-01

111

Short hairpin RNA targeting of fibroblast activation protein inhibits tumor growth and improves the tumor microenvironment in a mouse model  

PubMed Central

Fibroblast activation protein (FAP) is a specific serine protease expressed in tumor stroma proven to be a stimulatory factor in the progression of some cancers. The purpose of this study was to investigate the effects of FAP knockdown on tumor growth and the tumor microenvironment. Mice bearing 4T1 subcutaneous tumors were treated with liposome-shRNA complexes targeting FAP. Tumor volumes and weights were monitored, and FAP, collagen, microvessel density (MVD), and apoptosis were measured. Our studies showed that shRNA targeting of FAP in murine breast cancer reduces FAP expression, inhibits tumor growth, promotes collagen accumulation (38%), and suppresses angiogenesis (71.7%), as well as promoting apoptosis (by threefold). We suggest that FAP plays a role in tumor growth and in altering the tumor microenvironment. Targeting FAP may therefore represent a supplementary therapy for breast cancer. [BMB Reports 2013; 46(5): 252-257] PMID:23710635

Cai, Fan; Li, Zhiyong; Wang, Chunting; Xian, Shuang; Xu, Guangchao; Peng, Feng; Wei, Yuquan; Lu, You

2013-01-01

112

Natural killer cells: role in local tumor growth and metastasis  

PubMed Central

Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. PMID:22532775

Langers, Inge; Renoux, Virginie M; Thiry, Marc; Delvenne, Philippe; Jacobs, Nathalie

2012-01-01

113

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

114

Effect of puberty on rates of bone growth and mineralisation: with observations in male delayed puberty  

Microsoft Academic Search

The bone mineral content (BMC) and body height were measured in 301 normal children and adolescents aged 7--20 years, and in 8 boys with constitutional delayed puberty aged 14--17 years. Serum testosterone was measured in the last group as well as in a subpopulation of the normal children and adolescents. The growth spurt, which coincided with a steep increase of

S Krabbe; C Christiansen; P Rřdbro; I Transbřl

1979-01-01

115

Are Constitutional Delay of Growth and Familial Short Stature Different Conditions?  

Microsoft Academic Search

Children between 2 and 4 standard deviations below the mean height for age with no specific cause to account for their short stature are usually considered to represent either constitutional delay of growth (CDG) or familial short stat ure (FSS). This study was undertaken to determine whether 167 patients who were referred to our clinic for short stature could be

Roberto Lanes; Peter A. Lee; Leslie P. Plotnick; A. Avinoam Kowarski; Claude J. Migeon

1980-01-01

116

Dominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivo  

Microsoft Academic Search

Angiogenesis, the sprouting of new blood vessels from existing vessels, occurs in many physiological and pathological processes, including em bryonic development, wound healing, and tumor growth. It is required for tumor growth because new blood vessel formation is necessary for tumors to expand beyond a minimum volume. Several growth factor receptor tyrosine kinases have been implicated in angiogenesis, including receptors

Birgit Millauer; Michael P. Longhi; Karl H. Plate; Laura K. Shawver; Werner Risau; Axel Ullrich; Laurie M. Strawn

117

Homeostatic competition drives tumor growth and metastasis nucleation  

E-print Network

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

Basan, Markus; Joanny, Jean-Francois; Sastre-Garau, Xavier; Prost, Jacques

2009-01-01

118

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

119

[Seasonal patterns of breast tumor growth in Far North residents].  

PubMed

Earlier, we established a relationship between sex hormone receptor concentration in tumor and 5-year survival, on the one hand, and seasonality, on the other. The parameters showed a distinct 6-month cycle. That pointed to certain environmental factors which could synchronize hormone-dependent tumor process in the breast of women living in the North. The present study is concerned with a relationship of 6-month rhythm of tumor growth and latitude of residence. Said rhythm was reliably identified as a parameter of 5-year survival in the Far North (68 deg. northern latitude, p < 0.001). Maximum values of 5-year survival were registered in those diagnosed with cancer in winter or summer, while those diagnosed in spring or fall had unfavorable prognosis. Northern magnetic storms recur at 6-month intervals and most frequently in spring and fall. Electromagnetic radiation is known to suppress melatonin production and, that might have stimulated tumor process. Therefore, it is most likely that solar electromagnetic radiation might synchronize hormone-dependent tumor process in women resident in the North. PMID:17037040

Borisenkov, M F; Bazhenov, S M

2005-01-01

120

Interfacial properties in a discrete model for tumor growth  

NASA Astrophysics Data System (ADS)

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

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

2013-03-01

121

Reactivation of the Silenced Thyroid Hormone Receptor ? Gene Expression Delays Thyroid Tumor Progression  

PubMed Central

That a knock-in mouse harboring a dominant-negative thyroid hormone receptor (TR)-? (Thrb) mutation develops metastatic thyroid cancer strongly suggests the involvement of TR? in carcinogenesis. Epigenetic silencing of the THRB gene is common in human cancers. The aim of the present study was to determine how DNA methylation affected the expression of the THRB gene in differentiated thyroid cancer (DTC) and how reexpression of the THRB gene attenuated the cancer phenotypes. We used methylation-specific PCR to examine the expression and promoter methylation of the THRB gene in DTC tissues. Thyroid cancer cells with hypermethylated THRB were treated with the demethylating agents 5?-aza-2?-deoxycytidine (5?-aza-CdR) and zebularine to evaluate their impact on the cancer cell phenotypes. THRB mRNA expression in DTC was 90% lower than in normal controls, and this decrease was associated with a higher tumor/lymph node staging. The promoter methylation level of the THRB gene had a significant negative correlation with the expression level of the THRB gene. Treatment of FTC-236 cells with 5?-aza-CdR or zebularine induced reexpression of the THRB gene and inhibited cell proliferation and migration. FTC-236 cells stably expressing TR? exhibited lower cell proliferation and migration through inhibition of ?-catenin signaling pathways compared with FTC-236 without TR?. 5?-Aza-CdR also led to suppression of tumor growth in an in vivo xenograft model using FTC-236 cells consistent with the cell-based studies. These finding indicate that TR? is a tumor suppressor and could be tested as a potential therapeutic target. PMID:23183175

Kim, Won Gu; Zhu, Xuguang; Kim, Dong Wook; Zhang, Lisa; Kebebew, Electron

2013-01-01

122

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

123

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

124

Curcumin in combination with visible light inhibits tumor growth in a xenograft tumor model.  

PubMed

It is known that curcumin, a dietary pigment from the plant Curcuma longa, inhibits cell proliferation and induces apoptosis in different cell lines; however, the therapeutic benefit is hampered by very low absorption after transdermal or oral application. Recent studies from our laboratory have demonstrated that curcumin at low concentrations (0.2-1 microg/ml) offered the described effects only when applied with UVA or visible light. Nevertheless, the in vivo efficacy of this combination is lacking. In the present study, we used a xenograft tumor model with human epithelial carcinoma A431 cells to test the effect of curcumin and visible light on tumor growth. It was found that tumor growth was significantly inhibited in mice that were i.p. injected with curcumin and consecutively irradiated with visible light. Furthermore, immunohistochemistry showed a reduction of Ki 67 expression, indicating a decrease of cycling cells and induction of apoptotic bodies. The effect on apoptosis was further confirmed by Western blot analysis showing enhanced activation of caspases-9. Vice versa inhibition of extracellular regulated kinases (ERK) 1/2 and epidermal growth factor receptor (EGF-R) was observed which may aid inhibition of proliferation and induction of apoptosis. In summary, the present findings suggest a combination of curcumin and light as a new therapeutic concept to increase the efficacy of curcumin in the treatment of cancer. PMID:19035461

Dujic, Jadranka; Kippenberger, Stefan; Ramirez-Bosca, Ana; Diaz-Alperi, Joaquin; Bereiter-Hahn, Jürgen; Kaufmann, Roland; Bernd, August; Hofmann, Matthias

2009-03-15

125

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

126

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.  

PubMed

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

127

PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition  

Microsoft Academic Search

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist

Dipak Panigrahy; Arja Kaipainen; Sui Huang; Catherine E. Butterfield; Carmen M. Barnés; Michael Fannon; Andrea M. Laforme; Deviney M. Chaponis; Judah Folkman; Mark W. Kieran

2008-01-01

128

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

129

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

130

Activation of growth hormone secretagogue receptor induces time-dependent clock phase delay in mice.  

PubMed

Early studies have reported a phase-shifting effect of growth hormone secretagogues (GHSs). This study aimed to determine the mechanism of action of GHSs. We examined the response of the hypothalamic suprachiasmatic nuclei (SCN) to growth hormone releasing peptide-6 (GHRP-6) by assessing effects on the phase of locomotor activity rhythms, SCN neuronal discharges, and the potential signaling pathways involved in the drug action on circadian rhythms. The results showed that bolus administration of GHRP-6 (100 ?g/kg ip) at the beginning of subjective night (CT12) induced a phase delay of the free-running rhythms in male C57BL/6J mice under constant darkness, but did not elicit phase shift at other checked circadian time (CT) points. The phase-delay effect of GHRP-6 was abolished by d-(+)-Lys-GHRP-6 (GHS receptor antagonist), KN-93 [calcium/calmodulin-dependent protein kinase II (CaMK) II inhibitor], or anti-phosphorylated (p)-cAMP response element-binding protein (CREB) antibody. Further analyses demonstrated that GHRP-6 at CT12 induced higher calcium mobilization and neuronal discharge in the SCN compared with that at CT6, decreased the levels of glutamate and ?-aminobutyric acid, increased the levels of p-CaMKII, p-CREB, and period 1, and delayed the circadian expressions of circadian locomotor output cycles kaput, Bmal1, and prokineticin 2 in the SCN; these signaling changes resulted in behavioral phase delay. Collectively, GHRP-6 induces a CT-dependent phase delay via activating GHS receptor and the downstream signaling, which is partially similar to the signaling cascade of light-induced phase delay at early night. These novel observations may help to better understand the role of GHSs in circadian physiology. PMID:25074983

Zhou, Lan; Gao, Qian; Zhang, Peng; Guo, Shu; Gu, Jingli; Hao, Wei; Cao, Ji-Min

2014-09-15

131

BMP4 Promotes Prostate Tumor Growth in Bone Through Osteogenesis  

PubMed Central

Induction of new bone formation is frequently seen in the bone lesions from prostate cancer (PCa). However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, two xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from PCa bone metastases. When implanted subcutaneously in SCID mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (“secretome”) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of BMP-4 and several cytokines including IL-8, Gro, and CCL2. We demonstrated that BMP-4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treating with BMP-4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP-4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of PCa in bone. PMID:21670081

Lee, Yu-Chen; Cheng, Chien-Jui; Bilen, Mehmet A.; Lu, Jing-Fang; Satcher, Robert L.; Yu-Lee, Li-Yuan; Gallick, Gary E.; Maity, Sankar N.; Lin, Sue-Hwa

2011-01-01

132

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

133

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

PubMed Central

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

Poleszczuk, Jan; Enderling, Heiko

2014-01-01

134

Interferon-? and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment  

PubMed Central

Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFN? and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFN? alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFN? alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFN? and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFN? and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFN? and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFN? and celecoxib have potential to be further optimized into a new anticancer therapy. PMID:25284985

Ren, Fuqiang; Fan, Mingyu; Mei, Jiandong; Wu, Yongqiang; Liu, Chengwu; Pu, Qiang; You, Zongbing; Liu, Lunxu

2014-01-01

135

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

136

Global Practical Tracking by Output Feedback for Nonlinear Systems with Unknown Growth Rate and Time Delay  

PubMed Central

This paper is the further investigation of work of Yan and Liu, 2011, and considers the global practical tracking problem by output feedback for a class of uncertain nonlinear systems with not only unmeasured states dependent growth but also time-varying time delay. Compared with the closely related works, the remarkableness of the paper is that the time-varying time delay and unmeasurable states are permitted in the system nonlinear growth. Motivated by the related tracking results and flexibly using the ideas and techniques of universal control and dead zone, an adaptive output-feedback tracking controller is explicitly designed with the help of a new Lyapunov-Krasovskii functional, to make the tracking error prescribed arbitrarily small after a finite time while keeping all the closed-loop signals bounded. A numerical example demonstrates the effectiveness of the results.

Yan, Xuehua

2014-01-01

137

Global practical tracking by output feedback for nonlinear systems with unknown growth rate and time delay.  

PubMed

This paper is the further investigation of work of Yan and Liu, 2011, and considers the global practical tracking problem by output feedback for a class of uncertain nonlinear systems with not only unmeasured states dependent growth but also time-varying time delay. Compared with the closely related works, the remarkableness of the paper is that the time-varying time delay and unmeasurable states are permitted in the system nonlinear growth. Motivated by the related tracking results and flexibly using the ideas and techniques of universal control and dead zone, an adaptive output-feedback tracking controller is explicitly designed with the help of a new Lyapunov-Krasovskii functional, to make the tracking error prescribed arbitrarily small after a finite time while keeping all the closed-loop signals bounded. A numerical example demonstrates the effectiveness of the results. PMID:25276859

Yan, Xuehua; Song, Xinmin

2014-01-01

138

The influence of inspiratory hyperoxia on ischemia-reperfusion-induced tumour growth delay.  

PubMed

We investigated the ischemia-reperfusion-induced tumour growth delay as a function of ischemic time, tumour temperature, and the amount of inspired oxygen during reperfusion. The rhabdomyosarcoma R1H growing on the right flank of male WAG/Rij rats was clamped for 2 or 4 h at 20 degrees C or 37 degrees C. Five minutes prior to and 10 min during reperfusion the animals respired air, pure oxygen or carbogen (95% O2, 5% CO2). Comparison of single treatment modalities with untreated controls revealed significant tumour growth delays after clamping times of 4 h at 37 degrees C for air and pure oxygen, but not for carbogen. PMID:10601606

Hartmann, K A; Carl, U M; Sminia, P; Lammering, G; Becker, K A; Schmitt, G

2000-01-01

139

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

140

[The effect of the spleen on tumor growth in mouse lines with various spleen sizes].  

PubMed

Selectively raised laboratory mice differ according to spleen size in their immunologic behavior against various tumors. A small spleen and splenectomy reduce tumor growth, whereas a large spleen or additional transfer of tumor antigen-specific spleen cells ("suppressor cells") stimulate tumor incidence. PMID:313319

von Wallenberg, H; Mainusch, P; Meyer, J; Hammer, C

1979-01-01

141

A Nonradiated Grade II Glioma That Underwent Delayed Malignant Transformation to a Gliosarcoma with Meningeal Growth and Dissemination.  

PubMed

Background?Secondary gliosarcomas are rare tumors, especially those arising from a World Health Organization (WHO) grade II glioma not irradiated. We report a case with subtotal resection for a WHO grade II oligoastrocytoma, without adjuvant treatment, whose metaplastic transformation into gliosarcoma suddenly occurred 4 years later with meningeal dissemination. We show a favorable outcome after therapeutic management of this rare entity. Patient?A 46 year-old woman underwent surgery for a right premotor WHO grade II oligoastrocytoma discovered incidentally. Because of a subtotal resection with only 1?cc of residue, no complementary therapy was given, and the patient enjoyed a normal life for 4 years. In the meantime, the magnetic resonance images performed every 6 months showed a very low growth rate. Suddenly, the tumor switched toward a gliosarcoma profile with meningeal dissemination. Results?Reoperation, radiotherapy, and chemotherapy were performed, enabling a control of the disease with 15 months of follow-up (i.e., with radiologic shrinkage of the multiple lesions and preservation of quality of life). Conclusion?A delayed sarcomatous transformation can acutely occur with a low proliferation index in a nonirradiated WHO grade II oligoastrocytoma. Furthermore, an aggressive therapeutic strategy can allow control of secondary gliosarcomas, even in cases of leptomeningeal spreading. PMID:24971682

Rech, Fabien; Rigau, Valerie; Fabbro, Michel; Kerr, Christine; Gauchotte, Guillaume; Taillandier, Luc; Duffau, Hugues

2014-11-01

142

Dynamic density functional theory of solid tumor growth: Preliminary models  

PubMed Central

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

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

2012-01-01

143

Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages.  

PubMed

GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response. PMID:22753274

Pickert, Geethanjali; Lim, Hee-Young; Weigert, Andreas; Häussler, Annett; Myrczek, Thekla; Waldner, Maximilian; Labocha, Sandra; Ferreirós, Nerea; Geisslinger, Gerd; Lötsch, Jörn; Becker, Christoph; Brüne, Bernhard; Tegeder, Irmgard

2013-02-01

144

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models  

PubMed Central

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature. PMID:19809158

Maione, Federica; Molla, Fabiola; Meda, Claudia; Latini, Roberto; Zentilin, Lorena; Giacca, Mauro; Seano, Giorgio; Serini, Guido; Bussolino, Federico; Giraudo, Enrico

2009-01-01

145

Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth.  

PubMed

Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells. PMID:25042803

Shan, Changliang; Elf, Shannon; Ji, Quanjiang; Kang, Hee-Bum; Zhou, Lu; Hitosugi, Taro; Jin, Lingtao; Lin, Ruiting; Zhang, Liang; Seo, Jae Ho; Xie, Jianxin; Tucker, Meghan; Gu, Ting-Lei; Sudderth, Jessica; Jiang, Lei; DeBerardinis, Ralph J; Wu, Shaoxiong; Li, Yuancheng; Mao, Hui; Chen, Peng R; Wang, Dongsheng; Chen, Georgia Zhuo; Lonial, Sagar; Arellano, Martha L; Khoury, Hanna J; Khuri, Fadlo R; Lee, Benjamin H; Brat, Daniel J; Ye, Keqiang; Boggon, Titus J; He, Chuan; Kang, Sumin; Fan, Jun; Chen, Jing

2014-08-21

146

Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression  

PubMed Central

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET), are essential morphological processes during development and in the regulation of stem cell pluripotency, yet these processes are also activated in pathological contexts, such as in fibrosis and cancer progression. Multi-component signaling pathways cooperate in initiation of EMT and MET programs, via transcriptional, post-transcriptional, translational, and post-translational regulation. EMT is required for tissue regeneration and normal embryonic development as it enables epithelial cells to acquire the mesenchymal phenotype, conferring them migratory and dynamic properties towards forming three-dimensional structures during gastrulation and organ formation. Uncontrolled activation of such phenomenon and the pathways signaling EMT events in adult life, leads to cancer growth and orchestrated by signaling interactions from the microenvironment, epithelial tumor cells with enhanced polarity, become invasive and rapidly metastasize to distant sites. Loss of epithelial markers (E-cadherin) and gain of mesenchymal markers (N-cadherin), at the leading edge of solid tumors is associated with progression to metastasis. This review will explore the contribution of EMT to embryonic development of GU organs and the functional consequences of EMT-MET cycles in prostate tumorigenesis. Recent insights identifying key players driving EMT and its reversal to MET during prostate cancer progression to metastatic castration-resistant disease will be discussed, with specific focus on androgen receptor (AR) and transforming growth factor-? (TGF-?) signaling in the context of their predictive and targeting value in prostate cancer progression.

Grant, Campbell M.; Kyprianou, Natasha

2014-01-01

147

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

E-print Network

Glioblastoma are known to infiltrate the brain parenchyma instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In clinical practice, a uniform margin is applied to account for microscopic spread of disease. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth: Anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain...

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

2013-01-01

148

Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth  

SciTech Connect

Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloid fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.

Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.; Russell, J.D.; Trupin, J.S.

1988-01-01

149

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

PubMed Central

Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion. PMID:25111061

Papageorgis, Panagiotis; Odysseos, Andreani D.; Stylianopoulos, Triantafyllos

2014-01-01

150

The A3 Adenosine Receptor Is Highly Expressed in Tumor versus Normal Cells: Potential Target for Tumor Growth Inhibition  

Microsoft Academic Search

Purpose: A3 adenosine receptor (A3AR) activation was shown to inhibit the growth of various tumor cells via the down-regulation of nuclear factor B and cyclin D1. To additionally elucidate whether A3AR is a specific target, a survey of its expression in tumor versus adjacent normal cells was conducted. Experimental Design: A3AR mRNA expression in vari- ous tumor tissues was tested

Lea Madi; Avivit Ochaion; Lea Rath-Wolfson; Sara Bar-Yehuda; Abigail Erlanger; Gil Ohana; Arie Harish; Ofer Merimski; Faina Barer; Pnina Fishman

2004-01-01

151

Axonal regeneration of sensory nerves is delayed by continuous intrathecal infusion of nerve growth factor.  

PubMed

While it is well established that nerve growth factor is growth promoting for sensory neurons in culture, it is unclear whether it serves such a function in vivo. In fact, our previous studies led to the hypothesis that nerve growth factor could actually impair axonal regeneration by reducing the neuronal cell body response to injury. In the present study, the consequence of continuous intrathecal infusion of nerve growth factor on regeneration of sensory neurons was examined in rats given a bilateral sciatic nerve crush. Rats received nerve growth factor (125 ng/h) as a continuous infusion into the subarachnoid space of the lumbar spinal cord via an osmotic minipump (Alzet); controls received cytochrome C. At seven or 10 days, the pump was removed and L4 or L5 dorsal root ganglion exposed and injected with 50 microCi of (3H)leucine. Animals were killed 24 h later, the sciatic nerves removed, cut into 3 mm segments and the radioactivity in each segment determined by liquid scintillation spectrophotometry. Maximal regeneration distances (determined from the front of the resultant transport curves) were similarly reduced (by approximately 6 mm) in nerve growth factor-infused compared to cytochrome C-infused rats. Thus, regeneration rates (determined between eight and 11 days) were unaltered by nerve growth factor infusion; regeneration rates from cytochrome C-infused and nerve growth factor-infused animals were 2.8 mm/day and 3.1 mm/day, respectively. However, nerve growth factor significantly (P < 0.005) increased the delay to onset for regeneration by two days. Taken together, the present study demonstrates that nerve growth factor delays the onset of regeneration without affecting the rate of regeneration. The results implicate the involvement of at least two signals in the regulation of axonal regeneration in dorsal root ganglion neurons. It is suggested that the loss of nerve growth factor serves as an early, induction signal regulating the onset of regeneration and that a second, unidentified signal independently serves to maintain regeneration. PMID:9027875

Gold, B G

1997-02-01

152

Depletion of m2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.  

PubMed

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

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

2014-11-01

153

Inhibition of Fibroblast Growth Factor 19 Reduces Tumor Growth by Modulating B-Catenin Signaling  

Microsoft Academic Search

Fibroblast growth factors (FGF) play important roles in development, angiogenesis, and cancer. FGF19 uniquely binds to FGF receptor 4 (FGFR4). Our previous study has shown that FGF19 transgenic tumors have an activated Wnt-pathway phenotype. Wnt signaling is implicated in initiating or promoting FGF signaling in various cell types and organs. In this study, we examined whether FGF19 or inhibition of

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

2008-01-01

154

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

Microsoft Academic Search

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

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

1997-01-01

155

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

156

Phosphocaveolin-1 enforces tumor growth and chemoresistance in rhabdomyosarcoma.  

PubMed

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

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

2014-01-01

157

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

PubMed Central

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

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

2013-01-01

158

A validated mathematical model of tumor growth including tumor-host interaction, cell-mediated immune response and chemotherapy.  

PubMed

We consider a dynamical model of cancer growth including three interacting cell populations of tumor cells, healthy host cells and immune effector cells. The tumor-immune and the tumor-host interactions are characterized to reproduce experimental results. A thorough dynamical analysis of the model is carried out, showing its capability to explain theoretical and empirical knowledge about tumor development. A chemotherapy treatment reproducing different experiments is also introduced. We believe that this simple model can serve as a foundation for the development of more complicated and specific cancer models. PMID:25348062

López, Alvaro G; Seoane, Jesús M; Sanjuán, Miguel A F

2014-11-01

159

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

PubMed

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

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

2014-07-01

160

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

161

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

PubMed Central

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

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

2014-01-01

162

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

163

Inhibition of Angiopoietin-2 in LuCaP 23.1 Prostate Cancer Tumors Decreases Tumor Growth and Viability  

PubMed Central

Background Angiopoietin-2 is expressed in prostate cancer (PCa) bone, liver, and lymph node metastases, whereas, its competitor angiopoietin-1 has limited expression in these tissues. Therefore, we hypothesized that the inhibition of angiopoietin-2 activity in PCa metastasis (removed) will impede angiogenesis, tumor growth and alter bone response in vivo. Methods To test our hypothesis we used L1–10, a peptide-Fc fusion that inhibits interactions between angiopoietin-2 and its receptor tie2. We blocked angiopoietin-2 activity using L1–10 in established subcutaneous and intra-tibial LuCaP 23.1 xenografts. We then determined the effect of L1–10 on survival, tumor growth, serum PSA, proliferation, microvessel density, and angiogenesis-associated gene expression in subcutaneous tumors. We also determined serum PSA, tumor area and bone response in intra-tibial tumors. Results The administration of L1–10 decreased tumor volume and serum PSA, and increased survival in SCID mice bearing subcutaneous LuCaP 23.1 tumors. Histomorphometric analysis, showed a further significant decrease in tumor epithelial area within the L1–10-treated LuCaP 23.1 subcutaneous tumors (p=0.0063). There was also a significant decrease in cell proliferation (p=0.012), microvessel density (p=0.012), and a significant increase in ANGPT-2 and HIF-1? mRNA expression (p?0.05) associated with L1–10 treatment. Alternatively, in LuCaP 23.1 intra-tibial tumors L1–10 treatment did not significantly change serum PSA, tumor area or bone response. Conclusions Our results demonstrate that inhibiting angiopoietin-2 activity impedes angiogenesis and growth of LuCaP 23.1 PCa xenografts. Based on these data, we hypothesize that angiopoietin-2 inhibition in combination with other therapies may represent a potential therapy for patients with metastatic disease. PMID:20583134

Morrissey, Colm; Dowell, Alex; Koreckij, Theodore D.; Nguyen, Holly; Lakely, Bryce; Fanslow, William C.; True, Lawrence D.; Corey, Eva; Vessella, Robert L.

2011-01-01

164

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

165

Development of tumor-induced osteomalacia in a subcutaneous tumor, defined by venous blood sampling of fibroblast growth factor-23.  

PubMed

A 25-year-old man with severe lumbago was referred to our department for further evaluation. Serum phosphate and TmP/GFR levels were decreased. Physical examination revealed an elastic tumor in the instep of the right foot, which the patient reported having since the age of 10 years. He had no symptoms of osteomalacia at that time. Within the recent years, the tumor had grown in size and the patient developed lumbago. To examine the existence of a fibroblast growth factor-23 (FGF-23)-producing tumor, venous blood was collected from four main veins. FGF-23 levels were significantly increased in the right femoral vein, compared with other veins. After the resection of the tumor, the histopathology was consistent with a phosphaturic mesenchymal tumor (mixed connective tissue variant). Taken together, these results indicated that the development of osteomalacia in this patient was associated with the production of FGF-23 in the subcutaneous tumor. PMID:18379151

Ogura, Eriko; Kageyama, Kazunori; Fukumoto, Seiji; Yagihashi, Norito; Fukuda, Yoshiko; Kikuchi, Toru; Masuda, Mitsuo; Suda, Toshihiro

2008-01-01

166

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

167

Effects of the Tyrosine Kinase Inhibitor Imatinib on Neuroendocrine Tumor Cell Growth  

Microsoft Academic Search

Aim: We investigated the effects of the tyrosine kinase inhibitor imatinib (Gleevec®) on neuroendocrine tumor cells. Methods: Neuroendocrine tumor cells were incubated without and with imatinib. The effects on growth were examined by methylthiazoletetrazolium (MTT) assay. The c-Kit expression in human endocrine tumor tissue and cell lines was determined by immunohistochemistry and Western blot analysis, respectively. Cytotoxicity assay was performed

Brigitte Lankat-Buttgereit; Dieter Hörsch; Peter Barth; Rudolf Arnold; Silke Blöcker; Rüdiger Göke

2005-01-01

168

The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics  

PubMed Central

Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1–RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression. PMID:23318458

Kang, R; Tang, D; Schapiro, NE; Loux, T; Livesey, KM; Billiar, TR; Wang, H; Van Houten, B; Lotze, MT; Zeh, HJ

2013-01-01

169

The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics.  

PubMed

Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression. PMID:23318458

Kang, R; Tang, D; Schapiro, N E; Loux, T; Livesey, K M; Billiar, T R; Wang, H; Van Houten, B; Lotze, M T; Zeh, H J

2014-01-30

170

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

PubMed Central

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

2013-01-01

171

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

172

Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis  

Microsoft Academic Search

The mammalian target of rapamycin (mTOR) is a controller of cell growth with multiple effects on cancer development and progression.\\u000a Being closely linked to key oncogenic pathways that regulate tumor cell growth and cell cycle progression, mTOR integrates\\u000a the cellular response to mitogenic and growth stimuli. Rapamycin and its analogs temsirolimus and everolimus are specific\\u000a inhibitors of mTOR that exert

Hendrik Seeliger; Markus Guba; Axel Kleespies; Karl-Walter Jauch; Christiane J. Bruns

2007-01-01

173

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

PubMed

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

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

2011-11-01

174

In vivo delivery of siRNA targeting vasohibin-2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer.  

PubMed

Vasohibin-2 (VASH2) is a homolog of vasohibin-1 and exhibits pro-angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV-3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2-treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment. PMID:24118388

Koyanagi, Takahiro; Suzuki, Yasuhiro; Saga, Yasushi; Machida, Shizuo; Takei, Yuji; Fujiwara, Hiroyuki; Suzuki, Mitsuaki; Sato, Yasufumi

2013-12-01

175

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

176

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

NASA Astrophysics Data System (ADS)

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

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

2014-05-01

177

Growth Patterns and Metastatic Behavior of Human Tumors Growing in Athymic Mice1  

Microsoft Academic Search

The growth characteristics and metastatic behavior of human tumors growing in athymic nude mice were stud ied. Human tumor cell lines HEp-2 (carcinoma of larynx) and SW480 (colon carcinoma) were transplanted into athymic nude mice of BALB\\/c origin. Tumor cells (1 x 106 and 2 x 107) were given either s.c. or i.p. Following s.c. injection tumors developed rapidly to

Andreas P. Kyriazis; Linda DiPersio; Gabriel J. Michael; Amadeo J. Pesce; J. Dwight Stinnett

178

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.

179

Effects of cytotoxic agents on TdR incorporation and growth delay in human colonic tumour xenografts.  

PubMed Central

The relationship between the utilization of 3H-thymidine in situ ([3H]-TdR fractional incorporation or TFI) and tumour growth delay after treatment with various cytotoxic agents has been examined. It is shown that (a) it is not possible to predict tumour growth delay, or to select the most effective agent, from changes in TFI 1 day after treatment; (b) there is a good correlation between tumour growth delay and the time for recovery of TFI to the pretreatment level; (c) there is a relationship within a tumour line between the depression of TFI 4 days after treatment and growth dealy induced by the same treatment. This relationship appears to be independent of the mechanism by which the agent exerts its cytotoxic effect. PMID:911658

Houghton, P. J.; Houghton, J. A.; Taylor, D. M.

1977-01-01

180

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

PubMed Central

Kaposi’s Sarcoma (KS) originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi Sarcoma-associated Herpes Virus (KSHV) are endemic, KS is the most common cancer overall, but model systems for disease study are insufficient. Here we report the development of a novel mouse model of KS where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results demonstrated that mTOR inhibitors exert a direct anti-KS effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for KS and other cancers of endothelial origin. PMID:23382046

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

2013-01-01

181

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

PubMed

Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin. PMID:23382046

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

2013-04-01

182

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma.  

PubMed

Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS. PMID:21460855

Su, Y; Wagner, E R; Luo, Q; Huang, J; Chen, L; He, B-C; Zuo, G-W; Shi, Q; Zhang, B-Q; Zhu, G; Bi, Y; Luo, J; Luo, X; Kim, S H; Shen, J; Rastegar, F; Huang, E; Gao, Y; Gao, J-L; Yang, K; Wietholt, C; Li, M; Qin, J; Haydon, R C; He, T-C; Luu, H H

2011-09-15

183

The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth  

PubMed Central

Purpose Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. Experimental design Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat. Results Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45?M). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg q3d) showed ?70% inhibition of telomerase activity. Chronic systemic treatment on the same dose schedule produced a marked decrease in the rate of xenograft subcutaneous tumor growth. Conclusion This pre-clinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. PMID:20048334

Marian, Calin O.; Cho, Steve K.; McEllin, Brian M.; Maher, Elizabeth A.; Hatanpaa, Kimmo J.; Madden, Christopher J.; Mickey, Bruce E.; Wright, Woodring E.; Shay, Jerry W.; Bachoo, Robert M.

2010-01-01

184

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

185

pH control mechanisms of tumor survival and growth.  

PubMed

A distinguishing phenotype of solid tumors is the presence of an alkaline cellular feature despite the surrounding acidic microenvironment. This phenotypic characteristic of tumors, originally described by Otto Warburg, arises due to alterations in metabolism of solid tumors. Hypoxic regions of solid tumors develop due to poor vascularization and in turn regulate the expression of numerous genes via the transcription factor HIF-1. Ultimately, the tumor microenvironment directs the development of tumor cells adapted to survive in an acidic surrounding where normal cells perish. The provision of unique pH characteristics in tumor cells provides a defining trait that has led to the pursuit of treatments that target metabolism, hypoxia, and pH-related mechanisms to selectively kill cancer cells. Numerous studies over the past decade involving the cancer-specific carbonic anhydrase IX have re-kindled an interest in pH disruption-based therapies. Although an acidification of the intracellular compartment is established as a means to induce normal cell death, the defining role of acid-base disturbances in tumor physiology and survival remains unclear. The aim of this review is to summarize recent data relating to the specific role of pH regulation in tumor cell survival. We focus on membrane transport and enzyme studies in an attempt to elucidate their respective functions regarding tumor cell pH regulation. These data are discussed in the context of future directions for the field of tumor cell acid-base-related research. PMID:20857482

Parks, Scott K; Chiche, Johanna; Pouyssegur, Jacques

2011-02-01

186

Antiangiogenic Therapy Using Sunitinib Combined with Rapamycin Retards Tumor Growth But Promotes Metastasis1  

PubMed Central

BACKGROUND: This study investigated the synergistic effect of sunitinib and rapamycin on tumor growth and metastasis in murine breast cancer model. METHODS: The synergistic antitumor effect of sunitinib and rapamycin on tumor growth and metastasis was investigated. Myeloid-derived suppressor cells (MDSCs) in spleens and lungs were assessed. Tumor hypoxia, vessel density and micrometastasis were evaluated. Versican, indoleamine 2,3-dioxygenase (IDO), arginase 1, interleukin-6 (IL-6), IL-10, and transforming growth factor ? (TGF-?) in the lungs and tumors were examined. IL-6 and TGF-? in the blood were evaluated. RESULTS: Synergism between sunitinib and rapamycin on tumor growth was observed. Sunitinib plus rapamycin reduced splenomegaly, MDSCs in spleens and lungs, and microvessel density in tumor microenvironment, while exacerbated hypoxia and promoted cancer lung metastasis. Sunitinib plus rapamycin markedly induced versican, IDO, arginase 1, IL-6, and TGF-? expression in the lungs, whereas it reduced IDO and IL-10 expression in the primary tumor tissues. IL-6 levels in the circulation were increased after rapamycin and combination therapies. CONCLUSIONS: The combination of sunitinib plus rapamycin reduced the tumor growth but promoted tumor metastasis. This study warrants that further mTOR inhibition treatment should be closely watched in clinical setting, especially combined with antiangiogenic therapy. PMID:24742865

Yin, Tao; He, Sisi; Ye, Tinghong; Shen, Guobo; Wan, Yang; Wang, Yongsheng

2014-01-01

187

Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression  

Microsoft Academic Search

Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the epidermal growth factor receptor (EGFR) in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear. We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and eight malignant) by means of egfr fluorescence in

Christian Kersting; Arno Kuijper; Hartmut Schmidt; Jens Packeisen; Cornelia Liedtke; Nicola Tidow; Christian Gustmann; Bernd Hinrichs; Pia Wülfing; Joke Tio; Werner Boecker; Paul van Diest; Burkhard Brandt; Horst Buerger

2006-01-01

188

Potentiation of Radiation-induced Regrowth Delay in Murine Tumors by Fludarabine I  

Microsoft Academic Search

Fludarabine (9-\\/3-n-arabinofuranosyl-2-fluoroadenine-5'-monophos- phate), an adenine nucleoside analogue, has previously been shown to inhibit the repair of radiation-induced chromosome damage. Thus fludarabine may have therapeutic utility in combination with photon irradiation. The purpose of this study was to determine whether fludarabine could enhance radiation-induced murine tumor regrowth de- lay and to determine the most effective dose and schedule of the combi-

Vincent Gr; Nancy Hunter; Luka Milas; William A. Brock; William Plunkett; Walter N. Hittelman

189

The enhancement of tumor growth after partial hepatectomy and the effect of sera obtained from hepatectomized rats on tumor cell growth.  

PubMed

In the process of liver regeneration, the participation of various types of growth stimulators and changes in immune responses have been reported. Here, we examined the growth of subcutaneously transplanted AH130 cells and Walker 256 cells after partial hepatectomy. In the case of tumor cells being transplanted on the same day as partial hepatectomy, the increase in tumor size in hepatectomized rats was significantly greater compared with that in non-treated rats or in those having undergone a simple laparotomy. When the transplantation of tumor cells was done on the 7th day after partial hepatectomy, however, the increase was less marked. We also examined the effect of serum obtained from rats after partial hepatectomy on the in vitro growth of these tumor cells. Growth enhancement was observed with medium containing serum drawn from rats 1 to 4 days after partial hepatectomy. These results suggest that the growth of tumor cells was stimulated during liver regeneration and that some humoral factors participated in the process. Furthermore, as the conditions of the in vitro method appear to mimic those of the in vivo method, the in vitro approach should be very useful for analysis of the factors responsible. PMID:1787614

Asaga, T; Suzuki, K; Umeda, M; Sugimasa, Y; Takemiya, S; Okamoto, T

1991-11-01

190

The concept of delayed nucleation in nanocrystal growth demonstrated for the case of iron oxide nanodisks.  

PubMed

A comprehensive study of iron oxide nanocrystal growth through non-hydrolitic, surfactant-mediated thermal reaction of iron pentacarbonyl and an oxidizer has been conducted, which includes size control, anisotropic shape evolution, and crystallographic phase transition of monodisperse iron oxide colloidal nanocrystals. The reaction was monitored via in situ UV-vis spectroscopy, taking advantage of the color change accompanying the iron oxide colloid formation, allowing measurement of the induction time for nucleation. Features of the synthesis such as the size control and reproducibility are related to the occurrence of the observed delayed nucleation process. As a separate source of iron and oxygen is adopted, phase control could also be achieved by sequential injections of oxidizer. PMID:16448141

Casula, Maria F; Jun, Young-Wook; Zaziski, David J; Chan, Emory M; Corrias, Anna; Alivisatos, A Paul

2006-02-01

191

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

PubMed Central

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

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

2013-01-01

192

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

193

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

194

The Effect of Electroacupuncture on Osteosarcoma Tumor Growth and Metastasis: Analysis of Different Treatment Regimens  

PubMed Central

Osteosarcoma is the most common malignant bone tumor found in children and adolescents and is associated with many complications including cancer pain and metastasis. While cancer patients often seek complementary and alternative medicine (CAM) approaches to treat cancer pain and fatigue or the side effects of chemotherapy and treatment, there is little known about the effect of acupuncture treatment on tumor growth and metastasis. Here we evaluate the effects of six different electroacupuncture (EA) regimens on osteosarcoma tumor growth and metastasis in both male and female mice. The most significant positive effects were observed when EA was applied to the ST-36 acupoint twice weekly (EA-2X/3) beginning at postimplantation day 3 (PID 3). Twice weekly treatment produced robust reductions in tumor growth. Conversely, when EA was applied twice weekly (EA-2X/7), starting at PID 7, there was a significant increase in tumor growth. We further demonstrate that EA-2X/3 treatment elicits significant reductions in tumor lymphatics, vasculature, and innervation. Lastly, EA-2X/3 treatment produced a marked reduction in pulmonary metastasis, thus providing evidence for EA's potential antimetastatic capabilities. Collectively, EA-2X/3 treatment was found to reduce both bone tumor growth and lung metastasis, which may be mediated in part through reductions in tumor-associated vasculature, lymphatics, and innervation. PMID:24228059

Smeester, Branden A.; O'Brien, Elaine E.; Ericson, Marna E.; Triemstra, Jennifer L.; Beitz, Alvin J.

2013-01-01

195

Pharmacological Inhibition of Microsomal Prostaglandin E Synthase-1 Suppresses Epidermal Growth Factor Receptor-Mediated Tumor Growth and Angiogenesis  

PubMed Central

Background Blockade of Prostaglandin (PG) E2 production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE2 promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. Methodology/Principal Findings Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1?) increased mPGES-1 expression, PGE2 production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE2 production, both in quiescent and in cells stimulated by IL-1?. AF3485 abolished IL-1?-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. Conclusion Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE2 mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth. PMID:22815767

Bocci, Elena; Coletta, Isabella; Polenzani, Lorenzo; Mangano, Giorgina; Alisi, Maria Alessandra; Cazzolla, Nicola; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

2012-01-01

196

Sucrose octasulfate regulates fibroblast growth factor-2 binding, transport, and activity: potential for regulation of tumor growth.  

PubMed

The antithrombotic activity of heparin has largely been credited with the success found in some cancer treatment by heparin. There are, however, many potent growth factors involved in tumor and blood vessel growth that bind to heparin with high affinity and their regulation by heparin may play a role in heparin's efficacy. We therefore chose to study the activity of a heparin analog, sucrose octasulfate (SOS), which has been similarly shown to interact with heparin-binding growth factors. Using mouse melanoma and lung carcinoma models, we demonstrate in vivo inhibition of tumor growth by SOS. SOS, however, showed little effect in coagulation assays indicating that this activity was not a primary mechanism of action for this molecule. Studies were then performed to assess the effect of SOS on basic fibroblast growth factor (FGF-2) activity, a growth factor which promotes tumor and blood vessel growth and is produced by B16 melanoma cells. SOS potently inhibited FGF-2 binding to endothelial cells and stripped pre-bound FGF-2 from cells. SOS also regulated FGF-2 stimulated proliferation. Further, SOS facilitated FGF-2 diffusion through Descemet's membrane, a heparan sulfate-rich basement membrane from the cornea, suggesting a possible role in FGF-2 clearance. Our results suggest that molecules such as SOS have the potential to remove growth factors from tumor microenvironments and the approach offers an attractive area for further study. PMID:18163458

Fannon, Michael; Forsten-Williams, Kimberly; Nugent, Matthew A; Gregory, Kalvin J; Chu, Chia Lin; Goerges-Wildt, Adrienne L; Panigrahy, Dipak; Kaipainen, Arja; Barnes, Carmen; Lapp, Cathy; Shing, Yuen

2008-05-01

197

Sucrose Octasulfate Regulates Fibroblast Growth Factor-2 Binding, Transport, and Activity: Potential for Regulation of Tumor Growth  

PubMed Central

The antithrombotic activity of heparin has largely been credited with the success found in some cancer treatment by heparin. There are, however, many potent growth factors involved in tumor and blood vessel growth that bind to heparin with high affinity and their regulation by heparin may play a role in heparin’s efficacy. We therefore chose to study the activity of a heparin analog, sucrose octasulfate (SOS), which has been similarly shown to interact with heparin-binding growth factors. Using mouse melanoma and lung carcinoma models, we demonstrate in vivo inhibition of tumor growth by SOS. SOS, however, showed little effect in coagulation assays indicating that this activity was not a primary mechanism of action for this molecule. Studies were then performed to assess the effect of SOS on basic fibroblast growth factor (FGF-2) activity, a growth factor which promotes tumor and blood vessel growth and is produced by B16 melanoma cells. SOS potently inhibited FGF-2 binding to endothelial cells and stripped pre-bound FGF-2 from cells. SOS also regulated FGF-2 stimulated proliferation. Further, SOS facilitated FGF-2 diffusion through Descemet’s membrane, a heparan sulfate-rich basement membrane from the cornea, suggesting a possible role in FGF-2 clearance. Our results suggest that molecules such as SOS have the potential to remove growth factors from tumor microenvironments and the approach offers an attractive area for further study. PMID:18163458

FANNON, MICHAEL; FORSTEN-WILLIAMS, KIMBERLY; NUGENT, MATTHEW A.; GREGORY, KALVIN J.; CHU, CHIA LIN; GOERGES-WILDT, ADRIENNE L; PANIGRAHY, DIPAK; KAIPAINEN, ARJA; BARNES, CARMEN; LAPP, CATHY; SHING, YUEN

2008-01-01

198

Growth Delay as an Index of Allostatic Load in Young Children: Predictions to Disinhibited Social Approach and Diurnal Cortisol Activity  

PubMed Central

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

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

2012-01-01

199

Oncolytic HSV and Erlotinib Inhibit Tumor Growth and Angiogenesis in a Novel Malignant Peripheral Nerve Sheath Tumor Xenograft Model  

Microsoft Academic Search

Malignant peripheral nerve sheath tumors (MPNSTs), driven in part by hyperactive Ras and epidermal growth factor receptor (EGFR) signaling, are often incurable. Testing of therapeutics for MPNST has been hampered by lack of adequate xenograft models. We previously documented that human MPNST cells are permissive for lytic infection by oncolytic herpes simplex viruses (oHSV). Herein we developed and characterized a

Yonatan Y Mahller; Sachin S Vaikunth; Mark A Currier; Shyra J Miller; Maria C Ripberger; Ya-Hsuan Hsu; Ruty Mehrian-Shai; Margaret H Collins; Timothy M Crombleholme; Nancy Ratner; Timothy P Cripe

2007-01-01

200

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

201

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

PubMed Central

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

Schnitzer, Jan E

2013-01-01

202

Molecularly Targeted Drug Slows Tumor Growth in Patients with Metastatic Kidney Cancer  

Cancer.gov

Researchers from the National Cancer Institute (NCI) reported today that the molecularly targeted drug bevacizumab slowed tumor growth in patients with metastatic renal cell carcinoma, the most common form of kidney cancer in adults.

203

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.

204

Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis.  

PubMed

Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development. PMID:22139075

Cronan, M R; Nakamura, K; Johnson, N L; Granger, D A; Cuevas, B D; Wang, J-G; Mackman, N; Scott, J E; Dohlman, H G; Johnson, G L

2012-08-23

205

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

E-print Network

Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept, forming a diffuse spread of tumor cells. Most high grade gliomas, i.e. glioblastoma multiform (GBM), form

Paris-Sud XI, Université de

206

Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis  

Microsoft Academic Search

Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a soilid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic

Israel Vlodavsky; Gil Korner; Rivka Ishai-Michaeli; Pnina Bashkin; Rachel Bar-Shavit; Zvi Fuks

1990-01-01

207

Human primary brain tumor cell growth inhibition in serum-free medium optimized for neuron survival  

Microsoft Academic Search

Glioblastoma is the most common primary brain tumor in adults from which about 15,000 patients die each year in the United States. Despite aggressive surgery, radiotherapy and chemotherapy, median survival remains only 1 year. Here we evaluate growth of primary human brain tumor cells in a defined nutrient culture medium (Neuregen) that was optimized for neuron regeneration. We hypothesized that

Gregory J. Brewer; Peter D. LeRoux

2007-01-01

208

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.

209

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

210

Myeloid-specific expression of Ron receptor kinase promotes prostate tumor growth.  

PubMed

Ron receptor kinase (MST1R) is important in promoting epithelial tumorigenesis, but the potential contributions of its specific expression in stromal cells have not been examined. Herein, we show that the Ron receptor is expressed in mouse and human stromal cells of the prostate tumor microenvironment. To test the significance of stromal Ron expression, prostate cancer cells were orthotopically implanted into the prostates of either wild-type or Ron tyrosine kinase deficient (TK(-/-); Mst1r(-/-)) hosts. In TK(-/-) hosts, prostate cancer cell growth was significantly reduced as compared with tumor growth in TK(+/+) hosts. Prostate tumors in TK(-/-) hosts exhibited an increase in tumor cell apoptosis, macrophage infiltration and altered cytokine expression. Reciprocal bone marrow transplantation studies and myeloid cell-specific ablation of Ron showed that loss of Ron in myeloid cells is sufficient to inhibit prostate cancer cell growth. Interestingly, depletion of CD8(+) T cells, but not CD4(+) T cells, was able to restore prostate tumor growth in hosts devoid of myeloid-specific Ron expression. These studies show a critical role for the Ron receptor in the tumor microenvironment, whereby Ron loss in tumor-associated macrophages inhibits prostate cancer cell growth, at least in part, by derepressing the activity of CD8(+) T cells. PMID:23328584

Gurusamy, Devikala; Gray, Jerilyn K; Pathrose, Peterson; Kulkarni, Rishikesh M; Finkleman, Fred D; Waltz, Susan E

2013-03-15

211

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

212

Iron and copper act synergistically to delay anaerobic growth of bacteria.  

PubMed

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 F(o)F(1) 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; Newman, Dianne K

2013-06-01

213

Blocking CXCR4-Mediated Cyclic AMP Suppression Inhibits Brain Tumor Growth In vivo  

Microsoft Academic Search

The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells.

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

2007-01-01

214

Noninvasive and Real-time Monitoring of the Regulation of Plant Growth and Development Using Delayed Fluorescence Technique  

Microsoft Academic Search

The structure and function of photosynthetic apparatus in plant leaves can be affected by plant growth regulators (PGRs) and other exogenous chemical factors. The photosystem II in a plant is considered the primary site where light-induced delayed fluorescence (DF) is produced. With the lamina of soybean (Glycine max (L.) Merr.) seedlings as testing models, we have studied the effects of

Lingrui Zhang; Da Xing; Junsheng Wang; Lizhang Zeng; Qiang Li; Bo Li; Xuejun Liu

2006-01-01

215

Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty  

Microsoft Academic Search

Seventy-eight patients who had constitutional delay of growth and puberty were included in a retrospective study to determine whether, at the time of first evaluation, any predictive features could suggest final height outcome. Mean chronologic age was 14.3 years (range, 12 to 18 years), and all were either prepubertal or in an early stage of pubertal maturation (4 ml testicular

A. Albanese; R. Stanhope

1995-01-01

216

Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6.  

PubMed

The transforming and tumor growth-promoting properties of Axl, a member of the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), are well recognized. In contrast, little is known about the role of the TAMR ligand growth arrest-specific gene 6 (Gas6) in tumor biology. By using Gas6-deficient (Gas6(-/-)) mice, we show that bone marrow-derived Gas6 promotes growth and metastasis in different experimental cancer models, including one resistant to vascular endothelial growth factor inhibitors. Mechanistic studies reveal that circulating leukocytes produce minimal Gas6. However, once infiltrated in the tumor, leukocytes up-regulate Gas6, which is mitogenic for tumor cells. Consistent herewith, impaired tumor growth in Gas6(-/-) mice is rescued by transplantation of wild-type bone marrow and, conversely, mimicked by transplantation of Gas6(-/-) bone marrow into wild-type hosts. These findings highlight a novel role for Gas6 in a positive amplification loop, whereby tumors promote their growth by educating infiltrating leukocytes to up-regulate the production of the mitogen Gas6. Hence, inhibition of Gas6 might offer novel opportunities for the treatment of cancer. PMID:19965679

Loges, Sonja; Schmidt, Thomas; Tjwa, Marc; van Geyte, Katie; Lievens, Dirk; Lutgens, Esther; Vanhoutte, Davy; Borgel, Delphine; Plaisance, Stephane; Hoylaerts, Marc; Luttun, Aernout; Dewerchin, Mieke; Jonckx, Bart; Carmeliet, Peter

2010-03-18

217

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

PubMed Central

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

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

2013-01-01

218

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

219

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

220

[Effect of sodium fluoroacetate on Ehrlich solid tumor and autochthonous sarcoma growth in mice].  

PubMed

Due to biochemical characteristics of toxic action of fluoroacetate on energetics and metabolism of cells, including tumor cells, it was interesting to testify sodium fluoroacetate (SFA) for its antitumor activity in vivo. We have estimated that SFA significantly inhibits growth of Ehrlich tumor carcinoma. In experiments with autochthonous induced by benzo[a]pyrene subcutaneous tumors, SFA was not active in monotherapy regime, though potentiated antitumor effect of cyclophosphamide, significantly increasing the relative number of mice with stabilized or decreased tumor volume as well as the duration of this effect. The data obtained render basis for additional studies of mechanism of antitumor effect of SFA. PMID:24624791

Anikin, I V; Goncharov, N V; Tyndyk, M L; Vo?tenko, N G; Pliss, G B; Zabezhinski?, M A; Popovich, I G; Anisimov, V N

2013-01-01

221

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

222

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

PubMed Central

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

2013-01-01

223

DNA vaccines designed to inhibit tumor growth by suppression of angiogenesis.  

PubMed

The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1-2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor's vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel orally delivered DNA vaccines which suppress tumor angiogenesis and induce a robust cell-mediated immune response that provides for long-lived protection against melanoma, colon, breast and non-small-cell lung carcinoma in mouse model systems. These vaccines, which are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs, are directed against such targets as vascular endothelial growth factor receptor 2 (FLK-1) and transcription factor Fos-related antigen 1 (Fra-1). Both vaccines break peripheral T cell tolerance against these self-antigens and induce a robust T cell-mediated immune response leading to suppression of tumor angiogenesis and resulting in effective suppression of tumor growth and metastases. Such research efforts may open up new possibilities for the rational design of future DNA vaccines effective for the prevention and treatment of cancer. PMID:14988601

Reisfeld, Ralph A; Niethammer, A G; Luo, Y; Xiang, R

2004-03-01

224

PPAR? agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition  

PubMed Central

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)? deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR? would promote tumor growth. Surprisingly, the PPAR? agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR?-deficient tumors were still susceptible to fenofibrate, absence of PPAR? in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR? as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR? agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR? agonists in cancer treatment, alone and in combination with other therapies. PMID:18199835

Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E.; Barnes, Carmen M.; Fannon, Michael; Laforme, Andrea M.; Chaponis, Deviney M.; Folkman, Judah; Kieran, Mark W.

2008-01-01

225

PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition.  

PubMed

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies. PMID:18199835

Panigrahy, Dipak; Kaipainen, Arja; Huang, Sui; Butterfield, Catherine E; Barnés, Carmen M; Fannon, Michael; Laforme, Andrea M; Chaponis, Deviney M; Folkman, Judah; Kieran, Mark W

2008-01-22

226

Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth.  

PubMed

Exposure to stress has been associated with alterations in both immune function and tumor development in man and laboratory animals. In the present study, we investigated the effect of a particular type of inescapable footshock stress, known to cause an opioid mediated form of analgesia, on survival time of female Fischer 344 rats injected with a mammary ascites tumor. Rats subjected to inescapable footshock manifested an enhanced tumor growth indicated by a decreased survival time and decreased percent survival. This tumor enhancing effect of stress was prevented by the opiate antagonist, naltrexone, suggesting a role for endogenous opioid peptides in this process. In the absence of stress, naltrexone did not affect tumor growth. PMID:6686324

Lewis, J W; Shavit, Y; Terman, G W; Nelson, L R; Gale, R P; Liebeskind, J C

1983-01-01

227

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

PubMed

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. PMID:14595012

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

2003-11-11

228

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

PubMed Central

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. PMID:14595012

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.

2003-01-01

229

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

NASA Astrophysics Data System (ADS)

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

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

2014-02-01

230

Pancreatic endocrine tumors with intraductal growth into the main pancreatic duct and tumor thrombus within the portal vein: a case report and review of the literature.  

PubMed

Pancreatic endocrine tumors are rare tumors classified into "functioning" and "nonfunctioning" tumors. A 68-year-old man was admitted to our hospital with the chief compliant of abdominal pain. Various imaging studies demonstrated a mass in the head of the pancreas with intraductal growth into the main pancreatic duct and an intraportal mass. The patient underwent a curative surgical operation. Histopathological examination revealed that it was nonfunctioning endocrine carcinoma of the pancreas. This is the first reported case of a pancreatic endocrine tumor with intraductal growth into the main pancreatic duct and tumor thrombus within the portal vein. PMID:17379993

Kawakami, Hiroshi; Kuwatani, Masaki; Hirano, Satoshi; Kondo, Satoshi; Nakanishi, Yoshitsugu; Itoh, Tomoo; Asaka, Masahiro

2007-01-01

231

IgM response and resistance to ascites tumor growth  

Microsoft Academic Search

Antibody response and protection against Ehrlich ascites tumor (EAT) was studied in eight EAT-immunized strains of mice (AL\\/N, BALB\\/C, C57BL\\/6J, F1(C57BL\\/6×BALB\\/C), C57BL\\/10J, B10.BR, CBA\\/Ca, SW). The results showed a close association between IgM response and resistance to subsequent tumor challenge. Thus, protection was only achieved in those animals giving a measurable IgM response against EAT cell surface antigens, i.e., all

Jose L. Subiza; Javier Coll; Rita Alvarez; Manuel Valdivieso; Emilio G. de la Concha

1987-01-01

232

Image Guided Personalization of Reaction-Diffusion Type Tumor Growth Models Using Modified Anisotropic Eikonal Equations  

Microsoft Academic Search

Reaction-diffusion based tumor growth models have been widely used in the literature for modeling the growth of brain gliomas. Lately, recent models have started integrating medical images in their formulation. Including different tis sue types, geometry of the brain and the directions of white matter fiber tracts improved the spatial accuracy of reaction-diffusio n models. The adaptation of the general

Ender Konukoglu; Olivier Clatz; Bjoern H. Menze; Marc-Andre Weber; Bram Stieltjes; Emmanuel Mandonnet; Herve Delingette; Nicholas Ayache

2010-01-01

233

Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo  

PubMed Central

Cripto, a cell surface–associated protein belonging to the EGF-CFC family of growth factor–like molecules, is overexpressed in many human solid tumors, including 70–80% of breast and colon tumors, yet how it promotes cell transformation is unclear. During embryogenesis, Cripto complexes with Alk4 via its unique cysteine-rich CFC domain to facilitate signaling by the TGF-? ligand Nodal. We report, for the first time to our knowledge, that Cripto can directly bind to another TGF-? ligand, Activin B, and that Cripto overexpression blocks Activin B growth inhibition of breast cancer cells. This result suggests a novel mechanism for antagonizing Activin signaling that could promote tumorigenesis by deregulating growth homeostasis. We show that an anti–CFC domain antibody, A8.G3.5, both disrupts Cripto-Nodal signaling and reverses Cripto blockade of Activin B–induced growth suppression by blocking Cripto’s association with either Alk4 or Activin B. In two xenograft models, testicular and colon cancer, A8.G3.5 inhibited tumor cell growth by up to 70%. Both Nodal and Activin B expression was found in the xenograft tumor, suggesting that either ligand could be promoting tumorigenesis. These data validate that functional blockade of Cripto inhibits tumor growth and highlight antibodies that block Cripto signaling mediated through its CFC domain as an important class of antibodies for further therapeutic development. PMID:12925698

Adkins, Heather B.; Bianco, Caterina; Schiffer, Susan G.; Rayhorn, Paul; Zafari, Mohammad; Cheung, Anne E.; Orozco, Olivia; Olson, Dian; De Luca, Antonella; Chen, Ling Ling; Miatkowski, Konrad; Benjamin, Chris; Normanno, Nicola; Williams, Kevin P.; Jarpe, Matthew; LePage, Doreen; Salomon, David; Sanicola, Michele

2003-01-01

234

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

Microsoft Academic Search

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

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

2004-01-01

235

The von Hippel-Lindau Tumor Suppressor Protein Regulates Gene Expression and Tumor Growth through Histone Demethylase JARID1C  

PubMed Central

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 play 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 HIF-dependent, as depletion of HIF subunits by shRNA 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 IGFBP3, DNAJC12, COL6A1, GDF15, and DEP-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, Xiaohua; Zhang, Ting; Liao, Lili; Zhou, Liang; Lindner, Daniel J.; Zhou, Ming; Rini, Brian; Yan, Qin; Yang, Haifeng

2014-01-01

236

Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene.  

PubMed

RASSF1A, a major member of the RASSF1 gene family, is silenced by promoter methylation at a high frequency in a large number of human solid tumors. Controlled expression of RASSF1A reverts the tumorigenic phenotype of several human cancer cell lines. Here we investigated another main isoform, RASSF1C, and compared it with RASSF1A in the gene inactivation test (GIT), based on a tetracycline regulation system. In the small-cell lung cancer (SCLC) line U2020, only RASSF1A has shown growth inhibitory activity in vitro, while in the prostate cell line LNCaP and renal cell carcinoma (RCC) line KRC/Y both RASSF1A and RASSF1C showed similar (approximately 90%) suppressing activity in vitro. Both RASSF1C and RASSF1A suppressed the tumorigenicity of the KRC/Y RCC cell line in SCID mice. Mutations, deletions and loss of expression of RASSF1A and RASSF1C transgenes were identified in all 15 grown SCID tumors. In contrast, the mutant RASSF1A containing Cys65Arg and Val211Ala had reduced growth suppression activity both in vitro and in vivo and did not show any further changes in four grown SCID tumors. In addition, RASSF1C was shown to induce cell cycle arrest in KRC/Y cells. These results strongly imply that like RASSF1A the RASSF1C gene could serve a tumor suppressor function. PMID:15208682

Li, Jingfeng; Wang, Fuli; Protopopov, Alexey; Malyukova, Alena; Kashuba, Vladimir; Minna, John D; Lerman, Michael I; Klein, George; Zabarovsky, Eugene

2004-08-01

237

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

E-print Network

103 cm3 in size (which is reportedly lethal in primary breast cancer by Retsky, 1997), the clinical, including its relevance for tumor metastasis and recurrence, cell turnover rates, angiogenesis and invasion for the development of more successful treatment strategies. Given the lack of clinical data at non-symptomatic stages

Grether, Gregory

238

ORIGINAL ARTICLE Suppression of colorectal tumor growth by regulated  

E-print Network

. The potential of this system in cancer therapy was evaluated in experimental animals. Tumor xenograft models /Accepted: 11 August 2006 # Springer-Verlag 2006 Abstract A major goal in cancer gene therapy is to develop for cancer gene therapy. Specifically, they generated vectors for targeting survivin pathway. XINYUAN LIU

Tian, Weidong

239

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1? expression in tumor cells and hepatocytes  

Microsoft Academic Search

Hypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen-regulated transcription factor composed of ? and ? subunits. HIF-1 activates transcription of various genes including those involved in metastatic tumor growth. In the present study, HIF-1? expression in tumor-bearing mouse liver was examined after inoculation of tumor cells into portal vein. We found that tumor-bearing liver showed greatly increased HIF-1? expression. Plasmid

Y Takahashi; M Nishikawa; Y Takakura

2008-01-01

240

Rhein lysinate suppresses the growth of tumor cells and increases the anti-tumor activity of Taxol in mice.  

PubMed

In previous studies, rhein, one of the major bioactive constituents in the rhizome of rhubarb, inhibited the proliferation of various human cancer cells. However, because of its water insolubility, the anti-tumor efficacy of rhein was limited in vivo. In this study, we observed the anti-tumor activity of rhein lysinate (the salt of rhein and lysine easily dissolves in water) in vivo and investigated its mechanism. Inhibition of ovarian cancer SKOV-3 cell proliferation was determined by MTT assay and the mechanism of action of rhein lysinate was investigated by Western blot analysis. The therapeutic efficacy of rhein lysinate was evaluated by intragastric and intraperitoneal administrations in H22 hepatocellular carcinoma mice. Rhein lysinate inhibited the proliferation of SKOV-3 cells and the IC50 value was 80 microM. Rhein lysinate inhibited the phosphorylation of MEK and ERK and increased the anti-tumor activity of Taxol in vitro. It inhibited tumor growth by both intragastric and intraperitoneal administrations and improved the therapeutic effect of Taxol in H22 hepatocellular carcinoma mice. In conclusion, rhein lysinate offers an anti-tumor activity in vivo and is hopeful to be a chemotherapeutic drug. PMID:19885952

Lin, Ya-Jun; Zhen, Yong-Zhan; Shang, Bo-Yang; Zhen, Yong-Su

2009-01-01

241

Systemic and local injections of lupeol inhibit tumor growth in a melanoma-bearing mouse model  

PubMed Central

Melanoma is the most aggressive type of skin cancer and it is procured from activated or genetically altered epidermal melanocytes. In the present study, the tumor-suppressive effects of systemic and local injections of lupeol, a triterpene extracted from Indian lettuce (Lactuca indica), in a melanoma-bearing mouse model were evaluated. Mice were injected once with lupeol or olive oil (solvent control) subcutaneously into the skin of the back or into the tumor tissue. Seven days after the injection, the tumor growth rates were calculated and the tumor tissues were collected. Immunohistochemical staining for Ki-67 and proliferating cell nuclear antigen (PCNA) were performed. The tumor growth rates in the lupeol-injected group were significantly decreased compared to those observed in the non-treated (NT) and solvent control groups. Lupeol also significantly decreased the areas positively stained for Ki-67 and PCNA in the tumor tissues compared to those in the NT and solvent control groups. The results of the present study demonstrated that systemic and local injections of lupeol suppress tumor growth and induce cell cycle arrest in a melanoma-bearing mouse model. These data suggest that lupeol may be effective as a novel therapeutic option for melanoma patients. PMID:24649001

NITTA, MAKIKO; AZUMA, KAZUO; HATA, KEISHI; TAKAHASHI, SAORI; OGIWARA, KIKUMI; TSUKA, TAKESHI; IMAGAWA, TOMOHIRO; YOKOE, INORU; OSAKI, TOMOHIRO; MINAMI, SABURO; OKAMOTO, YOSHIHARU

2013-01-01

242

Neutralizing monoclonal antibody to periostin inhibits ovarian tumor growth and metastasis.  

PubMed

Periostin, an extracellular matrix protein, is reported to be overexpressed in a variety of human cancers and its functions seem to be linked to tumor metastasis. Our previous results show that engineered periostin overexpression promotes ovarian tumor growth and dissemination in vivo. In this study, we developed a neutralizing monoclonal antibody to periostin, named MZ-1, and investigated its effects on human ovarian tumor growth and metastasis. Our in vivo studies showed significant growth inhibition by MZ-1 on both subcutaneous and intraperitoneal (i.p.) tumors derived from the periostin-expressing ovarian cancer cell line A2780. In addition, MZ-1 treatment led to a reduction of the metastatic potential of these A2780 i.p. tumors. The in vivo antitumor effects of MZ-1 were linked to its specific inhibition of anchorage-independent growth and survival of periostin-expressing cells, as well as its neutralizing effects on periostin-induced cancer cell migration and invasion. The data suggest that blocking periostin expression may be a novel approach for treating the subset of invasive ovarian tumors that overexpress periostin protein. PMID:21670235

Zhu, Min; Saxton, Romaine E; Ramos, Lillian; Chang, David D; Karlan, Beth Y; Gasson, Judith C; Slamon, Dennis J

2011-08-01

243

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

244

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

245

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

246

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

NASA Astrophysics Data System (ADS)

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

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

1995-03-01

247

Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage.  

PubMed

Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of limited efficacy of the current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. Here, we identify Olfactomedin-like 3 (Olfml3) as a novel proangiogenic cue within the tumor microenvironment. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelioma cell migration and sprouting. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Therefore, Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule. PMID:23002094

Miljkovic-Licina, Marijana; Hammel, Philippe; Garrido-Urbani, Sarah; Lee, Boris P-L; Meguenani, Mehdi; Chaabane, Chiraz; Bochaton-Piallat, Marie-Luce; Imhof, Beat A

2012-12-01

248

Measuring Growth and Gene Expression Dynamics of Tumor-Targeted S. Typhimurium Bacteria  

PubMed Central

The goal of these experiments is to generate quantitative time-course data on the growth and gene expression dynamics of attenuated S. typhimurium bacterial colonies growing inside tumors. We generated model xenograft tumors in mice by subcutaneous injection of a human ovarian cancer cell line, OVCAR-8 (NCI DCTD Tumor Repository, Frederick, MD). We transformed attenuated strains of S. typhimurium bacteria (ELH430:SL1344 phoPQ- 1) with a constitutively expressed luciferase (luxCDABE) plasmid for visualization2. These strains specifically colonize tumors while remaining essentially non-virulent to the mouse1. Once measurable tumors were established, bacteria were injected intravenously via the tail vein with varying dosage. Tumor-localized, bacterial gene expression was monitored in real time over the course of 60 hours using an in vivo imaging system (IVIS). At each time point, tumors were excised, homogenized, and plated to quantitate bacterial colonies for correlation with gene expression data. Together, this data yields a quantitative measure of the in vivo growth and gene expression dynamics of bacteria growing inside tumors. PMID:23851642

Hasty, Jeff; Bhatia, Sangeeta

2013-01-01

249

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

PubMed Central

This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INF?, IL-1?, IL-4, IL-6, IL-8, IL-10, and TNF?, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers. PMID:22941871

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

2012-01-01

250

A ribonuclease inhibitor expresses anti-angiogenic properties and leads to reduced tumor growth in mice.  

PubMed Central

Our experiments were designed to determine whether recombinant ribonuclease inhibitor (RNasin) could inhibit angiogenesis and reduce tumor growth in adult mice. We used the Fajardo disc angiogenesis assay as the primary means of measuring new blood vessel growth. This assay measures the penetration of cells into a polyvinyl alcohol sponge with a central core of ELVAX-coated sponge containing test substances. Cell penetration was reduced to 29.3% of control (phosphate-buffered saline; heat-inactivated RNasin) values. Endothelial cell influx was measured by lectin staining and confirmed by culturing cells isolated from sponges by collagenase treatment. RNasin also reduced the augmented reaction evoked by either basic fibroblast growth factor (bFGF) or sodium orthovanadate. To confirm the anti-angiogenic activity of RNasin, Hydron-coated polyvinyl sponges containing bFGF or bFGF plus RNasin were implanted into adult mouse corneas. bFGF induced a strong angiogenic response that was almost completely inhibited by RNasin. RNasin-containing ELVAX-coated sponges implanted subcutaneously underneath an intradermal inoculum of C755 mammary tumor cells caused significant reduction in tumor growth (P < 0.005). The antitumor effect of RNasin correlated with its effect on tumor-induced neovascularization, suggesting that the ability of RNasin to affect tumor growth was due to its ability to inhibit angiogenesis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:7688185

Polakowski, I. J.; Lewis, M. K.; Muthukkaruppan, V. R.; Erdman, B.; Kubai, L.; Auerbach, R.

1993-01-01

251

Tumor-induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23: report of a case and review of the literature.  

PubMed

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23. PMID:20219587

Mori, Yoshiyuki; Ogasawara, Toru; Motoi, Toru; Shimizu, Yuichiro; Chikazu, Daichi; Tamura, Kazumi; Fukumoto, Seiji; Takato, Tsuyoshi

2010-03-01

252

News Note: Gene Therapy Method Slows Tumor Growth in Mice  

Cancer.gov

NCI researchers have developed a novel method in mice of delivering genes to cancer cells, that when expressed, promote cell death. These genes, known as suicide genes, cause a cell to kill itself through a process known as apoptosis. The new technique uses the survivin gene promoter to express the suicide gene and induce apoptosis in cancer cells. This method of gene delivery effectively targeted tumor cells with a minimum effect on normal cells.

253

Impact of Circulating Cholesterol Levels on Growth and Intratumoral Androgen Concentration of Prostate Tumors  

PubMed Central

Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R?=?0.3957, p?=?0.0049) and intratumoral levels of testosterone (R?=?0.41, p?=?0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R?=?0.4073, p?=?0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR. PMID:22279565

Pelton, Kristine; Freeman, Michael R.; Montgomery, R. Bruce

2012-01-01

254

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

Microsoft Academic Search

This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast

R. Perez; A. V. Schally; I. Vidaurre; R. Rincon; N. L. Block; F. G. Rick

2012-01-01

255

Various Human Hematopoietic Growth Factors (Interleukin3, GM-CSF, G-CSF) Stimulate Clonal Growth of Nonhematopoietic Tumor Cells  

Microsoft Academic Search

function after cytotoxic, myebosuppressive chemotherapy in patients with malignant tumors.3'4 This report describes the effects of rhIL-3, rhGM-CSF, and rhG-CSF on the clonal growth of human colon adenocarcinoma cell lines HTB-38, WiDr (CCL 218),and CCL 187.

Wolfgang E. Berdel; Susanne Danhauser-Riedl; Gabriele Steinhauser; Elliott F. Winton

2010-01-01

256

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

257

Blocking epidermal growth factor receptor activation by 3,3'-diindolylmethane suppresses ovarian tumor growth in vitro and in vivo.  

PubMed

Genetic alterations, including the overexpression of epidermal growth factor receptor (EGFR) (in approximately 70% of ovarian tumors), play a crucial role in the signal transduction pathways that regulate key cellular functions, such as cell survival and proliferation, and are responsible for compromising traditional chemotherapy. 3,3'-Diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we demonstrated that BR-DIM, a formulated version of DIM, suppressed the growth of ovarian cancer cells by causing cell cycle arrest and apoptosis. In the present study, we delineated the mechanism by which DIM suppressed the growth of SKOV-3, OVCAR-3, and TOV-21G human ovarian cancer cells. DIM treatment caused significant down-regulation of the constitutive EGFR protein level as well as phosphorylation of EGFR at Tyr1068, Tyr992, Tyr845, and Tyr1173 in various ovarian cancer cells. To determine whether DIM suppressed the activation of EGFR by activating phosphorylation, cells were treated with epidermal growth factor. Epidermal growth factor treatment significantly blocked the DIM-mediated inhibition of EGFR activation and apoptosis in both SKOV-3 and OVCAR-3 cells. In addition, DIM treatment drastically reduced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK), which are downstream to EGFR, without affecting their protein levels. DIM treatment also inhibited the kinase activity of ERK, as observed by the down-regulation of phospho-E twenty-six like transcription factor 1 (p-ELK1) in all three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK, and ERK. These results indicate that DIM induces apoptosis in ovarian cancer cells by inhibiting the EGFR-ERK pathway in vitro and in vivo. PMID:22205686

Kandala, Prabodh K; Wright, Stephen E; Srivastava, Sanjay K

2012-04-01

258

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

259

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

260

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

PubMed Central

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

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

2011-01-01

261

Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes  

Microsoft Academic Search

We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-derived mutants. Using a colony formation assay, we found that the majority of the mutants increased the number of colonies formed compared to the vector. Expression of tumor-derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have ‘gain of function’ properties. We have studied

Mariano J Scian; Katherine E R Stagliano; Debabrita Deb; Michelle A Ellis; Evie H Carchman; Anindita Das; Kristopher Valerie; Swati Palit Deb; Sumitra Deb

2004-01-01

262

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

263

Combination of Phenylbutyrate and 13-cis Retinoic Acid Inhibits Prostate Tumor Growth and Angiogenesis1  

Microsoft Academic Search

Differentiation-inducing agents, such as retinoids and short-chain fatty acids, have an inhibitory effect on tumor cell proliferation and tumor growth in preclinical studies. Clinical trials involving these compounds as single agents have been suboptimal in terms of clinical benefit. Our study evaluated the combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a differentiation and antiangiogenesis strategy for prostate

Roberto Pili; Mark P. Kruszewski; Brant W. Hager; Julie Lantz; Michael A. Carducci

2001-01-01

264

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

PubMed

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3? activation, while p38? phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID:24789042

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

2014-07-01

265

Oligomannurarate sulfate blocks tumor growth by inhibiting NF-?B activation  

PubMed Central

Aim: JG3, a novel marine-derived oligosaccharide, significantly inhibits angiogenesis and tumor metastasis by blocking heparanase activity. It also arrests tumor growth, an effect that is not fully explained by its anti-heparanase activity. Here we sought to identify the mechanisms underlying JG3-mediated inhibition of tumor growth. Methods: Heparanase expression was assessed by RT-PCR and Western blotting. NF-?B activation status was determined using immunofluorescence, Western blotting, DNA-binding and transcription-activity assays. The effect of JG3 on upstream components of the NF-?B pathway and on selected transcription factors were monitored by Western blotting. The antitumor effect of JG3 and its relation to NF-?B activation were evaluated using four different tumor xenograft models. Results: We found that JG3 effectively inhibited NF-?B activation independent of heparanase expression. Our results indicate that JG3 inactivated NF-?B by interfering with the activation of upstream components of the NF-?B pathway without generally affecting the nuclear translocation of transcription factors. Further, in vivo studies demonstrated that JG3 effectively arrested the growth of tumors derived from cell lines in which NF-?B was constitutively active (BEL-7402 liver carcinoma and MDA-MB-435s breast carcinoma), but did not affect the growth of tumors derived from NF-?B-negative cell lines (SGC-7901 gastric cancer and HO-8910 ovarian carcinoma). Conclusion: Our data indicate that NF-?B mediates the JG3-induced arrest of tumor growth. These results define a new mechanism of action of JG3 and highlight the potential for JG3 as a promising lead molecule in cancer therapy. PMID:20154712

Zhang, Jing; Chen, Yi; Xin, Xian-liang; Li, Qiu-ning; Li, Ming; Lin, Li-ping; Geng, Mei-yu; Ding, Jian

2010-01-01

266

A Novel Monoclonal Antibody to Secreted Frizzled Related Protein 2 Inhibits Tumor Growth  

PubMed Central

Secreted frizzled related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer, and stimulates angiogenesis via activation of the calcineurin/ NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of ß-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling, and to evaluate whether SFRP2 is a viable therapeutic target. The anti-angiogenic and anti-tumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, and tube formation assays; and in vivo angiosarcoma and triple negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic (PK) and biodistribution data were generated in tumor-bearing and non-tumor bearing mice. SFRP2 mAb was shown to induce anti-tumor and anti-angiogenic effects in vitro, and inhibit activation of ß-catenin and NFATc3 in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared to control (p=0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (p=0.03) compared to control, while bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of ß-catenin and NFATc3 in endothelial and tumor cells, and is a novel therapeutic approach to inhibiting angiosarcoma and triple negative breast cancer. PMID:23604067

Fontenot, Emily; Rossi, Emma; Mumper, Russell; Snyder, Stephanie; Siamakpour-Reihani, Sharareh; Ma, Ping; Hilliard, Eleanor; Bone, Bradley; Ketelsen, David; Santos, Charlene; Patterson, Cam; Klauber-DeMore, Nancy

2013-01-01

267

Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate.  

PubMed

Extracellular adenosine triphosphate (ATP) is known to boost immune responses in the tumor microenvironment but might also contribute directly to cancer cell death. CD39/ENTPD1 is the dominant ectonucleotidase expressed by endothelial cells and regulatory T cells and catalyzes the sequential hydrolysis of ATP to AMP that is further degraded to adenosine by CD73/ecto-5'-nucleotidase. We have previously shown that deletion of Cd39 results in decreased growth of transplanted tumors in mice, as a result of both defective angiogenesis and heightened innate immune responses (secondary to loss of adenosinergic immune suppression). Whether alterations in local extracellular ATP and adenosine levels as a result of CD39 bioactivity directly affect tumor growth and cytotoxicity has not been investigated to date. We show here that extracellular ATP exerts antitumor activity by directly inhibiting cell proliferation and promoting cancer cell death. ATP-induced antiproliferative effects and cell death are, in large part, mediated through P2X(7) receptor signaling. Tumors in Cd39 null mice exhibit increased necrosis in association with P2X(7) expression. We further demonstrate that exogenous soluble NTPDase, or CD39 expression by cocultured liver sinusoidal endothelial cells, stimulates tumor cell proliferation and limits cell death triggered by extracellular ATP. Collectively, our findings indicate that local expression of CD39 directly promotes tumor cell growth by scavenging extracellular ATP. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy in cancer management. PMID:21390184

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

2011-03-01

268

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

269

Tumor growth reduction in Walker 256 tumor-bearing rats performing anaerobic exercise: participation of Bcl-2, Bax, apoptosis, and peroxidation.  

PubMed

Physical activity has been used in cancer prevention and treatment. In this study, we investigated some of the mechanisms by which anaerobic exercise reduces tumor growth. To do so, rats were trained for 8 weeks. Training consisted of jumping in a swimming pool for ten 30-s sets, with a load that was 50% of body weight attached to the back, 4 times per week. At the sixth week, anaerobic exercise trained rats (EX group) were inoculated with a suspension of Walker 256 tumor cells. Tumor weight, apoptotic tumor cells, tumor Bax and Bcl-2 protein expression, tumor lipid peroxidation, and tumor cell proliferation ex vivo were evaluated. Tumor weight was significantly lower in the EX group (?30%) than in rats that did not undergo training (sedentary group) (p < 0.05). Apoptosis in the tumor cells of EX rats was 2-fold higher than in the tumor cells of sedentary rats; in addition, Bax expression increased by 10% and Bcl-2 decreased by 13% in EX rats. Lipid peroxidation was 4-fold higher in the tumor cells of EX rats than in those of sedentary rats (p < 0.05). Tumor cell proliferation ex vivo was 29% lower in the EX group than in the sedentary group (p < 0.05). In conclusion, Walker 256 tumor-bearing exercised rats presented more tumor cell apoptosis, a higher tumor content of lipid peroxides, pro-apoptotic protein expression balance, and reduced tumor weight and cell proliferation ex vivo, compared with sedentary rats. These events, together, account for the lower tumor growth we observed in the EX rats. PMID:21851206

de Lima, Carina; Alves, Luciana; Iagher, Fabíola; Machado, Andressa Franzoi; Kryczyk, Marcelo; Yamazaki, Ricardo Key; Brito, Gleisson Alisson Pereira; Nunes, Everson Araújo; Naliwaiko, Katya; Fernandes, Luiz Cláudio

2011-08-01

270

Fish oil supplementation reduces cachexia and tumor growth while improving renal function in tumor-bearing rats.  

PubMed

The objective of the present work was to study the renal function of healthy and tumor-bearing rats chronically supplemented with fish oil (FO), a source of n-3 polyunsaturated fatty acids. Weanling male rats were divided in two groups, one control (C) and another orally supplemented for 70 days with FO (1 g/kg body weight). After this time, half the animals of each group were injected in the right flank with a suspension of Walker 256 tumor cells (W and WFO). The W group had less proteinemia reflecting cachectic proteolysis, FO reversed this fact. Tumor weight gain was also reduced in WFO. Glomerular filtration rate (GFR) was not different in FO or W compared to C, but was higher in WFO. Renal plasma flow (RPF) was higher in the FO supplemented groups. The W group had lower plasma osmolality than the C group, but FO supplementation resulted in normalization of this parameter. Fractional sodium excretion (FE(Na+)) of FO rats was similar to C. Proximal Na(+) reabsorption, evaluated by lithium clearance, was similar among the groups. Urinary thromboxane B(2) (TXB(2)) excretion was lower in the supplemented groups. The number of macrophages in renal tissue was higher in W compared to C rats, but was lower in WFO rats compared to W rats. In conclusion, FO supplementation resulted in less tumor growth and cachexia, and appeared to be renoprotective, as suggested by higher RPF and GFR. PMID:23015313

Coelho, Isabela; Casare, Fernando; Pequito, Danielle C T; Borghetti, Gina; Yamazaki, Ricardo K; Brito, Gleisson A P; Kryczyk, Marcelo; Fernandes, Luiz Claudio; Coimbra, Terezila M; Fernandez, Ricardo

2012-11-01

271

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth.  

PubMed

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer. PMID:20407210

Zhang, Jun; Zhao, Deping; Park, Hwan Ki; Wang, Hong; Dyer, Roy B; Liu, Wanguo; Klee, George G; McNiven, Mark A; Tindall, Donald J; Molina, Julian R; Fei, Peiwen

2010-05-01

272

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth  

PubMed Central

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer. PMID:20407210

Zhang, Jun; Zhao, Deping; Park, Hwan Ki; Wang, Hong; Dyer, Roy B.; Liu, Wanguo; Klee, George G.; McNiven, Mark A.; Tindall, Donald J.; Molina, Julian R.; Fei, Peiwen

2010-01-01

273

Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review  

Microsoft Academic Search

Introduction  Brain tumors are one of the most common types of solid neoplasm in children. As life expectancy of these patients has increased\\u000a with new and improved therapies, the morbidities associated with the treatments and the tumor itself have become more important.\\u000a \\u000a \\u000a \\u000a Discussion  One of the most common morbidities is growth hormone deficiency, and since recombinant growth hormone (GH) became available,\\u000a its

Roberto Bogarin; Paul Steinbok

2009-01-01

274

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.

275

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

276

Hmgb1-IL-23-IL-17-IL-6-Stat3 Axis Promotes Tumor Growth in Murine Models of Melanoma  

PubMed Central

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, IL-17 deficiency results in reduced melanoma tumor size, diminished numbers of proliferating cells and blood vessels, and decreased percentage of CD11b+Gr-1+ MDSCs in tumor tissues. IL-17 promotes IL-6 induction and Stat3 activation. Treatment of Stat3 inhibitor WP1066 in B16-F10 tumor cells inoculated wild-type mice inhibits tumor growth. Additional administration of recombinant IL-6 into B16-F10 tumor-bearing IL-17?/? mice results in markedly increased tumor size and p-Stat3 expression, whereas additional recombinant IL-17 administration into B16-F10 tumor-bearing wild-type mice treated with anti-IL-6 mAb does not significantly alter the tumor growth and p-Stat3 expression. In our further study, blockade of Hmgb1-RAGE pathway inhibits melanoma tumor growth and reduces production of IL-23 and IL-17. All these data suggest that Hmgb1-IL-23-IL-17-IL-6-Stat3 axis plays a pivotal role in tumor development in murine models of melanoma, and blocking any portion of this axis will attenuate melanoma tumor growth. PMID:24453427

Tang, Qiu; Li, Jian; Li, Pan; Zou, Zhenwei; Xiao, Yin

2013-01-01

277

Hmgb1-IL-23-IL-17-IL-6-Stat3 axis promotes tumor growth in murine models of melanoma.  

PubMed

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, IL-17 deficiency results in reduced melanoma tumor size, diminished numbers of proliferating cells and blood vessels, and decreased percentage of CD11b(+)Gr-1(+) MDSCs in tumor tissues. IL-17 promotes IL-6 induction and Stat3 activation. Treatment of Stat3 inhibitor WP1066 in B16-F10 tumor cells inoculated wild-type mice inhibits tumor growth. Additional administration of recombinant IL-6 into B16-F10 tumor-bearing IL-17(-/-) mice results in markedly increased tumor size and p-Stat3 expression, whereas additional recombinant IL-17 administration into B16-F10 tumor-bearing wild-type mice treated with anti-IL-6 mAb does not significantly alter the tumor growth and p-Stat3 expression. In our further study, blockade of Hmgb1-RAGE pathway inhibits melanoma tumor growth and reduces production of IL-23 and IL-17. All these data suggest that Hmgb1-IL-23-IL-17-IL-6-Stat3 axis plays a pivotal role in tumor development in murine models of melanoma, and blocking any portion of this axis will attenuate melanoma tumor growth. PMID:24453427

Tang, Qiu; Li, Jian; Zhu, Hongfei; Li, Pan; Zou, Zhenwei; Xiao, Yin

2013-01-01

278

Translation of a tumor microenvironment mimicking 3D tumor growth co-culture assay platform to high-content screening.  

PubMed

For drug discovery, cell-based assays are becoming increasingly complex to mimic more realistically the nature of biological processes and their diversifications in diseases. Multicellular co-cultures embedded in a three-dimensional (3D) matrix have been explored in oncology to more closely approximate the physiology of the human tumor microenvironment. High-content analysis is the ideal technology to characterize these complex biological systems, although running such complex assays at higher throughput is a major endeavor. Here, we report on adapting a 3D tumor co-culture growth assay to automated microscopy, and we compare various imaging platforms (confocal vs. nonconfocal) with correlating automated image analysis solutions to identify optimal conditions and settings for future larger scaled screening campaigns. The optimized protocol has been validated in repeated runs where established anticancer drugs have been evaluated for performance in this innovative assay. PMID:22923784

Krausz, Eberhard; de Hoogt, Ronald; Gustin, Emmanuel; Cornelissen, Frans; Grand-Perret, Thierry; Janssen, Lut; Vloemans, Nele; Wuyts, Dirk; Frans, Sandy; Axel, Amy; Peeters, Pieter Johan; Hall, Brett; Cik, Miroslav

2013-01-01

279

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

PubMed

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

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

2014-08-30

280

Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor ?1  

PubMed Central

To determine if Neu is dominant over transforming growth factor ? (TGF-?), we crossed mouse mammary tumor virus (MMTV)-Neu mice with MMTV-TGF-?1S223/225 mice expressing active TGF-?1 in the mammary gland. Bigenic (NT) and Neu-induced mammary tumors developed with a similar latency. The bigenic tumors and their metastases were less proliferative than those occurring in MMTV-Neu mice. However, NT tumors exhibited less apoptosis and were more locally invasive and of higher histological grade. NT mice exhibited more circulating tumor cells and lung metastases than Neu mice, while NT tumors contained higher levels of phosphorylated (active) Smad2, Akt, mitogen-activated protein kinase (MAPK), and p38, as well as vimentin content and Rac1 activity in situ than tumors expressing Neu alone. Ex vivo, NT cells exhibited higher levels of P-Akt and P-MAPK than Neu cells. These were inhibited by the TGF-? inhibitor-soluble TGF-? type II receptor (T?RII:Fc), suggesting they were activated by autocrine TGF-?. TGF-? stimulated migration of Neu cells into surrounding matrix, while the soluble TGF-? inhibitor abrogated motility and invasiveness of NT cells. These data suggest that (i) the antimitogenic and prometastatic effects of TGF-? can exist simultaneously and (ii) Neu does not abrogate TGF-?-mediated antiproliferative action but can synergize with TGF-? in accelerating metastatic tumor progression. PMID:14612410

Muraoka, Rebecca S.; Koh, Yasuhiro; Roebuck, L. Renee; Sanders, Melinda E.; Brantley-Sieders, Dana; Gorska, Agnieszka E.; Moses, Harold L.; Arteaga, Carlos L.

2003-01-01

281

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

PubMed Central

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

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

2014-01-01

282

Hepatocyte growth factor-like protein is required for prostate tumor growth in the TRAMP mouse model.  

PubMed

The Ron receptor is deregulated in a variety of cancers. Hepatocyte growth factor-like protein (HGFL) is the ligand for Ron and is constitutively secreted from hepatocytes into the circulation. While a few recent reports have emerged analyzing ectopic HGFL overexpression of in cancer cells, no studies have examined host-produced HGFL in tumorigenesis. To examine HGFL function in prostate cancer, the TRAMP mouse model, which is predisposed to develop prostate tumors, was utilized. Prostate tumors from TRAMP mice exhibit elevated levels of HGFL, which correlated with upregulation in human prostate cancer. To directly implicate HGFL in prostate tumorigenesis, TRAMP mice deficient in HGFL (HGFL-/-TRAMP+) were generated. HGFL-/- TRAMP+ mice developed significantly smaller prostate tumors compared to controls. Analysis of HGFL-/- tumors revealed reduced tumor vascularization. No differences in cancer cell proliferation were detected between HGFL-/- TRAMP+ and HGFL+/+ TRAMP+ mice. However, a significant increase in cancer cell death was detected in HGFL-/- TRAMP+ prostates which correlated with decreased pro-survival targets. In vitro analysis demonstrated robust STAT3 activation resulting in Bcl2-dependent survival following treatment of prostate cancer cells with HGFL. These data document a novel function for endogenous HGFL in prostate cancer by imparting a critical survival signal to tumor cells. PMID:24980820

Vasiliauskas, Juozas; Nashu, Madison A; Pathrose, Peterson; Starnes, Sandra L; Waltz, Susan E

2014-07-30

283

Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.  

PubMed

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway. PMID:21203463

Yasuniwa, Yoshihiro; Izumi, Hiroto; Wang, Ke-Yong; Shimajiri, Shohei; Sasaguri, Yasuyuki; Kawai, Kazuaki; Kasai, Hiroshi; Shimada, Takashi; Miyake, Koichi; Kashiwagi, Eiji; Hirano, Gen; Kidani, Akihiko; Akiyama, Masaki; Han, Bin; Wu, Ying; Ieiri, Ichiro; Higuchi, Shun; Kohno, Kimitoshi

2010-01-01

284

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

285

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

PubMed Central

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

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

2013-01-01

286

Insulin-like growth factor-1 delays Fas-mediated apoptosis in human neutrophils through the phosphatidylinositol-3 kinase pathway.  

PubMed

Apoptosis of human neutrophils is a crucial mechanism for the resolution of inflammation. We previously showed that insulin-like growth factor-1 (IGF1) delays spontaneous neutrophil apoptosis without influencing the secretion of cytokines by these cells. In the present study, we further addressed the role of IGF1 in regulating neutrophil survival in the presence of other factors present during inflammation, and the mechanism involved in delaying apoptosis. We show that IGF1 delays neutrophil apoptosis triggered by the agonistic anti-Fas antibody CH11 and that the effect of IGF1 is comparable in magnitude to that of the acknowledged anti-apoptotic cytokines interferon-gamma (IFNG) and granulocyte-macrophage colony-stimulating factor (GM-CSF; now known as CSF2). Furthermore, IGF1 exerted additional effects on cell survival in the presence of these cytokines. IGF1 did not affect Fas expression or activation by anti-Fas of caspase-8, but inhibited the depolarization of the mitochondrial membrane. Inhibitor studies indicate that the phosphatidylinositol-3 kinase (PI3K) pathway, but not the MEK-ERK pathway, mediates the effects of IGF1. However, in contrast to CSF2, IGF1 did not induce phosphorylation and translocation to the membrane of AKT, the canonical downstream target of PI3K. We therefore speculate that other downstream targets of PI3K are involved in the delay of neutrophil apoptosis by IGF1, possibly through stabilization of the mitochondrial membrane. PMID:18653623

Himpe, Eddy; Degaillier, Céline; Coppens, Astrid; Kooijman, Ron

2008-10-01

287

Phytochemical potential of Eruca sativa for inhibition of melanoma tumor growth.  

PubMed

Solvent extracts from the aerial and root parts and seed oil from E. sativa (rocket salad) were assayed for anticancer activity against melanoma cells. The seed oil (isothiocyanates rich) significantly (p<0.01) reduced the tumor growth comparable to the control. Remarkably, the seed oil inhibited melanoma growth and angiogenesis in mice without any major toxicity. The findings qualify seed oil for further investigations in the real of cancer prevention and treatment. PMID:21316427

Khoobchandani, M; Ganesh, N; Gabbanini, S; Valgimigli, L; Srivastava, M M

2011-06-01

288

Control of Breast Tumor Cell Growth Using a Targeted Cysteine Protease Inhibitor1  

Microsoft Academic Search

The purpose of this study was to determine whether inhibition of lysosomal proteolysis could be used to selectively inhibit proliferation of tumor cells. The lysosomal cysteine protease inhibitor 9-fluorenylmethy- loxycarbonyl-tyrosylalanyl-diazomethane was found to inhibit growth of the breast cancer cell lines SK-Br-3 and MCF-7. A humanized monoclonal antibody (huMAb 4D5) directed against the extracellular domain of p,85HKR2 specifically inhibited growth

Ruye Xing; Fei Wu; Robert W. Mason

289

Multiphase modeling and qualitative analysis of the growth of tumor cords  

E-print Network

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

Andrea Tosin

2009-06-27

290

Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits ?-catenin degradation.  

PubMed

Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of ?-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSK?3 proteins. TSPAN12 ablation also altered expression of several genes regulated by ?-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced ?-catenin expression and function. PMID:23955570

Knoblich, Konstantin; Wang, Hong-Xing; Sharma, Chandan; Fletcher, Anne L; Turley, Shannon J; Hemler, Martin E

2014-04-01

291

An uncleavable form of pro–scatter factor suppresses tumor growth and dissemination in mice  

PubMed Central

Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF–induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions. PMID:15545993

Mazzone, Massimiliano; Basilico, Cristina; Cavassa, Silvia; Pennacchietti, Selma; Risio, Mauro; Naldini, Luigi; Comoglio, Paolo M.; Michieli, Paolo

2004-01-01

292

Adaptation of an automatic bacterial colony counter for measuring lung tumor growth in mice.  

PubMed

Adaptation of an automatic bacterial colony counter proved to be an efficient procedure for detecting and quantitating tumor growth in mouse lungs prepared by the Wexler method of India ink insufflation. After correlation of the size discriminator settings on the automatic counter with the Wexler visual scale, the amount of tumor growth in the lungs of 52 mice was determined by eye and independently by the automatic counter. There was no statistical difference between the two procedures. When the mouse lungs were grouped according to the number of tumors computed by eye, there was no statistical difference between the two counting procedures in any of the groups. The standard deviation was independent of the number of tumors in the lungs. This caused the precision of the automatic counter to be poor in lungs with few tumors because the error was a greater percentage of the total. In lungs with a large number of tumors, which were difficult to count by eye, close agreement between the two methods of counting was demonstrated. PMID:326389

Filardi, M J; Lininger, L; McKneally, M F

1977-08-01

293

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

PubMed Central

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

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

2014-01-01

294

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis.  

PubMed

Silent information regulator 1 (SIRT1) is involved in a number of cellular regulatory mechanisms affecting cellular life span, stress resistance, apoptosis and cellular metabolism. Recent studies have revealed that SIRT1 plays a dual role as a tumor suppressor and a tumor promoter in multiple stages of carcinogenesis. Increased lipogenesis has been found in cancer cells, sterol regulatory element binding protein 1 (SREBP1) are nuclear lipogenic transcription factors, which mainly regulate lipogenic processes by activating genes involved in fatty acid and triglyceride biosynthesis. In the present study, we detected expression of SIRT1 in endometrial cancer (EC) and illustrated the relationship between SIRT1 and SREBP1, which indicated that SIRT1 could stimulate endometrial tumor growth through the lipogenic pathway. Gene expression levels of SIRT1 were assayed using quantitative real-time PCR and protein expression levels were detected by western blotting. RNA interference was conducted in order to explore the subsequent effect on tumor cells and on the expression of SREBP1. Expression levels of SIRT1 in EC were found to be significantly higher than in normal endometrium. Knockdown of SIRT1 could downregulate expression of SREBP1 and suppress cell proliferation. These results demonstrated that SIRT1 may play a role as a tumor promoter in EC and can promote endometrial tumor growth by promoting lipogenesis. Our findings suggest that targeting SIRT1 may provide a theoretical basis for the management of EC. PMID:25270091

Lin, Li; Zheng, Xiaoxia; Qiu, Chunping; Dongol, Samina; Lv, Qingtao; Jiang, Jie; Kong, Beihua; Wang, Chenguang

2014-12-01

295

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

PubMed Central

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

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

2014-01-01

296

Higher Stromal Expression of Transforming Growth Factor-beta Type II Receptors is Associated with Poorer Prognosis Breast Tumors  

Microsoft Academic Search

Transforming growth factor-beta (TGFB) is a potent inhibitor of normal epithelial cell proliferation, and may be one of the regulatory factors that are perturbed during tumor development. While many tumor cell lines no longer respond to the inhibitory effects of TGFB due to a reduction or absence of the type II receptor (TGFBR2), the role of TGFBR2 in tumors from

John Barlow; David Yandell; Donald Weaver; Theresa Casey; Karen Plaut

2003-01-01

297

Digoxin and other cardiac glycosides inhibit HIF-1? synthesis and block tumor growth  

PubMed Central

A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 ?M. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1? protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1? by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy. PMID:19020076

Zhang, Huafeng; Qian, David Z.; Tan, Yee Sun; Lee, KangAe; Gao, Ping; Ren, Yunzhao R.; Rey, Sergio; Hammers, Hans; Chang, Daniel; Pili, Roberto; Dang, Chi V.; Liu, Jun O.; Semenza, Gregg L.

2008-01-01

298

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

299

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

300

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

301

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-Andre; Ayache, Nicholas; Golland, Polina

2011-01-01

302

Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo  

Microsoft Academic Search

Mesenchymal stem cells (MSCs) have generated a great deal of interest in clinical application because of their potential use in regenerative medicine and tissue engineering. However, the therapeutic application of MSCs still remain limited unless the favorable effect of MSCs for tumor growth in vivo and the long-term safety of the clinical applications of MSCs are better understood. In this

Wei Zhu; Wenrong Xu; Runqiu Jiang; Hui Qian; Miao Chen; Jiabo Hu; Weike Cao; Chongxu Han; Yongchang Chen

2006-01-01

303

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

PubMed

Tumors are appreciated to be an intrinsically heterogeneous population of cells with varying proliferation capacities and tumorigenic potentials. As a central tenet of the so-called cancer stem cell hypothesis, most cancer cells have only a limited lifespan, and thus cannot initiate or reinitiate tumors. Longevity and clonogenicity are properties unique to the subpopulation of cancer stem cells. To understand the implications of the population structure suggested by this hypothesis--a hierarchy consisting of cancer stem cells and progeny non-stem cancer cells which experience a reduction in their remaining proliferation capacity per division--we set out to develop a mathematical model for the development of the aggregate population. We show that overall tumor progression rate during the exponential growth phase is identical to the growth rate of the cancer stem cell compartment. Tumors with identical stem cell proportions, however, can have different growth rates, dependent on the proliferation kinetics of all participating cell populations. Analysis of the model revealed that the proliferation potential of non-stem cancer cells is likely to be small to reproduce biologic observations. Furthermore, a single compartment of non-stem cancer cell population may adequately represent population growth dynamics only when the compartment proliferation rate is scaled with the generational hierarchy depth. PMID:24840956

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

2014-07-01

304

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

E-print Network

in circulation, caus- ing 70% inhibition of primary tumor growth and metastasis. Con- trary to the effects of angiogenic diseases such as macular degeneration (1­4) and cancers (5­8). However, the mechanisms by which of omega-3 fatty acids by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes generates 3-series pros

Hammock, Bruce D.

305

A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth.  

PubMed

Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. We have developed a thermally responsive polypeptide, based on the sequence of Elastin-like polypeptide (ELP), that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. Following systemic administration, the ELP - delivered c-Myc inhibitory peptide was targeted to tumors using focused hyperthermia, and significantly reduced tumor growth in an orthotopic mouse model of breast cancer. This work provides a new modality for targeted delivery of a specific oncogene inhibitory peptide, and this strategy may be expanded for delivery of other therapeutic peptides or small molecule drugs. PMID:22261328

Bidwell, Gene L; Perkins, Eddie; Raucher, Drazen

2012-06-28

306

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

NASA Astrophysics Data System (ADS)

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

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

2014-05-01

307

Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond.  

PubMed

Our understanding of the dynamic tumor microenvironment (TME) has improved exponentially over the last few decades. In addition to traditional cytotoxic agents, anti-cancer strategies now include numerous molecular-targeted drugs that modulate distinct elements of the TME. Angiogenesis is an underlying promoter of tumor growth, invasion, and metastases. From traditional and emerging angiogenic cytokines and their receptors to novel immune checkpoint inhibitors, regulation of the tumor microenvironment is potentially key in countering tumor progression. In this article, an overview of the architecture of the TME and the orchestration of angiogenesis within the TME is provided. Additionally, traditional and novel angiogenic targets of current interest within the TME are reviewed. PMID:24787295

Mittal, Kriti; Ebos, John; Rini, Brian

2014-04-01

308

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth  

PubMed Central

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages. PMID:19726870

Soman, Neelesh R.; Baldwin, Steven L.; Hu, Grace; Marsh, Jon N.; Lanza, Gregory M.; Heuser, John E.; Arbeit, Jeffrey M.; Wickline, Samuel A.; Schlesinger, Paul H.

2009-01-01

309

Radiobiology of the rhabdomyosarcoma R1H of the rat: Influence of the size of irradiation field on tumor response, tumor bed effect, and neovascularization kinetics  

SciTech Connect

R1H tumors were irradiated with a single dose of 15 Gy X rays using varying sizes of treatment fields. Damage to tumor cells and tumor stroma was determined separately by analysis of growth delay to ten times treatment volume (GD10vo) and net growth delay. GD10vo comprises irradiation effects on tumor parenchymal cells and on tumor stroma, whereas net growth delay only measures effects on tumor parenchymal cells. Stromal damage was observed to increase with increasing field size; the effect on the tumor parenchymal cells, however, was independent of the field size. An increase of GD10vo of 13 days per cm increase of field size diameter was observed. From this the velocity of neovascularization of the irradiated tumor bed was calculated to be 0.30 to 0.38 mm per day.

Wuerschmidt, F.B.; Beck-Bornholdt, H.P.; Vogler, H. (Univ. of Hamburg (Germany, F.R.))

1990-04-01

310

Protein Kinase C Lies on the Signaling Pathway for Vascular Endothelial Growth Factor-mediated Tumor Development and Angiogenesis  

Microsoft Academic Search

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in tumor angiogenesis. However, to date, the signal transduction pathway initiated by VEGF is still not fully understood. It has been suggested that protein kinase C (PKC) plays an important role in the

Hitoshi Yoshiji; Shigeki Kuriyama; D. Kirk Ways; Junichi Yoshii; Yoji Miyamoto; Mitsuhiro Kawata; Yasuhide Ikenaka; Hirohisa Tsujinoue; Toshiya Nakatani; Masabumi Shibuya; Hiroshi Fukui

1999-01-01

311

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. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25231497

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

2014-12-20

312

Lysophosphatidic Acid Acyltransferase ? (LPAAT?) Promotes the Tumor Growth of Human Osteosarcoma  

PubMed Central

Background Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase ? (LPAAT?, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAAT? can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAAT? has been reported in several types of human tumors, the role of LPAAT? in osteosarcoma progression has yet to be elucidated. Methodology/Principal Findings Endogenous expression of LPAAT? in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAAT? and silencing LPAAT? expression is employed to determine the effect of LPAAT? on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAAT? is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAAT? promotes osteosarcoma cell proliferation and migration, while silencing LPAAT? expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAAT? effectively promotes tumor growth, while knockdown of LPAAT? expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma. Conclusions/Significance Our results strongly suggest that LPAAT? expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAAT? may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAAT? may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors. PMID:21152068

Rastegar, Farbod; Gao, Jian-Li; Shenaq, Deana; Luo, Qing; Shi, Qiong; Kim, Stephanie H.; Jiang, Wei; Wagner, Eric R.; Huang, Enyi; Gao, Yanhong; Shen, Jikun; Yang, Ke; He, Bai-Cheng; Chen, Liang; Zuo, Guo-Wei; Luo, Jinyong; Luo, Xiaoji; Bi, Yang; Liu, Xing; Li, Mi; Hu, Ning; Wang, Linyuan; Luther, Gaurav; Luu, Hue H.; Haydon, Rex C.; He, Tong-Chuan

2010-01-01

313

Enhancement of Cancer Vaccine Therapy by Systemic Delivery of a Tumor Targeting Salmonella-based STAT3 shRNA Suppresses the Growth of Established Melanoma Tumors  

PubMed Central

Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immune suppression. Towards that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN) referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a shRNA targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4+ and CD8+ T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, while the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy. PMID:21527558

Manuel, Edwin R.; Blache, Celine A.; Paquette, Rebecca; Kaltcheva, Teodora I.; Ishizaki, Hidenobu; Ellenhorn, Joshua D.I.; Hensel, Michael; Metelitsa, Leonid; Diamond, Don J.

2011-01-01

314

Cyclophilin A enhances cell proliferation and tumor growth of liver fluke-associated cholangiocarcinoma  

PubMed Central

Background Cyclophilin A (CypA) expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of CypA in liver fluke-associated cholangiocarcinoma (CCA) are not presently known. In this study, we investigated the expression of CypA in CCA tumor tissues and CCA cell lines as well as regulation mechanisms of CypA in tumor growth using CCA cell lines. Methods CypA expression was determined by real time RT-PCR, Western blot or immunohistochemistry. CypA silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell proliferation was assessed using MTS assay or Ki-67 staining. The effect of silencing CypA on CCA tumor growth was determined in nude mice. The effect of CypA knockdown on ERK1/2 activation was assessed by Western blot. Results CypA was upregulated in 68% of CCA tumor tissues. Silencing CypA significantly suppressed cell proliferation in several CCA cell lines. Likewise, inhibition of CypA peptidyl-prolyl cis-trans isomerase (PPIase) activity using cyclosporin A (CsA) decreased cell proliferation. In contrast, overexpression of CypA resulted in 30% to 35% increases in proliferation of CCA cell lines. Interestingly, neither silence nor overexpression of CypA affected cell proliferation of a non-tumor human cholangiocyte cell line, MMNK1. Suppression of CypA expression attenuated ERK1/2 activity in CCA M139 cells by using both transient and stable knockdown methods. In the in vivo study, there was a 43% reduction in weight of tumors derived from CypA-silenced CCA cell lines compared with control vector CCA tumors in mice; these tumors with stable CypA silencing showed a reduced cell proliferation. Conclusions CypA is upregulated in majority of CCA patients' tissues and confers a significant growth advantage in CCA cells. Suppression of CypA expression decreases proliferation of CCA cell lines in vitro and reduces tumor growth in the nude mouse model. Inhibition of CypA activity also reduces CCA cell proliferation. The ERK1/2 pathway may be involved in the CypA-mediated CCA cell proliferation. Thus, CypA may represent an important new therapeutic target for liver fluke-associated CCA. PMID:21871105

2011-01-01

315

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

316

Investigation of HT1080 tumor growth dynamics and ECM invasion in 3D  

NASA Astrophysics Data System (ADS)

Tumors are complex arrangements of tissues made up of several components, including dense masses of cancer cells and re-organized extracellular matrix (ECM). Recent studies have revealed the crucial role that extracellular matrix components have on single cancer cell behavior, but how the interaction of ECM components affects the growth dynamics of an entire tumor is not fully understood. Here, we use human derived fibrosarcoma cell (HT1080) aggregates in combination with live cell imaging, cryo-stat sectioning, immunostaining, and confocal imaging to study changes in cell aggregate size, proliferation, and spatial distribution within 3 dimensional (3D) matrices. We compare our experimental observations with a coupled partial differential equations based mathematical model to predict cell aggregate growth and cell density distribution and determine how cell interactions play a significant role in this dynamic growth. Using this model, we investigate the distinct contributions from cell migration, proliferation, cell-matrix interactions, and matrix remodeling to the aggregate dynamics.

Yogurtcu, Osman N.; Jimenez Valencia, Angela M.; Lee, Meng-Horng; Sun, Sean X.; Wirtz, Denis

2013-03-01

317

The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice.  

PubMed

Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin- and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion, and metastasis. To directly assess its role in tumor growth and metastasis in vivo, we stably transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT) and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2 to 3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT or QT cells, whereas only 42% of mice treated with WT cells developed lung metastases. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of each tumor group revealed 3- to 6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene expression analysis revealed that several human genes implicated in oncogenesis, invasion, metastasis, apoptosis, and angiogenesis had significantly altered levels of expression in WT tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in vivo by regulating pericellular extracellular matrix (ECM) remodeling and angiogenesis. PMID:14525759

Chand, Hitendra Singh; Du, Xin; Ma, Duan; Inzunza, Hector David; Kamei, Shintaro; Foster, Donald; Brodie, Steven; Kisiel, Walter

2004-02-01

318

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

PubMed Central

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 intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs. PMID:22932871

Stylianopoulos, Triantafyllos; Martin, John D.; Chauhan, Vikash P.; Diop-Frimpong, Benjamin; Bardeesy, Nabeel; Smith, Barbara L.; Ferrone, Cristina R.; Hornicek, Francis J.; Boucher, Yves; Munn, Lance L.; Jain, Rakesh K.

2012-01-01

319

A molecular mechanism regulating circadian expression of vascular endothelial growth factor in tumor cells.  

PubMed

Because angiogenesis is essential for tumor growth and metastasis, inhibition of angiogenesis has emerged as a new therapy to treat cancers. Hypoxia-induced expression of vascular endothelial growth factor (VEGF) plays a central role in tumor-induced angiogenesis. In this study, we found that expression of VEGF in hypoxic tumor cells was affected by the circadian organization of molecular clockwork. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop in which CLOCK and BMAL1 are positive regulators, and Period and Cryptochrome genes act as negative ones. The levels of VEGF mRNA in tumor cells implanted in mice rose substantially in response to hypoxia, but the levels fluctuated rhythmically in a circadian fashion. Luciferase reporter gene analysis revealed that Period2 and Cryptochrome1, whose expression in the implanted tumor cells showed a circadian oscillation, inhibited the hypoxia-induced VEGF promoter activity. These results suggest that the negative limbs of the molecular loop periodically inhibit the hypoxic induction of VEGF transcription, resulting in the circadian fluctuation of its mRNA expression. We also showed that the antitumor efficacy of antiangiogenic agents could be enhanced by administering the drugs at the time when VEGF production increased. These findings support the notion that monitoring of the circadian rhythm in VEGF production is useful for choosing the most appropriate time of day for administration of antiangiogenic agents. PMID:14612524

Koyanagi, Satoru; Kuramoto, Yukako; Nakagawa, Hiroo; Aramaki, Hironori; Ohdo, Shigehiro; Soeda, Shinji; Shimeno, Hiroshi

2003-11-01

320

Evidence for Control of Nitric Oxide Synthesis by Intracellular Transforming Growth Factor-?1 in Tumor Cells  

PubMed Central

Transforming growth factor-?1 (TGF-?1) has been shown to down-regulate NO synthesis in a variety of normal cells. In the present study, we investigated the influence of TGF-?1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon carcinoma cells intraperitoneally injected in syngeneic BDIX rats, intratumoral concentration of TGF-?1 increases while NO concentration stays very low. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-?1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-?1-secreting cells. Using PROb cells transfected with an expression vector coding for TGF-?1 antisense mRNA, we demonstrate in vitro that there is an inverse correlation between the amount of TGF-?1 secreted and the ability of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-? type II receptor neutralizing antibody, and as exogenous TGF-?1 is without any effect on NO secretion by PROb cells, TGF-?1 apparently down-regulates NO synthesis in PROb cells by an intracellular mechanism. These results suggest that endogenous TGF-?1 constitutes a potential target in a search for new antitumoral agents. PMID:10362813

Lagadec, Patricia; Raynal, Stephane; Lieubeau, Blandine; Onier, Nathalie; Arnould, Laurent; Saint-Giorgio, Valerie; Lawrence, David A.; Jeannin, Jean-Francois

1999-01-01

321

Imatinib and Dasatinib Inhibit Hemangiosarcoma and Implicate PDGFR-? and Src in Tumor Growth12  

PubMed Central

Hemangiosarcoma, a natural model of human angiosarcoma, is an aggressive vascular tumor diagnosed commonly in dogs. The documented expression of several receptor tyrosine kinases (RTKs) by these tumors makes them attractive targets for therapeutic intervention using tyrosine kinase inhibitors (TKIs). However, we possess limited knowledge of the effects of TKIs on hemangiosarcoma as well as other soft tissue sarcomas. We report here on the use of the TKIs imatinib and dasatinib in canine hemangiosarcoma and their effects on platelet-derived growth factor receptor ? (PDGFR-?) and Src inhibition. Both TKIs reduced cell viability, but dasatinib was markedly more potent in this regard, mediating cytotoxic effects orders of magnitude greater than imatinib. Dasatinib also inhibited the phosphorylation of the shared PDGFR-? target at a concentration approximately 1000 times less than that needed by imatinib and effectively blocked Src phosphorylation. Both inhibitors augmented the response to doxorubicin, suggesting that clinical responses likely will be improved using both drugs in combination; however, dasatinib was significantly (P < .05) more effective in this context. Despite the higher concentrations needed in cell-based assays, imatinib significantly inhibited tumor growth (P < .05) in a tumor xenograft model, highlighting that disruption of PDGFR-?/PDGF signaling may be important in targeting the angiogenic nature of these tumors. Treatment of a dog with spontaneously occurring hemangiosarcoma established that clinically achievable doses of dasatinib may be realized in dogs and provides a means to investigate the effect of TKIs on soft tissue sarcomas in a large animal model. PMID:23544168

Dickerson, Erin B; Marley, Kevin; Edris, Wade; Tyner, Jeffrey W; Schalk, Vidya; MacDonald, Valerie; Loriaux, Marc; Druker, Brian J; Helfand, Stuart C

2013-01-01

322

A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors  

PubMed Central

The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly down-regulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38–100% of multiple primary tumors. Treatment with 5-aza-2?-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis. PMID:21217778

Low, JSW; Tao, Q; Ng, KM; Goh, HK; Shu, X-S; Woo, WL; Ambinder, RF; Srivastava, G; Shamay, M; Chan, ATC; Popescu, NC; Hsieh, W-S

2011-01-01

323

Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth  

PubMed Central

The Warburg effect describes a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose even in the presence of oxygen. To better understand how tyrosine kinase signaling, which is commonly increased in tumors, regulates the Warburg effect, we performed phosphoproteomic studies. We found that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y105). This inhibits the formation of active, tetrameric PKM2 by disrupting binding of the PKM2 cofactor fructose-1,6-bisphosphate. Furthermore, we found that phosphorylation of PKM2 Y105 is common in human cancers. The presence of a PKM2 mutant in which phenylalanine is substituted for Y105 (Y105F) in cancer cells leads to decreased cell proliferation under hypoxic conditions, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenografts in nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth. PMID:19920251

Hitosugi, Taro; Kang, Sumin; Vander Heiden, Matthew G.; Chung, Tae-Wook; Elf, Shannon; Lythgoe, Katherine; Dong, Shaozhong; Lonial, Sagar; Wang, Xu; Chen, Georgia Z.; Xie, Jianxin; Gu, Ting-Lei; Polakiewicz, Roberto D.; Roesel, Johannes L.; Boggon, Titus J.; Khuri, Fadlo R.; Gilliland, D. Gary; Cantley, Lewis C.; Kaufman, Jonathan; Chen, Jing

2010-01-01

324

G-rich Oligonucleotides Inhibit HIF-1? and HIF-2? and Block Tumor Growth  

PubMed Central

Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in tumor promotion by upregulating its target genes, which are involved in energy metabolism, angiogenesis, cell survival, invasion, metastasis, and drug resistance. The HIF-1? subunit, which is regulated by O2-dependent hydroxylation, ubiquitination, and degradation, has been identified as an important molecular target for cancer therapy. We have rationally designed G-rich oligodeoxynucleotides (ODNs) as inhibitors of HIF-1? for human cancer therapy. The lead compounds, JG243 and JG244, which form an intramolecular parallel G-quartet structure, selectively target HIF-1? and decreased levels of both HIF-1? and HIF-2? (IC50 < 2 µmol/l) and also inhibited the expression of HIF-1-regulated proteins [vascular endothelial growth factor (VEGF), Bcl-2, and Bcl-XL], but did not disrupt the expression of p300, Stat3, or p53. JG-ODNs induced proteasomal degradation of HIF-1? and HIF-2? that was dependent on the hydroxylase activity of prolyl-4-hydroxylase-2. JG243 and JG244 dramatically suppressed the growth of prostate, breast, and pancreatic tumor xenografts. Western blots from tumor tissues showed that JG-ODNs significantly decreased HIF-1? and HIF-2? levels and blocked the expression of VEGF. The JG-ODNs are novel anticancer agents that suppress tumor growth by inhibiting HIF-1. PMID:19755960

Guan, Yongli; Ramasamy Reddy, Kavitha; Zhu, Qiqing; Li, Yifei; Lee, KangAe; Weerasinghe, Priya; Prchal, Josef; Semenza, Gregg L; Jing, Naijie

2009-01-01

325

G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth.  

PubMed

Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in tumor promotion by upregulating its target genes, which are involved in energy metabolism, angiogenesis, cell survival, invasion, metastasis, and drug resistance. The HIF-1alpha subunit, which is regulated by O2-dependent hydroxylation, ubiquitination, and degradation, has been identified as an important molecular target for cancer therapy. We have rationally designed G-rich oligodeoxynucleotides (ODNs) as inhibitors of HIF-1alpha for human cancer therapy. The lead compounds, JG243 and JG244, which form an intramolecular parallel G-quartet structure, selectively target HIF-1alpha and decreased levels of both HIF-1alpha and HIF-2alpha (IC50 < 2 micromol/l) and also inhibited the expression of HIF-1-regulated proteins [vascular endothelial growth factor (VEGF), Bcl-2, and Bcl-XL], but did not disrupt the expression of p300, Stat3, or p53. JG-ODNs induced proteasomal degradation of HIF-1alpha and HIF-2alpha that was dependent on the hydroxylase activity of prolyl-4-hydroxylase-2. JG243 and JG244 dramatically suppressed the growth of prostate, breast, and pancreatic tumor xenografts. Western blots from tumor tissues showed that JG-ODNs significantly decreased HIF-1alpha and HIF-2alpha levels and blocked the expression of VEGF. The JG-ODNs are novel anticancer agents that suppress tumor growth by inhibiting HIF-1. PMID:19755960

Guan, Yongli; Reddy, Kavitha Ramasamy; Zhu, Qiqing; Li, Yifei; Lee, KangAe; Weerasinghe, Priya; Prchal, Josef; Semenza, Gregg L; Jing, Naijie

2010-01-01

326

Contour instabilities and micro-structures in early tumor growth models  

NASA Astrophysics Data System (ADS)

Clinical diagnosis of skin cancers is based on several morphological criteria, among which growth, color, border instabilities and microstructures (e.g. dots, nests) sparsely distributed within the tumor lesion. We use the multiphase mixture models adapted to the skin to explain various patterning occurring in the avascular phase. Restricting to a simple but realistic version of these models with an elastic cell-to-cell interaction and a growth rate dependent on diffusing nutrients, we prove analytically that the tumor cell concentration at the border acts as a control parameter inducing a bifurcation with loss of circular symmetry which explains the instabilities of the tumor border. The finite wavelength at threshold has the size of the proliferating peritumoral zone. We apply our predictions to melanoma growth since these instabilities are crucial for the early diagnosis. The same model is used to show the existence of micro-structures. Taking into account a reaction-diffusion coupling between nutrient consumption and cellular proliferation, we show that two-phase models may undergo a spinodal decomposition even when considering mass exchanges between the phases. The cell-nutrient interaction defines a typical diffusive length in the problem, which is found to control the saturation of a growing separated domain, thus stabilizing the microstructural pattern. The distribution and the evolution of such emerging cluster morphologies are successfully compared to the clinical observation of microstructural patterns in tumor lesions.

Ben Amar, Martine; Ciarletta, Pasquale; Chatelain, Clément; Balois, Thibaut

2012-02-01

327

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

328

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

329

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

330

Toxicarioside A Inhibits Tumor Growth and Angiogenesis: Involvement of TGF-?/Endoglin Signaling  

PubMed Central

Toxicarioside A is a cardenolide isolated mainly from plants and animals. Emerging evidence demonstrate that cardenolides not only have cardiac effects but also anticancer effects. In this study, we used in vivo models to investigate the antitumor activities of toxicarioside A and the potential mechanisms behind them. Murine colorectal carcinoma (CT26) and Lewis lung carcinoma (LL/2) models were established in syngeneic BALB/c and C57BL/6 mice, respectively. We found that the optimum effective dose of toxicarioside A treatment significantly suppressed tumor growth and angiogenesis in CT and LL/2 tumor models in vivo. Northern and Western blot analysis showed significant inhibition of endoglin expression in toxicarioside A-treated human umbilical vein endothelial cells (HUVECs) in vitro and tumor tissues in vivo. Toxicarioside A treatment significantly inhibited cell proliferation, migration and invasion, but did not cause significant cell apoptosis and affected other membrane protein (such as CD31 and MHC I) expression. In addition, TGF-? expression was also significantly inhibited in CT26 and LL/2 tumor cells treated with toxicarioside A. Western blot analysis indicated that Smad1 and phosphorylated Smad1 but not Smad2/3 and phosphorylated Smad2/3 were attenuated in HUVECs treated with toxicarioside A. Smad1 and Smad2/3 signaling remained unchanged in CT26 and LL/2 tumor cells treated with toxicarioside A. Endoglin knockout by small interfering RNA against endoglin induced alternations in Smad1 and Smad2/3 signaling in HUVECs. Our results indicate that toxicarioside A suppresses tumor growth through inhibition of endoglin-related tumor angiogenesis, which involves in the endoglin/TGF-? signal pathway. PMID:23209720

Tan, Guang-hong; Dai, Hao-fu; Guo, Jun-li; Wang, Hua; Huang, Yong-hao; Zhao, Huan-ge; Zhou, Song-lin; Lin, Ying-ying

2012-01-01

331

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis.  

PubMed

Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are defining events in several tumors, including anaplastic large-cell lymphoma (ALCL) and non-small cell lung carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared with other types of T-cell lymphoma or EGFR- and K-RAS-mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC, we found that under hypoxic conditions, ALK directly regulated the abundance of hypoxia-inducible factors (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1? and HIF2? in hypoxic conditions required ALK activity and its downstream signaling proteins STAT3 and C/EBP?. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF2?, but not HIF1?, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1? and HIF2?. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK(+) tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC. Cancer Res; 74(21); 6094-106. ©2014 AACR. PMID:25193384

Martinengo, Cinzia; Poggio, Teresa; Menotti, Matteo; Scalzo, Maria Stella; Mastini, Cristina; Ambrogio, Chiara; Pellegrino, Elisa; Riera, Ludovica; Piva, Roberto; Ribatti, Domenico; Pastorino, Fabio; Perri, Patrizia; Ponzoni, Mirco; Wang, Qi; Voena, Claudia; Chiarle, Roberto

2014-11-01

332

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.

333

The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity  

PubMed Central

Background HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ. Methods The gefitinib and RAD001 combination was broadly evaluated in TZ sensitive (SKBR3 and MCF7-HER2) and TZ resistant (JIMT-1) breast cancer models. The effects on cell growth were measured in cell based assays using the fixed molar ratio design and the median effect principle. In vivo studies were performed in Rag2M mice bearing established tumors. Analysis of cell cycle, changes in targeted signaling pathways and tumor characteristics were conducted to assess gefitinib and RAD001 interactions. Results The gefitinib and RAD001 combination inhibited cell growth in vitro in a synergistic fashion as defined by the Chou and Talalay median effect principle and increased tumor xenograft growth delay. The improvement in therapeutic efficacy by the combination was associated in vitro with cell line dependent increases in cytotoxicity and cytostasis while treatment in vivo promoted cytostasis. The most striking and consistent therapeutic effect of the combination was increased inhibition of the mTOR pathway (in vitro and in vivo) and EGFR signaling in vivo relative to the single drugs. Conclusions The gefitinib and RAD001 combination provides effective control over growth of HER2 overexpressing cells and tumors irrespective of the TZ sensitivity status. PMID:21961653

2011-01-01

334

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

335

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

336

Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways.  

PubMed

This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 2 x 2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-alpha, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways. PMID:19904759

Saggar, Jasdeep Kaur; Chen, Jianmin; Corey, Paul; Thompson, Lilian U

2010-03-01

337

Delayed Myelination in an Intrauterine Growth Retardation Model Is Mediated by Oxidative Stress Upregulating Bone Morphogenetic Protein 4  

PubMed Central

Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We employed a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation. PMID:22710965

Reid, Mary V.; Murray, Kaitlin A.; Marsh, Eric D.; Golden, Jeffrey A.; Simmons, Rebecca A.; Grinspan, Judith B.

2012-01-01

338

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

339

Optimization of vascular-targeting drugs in a computational model of tumor growth  

NASA Astrophysics Data System (ADS)

A biophysical tool is introduced that seeks to provide a theoretical basis for helping drug design teams assess the most promising drug targets and design optimal treatment strategies. The tool is grounded in a previously validated computational model of the feedback that occurs between a growing tumor and the evolving vasculature. In this paper, the model is particularly used to explore the therapeutic effectiveness of two drugs that target the tumor vasculature: angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs). Using sensitivity analyses, the impact of VDA dosing parameters is explored, as is the effects of administering a VDA with an AI. Further, a stochastic optimization scheme is utilized to identify an optimal dosing schedule for treatment with an AI and a chemotherapeutic. The treatment regimen identified can successfully halt simulated tumor growth, even after the cessation of therapy.

Gevertz, Jana

2012-04-01

340

Subverting sterols: rerouting an oxysterol-signaling pathway to promote tumor growth  

PubMed Central

Oxysterols are oxidized derivatives of cholesterol that are generated enzymatically or through autoxidation. Initially identified as important lipid signaling molecules in the context of atherosclerosis and inflammation, accumulated evidence indicates that these lipid-signaling molecules can have pleiotropic effects on the fate and function of the immune system. These effects range from the regulation of immune cell survival and proliferation to chemotaxis and antiviral immunity. New studies now indicate that tumor-derived oxysterols can serve to subvert the immune system by recruiting protumorigenic neutrophils into the tumor microenvironment. The consequence of this recruitment is the generation of proangiogenic factors and matrix metalloproteinase proteins that provide a tumor a significant growth and survival advantage. In combination with other recent studies, these data highlight the ongoing cross talk between sterol metabolism and the immune system, and they raise the intriguing possibility that targeting oxysterol pathways could serve as a novel therapeutic approach in the war on cancer. PMID:23980123

York, Autumn G.

2013-01-01

341

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

PubMed Central

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. PMID:22841774

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

2012-01-01

342

Relationship Between Vascular Endothelial Growth Factor and Nuclear Factor-?B in Renal Cell Tumors  

PubMed Central

Aim To assess the relationship between protein and messenger RNA (mRNA) levels of vascular endothelial growth factor (VEGF) and subcellular localization of nuclear factor-kappa B (NF-?B), proliferation rate of tumor cells, and clinicopathological characteristics of renal cell tumors. Methods We analyzed 31 one renal cell tumors – 22 clear cell renal cell carcinomas (CCRCC) and 9 other histologic types (non-CCRCC). VEGF expression and subcellular localization of p65 member of NF-?B and Ki67 were immunohistochemically evaluated for the proliferation rate of tumor cells. Expression of VEGF mRNA was assessed using quantitative real-time polymerase chain reaction after total RNA extraction from snap-frozen tumor tissue samples. Results Cytoplasmic localization of VEGF protein in renal cell tumors showed a perimembranous and diffuse pattern, the former being more evident in CCRCC (27.1 ± 18.9 vs 3.3?±?10 % tumors, P?=?0.001) and the latter in non-CCRCC type (71.7 ± 23.2 vs 31.1?±?22.1 % tumors, P?tumor cells. A significant association was recorded between cytoplasmic NK-?B/65 staining and VEGF staining of diffuse pattern (P?=?0.026). Association between NF-?B/65 and proliferation rate of tumor cells was significant for cytoplasmic staining (P?=?0.039) but not for nuclear NFkB/p65 staining (P?=?0.099). Conclusion Higher but inhomogeneous expression of VEGF in tumor cells, especially in CCRCCs, is associated with NF-?B/65 activity. This indicates that both VEGF and NF-?B/65 may be important in renal carcinogenesis, representing a possible molecular target in the treatment of renal cell carcinoma. PMID:18925694

?or?evi?, Gordana; Matušan-Ilijaš, Koviljka; Sinoži?, Emina; Damante, Giuseppe; Fabbro, Dora; Grahovac, Blaženka; Lu?in, Ksenija; Jonji?, Nives

2008-01-01

343

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; Kogel, Donat; Weissenberger, Jakob

2013-01-01

344

Recombinant TIMP-1-GPI inhibits growth of fibrosarcoma and enhances tumor sensitivity to doxorubicin.  

PubMed

Fibrosarcomas show a high incidence of recurrence and general resistance to apoptosis. Limiting tumor regrowth and increasing their sensitivity to chemotherapy and apoptosis represent key issues in developing more effective treatments of these tumors. Tissue inhibitor of metalloproteinase 1 (TIMP-1) broadly blocks matrix metalloproteinase (MMP) activity and can moderate tumor growth and metastasis. We previously described generation of a recombinant fusion protein linking TIMP-1 to glycosylphophatidylinositol (GPI) anchor (TIMP-1-GPI) that efficiently directs the inhibitor to cell surfaces. In the present report, we examined the effect of TIMP-1-GPI treatment on fibrosarcoma biology. Exogenously applied TIMP-1-GPI efficiently incorporated into surface membranes of human HT1080 fibrosarcoma cells. It inhibited their proliferation, migration, suppressed cancer cell clone formation, and enhanced apoptosis. Doxorubicin, the standard chemotherapeutic drug for fibrosarcoma, was tested alone or in combination with TIMP-1-GPI. In parallel, the influence of treatment on HT1080 side population cells (exhibiting tumor stem cell-like characteristics) was investigated using Hoechst 33342 staining. The sequential combination of TIMP-1-GPI and doxorubicin showed more than additive effects on apoptosis, while TIMP-1-GPI treatment alone effectively decreased "stem-cell like" side population cells of HT1080. TIMP-1-GPI treatment was validated using HT1080 fibrosarcoma murine xenografts. Growing tumors treated with repeated local injections of TIMP-1-GPI showed dramatically inhibited fibrosarcoma growth and reduced angiogenesis. Intraoperative peritumoral application of GPI-anchored TIMP-1 as an adjuvant to surgery may help maintain tumor control by targeting microscopic residual fibrosarcoma cells and increasing their sensitivity to chemotherapy. PMID:23934106

Bao, Q; Niess, H; Djafarzadeh, R; Zhao, Y; Schwarz, B; Angele, M K; Jauch, K-W; Nelson, P J; Bruns, C J

2014-09-01

345

DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesis.  

PubMed

Four novel oral DNA vaccines provide long-lived protection against melanoma, colon, breast, and non-small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine-related protein, vascular endothelial growth factor receptor-2 [also called fetal liver kinase-1 (FLK-1)], and transcription factor Fos-related antigen-1 (Fra-1). The FLK-1 and Fra-1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell-mediated protective immunity, breaking peripheral T-cell tolerance against these self-antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer. PMID:15233734

Reisfeld, Ralph A; Niethammer, Andreas G; Luo, Yunping; Xiang, Rong

2004-06-01

346

A Synthetic Manassantin A Derivative Inhibits Hypoxia-Inducible Factor 1 and Tumor Growth  

PubMed Central

The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1? nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers. PMID:24925080

Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

2014-01-01

347

Transmembrane Domain Targeting Peptide Antagonizing ErbB2/Neu Inhibits Breast Tumor Growth and Metastasis.  

PubMed

Breast cancer is still a deadly disease despite major achievements in targeted therapies designed to block ligands or ligand-binding subunits of major tyrosine kinase receptors. Relapse is significant and metastases deleterious, which demands novel strategies for fighting this disease. Here, we report a proof-of-concept experiment demonstrating that small peptides interfering with the transmembrane domain of the tyrosine kinase epidermal growth factor receptor ErbB2 exhibit anticancer properties when used at micromolar dosages in a genetically engineered mouse model of breast cancer. Different assays demonstrate the specificity of the ErbB2-targeting peptide, which induces long-term reduction of ErbB2 phosphorylation and Akt signaling consistent with reduced tumor cell proliferation and increased survival. Microcomputed tomography analysis established the antimetastatic activity of the peptide and its impact on primary tumor growth. This reveals the interior of the cell membrane as an unexplored dimension for drug design. PMID:25220456

Arpel, Alexia; Sawma, Paul; Spenlé, Caroline; Fritz, Justine; Meyer, Lionel; Garnier, Norbert; Velázquez-Quesada, Inés; Hussenet, Thomas; Aci-Sčche, Samia; Baumlin, Nadčge; Genest, Monique; Brasse, David; Hubert, Pierre; Crémel, Gérard; Orend, Gertraud; Laquerričre, Patrice; Bagnard, Dominique

2014-09-25

348

A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth  

PubMed Central

Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor ? (?-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of ?-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for ?-PDGFR in PCa and showed that PDGF-D is activated by serine protease-mediated proteolytic removal of the CUB domain in a two-step process, yielding first a hemidimer (HD) and then a growth factor domain dimer. Herein, we demonstrate that the expression of PDGF-D in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice. Histopathological analyses of bone tumors generated by PDGF-D-expressing LNCaP cells (LNCaP-PDGF-D) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases. Importantly, we discovered a novel function of PDGF-D in the regulation of osteoclast differentiation, independent of the RANKL/RANK signaling axis. Although both PDGF-B and -D were able to activate ?-PDGFR, only PDGF-D was able to induce osteoclastic differentiation in vitro, and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1, a master transcription factor for osteoclastogenesis. Taken together, these results reveal a new function of PDGF-D as a regulator of osteoclastic differentiation, an activity critical for the establishment of skeletal metastatic deposit in PCa patients. PMID:22158043

Huang, W; Fridman, Y; Bonfil, R D; Ustach, C V; Conley-LaComb, M K; Wiesner, C; Saliganan, A; Cher, M L; Kim, H-R C

2012-01-01

349

Growth Hormone Secretion After Conformal Radiation Therapy in Pediatric Patients With Localized Brain Tumors  

PubMed Central

Purpose Growth hormone deficiency (GHD) after radiation therapy negatively affects growth and development and quality of life in children with brain tumors. Patients and Materials Between 1997 and 2008, 192 pediatric patients with localized primary brain tumors (ependymoma, n = 88; low-grade glioma, n = 51; craniopharyngioma, n = 28; high-grade glioma, n = 23; and other tumor types, n = 2) underwent provocative testing of GH secretion by using the secretogogues arginine and l-dopa before and after (6, 12, 36, and 60 months) conformal radiation therapy (CRT). A total of 664 arginine/l-dopa test procedures were performed. Results Baseline testing revealed preirradiation GHD in 22.9% of tested patients. On the basis of data from 118 patients, peak GH was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus. The average patient was predicted to develop GHD with the following combinations of the time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 to 30 Gy; and 60 months and 15 to 20 Gy. A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of GHD at 5 years (TD50/5). Conclusion GH secretion after CRT can be predicted on the basis of dose and time after irradiation in pediatric patients with localized brain tumors. These findings provide an objective radiation dose constraint for the hypothalamus. PMID:22042949

Merchant, Thomas E.; Rose, Susan R.; Bosley, Christina; Wu, Shengjie; Xiong, Xiaoping; Lustig, Robert H.

2011-01-01

350

Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles.  

PubMed

The hepatocyte growth factor receptor (HGFR, c-Met or Met) is a receptor tyrosine kinase that is involved in embryogenesis, tissue regeneration and wound healing. Abnormal activation of this proto-oncogene product is implicated in the development, progression and metastasis of many cancers. Current therapies directed against Met, such as ligand- or, dimerization-blocking antibodies or kinase inhibitors, reduce tumor growth but hardly eradicate the tumor. In order to improve anti-Met therapy, we have designed a drug delivery system consisting of crosslinked albumin nanoparticles decorated with newly selected anti-Met nanobodies (anti-Met-NANAPs). The anti-Met NANAPs bound specifically to and were specifically taken up by Met-expressing cells and transported to lysosomes for degradation. Treatment of tumor cells with anti-Met NANAPs also resulted in downregulation of the total Met protein. This study shows that anti-Met NANAPs offer a potential system for lysosomal delivery of drugs into Met-positive tumor cells. PMID:24139763

Heukers, Raimond; Altintas, Isil; Raghoenath, Smiriti; De Zan, Erica; Pepermans, Richard; Roovers, Rob C; Haselberg, Rob; Hennink, Wim E; Schiffelers, Raymond M; Kok, Robbert J; van Bergen en Henegouwen, Paul M P

2014-01-01

351

Metastasis Suppressor Genes: At the Interface Between the Environment and Tumor Cell Growth  

PubMed Central

The molecular mechanisms and genetic programs required for cancer metastasis are sometimes overlapping, but components are clearly distinct from those promoting growth of a primary tumor. Every sequential, rate-limiting step in the sequence of events leading to metastasis requires coordinated expression of multiple genes, necessary signaling events, and favorable environmental conditions or the ability to escape negative selection pressures. Metastasis suppressors are molecules that inhibit the process of metastasis without preventing growth of the primary tumor. The cellular processes regulated by metastasis suppressors are diverse and function at every step in the metastatic cascade. As we gain knowledge into the molecular mechanisms of metastasis suppressors and cofactors with which they interact, we learn more about the process, including appreciation that some are potential targets for therapy of metastasis, the most lethal aspect of cancer. Until now, metastasis suppressors have been described largely by their function. With greater appreciation of their biochemical mechanisms of action, the importance of context is increasingly recognized especially since tumor cells exist in myriad microenvironments. In this review, we assemble the evidence that selected molecules are indeed suppressors of metastasis, collate the data defining the biochemical mechanisms of action, and glean insights regarding how metastasis suppressors regulate tumor cell communication to–from microenvironments. PMID:21199781

Hurst, Douglas R.; Welch, Danny R.

2013-01-01

352

Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer.  

PubMed

The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 10(7) infectious units/ml was obtained. Retrovirus-mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a "bona fide" tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer. PMID:10667590

Claudio, P P; Howard, C M; Pacilio, C; Cinti, C; Romano, G; Minimo, C; Maraldi, N M; Minna, J D; Gelbert, L; Leoncini, L; Tosi, G M; Hicheli, P; Caputi, M; Giordano, G G; Giordano, A

2000-01-15

353

Acoustic neuroma: An investigation of associations between tumor size and diagnostic delays, facial weakness, and surgical complications.  

PubMed

We conducted a retrospective case review to ascertain the clinical characteristics associated with acoustic neuromas and their treatment. Our study population was made up of 96 patients-41 men and 55 women, aged 17 to 84 years (mean: 54)-who had undergone treatment for acoustic neuromas and for whom necessary data were available. We compiled data on presenting symptoms, the interval from symptom onset to diagnosis, tumor size at diagnosis, facial weakness, the interval from diagnosis to surgery, the type of surgical approach, and surgical complications. Our primary goals were to determine if tumor size was correlated to (1) the interval from symptom onset to diagnosis, (2) the degree of preoperative facial weakness, and (3) surgical complications. We also sought to document various other clinical characteristics of these cases. The mean interval from the first symptom to diagnosis was 4.5 years; the time to diagnosis did not correlate with tumor size. Nor was tumor size correlated with the degree of preoperative facial weakness as determined by facial electroneurography. Surgical complications occurred in 15 of the 67 patients who underwent surgery (22.4%), and they did correlate with tumor size. The most common complications were postoperative facial weakness (13.4% of operated patients), cerebrospinal fluid leak (6.0%), and infection (3.0%). Since tumors typically grow about 2 mm per year and since larger tumors are associated with more severe symptoms and surgical complications, we expected that the time to diagnosis would correlate with tumor size, but we found no significant association. PMID:25181660

Olshan, Marc; Srinivasan, Visish M; Landrum, Tre; Sataloff, Robert T

2014-08-01

354

In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imaging  

PubMed Central

In vitro three-dimensional models for metastatic ovarian cancer have been useful for recapitulating the human disease. These spheroidal tumor cultures, however, can grow in excess of 1 mm in diameter, which are difficult to visualize without suitable imaging technology. Optical coherence tomography (OCT) is an ideal live imaging method for non-perturbatively visualizing these complex systems. OCT enabled detailed observations of the model at both nodular and cellular levels, revealing growth dynamics not previously observed. The development of a time-lapse OCT system, capable of automated, multidimensional acquisition, further provided insights into the growth and chemotherapeutic response of ovarian cancer. PMID:19466138

Evans, Conor L.; Rizvi, Imran; Hasan, Tayyaba; de Boer, Johannes F.

2010-01-01

355

Kimmel Cancer Center study shows how aging normal cells fuel tumor growth and metastasis  

Cancer.gov

It has long been known that cancer is a disease of aging, but a molecular link between the two has remained elusive. Now, researchers at the Kimmel Cancer Center at Jefferson (KCC) have shown that senescence (aging cells which lose their ability to divide) and autophagy (self-eating or self-cannibalism) in the surrounding normal cells of a tumor are essentially two sides of the same coin, acting as “food” to fuel cancer cell growth and metastasis... Simply put, aging is the metabolic engine that drives cancer growth.

356

Flt3 Ligand Inhibits Growth of Human Ovarian Tumors Engrafted in Severe Combined Immunodeficient Mice  

Microsoft Academic Search

Objective. The current study evaluated the effects of Flt-3 ligand (FL) on the growth of human malignant ovarian tumors engrafted in severe combined immunodeficient (SCID) mice with particular attention directed at FL's effect on the host natural killer (NK) cell response against ovarian cancer xenografts.Methods. Equal portions of surgical specimen-derived human ovarian carcinomas were engrafted subcutaneously (SC) into SCID mice.

David F. Silver; Ronald E. Hempling; M. Steven Piver; Elizabeth A. Repasky

2000-01-01

357

Nonlinear simulations of solid tumor growth using a mixture model: invasion and branching  

Microsoft Academic Search

We develop a thermodynamically consistent mixture model for avascular solid tumor growth which takes into account the effects\\u000a of cell-to-cell adhesion, and taxis inducing chemical and molecular species. The mixture model is well-posed and the governing\\u000a equations are of Cahn–Hilliard type. When there are only two phases, our asymptotic analysis shows that earlier single-phase\\u000a models may be recovered as limiting

Vittorio Cristini; Xiangrong Li; John S. Lowengrub; Steven M. Wise

2009-01-01

358

Fibroblast Growth Factor23 Mutants Causing Familial Tumoral Calcinosis Are Differentially Processed  

Microsoft Academic Search

Familial tumoral calcinosis (TC, OMIM 211900) is a heritable disorder characterized by hyperphosphatemia, normal or el- evated serum 1,25-dihydroxyvitamin D, and often severe ec- topic calcifications. Two recessive mutations in fibroblast growth factor-23 (FGF23), serine 71\\/glycine (S71G) and serine 129\\/phenylalanine (S129F), were identified as causing TC. Herein,weundertookcomprehensivebiochemicalanalysesof an extended TC family carrying the S71G FGF23 mutation, which revealed that heterozygous

Tobias Larsson; Siobhan I. Davis; Holly J. Garringer; Sean D. Mooney; Mohamad S. Draman; Michael J. Cullen; Kenneth E. White

2010-01-01

359

Potential Applications for Circulating Tumor Cells Expressing the Insulin-Like Growth Factor-I Receptor  

Microsoft Academic Search

Purpose: To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR ^ positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This

Johann S. de Bono; Gerhardt Attard; Alex Adjei; Michael N. Pollak; Peter C. Fong; Paul Haluska; Luisa Roberts; Carrie Melvin; Madeline Repollet; David Chianese; Mark Connely; Leon W. M. M. Terstappen; Antonio Gualberto

2007-01-01

360

Autocrine Tumor Cell Growth-inhibiting Activities from Human Malignant Melanoma  

Microsoft Academic Search

Autocrine-secreted tumor cell growth-inhibiting activities were isolated from supernatants of a malignant melanoma cell line, HTZ 19-dM, established from a central nervous system melanoma metastasis. HTZ 19-dM was characterized by cyto- and immunocytochemistry and kary- otyping; cells were propagated in defined serum-free tissue culture me dium for up to 8 months. Supernatants were ultrafiltrated, dialyzed, lyophilized, and purified by Bio-Gel

U. Bogdahn; R. Apfel; M. Hahn; M. Gerlach; C. Behl; J. Hoppe; R. Martin

2000-01-01

361

Suppression of Growth of Ehrlich Ascites Tumor Cells in Mice by Trehalose-6, 6? -Dimycolate (Cord Factor) and BCG  

PubMed Central

Growth of Ehrlich ascites tumor cells in mice pretreated with cord factor was compared to growth of the tumor cells after pretreatment with Calmette-Guérin bacilli. Growth of Ehrlich ascites cells was strongly inhibited in the peritoneal cavities of mice pretreated with 80 ?g of cord factor. The median survival time of the animals was prolonged (70 versus 17 days), and 40% of the mice survived more than 90 days. Tumor suppression was still detectable 36 days after administration of cord factor. The effect of cord factor was local. Comparable results were obtained with living or killed Calmette-Guérin bacilli. The results are discussed. PMID:4208531

Yarkoni, E.; Wang, L.; Bekierkunst, A.

1974-01-01

362

A mathematical model for the onset of avascular tumor growth in response to the loss of p53 function  

PubMed Central

We present a mathematical model for the formation of an avascular tumor based on the loss by gene mutation of the tumor suppressor function of p53. The wild type p53 protein regulates apoptosis, cell expression of growth factor and matrix metalloproteinase, which are regulatory functions that many mutant p53 proteins do not possess. The focus is on a description of cell movement as the transport of cell population density rather than as the movement of individual cells. In contrast to earlier works on solid tumor growth, a model is proposed for the initiation of tumor growth. The central idea, taken from the mathematical theory of dynamical systems, is to view the loss of p53 function in a few cells as a small instability in a rest state for an appropriate system of differential equations describing cell movement. This instability is shown (numerically) to lead to a second, spatially inhomogeneous, solution that can be thought of as a solid tumor whose growth is nutrient diffusion limited. In this formulation, one is led to a system of nine partial differential equations. We show computationally that there can be tumor states that coexist with benign states and that are highly unstable in the sense that a slight increase in tumor size results in the tumor occupying the sample region while a slight decrease in tumor size results in its ultimate disappearance. PMID:19458766

Levine, Howard A.; Smiley, Michael W.; Tucker, Anna L.; Nilsen-Hamilton, Marit

2006-01-01

363

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation  

PubMed Central

Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-? (IFN-?) and tumor necrosis factor-? (TNF-?). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution. PMID:19011222

Jenq, Robert R.; King, Christopher G.; Volk, Christine; Suh, David; Smith, Odette M.; Rao, Uttam K.; Yim, Nury L.; Holland, Amanda M.; Lu, Sydney X.; Zakrzewski, Johannes L.; Goldberg, Gabrielle L.; Diab, Adi; Alpdogan, Onder; Penack, Olaf; Na, Il-Kang; Kappel, Lucy W.; Wolchok, Jedd D.; Houghton, Alan N.; Perales, Miguel-Angel

2009-01-01

364

Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.  

PubMed

Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-? and IL-12. The cytotoxic T-lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8(+) T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines. PMID:24069344

Abdul Hafid, Sitti Rahma; Chakravarthi, Srikumar; Nesaretnam, Kalanithi; Radhakrishnan, Ammu Kutty

2013-01-01

365

The effect of ELF magnetic field on tumor growth after electrochemotherapy.  

PubMed

From a fundamental point of view, chemotherapy is the most widely used treatment for cancers despite its side effects on normal cells and tissues. Electrochemotherapy (ECT) is a method for increasing the permeability of cancer cells to drugs and, hence, decreasing their dosage. It apparently creates electropores on the cell membrane using electric pulses. ECT can decrease tumor volume; but this effect is not permanent, and partial regrowth has been reported. The aim of this study was to investigate the potential of magnetic fields in preventing the regrowth of tumors after ECT. Tumoral Balb/c mice were exposed to a magnetic field (15 mT, 50 Hz) for 12 days after treating additionally with 70 V/cm electric pulses and bleomycin at the first day. The magnetic field caused a significant reduction in tumor volumes, while there was no significant difference between the ECT and the electroporation with ECT and magnetic field groups. The exploited magnetic field (15 mT, 50 Hz) could decrease the tumor growth rate significantly, without any effect on ECT efficiency. PMID:24186355

Mahna, A; Firoozabadi, S M P; Shankayi, Z

2014-01-01

366

Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.  

PubMed

Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. PMID:24952430

Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S; Schaffner, Carl P; Zurakowski, David; Solomon, Keith R; Moses, Marsha A

2014-07-01

367

Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis  

PubMed Central

Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated factor-receptor (PAF-R) agonistic activity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxidized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system. PMID:25002816

Hackler, Patrick C; Reuss, Sarah; Konger, Raymond L; Travers, Jeffrey B; Sahu, Ravi P

2014-01-01

368

Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis  

PubMed Central

The aberrantly increased lipogenesis is a universal metabolic feature of proliferating tumor cells. Although most normal cells acquire the bulk of their fatty acids from circulation, tumor cells synthesize more than 90% of required lipids de novo. The sterol regulatory element-binding protein 1 (SREBP1), encoded by SREBF1 gene, is a master regulator of lipogenic gene expression. SREBP1 and its target genes are overexpressed in a variety of cancers; however, the role of SREBP1 in endometrial cancer is largely unknown. We have screened a cohort of endometrial cancer (EC) specimen for their lipogenic gene expression and observed a significant increase of SREBP1 target gene expression in cancer cells compared with normal endometrium. By using immunohistochemical staining, we confirmed SREBP1 protein overexpression and demonstrated increased nuclear distribution of SREBP1 in EC. In addition, we found that knockdown of SREBP1 expression in EC cells suppressed cell growth, reduced colonigenic capacity and slowed tumor growth in vivo. Furthermore, we observed that knockdown of SREBP1 induced significant cell death in cultured EC cells. Taken together, our results show that SREBP1 is essential for EC cell growth both in vitro and in vivo, suggesting that SREBP1 activity may be a novel therapeutic target for endometrial cancers. PMID:22672904

Li, Weihua; Tai, Yanhong; Zhou, Jie; Gu, Weiting; Bai, Zhaofang; Zhou, Tao; Zhong, Zhijiu; McCue, Peter A.; Sang, Nianli; Ji, Jun-Yuan; Kong, Beihua; Jiang, Jie; Wang, Chenguang

2012-01-01

369

Glucagon-induced angiogenesis and tumor growth through the HIF-1-VEGF-dependent pathway in hyperglycemic nude mice.  

PubMed

In this study, we examined the effect glucagon-induced hyperglycemia on tumor growth as well as the role of the hypoxia-inducible factor 1 (HIF-1)-vascular endothelial growth factor (VEGF) pathway in this condition. A high concentration of glucose (HG) was utilized to treat HeLa cells under hypoxic or normoxic conditions, and transcriptional levels of HIF-1, VEGF, and basic fibroblast growth factor (bFGF) were evaluated. Moreover, the ability of an HIF-1 inhibitor to block the effect induced by HG was examined. By contrast, hyperglycemia was induced in nude mice by glucagon released from an osmotic pump, and microvessel density was determined with CD31 staining. Thus, the relationship among hyperglycemia, microvessel density, tumor growth, and the HIF-1 inhibitor were analyzed. We found that HG increased transcription of the VEGF gene, which is downstream of HIF-1. Moreover, HG impaired the function of HIF-1 inhibitors [HIF-1 small interfering RNA (siRNA) and berberine] to affect the VEGF transcription level in tumor cells. By contrast, hyperglycemia increased tumor microvessel density and promoted tumor growth, which was inhibited by the HIF-1 inhibitor. However, hyperglycemia attenuated the effect of the HIF-1 inhibitor. Glucagon-induced hyperglycemia influenced tumor microenvironments through the HIF-1-VEGF-dependent pathway and promoted tumor growth and resistance to HIF-1 inhibition treatments. PMID:25222223

Wang, Y; Zhu, Y D; Gui, Q; Wang, X D; Zhu, Y X

2014-01-01

370

Rosemary (Rosmarinus officinalis) Extract Modulates CHOP/GADD153 to Promote Androgen Receptor Degradation and Decreases Xenograft Tumor Growth  

PubMed Central

The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease, diabetes and various solid organ cancers. In this particular study, a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry, MTT, BrdU, Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells a