Note: This page contains sample records for the topic tumor growth delay from Science.gov.
While these samples are representative of the content of Science.gov,
they are not comprehensive nor are they the most current set.
We encourage you to perform a real-time search of Science.gov
to obtain the most current and comprehensive results.
Last update: November 12, 2013.
1

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

PubMed

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; Håvik, Bjarte; Fitzsimons, Carlos P; Vreugdenhil, Erno

2013-09-26

2

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.

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

3

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

Microsoft Academic Search

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

Janneke Schuuring; Johan. Bussink; Hans J. J. A. Bernsen; Wenny Peeters; Albert J. van Der Kogel

2005-01-01

4

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. See the following for more ...

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

Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: prolonged growth delay but reduced curability. [Mice  

SciTech Connect

The effect of tumor bed irradiation (TBX) on subsequent tumor response to treatment with cyclophosphamide (CY) or further irradiation was studied in mice. Using the growth delay assay, the therapeutic response was enhanced by prior TBX. This effect was independent of time between TBX and tumor cell inoculation over the range 1-56 days. When tumor cure experiments were performed, however, the effect of prior TBX was to decrease significantly the proportion of tumors controlled by either CY or irradiation and to make the dose-response curve for radiocurability less steep. These data are best interpreted by postulating that TBX increases the environmental heterogeneity of tumors growing in preirradiated sites, with an overall net decrease in the cell kill achieved by a given dose of CY or radiation. This results in increased resistance to cure and a lack of dose response. However, the TBX also causes slower regrowth of surviving cells, so that an increase in tumor growth delay is realized.

Ito, H.; Barkley, T. Jr.; Peters, L.J.; Milas, L.

1985-03-01

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

Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo.  

PubMed

We report in this study the complexation of the chemotherapeutic drug doxorubicin (DOX) with the novel sixth-generation cationic poly-l-lysine dendrimer (DM) (MW 8149 kDa), which we previously reported to exhibit systemic antiangiogenic activity in tumor-bearing mice. DOX-DM complexation was confirmed by florescence polarization measurement, proton nuclear magnetic resonance spectroscopy, and molecular modeling. Enhanced penetration of DOX-DM (at 1:10 molar ratio), compared to the free DOX, into prostate 3D multicellular tumor spheroids (MTS) was confirmed by confocal laser scanning microscopy. Furthermore, DOX-DM complexes achieved a significantly higher cytotoxicity in DU145 MTS system compared to the free drug, as shown by growth delay curves. Incubation of MTS with low DOX concentration (1 ?M) complexed with DM led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX-DM complex retention was also achieved in a Calu-6 lung cancer xenograft model in tumor-bearing mice, as shown by live whole animal fluorescence imaging. Therapeutic experiments in B16F10 tumor bearing mice have shown enhanced therapeutic efficacy of DOX when complexed to DM. This study suggests that the cationic poly-l-lysine DM molecules studied here could, in addition to their systemic antiangiogenic property, complex chemotherapeutic drugs such as DOX and improve their accumulation and cytotoxicity into MTS and solid tumors in vivo. Such an approach offers new capabilities for the design of combinatory antiangiogenic/anticancer therapeutics. PMID:23527750

Al-Jamal, Khuloud T; Al-Jamal, Wafa' T; Wang, Julie T-W; Rubio, Noelia; Buddle, Joanna; Gathercole, David; Zloh, Mire; Kostarelos, Kostas

2013-03-07

9

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model.  

PubMed

Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors. PMID:23412344

Sanchez-Macedo, N; Feng, J; Faubert, B; Chang, N; Elia, A; Rushing, E J; Tsuchihara, K; Bungard, D; Berger, S L; Jones, R G; Mak, T W; Zaugg, K

2013-02-15

10

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

Microsoft Academic Search

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

Timothy D. Solberg; Jessica Nearman; John Mullins; Sicong Li; Janina Baranowska-Kortylewicz

2008-01-01

11

Correlation between tumor growth delay and expression of cancer and host VEGF, VEGFR2 and osteopontin in response to radiotherapy  

PubMed Central

Purpose to determine late effects of radiotherapy on the VEGF, VEGFR2 and 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: 5×7 Gy and 1×20 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-sized tumors in the 5×7 Gy group. Host VEGF and OPN levels were directly proportional to tumor doubling time (TD) and were independent of the fractionation scheme. Host and cancer cell VEGFR2 levels in tumor were also directly related to the tumor response to radiotherapy. Conclusion Upregulated VEGFR2 in cancer cells suggest paracrine signaling in the VEGFR2 pathway of cancer cells as the factor contributing to the radiotherapy 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 may contribute to the failure of radiotherapy by escalating the rate of vascular repair. Co-expression of host OPN and VEGF, two factors closely associated with angiogenesis, indicate that OPN can serve as a surrogate marker of the tumor recovery after radiotherapy. Taken together these results strongly support the notion that to achieve optimal therapeutic outcome, the scheduling of radiation and anti-angiogenic therapies will require patient-specific post-treatment monitoring of the VEGF/VEGFR2 pathway and that tumor-associated OPN can serve as an indicator of the tumor regrowth.

Solberg, Timothy D.; Nearman, Jessica; Mullins, John; Li, Sicong; Baranowska-Kortylewicz, Janina

2008-01-01

12

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

PubMed Central

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

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

2012-01-01

13

Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin-1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model.  

PubMed

Some anaerobic and facultative anaerobic bacteria have been used experimentally as anticancer agents because of their selective growth in the hypoxia regions of solid tumors after systemic administration. We have previously shown the feasibility of using attenuated Salmonella choleraesuis as a gene delivery vector. In this study, we exploited S. choleraesuis carrying thrombospondin-1 (TSP-1) gene for treating primary melanoma and experimental pulmonary metastasis in the syngeneic murine B16F10 melanoma model. Systemic administration of S. choleraesuis allowed targeted gene delivery to tumors. The bacteria accumulated preferentially in tumors over livers and spleens at ratios ranging from 1000:1 to 10,000:1. The level of transgene expression via S. choleraesuis-mediated gene transfer in tumors could reach more than 1800-fold higher than in livers and spleens. Notably, bacterial accumulation was also observed in the lungs with metastatic nodules, but not in healthy lungs. When administered into mice bearing subcutaneous or pulmonary metastatic melanomas, S. choleraesuis carrying TSP-1 gene significantly inhibited tumor growth and enhanced survival of the mice. Immunohistochemical studies in the tumors from these mice displayed decreased intratumoral microvessel density. Taken together, these findings suggest that TSP-1 gene therapy delivered by S. choleraesuis may be effective for the treatment of primary as well as metastatic melanomas. PMID:15375381

Lee, Che-Hsin; Wu, Chao-Liang; Shiau, Ai-Li

2005-02-01

14

Arsenic Trioxide as a Vascular Disrupting Agent: Synergistic Effect with Irinotecan on Tumor Growth Delay in a CT26 Allograft Model1  

PubMed Central

The mechanism of action of arsenic trioxide (ATO) has been shown to be complex, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects. Among these mechanisms of action, ATO has been shown to cause acute vascular shutdown and massive tumor necrosis in a murine solid tumor model like vascular disrupting agent (VDA). However, relatively little is understood about this VDA-like property and its potential utility in developing clinical regimens. We focused on this VDA-like action of ATO. On the basis of the endothelial cell cytotoxicity assay and tubulin polymerization assay, we observed that higher concentrations and longer treatment with ATO reduced the level of ?- and ?-tubulin and inhibited the polymerization of tubulin. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced murine CT26 colon carcinoma grown in female BALB/c mice. A single injection of ATO intraperitoneally displayed central necrosis of the tumor tissue by 24 hours. T1-weighted dynamic contrast-enhanced magnetic resonance image revealed a significant decrease in tumor enhancement in the ATO-treated group. Similar to other VDAs, ATO treatment alone did not delay the progression of tumor growth; however, ATO treatment after injection of other cytotoxic agent (irinotecan) showed significant additive antitumor effect compared to control and irinotecan alone therapy. In summary, our data demonstrated that ATO acts as a VDA by means of microtubule depolymerization. It exhibits significant vascular shutdown activity in CT26 allograft model and enhances antitumor activity when used in combination with another cytotoxic chemotherapeutic agent.

Lee, Jong Cheol; Lee, Ho Yong; Moon, Chang Hoon; Lee, Seung Ju; Lee, Won Hyeok; Cha, Hee Jeong; Park, Sungchan; Lee, Young Han; Park, Hyun Jin; Song, Ho-Taek; Min, Young Joo

2013-01-01

15

Arsenic Trioxide as a Vascular Disrupting Agent: Synergistic Effect with Irinotecan on Tumor Growth Delay in a CT26 Allograft Model.  

PubMed

The mechanism of action of arsenic trioxide (ATO) has been shown to be complex, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects. Among these mechanisms of action, ATO has been shown to cause acute vascular shutdown and massive tumor necrosis in a murine solid tumor model like vascular disrupting agent (VDA). However, relatively little is understood about this VDA-like property and its potential utility in developing clinical regimens. We focused on this VDA-like action of ATO. On the basis of the endothelial cell cytotoxicity assay and tubulin polymerization assay, we observed that higher concentrations and longer treatment with ATO reduced the level of ?- and ?-tubulin and inhibited the polymerization of tubulin. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced murine CT26 colon carcinoma grown in female BALB/c mice. A single injection of ATO intraperitoneally displayed central necrosis of the tumor tissue by 24 hours. T1-weighted dynamic contrast-enhanced magnetic resonance image revealed a significant decrease in tumor enhancement in the ATO-treated group. Similar to other VDAs, ATO treatment alone did not delay the progression of tumor growth; however, ATO treatment after injection of other cytotoxic agent (irinotecan) showed significant additive antitumor effect compared to control and irinotecan alone therapy. In summary, our data demonstrated that ATO acts as a VDA by means of microtubule depolymerization. It exhibits significant vascular shutdown activity in CT26 allograft model and enhances antitumor activity when used in combination with another cytotoxic chemotherapeutic agent. PMID:23418620

Lee, Jong Cheol; Lee, Ho Yong; Moon, Chang Hoon; Lee, Seung Ju; Lee, Won Hyeok; Cha, Hee Jeong; Park, Sungchan; Lee, Young Han; Park, Hyun Jin; Song, Ho-Taek; Min, Young Joo

2013-02-01

16

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.

Lu, Bo

2008-01-01

17

In vivo plasmid electroporation induces tumor antigen-specific CD8+ T-cell responses and delays tumor growth in a syngeneic mouse melanoma model.  

PubMed

Plasmid DNA-based molecular cancer vaccines generally suffer from suboptimal immunogenicity. One of the key limitations is insufficient level of gene expression, which was surmounted in our approach by using the novel technique of in vivo plasmid electroporation-enhanced vaccination (electrovaccination). Electrovaccination with plasmids encoding the full-length autologous melanocyte antigen tyrosinase-related protein-2 induced limited melanocyte destruction in a subset of mice. Despite examples of vitiligo, vaccinated mice were not protected from a subsequent challenge of B16F10M melanoma cells. Novel constructs were then designed and submitted to a functional screen. Best performance was obtained when the relevant H-2K(b)-restricted epitope SVYDFFVWL was placed into a context of sequences of the HLA-Cw3 molecule. After animals were electrovaccinated using this construct, direct enzyme-linked immunospot analysis of peripheral blood mononuclear cells indicated that very high numbers of T cells recognizing the specific tyrosinase-related protein-2 epitope were generated. CD8+ T cells isolated from the spleen also displayed a high degree of antigen-specific reactivity and vigorously reacted toward unmodified B16F10M cells. In vivo protective effects of this construct were demonstrated in mice using two different models; outgrowth of s.c. implanted B16F10M tumor cells was significantly delayed, and vaccinated mice developed no or only very few tumor nodules in an i.v. lung metastasis model. Thus, improved antigen vectors delivered by highly effective gene transfer methods may form the basis for future human applications. PMID:12359758

Kalat, Milena; Küpcü, Zaruhi; Schüller, Susanne; Zalusky, Doris; Zehetner, Margit; Paster, Wolfgang; Schweighoffer, Tamás

2002-10-01

18

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

19

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

20

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.

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

2013-01-01

21

Delay eect in models of population growth  

Microsoft Academic Search

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

Dang Vu Giang; Yongwimon Lenbury; Thomas I. Seidman

22

Circadian rhythms and tumor growth.  

PubMed

Hormone secretion, metabolism, and the cell cycle are under rhythmic control. Lack of rhythmic control has been predicted to lead to uncontrolled proliferation and cancer. Consistent with this prediction are findings that circadian disruption by dim light at night or chronic jet lag accelerates tumor growth in desynchronized animals. Circadian controlled factors such as insulin/IGF-1, glucocorticoids, catecholamines, and melatonin have be implicated in controlling tumor growth in the desynchronized animals. Recent attention has focused on the signaling pathways activated by the circadian controlled factors because these pathways hold the potential for the development of novel strategies for cancer prevention and treatment. PMID:22252116

Greene, Michael W

2012-01-15

23

Stationary Densities and Parameter Estimation for Delayed Stochastic Logistic Growth Laws with Application in Biomedical Studies  

Microsoft Academic Search

Abstract–The study of nonlinear stochastic delayed process is significant for understanding nature of complex system in reductionistic viewpoints. This paper investigates the stochastic linear and logistic (Verhulst, Gompertz and Richards) models, and simulates the growth process of Ehrilch ascities tumor (EAT) in a mouse. Inorder to explain ,the oscillations of EAT growth we use a system ,of stochastic differential equations

Petras Rupšys

24

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

PubMed

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

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

2011-09-14

25

Angiogenesis inhibitor DC101 delays growth of intracerebral glioblastoma but induces morbidity when combined with irradiation.  

PubMed

The combination of irradiation with angiogenic inhibition is increasingly being investigated for treatment of glioblastoma multiforme (GBM). We investigated whether vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor DC101 affects morbidity and tumor growth in irradiated and non-irradiated intracerebral GBM-bearing mice, controlled with sham treatments. End-points were toxicity, morbidity and histology. Irradiation either or not combined, reduced tumor size strongly, whereas DC101 mono-treatment reduced tumor size by 64%. Irradiation delayed morbidity from 5.8 weeks in sham-treated mice to 10.3 weeks. Morbidity after combined treatment occurred after 5.9 weeks. Treatment with angiogenesis inhibitor DC101 delays tumor growth but it induces morbidity, by itself or combined with irradiation. PMID:19473756

Verhoeff, Joost J C; Stalpers, Lukas J A; Van Noorden, Cornelis J F; Troost, Dirk; Ramkema, Marja D; van Bree, Chris; Song, Ji-Ying; Donker, Mila; Chekenya, Martha; Vandertop, W Peter; Richel, Dick J; van Furth, Wouter R

2009-05-26

26

Statistical mechanics model of angiogenic tumor growth.  

PubMed

We examine a lattice model of tumor growth where the survival of tumor cells depends on the supplied nutrients. When such a supply is random, the extinction of tumors belongs to the directed percolation universality class. However, when the supply is correlated with the distribution of tumor cells, which as we suggest might mimic the angiogenic growth, the extinction shows different critical behavior. Such a correlation affects also the morphology of the growing tumors and drastically raises tumor-survival probability. PMID:22400505

Ferreira, António Luis; Lipowska, Dorota; Lipowski, Adam

2012-01-10

27

Study of Tumor Growth under Hyperthermia Condition  

PubMed Central

The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. To simulate the tumor growth, a continuum mathematical model has been introduced. The newest understanding of the Warburg effect on the cellular metabolism and diffusion of the nutrients in the tissue has been taken into consideration. The numerical results are compared with the in vivo experimental data by fitting the tumor cell doubling time/tumor cell growth rate under different thermal conditions. Both the tumor growth curve and corresponding average glucose concentration have been predicted. The numerical results have quantitatively illustrated the controlling effect on tumor growth under hyperthermia condition in the initial stage.

Zhu, Qing; Zhang, Aili; Liu, Ping; Xu, Lisa X.

2012-01-01

28

Modelling Early Tumor Growth with Diffusion Equation  

Microsoft Academic Search

Abstract This essay is aimed at forming a lecture series on the modelling of early tumor growth using diffusion equations. We present basic models for tumor growth and discuss the linear stability of their steady states. The models discussed predict the size of the proliferating layer, the size of the tumor, and the effects of the immune system response, on

Asha Saidi Kalula; Jacek Banasiak

29

On the Distinction Between Lag and Delay in Population Growth  

Microsoft Academic Search

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

Peter Vadasz; Alisa S. Vadasz

2010-01-01

30

An approach to constitutional delay of growth and puberty  

PubMed Central

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.

Soliman, Ashraf T.; Sanctis, Vincenzo De

2012-01-01

31

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

32

Delays and Growth Rates of Multiple TEOAE Components  

NASA Astrophysics Data System (ADS)

Bandpass-filtered transient-evoked otoacoustic emissions (TEOAEs) show multiple energy peaks with time delays that are invariant with level and growth rates that vary with delay and stimulus level, suggesting that multiple generation mechanisms may be involved at moderate and high stimulus levels. We measured delays and magnitude growths of multiple TEOAE energy peaks and compared the results obtained from linear and nonlinear extraction methods. To test the hypothesis that early components are generated at the basal portion of the cochlea, delays and growth rates were also measured in the presence of highpass masking noise for a subset of subjects. No effect of the highpass masking was seen. The results are discussed in terms of potential generation mechanisms of the multiple energy peaks.

Goodman, Shawn S.; Mertes, Ian B.; Scheperle, Rachel A.

2011-11-01

33

CD73 promotes tumor growth and metastasis  

PubMed Central

Our recent data and that of others demonstrate that both tumor and host CD73-generated adenosine promote tumor growth and metastasis in a multifactorial manner. Results with small molecule inhibitors or monoclonal antibodies against CD73 in multiple tumor models suggest that CD73 is a previously unappreciated important target for effective cancer therapy.

Zhang, Bin

2012-01-01

34

A Multiscale Model for Avascular Tumor Growth  

Microsoft Academic Search

The desire to understand tumor complexity has given rise to mathematical models to describe the tumor microenvironment. We present a new mathematical model for avascular tumor growth and development that spans three distinct scales. At the cellular level, a lattice Monte Carlo model describes cellular dynamics (proliferation, adhesion, and viability). At the subcellular level, a Boolean network regulates the expression

Y. Jiang; Jelena Pjesivac-Grbovic; Charles Cantrell; James P. Freyer

2005-01-01

35

Inhibition of Vascularization in Tumor Growth  

NASA Astrophysics Data System (ADS)

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

Scalerandi, M.; Sansone, B. Capogrosso

2002-11-01

36

Tumor growth dynamics: insights into evolutionary processes.  

PubMed

Identifying the types of event that drive tumor evolution and progression is crucial for understanding cancer. We suggest that the analysis of tumor growth dynamics can provide a window into tumor biology and evolution by connecting them with the types of genetic change that have occurred. Although fundamentally important, the documentation of tumor growth kinetics is more sparse in the literature than is the molecular analysis of cells. Here, we provide a historical summary of tumor growth patterns and argue that they can be classified into five basic categories. We then illustrate how those categories can provide insights into events that drive tumor progression, by discussing a particular evolutionary model as an example and encouraging such analysis in a more general setting. PMID:23816268

Rodriguez-Brenes, Ignacio A; Komarova, Natalia L; Wodarz, Dominik

2013-06-28

37

Delayed contrast extravasation MRI for depicting tumor and non-tumoral tissues in primary and metastatic brain tumors.  

PubMed

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

2012-12-14

38

Hypertrichosis, Fallot tetralogy, growth and developmental delay.  

PubMed

We report a female patient with a unique pattern of pre- and postnatal growth deficiency, tetralogy of Fallot, very long eyelashes (trichomegaly), progressive and generalized hypertrichosis lanuginosa, brain atrophy with epilepsy, and puffy hands and feet. This appears to be a "new" entity within the group of syndromal hypertrichoses, possibly pathogenetically related to, but clinically distinct from Ambras or Oliver-McFarlane syndromes. PMID:15365462

Verloes, Alain; Massin, Martial; Fransolet, Anne-Catherine; Misson, Jean-Paul

2004-10-01

39

Simulating tumor growth in confined heterogeneous environments  

NASA Astrophysics Data System (ADS)

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

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

2008-09-01

40

Growth and pubertal delay in patients with epidermolysis bullosa.  

PubMed

Puberty is the acquisition of secondary sexual characteristics, associated with a growth spurt, resulting in the attainment of reproductive function and final adult height. Delayed puberty is defined as the absence of any pubertal development at an age 2 standard deviations (SD) more than the mean, which corresponds to an age of approximately 14 years for boys and 13 years for girls. The degree to which growth and pubertal development are affected in chronic illness depends on the disease itself, as well as factors such as age of onset, duration and severity; the earlier the onset and the more severe the disease, the greater the effect on growth and pubertal development. Most children with severe types of epidermolysis bullosa have abnormal growth and pubertal delay. The possible pathophysiology is discussed. PMID:20447503

Martinez, Anna E; Allgrove, Jeremy; Brain, Caroline

2010-04-01

41

FTY720 inhibits tumor growth and angiogenesis  

Microsoft Academic Search

De novo malignancies and recurrence of tumors are some of the biggest threats to allograft recipients subjected to chronic immunosuppression. FTY720, a synthetic myriocin analogue, is an immunosuppressant that induces apoptosis of activated lymphocytes and prevents infiltration of lymphocytes into allografts, thereby prolonging allograft survival in a dose-dependent manner. Additionally, FTY720 was shown to prevent tumor growth and metastasis. Therefore,

G. Schmid; M. Guba; A. Papyan; I. Ischenko; M. Brückel; C. J. Bruns; K.-W. Jauch; C. Graeb

2005-01-01

42

Tumor Growth Rate Approximation-Assisted Estimation  

PubMed Central

From tumor to tumor, there is a great variation in the proportion of cancer cells growing and making daughter cells that ultimately metastasize. The differential growth within a single tumor, however, has not been studied extensively and this may be helpful in predicting the aggressiveness of a particular cancer type. The estimation problem of tumor growth rates from several populations is studied. The baseline growth rate estimator is based on a family of interacting particle system models which generalize the linear birth process as models of tumor growth. These interacting models incorporate the spatial structure of the tumor in such a way that growth slows down in a crowded system. Approximation-assisted estimation strategy is proposed when initial values of rates are known from the previous study. Some alternative estimators are suggested and the relative dominance picture of the proposed estimator to the benchmark estimator is investigated. An over-riding theme of this article is that the suggested estimation method extends its traditional counterpart to non-normal populations and to more realistic cases.

An, Lihua; Ahmed, S. Ejaz; Ali, Adnan

2007-01-01

43

Autocrine growth factors and solid tumor malignancy.  

PubMed Central

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

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

1991-01-01

44

Ethyl pyruvate administration inhibits hepatic tumor growth  

Microsoft Academic Search

EP is a potent inhibitor of HMGB1 release that has sig- nificant anti-inflammatory activities and exerts a pro- tective effect in animal models of inflammation. As in- flammation is linked to cancer growth, we hypothesized that EP would have anti-tumor activity and explored its effects in a liver tumor model. Mice injected intrapor- tally with MC38 colorectal cancer cells led

Xiaoyan Liang; A. Romo de Vivar Chavez; Nicole E. Schapiro; Patricia Loughran; Stephen H. Thorne; Andrew A. Amoscato; Herbert J. Zeh; Donna Beer-Stolz; Michael T. Lotze; Michael E. de Vera

2009-01-01

45

Blood porphyrin luminescence and tumor growth correlation  

NASA Astrophysics Data System (ADS)

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

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

2007-02-01

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

Connective tissue growth factor in tumor pathogenesis  

PubMed Central

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.

2012-01-01

48

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

PubMed

Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors. PMID:21251614

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

2011-01-18

49

Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor  

PubMed Central

Growth of tumors and metastasis are processes known to require neovascularization. To ascertain the participation of the endogenous angiogenic inhibitor thrombospondin-1 (TSP1) in tumor progression, we generated mammary tumor-prone mice that either lack, or specifically overexpress, TSP1 in the mammary gland. Tumor burden and vasculature were significantly increased in TSP1-deficient animals, and capillaries within the tumor appeared distended and sinusoidal. In contrast, TSP1 overexpressors showed delayed tumor growth or lacked frank tumor development (20% of animals); tumor capillaries showed reduced diameter and were less frequent. Interestingly, absence of TSP1 resulted in increased association of vascular endothelial growth factor (VEGF) with its receptor VEGFR2 and higher levels of active matrix metalloproteinase-9 (MMP9), a molecule previously shown to facilitate both angiogenesis and tumor invasion. In vitro, enzymatic activation of proMMP9 was suppressed by TSP1. Together these results argue for a protective role of endogenous inhibitors of angiogenesis in tumor growth and implicate TSP1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling.

Rodriguez-Manzaneque, Juan Carlos; Lane, Timothy F.; Ortega, Maria Asuncion; Hynes, Richard O.; Lawler, Jack; Iruela-Arispe, M. Luisa

2001-01-01

50

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

PubMed

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

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

2012-05-22

51

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

PubMed Central

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

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

2013-01-01

52

[Effect of epidermal chalones on induction and growth of tumors of the cervicovaginal epithelium of mice].  

PubMed

Tumors of the cervicovaginal epithelium were induced in BALB/c female mice with local application of dimethylbenzanthra cene. In the course of inducing tumors or after their appearance the mice were treated intravaginally with 55-81% ethanolic extract of the rat skin or liver (control) containing 1% chalones. The skin extract rather than liver one delays slightly the growth and incidence of cervical and vaginal tumours, and increases the survival of animals. PMID:6446331

Okulov, V B; Anisimov, V N; Chepik, O F; Azarova, M A

1980-03-01

53

Incidence and growth of methylcholanthrene-induced tumors in mice with altered immunological status.  

PubMed

BALB/c mice were treated s.c. with 3-methylcholanthrene (MCA), and tumor incidence and growth were followed for 9 months. Immunological status of mice was altered by various treatments. Thymectomized, lethally irradiated, bone marrow reconstituted mice served as T-cell deficient recipients. In order to suppress natural killer (NK)-cell/macrophage functions some mice were injected with silica particles; to enhance these functions some mice were given Corynebacterium parvum (CP). Silica and CP were given simultaneously with MCA to test their influence on the presumed function of surveillance of tumor incidence, and also 2 months after MCA to test their influence on the growth of greater numbers of transformed host cells. Almost all mice developed tumors at the inoculation site and at the end of the observation period there was no difference in tumor incidence among 9 experimental groups. However, in T-cell deficient mice we observed shorter tumor duration and earlier death than in normal mice. Silica particles appeared to enhance tumor growth but the differences compared to normal controls were not significant. A single injection of CP simultaneously with MCA caused earlier tumor appearance but also slowed its growth. In contrast, CP given 2 months after MCA significantly delayed the appearance of the tumors. In regard to the tumor growth immunosuppression had stronger effects in males than in females; the opposite was true for immunostimulation treatments. We concluded that immunological status does not influence long-term tumor incidence, but that both T-cell and NK-cell/macrophage compartments strongly influence the parameters of growth of chemically induced tumors, i.e., the immune and natural resistance mechanisms do not influence the frequency of de novo arising tumors but both can slow down tumor growth. PMID:3490910

Trutin-Ostovi?, C; Golubi?, M; Matovi?, M; Marusi?, M

1986-01-01

54

Nonlinear simulation of the effect of microenvironment on tumor growth  

Microsoft Academic Search

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

Paul Macklin; John Lowengrub

2007-01-01

55

Growth patterns of microscopic brain tumors  

NASA Astrophysics Data System (ADS)

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

Sander, Leonard M.; Deisboeck, Thomas S.

2002-11-01

56

Delayed Frost Growth on Jumping-Drop Superhydrophobic Surfaces  

SciTech Connect

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

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

2013-01-01

57

Pancreatic cancers require autophagy for tumor growth.  

PubMed

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack. PMID:21406549

Yang, Shenghong; Wang, Xiaoxu; Contino, Gianmarco; Liesa, Marc; Sahin, Ergun; Ying, Haoqiang; Bause, Alexandra; Li, Yinghua; Stommel, Jayne M; Dell'antonio, Giacomo; Mautner, Josef; Tonon, Giovanni; Haigis, Marcia; Shirihai, Orian S; Doglioni, Claudio; Bardeesy, Nabeel; Kimmelman, Alec C

2011-03-15

58

Potential new way to suppress tumor growth  

Cancer.gov

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

59

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.

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

2013-01-01

60

Properties of Tumor Spheroid Growth Exhibited by Simple Mathematical Models  

PubMed Central

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

Wallace, Dorothy I.; Guo, Xinyue

2013-01-01

61

Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery.  

PubMed

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 effects 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 and 24h 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

2013-07-18

62

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

PubMed Central

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

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

1985-01-01

63

Inhibition of tumor growth by elimination of granulocytes  

PubMed Central

As observed for many types of cancers, heritable variants of ultraviolet light-induced tumors often grow more aggressively than the parental tumors. The aggressive growth of some variants is due to the loss of a T cell-recognized tumor-specific antigen; however, other variants retain such antigens. We have analyzed an antigen retention variant and found that the variant tumor cells grow at the same rate as the parental tumor cells in vitro, but grew more rapidly than the parental cells in the T cell-deficient host. The growth of the variant cells was stimulated in vitro by factors released from tumor-induced leukocytes and by several defined growth factors. In addition, the variant cancer cells actually attracted more leukocytes in vitro than the parental cells. Furthermore, elimination of granulocytes in vivo in nude mice by a specific antigranulocyte antibody inhibited the growth of the variant cancer, indicating that this tumor requires granulocytes for rapid growth.

1995-01-01

64

Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.  

PubMed

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions. PMID:10502827

Gohongi, T; Fukumura, D; Boucher, Y; Yun, C O; Soff, G A; Compton, C; Todoroki, T; Jain, R K

1999-10-01

65

Fibroblast growth factors are required for efficient tumor angiogenesis.  

PubMed

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF receptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and inhibited tumor angiogenesis in an ex vivo bioassay, in which endothelial cells were cocultured with angiogenic tumor biopsies in a collagen gel. Moreover, AdsFGFR repressed tumor angiogenesis and hence tumor growth in vivo in allograft transplantation experiments. Whereas adenoviral expression of a soluble form of VEGF receptor 1 (AdsFlt) predominantly affected the initiation of tumor angiogenesis, soluble FGF receptor (sFGFR) appeared to impair the maintenance of tumor angiogenesis. The combination of sFGFR and soluble Flt exhibited a synergistic effect in the repression of tumor growth. Finally, i.v. injection of AdsFGFR resulted in a dramatic repression of tumor growth in a transgenic mouse model of pancreatic beta cell carcinogenesis. Similar to control infections with AdsFlt, tumor-associated vessel density was decreased, indicating that the expression of sFGFR impaired tumor angiogenesis. These data indicate that FGFs play a critical role in tumor angiogenesis. PMID:11156426

Compagni, A; Wilgenbus, P; Impagnatiello, M A; Cotten, M; Christofori, G

2000-12-15

66

Decreased mitochondrial OGG1 expression is linked to mitochondrial defects and delayed hepatoma cell growth.  

PubMed

Many solid tumor cells exhibit mitochondrial respiratory impairment; however, the mechanisms of such impairment in cancer development remain unclear. Here, we demonstrate that SNU human hepatoma cells with declined mitochondrial respiratory activity showed decreased expression of mitochondrial 8-oxoguanine DNA glycosylase/lyase (mtOGG1), a mitochondrial DNA repair enzyme; similar results were obtained with human hepatocellular carcinoma tissues. Among several OGG1-2 variants with a mitochondrial-targeting sequence (OGG1-2a, -2b, -2c, -2d, and -2e), OGG1-2a was the major mitochondrial isoform in all examined hepatoma cells. Interestingly, hepatoma cells with low mtOGG1 levels showed delayed cell growth and increased intracellular reactive oxygen species (ROS) levels. Knockdown of OGG1-2 isoforms in Chang-L cells, which have active mitochondrial respiration with high mtOGG1 levels, significantly decreased cellular respiration and cell growth, and increased intracellular ROS. Overexpression of OGG1-2a in SNU423 cells, which have low mtOGG1 levels, effectively recovered cellular respiration and cell growth activities, and decreased intracellular ROS. Taken together, our results suggest that mtOGG1 plays an important role in maintaining mitochondrial respiration, thereby contributing to cell growth of hepatoma cells. PMID:23677377

Lee, Young-Kyoung; Youn, Hwang-Guem; Wang, Hee-Jung; Yoon, Gyesoon

2013-05-14

67

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

PubMed Central

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

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

2012-01-01

68

Basic fibroblast growth factor in an animal model of spontaneous mammary tumor progression.  

PubMed

Although basic fibroblast growth factor (FGF2) was the first pro-angiogenic molecule discovered, it has numerous activities on the growth and differentiation of non-vascular cell types. FGF2 is both stimulatory and inhibitory, depending on the cell type evaluated, the experimental design used and the context in which it is tested. Here, we investigated the effects of manipulating endogenous FGF2 on the development of mammary cancer to determine whether its endogenous contribution in vivo is pro- or anti-tumorigenic. Specifically, we examined the effects of FGF2 gene dosing in a cross between a spontaneous breast tumor model (PyVT+ mice) and FGF2-/- (FGF KO) mice. Using these mice, the onset and progression of mammary tumors was determined. As predicted, female FGF2 WT mice developed mammary tumors starting around 60 days after birth and by 80 days, 100% of FGF2 WT female mice had mammary tumors. In contrast, 80% of FGF2 KO female mice had no palpable tumors until nearly three weeks later (85 days) at times when 100% of the WT cohort was tumor positive. All FGF KO mice were tumor-bearing by 115 days. When we compared the onset of mammary tumor development and the tumor progression curves between FGF het and FGF KO mice, we observed a difference, which suggested a gene dosing effect. Analysis of the tumors demonstrated that there were significant differences in tumor size depending on FGF2 status. The delay in tumor onset supports a functional role for FGF2 in mammary tumor progression, but argues against an essential role for FGF2 in overall mammary tumor progression. PMID:22407271

Kao, Steven; Mo, Jeffrey; Baird, Andrew; Eliceiri, Brian P

2012-03-07

69

Caloric restriction reduces growth of mammary tumors and metastases  

PubMed Central

We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-?, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases.

De Lorenzo, Mariana S.; Baljinnyam, Erdene; Vatner, Dorothy E.; Abarzua, Patricio; Vatner, Stephen F.; Rabson, Arnold B.

2011-01-01

70

Caloric restriction reduces growth of mammary tumors and metastases.  

PubMed

We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-?, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases. PMID:21665891

De Lorenzo, Mariana S; Baljinnyam, Erdene; Vatner, Dorothy E; Abarzúa, Patricio; Vatner, Stephen F; Rabson, Arnold B

2011-06-10

71

Tumor-derived Expression of Vascular Endothelial Growth Factor Is a Critical Factor in Tumor Expansion and Vascular Function1  

Microsoft Academic Search

There is considerable controversy concerning the importance of tumor- derived angiogenic factors to the neovascularization of solid tumors. Tumor, endothelial, and stromal expression of vascular endothelial growth factor (VEGF) have been hypothesized to be critical for tumor angiogenesis. To determine the relative contribution of tumor versus nontransformed tissue expression of VEGF to tumor growth, we used gene targeting and cre-loxP

Jeremy Grunstein; W. Gregory Roberts; Odile Mathieu-Costello; Douglas Hanahan; Randall S. Johnson

1999-01-01

72

Tumor growth inhibition by ammonium chloride-induced acidosis.  

PubMed

Ammonium chloride-induced metabolic acidosis decreases the growth of various experimental tumors. Spleen exhibits the same effects. There is a sex factor which seems to affect the growth of both tumor and spleen. The observed tumor inhibition appears to be related to a systemic impairment of the anabolic mechanisms. The decrease in tumor calcium suggests that this element may play a role in the tissue growth. The possible implication of cell membrane changes and of a block in glycolysis in the acidosis effects are discussed. PMID:51839

Anghileri, L J

1975-10-01

73

Fibroblast Growth Factors Are Required for Efficient Tumor Angiogenesis1  

Microsoft Academic Search

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

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

74

Proangiogenic Contribution of Adiponectin toward Mammary Tumor Growth In vivo  

PubMed Central

Purpose Adipocytes represent one of the most abundant constituents of the mammary gland. They are essential for mammary tumor growth and survival. Metabolically, one of the more important fat-derived factors (“adipokines”) is adiponectin (APN). Serum concentrations of APN negatively correlate with body mass index and insulin resistance. To explore the association of APN with breast cancer and tumor angiogenesis, we took an in vivo approach aiming to study its role in the mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor model. Experimental Design We compared the rates of tumor growth in MMTV-PyMT mice in wild-type and APN-null backgrounds. Results Histology and micro-positron emission tomography imaging show that the rate of tumor growth is significantly reduced in the absence of APN at early stages. PyMT/APN knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease, tumor growth develops more aggressively in mice lacking APN, giving rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells, and a gene expression fingerprint indicative of more aggressive tumor cells. Conclusions These observations highlight a novel important contribution of APN in mammary tumor development and angiogenesis, indicating that APN has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of APN, this antiangiogenic stress results in an adaptive response that fuels tumor growth through mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell proliferation despite a chronically hypoxic micro-environment.

Landskroner-Eiger, Shira; Qian, Binzhi; Muise, Eric S.; Nawrocki, Andrea R.; Berger, Joel P.; Fine, Eugene J.; Koba, Wade; Deng, Yingfeng; Pollard, Jeffrey W.; Scherer, Philipp E.

2011-01-01

75

Translocator Receptor Blockade Reduces Prostate Tumor Growth  

PubMed Central

Statement of Translational Relevance Although benzodiazepines have been used clinically for over 50 years, their application as a form of cancer therapy is largely unexplored. Here we show that lorazepam, a benzodiazepine commonly prescribed to treat anxiety disorders and acts on both central and peripheral receptors, inhibits prostate cancer cell growth and survival. Our studies further elucidate the mechanism by which Translocator Protein (TSPO) antagonists alter cancer cell function. Antagonists for TSPO are already used in the clinic for other indications and demonstrate very minor side effects. Because lorazepam is a commonly prescribed FDA-approved drug, the translation of our preclinical results to the prostate cancer patient population could be readily achieved. Our studies could lead to a significant change in the management of prostate cancer by providing a treatment option with minimal toxicity for use after failure of androgen-deprivation therapy and could ultimately prevent prostate cancer deaths. Purpose The transmembrane molecule, Translocator Protein (TSPO) has been implicated in the progression of epithelial tumors. TSPO gene expression is high in tissues involved in steroid biosynthesis, neurodegenerative disease and in cancer and overexpression has been shown to contribute to pathologic conditions including cancer progression in several different models. The goal of our study was to examine the expression and biological relevance of TSPO in prostate cancer and demonstrate that the commonly prescribed benzodiazepine lorazepam, a ligand for TSPO, exhibits anti-cancer properties. Experimental Design Immunohistochemical analysis using tissue microarrays was used to determine the expression profile of TSPO in human prostate cancer tissues. To demonstrate the effect of benzodiazepines (lorazepam and PK11195) in prostate cancer, we utilized cell proliferation assays, apoptosis ELISA, prostate cancer xenograft study, and immunohistochemistry. Results TSPO expression is increased in prostatic intraepithelial neoplasia, primary prostate cancer, and metastases compared to normal prostate tissue and benign prostatic hyperplasia. Furthermore, TSPO expression correlates with disease progression, as TSPO levels increased with increasing Gleason sum and stage with prostate cancer metastases demonstrating the highest level of expression among all tissues examined. Functionally, we have demonstrated that lorazepam has anti-proliferative and pro-apoptotic properties in vitro and in vivo. Additionally, we have shown that TSPO overexpression in nontumorigenic cells conferred susceptibility to lorazepam-induced growth inhibition. Conclusion These data suggest that blocking TSPO function in tumor cells induces cell death and denotes a survival role for TSPO in prostate cancer and provide the first evidence for the use of benzodiazepines in prostate cancer therapeutics.

Fafalios, Arlee; Akhavan, Ardavan; Parwani, Anil V.; Bies, Robert R.; McHugh, Kevin J.; Pflug, Beth R.

2009-01-01

76

ANALYSIS OF SOLID TUMOR GROWTH MODELS: MECHANISMS OF VOLUME LOSS AND SLOWED GROWTH RATE  

Microsoft Academic Search

Abstract Studies on the mathematical modeling of solid, avascular tumor growth have been prevalent since the 1960s, with pioneers such as Greenspan and Hill. As experimental studies have improved, the mathematical models have evolved in order to remain relevant. One important issue in modeling tumor growth is the assumed method of volume loss within the tumor. McElwain and Morris constructed

Lacey Huebel

2007-01-01

77

Tumor growth modeling based on cell and tumor lifespans.  

PubMed

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- and second-order moments as well as the cumulative distribution functions and confidence intervals are expressed for the two lifespans with respect to the model parameters. One interesting result is that the mean value of the tumor lifespan can be approached by a logarithmic function of the initial cancer cell number. Moreover, we show that TCP and NTCP, used in radiotherapy to evaluate, optimize and compare treatment plans, can be derived from the tumor lifespan and the surrounding healthy tissue, respectively. Finally, we propose a ROC curve, entitled ECT (Efficiency-Complication Trade-off), suited to the selection by clinicians of the appropriate treatment planning. PMID:22820494

Keinj, R; Bastogne, T; Vallois, P

2012-07-20

78

Effect of Angiogenic Growth on Tumor Growth, Vascular Function, and the Development of Hypoxic Therapeutic Resistance.  

National Technical Information Service (NTIS)

The primary objectives of this grant were to determine the effects of either angiogenic growth factor overexpression or inhibition on mammary tumor pathophysiology. We evaluated four transfected human breast tumors and two murine mammary carcinoma lines b...

B. M. Fenton

2003-01-01

79

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

Microsoft Academic Search

During a 10-year period, 23 girls compared to 118 boys presented with constitutional delay in growth and puberty. Of these girls, 15 were followed to final height to determine the outcome of the untreated condition in terms of both growth and psychological well-being. At presentation chronological age was 13.2 (1.7) years [mean (S.D.)], bone age delay 2.7 (0.9) years, standing

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

1991-01-01

80

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

81

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

82

A two-phase mixture model of avascular tumor growth  

NASA Astrophysics Data System (ADS)

Interactions with biological environment surrounding a growing tumor have major influence on tumor invasion. By recognizing that mechanical behavior of tumor cells could be described by biophysical laws, the research on physical oncology aims to investigate the inner workings of cancer invasion. In this study, we introduce a mathematical model of avascular tumor growth using the continuum theory of mixtures. Mechanical behavior of the tumor and physical interactions between the tumor and host tissue are represented by biophysically founded relationships. In this model, a solid tumor is embedded in inviscid interstitial fluid. The tumor has viscous mechanical properties. Interstitial fluid exhibits properties of flow through porous medium. Associated with the mixture saturation constraint, we introduce a Lagrange multiplier which represents hydrostatic pressure of the interstitial fluid. We solved the equations using Finite Element Method in two-dimensions. As a result, we have introduced a two-phase mixture model of avascular tumor growth that provided a flexible mathematical framework to include cells' response to mechanical aspects of the tumor microenvironment. The model could be extended to capture tumor-ECM interactions which would have profound influence on tumor invasion.

Ozturk, Deniz; Burcin Unlu, M.; Yonucu, Sirin; Cetiner, Ugur

2012-02-01

83

Delayed adolescent growth in homozygous sickle cell disease  

Microsoft Academic Search

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

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

1994-01-01

84

Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting  

PubMed Central

Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm3) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the oxygenation and subsequent radiation response of tumors. We surmise that these cells are preferentially stimulated to divide in the tumor microenvironment, thereby inducing the significant increase in tumor growth observed and that the use of injected BOECs could be a viable approach to modulate the tumor microenvironment for therapeutic gain. Conversely, agents or approaches to block their recruitment and integration of BOECs into primary or metastatic lesions may be an effective way to restrain cancer progression before or after other treatments are applied.

Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

2013-01-01

85

Population Ecology Issues in Tumor Growth  

Microsoft Academic Search

Mathematical models developed from population ecology are applied to tumor-host interactions and demonstrate the importance of increased efficiency in substrate absorption as a mechanism enabling tumor cells to (a) proliferate despite inefficient energy production and (b) compete successfully for resources with the numerically superior host cells. As with many biological invasions observed in nature, success of the invaders can be

Robert A. Gatenby

1991-01-01

86

Clinical value of proton magnetic resonance spectroscopy for differentiating recurrent or residual brain tumor from delayed cerebral necrosis  

Microsoft Academic Search

Purpose: Delayed cerebral necrosis (DN) is a significant risk for brain tumor patients treated with high-dose irradiation. Although differentiating DN from tumor progression is an important clinical question, the distinction cannot be made reliably by conventional imaging techniques. We undertook a pilot study to assess the ability of proton magnetic resonance spectroscopy (1H MRS) to differentiate prospectively between DN or

June S. Taylor; James W. Langston; Wilburn E. Reddick; Peter B. Kingsley; Robert J. Ogg; Margaret H. Pui; Larry E. Kun; Jesse J. Jenkins; Gang Chen; Judith J. Ochs; Robert A. Sanford; Richard L. Heideman

1996-01-01

87

VEGF-integrin interplay controls tumor growth and vascularization  

NASA Astrophysics Data System (ADS)

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

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

2005-05-01

88

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.

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

89

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

90

Phase transition in tumor growth: I avascular development  

NASA Astrophysics Data System (ADS)

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

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

2013-12-01

91

[Effects of parenteral nutrition on tumor growth: experimental aspects].  

PubMed

There still exist controversies about the effect of parenteral nutrition on cancer growth. For elucidation of this question the development of Walker 256 carcinosarcoma in rats submitted to parenteral nutrition (PN) was studied. Thirty-five Wistar rats were randomly distributed in three groups: OT group (11), tumor-bearing animals always under oral feeding for 14 days; PC group (14), tumor free animals under PN for 7 days; PT group (10), tumor-bearing rats under PT for 7 days. PT solution contained 15% glucose, 3% aminoacids and essential micronutrients. Body and tumor weight (in OT and PT groups) were evaluated daily. Carcass weight was obtained by the difference between the body and tumor weight. The rats of the PC group had an initial body weight loss that became stabilized afterwards at a lower plateau level. The rats of the PT group also presented an initial body weight loss recovered progressively afterwards. This difference is probably due to tumor mass expansion in PT animals, since PT rats carcass weight remained similar to that of body weight in PC group. The tumor growth has shown no difference between the oral and parenteral feeding groups, particularly when tumor weight/carcass weight ratio was considered. It is concluded that parenteral nutrition does not favor tumor growth in detriment to carcass weight development. PMID:2135817

Yamaguchi, N; Lima-Gonçalves, E; Waitzberg, D L; Diniz Filho, A M; Goffi, F S

92

Effect of Testosterone Therapy for Delayed Growth and Puberty in Boys with Inflammatory Bowel Disease  

Microsoft Academic Search

Background: Pubertal delay and growth retardation are common in children with inflammatory bowel disease (IBD). Aims: To assess pubertal status and growth in a group of boys with IBD undergoing testosterone therapy for pubertal induction. Methods: Retrospective study of height, weight and pubertal status in 8 boys with IBD before and after testosterone therapy. Height velocity (HV) over the 6

A. Mason; S. C. Wong; P. McGrogan; S. F. Ahmed

2011-01-01

93

Mirtazapine Inhibits Tumor Growth via Immune Response and Serotonergic System  

PubMed Central

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

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

2012-01-01

94

Melanoma Proteoglycan Modifies Gene Expression to Stimulate Tumor Cell Motility, Growth and Epithelial to Mesenchymal Transition  

PubMed Central

Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane-associated proteoglycan that facilitates the growth, motility and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk 1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results demonstrate that MCSP expression in radial growth phase (RGP), vertical growth phase (VGP) or metastatic cell lines causes sustained activation of Erk 1,2, enhanced growth and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in an RGP cell line also promotes an epithelial to mesenchymal transition (EMT) based on changes in cell morphology and the expression of several EMT markers. Finally MCSP enhances the expression of c-Met and HGF, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively demonstrate an importance for MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients.

Yang, Jianbo; Price, Matthew A.; Li, GuiYuan; Bar-Eli, Menashe; Salgia, Ravi; Jagedeeswaran, Ramasamy; Carlson, Jennifer H.; Ferrone, Soldano; Turley, Eva A.; McCarthy, James B.

2009-01-01

95

Mesenchymal Stem Cell 1 (MSC1)-Based Therapy Attenuates Tumor Growth Whereas MSC2-Treatment Promotes Tumor Growth and Metastasis  

PubMed Central

Background Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs) in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2. Methodology/Principal Findings Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co-culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1-therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation. Conclusion/Significance These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease.

Waterman, Ruth S.; Henkle, Sarah L.; Betancourt, Aline M.

2012-01-01

96

Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability.  

PubMed

Vascular endothelial growth factor (VEGF)-induced vascular permeability (VP) is a hallmark of tumor growth and metastasis. Previous studies have shown a requirement for Src kinase in VEGF-mediated VP and signaling in blood vessels. In this study, we have examined the effect of Src-mediated reduced VP on tumor growth and metastasis. The growth and spontaneous metastasis of VEGF-expressing tumor cells were determined in Src-knockout (src(-/-)) or control mice (src(+/+) or src(+/-)). In comparison to control mice, src-null mice had a significant reduction in tumor-induced VP as well as a subsequent reduction in spontaneous metastasis. In contrast, primary tumor weight and vascular density were unchanged between src-null and control mice. Consistent with a role for Src in the extravasation of tumor cells from the circulation, direct intravenous injection of lung carcinoma cells resulted in a more than 2-fold reduction in lung tumor burden in src-null mice compared to control mice. The comparison of the results from the experimental metastasis and the spontaneous metastasis models suggests that there are defects in VP in the primary site of Src-deficient mice and that there may be an essential role for Src and Src-mediated VP in tumor metastasis to the lung. PMID:15486073

Criscuoli, Michele L; Nguyen, Mai; Eliceiri, Brian P

2004-10-14

97

Divalent cation-phospholipid complexes and tumor growth inhibition.  

PubMed

Growth inhibition of DS sarcomas provoked by calcitonin treatment is accompanied by an increase of calcium and magnesium in the phospholipid fraction. Changes in tumor cell membrane characteristics reflected in ionic or molecular transport modifications seem to be involved in the growth impairment phenomenon. PMID:520494

Anghileri, L J; Delbrück, H

1979-12-15

98

RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors  

PubMed Central

Purpose The purpose of this preclinical study was to determine the effectiveness of RAF265, a multi-kinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated. Results Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAFWT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which 1 carried c-KITL576P and another N-RASQ61R mutation, while only 2 (29%) of the responding tumors were BRAFV600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Conclusions Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.

Su, Yingjun; Vilgelm, Anna E.; Kelley, Mark C.; Hawkins, Oriana E.; Liu, Yan; Boyd, Kelli L.; Kantrow, Sara; Splittgerber, Ryan C.; Short, Sarah P.; Sobolik, Tammy; Zaja-Milatovic, Snjezana; Dahlman, Kimberly Brown; Amiri, Katayoun I.; Jiang, Aixiang; Lu, Pengcheng; Shyr, Yu; Stuart, Darrin D.; Levy, Shawn; Sosman, Jeffrey A.; Richmond, Ann

2013-01-01

99

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.

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

1995-01-01

100

ADAM12 Transmembrane and Secreted Isoforms Promote Breast Tumor Growth  

PubMed Central

Increased levels of ADAM12 have been reported in a variety of human cancers. We have previously reported that urinary ADAM12 is predictive of disease status in breast cancer patients and that ADAM12 protein levels in urine increase with progression of disease. On the basis of these findings, the goal of this study was to elucidate the contribution of ADAM12 in breast tumor growth and progression. Overexpression of both the ADAM12-L (transmembrane) and ADAM12-S (secreted) isoforms in human breast tumor cells resulted in a significantly higher rate of tumor take and increased tumor size. Cells expressing the enzymatically inactive form of the secreted isoform, ADAM12-S, had tumor take rates and tumor volumes similar to those of wild-type cells, suggesting that the tumor-promoting activity of ADAM12-S was a function of its proteolytic activity. Of the two isoforms, only the secreted isoform, ADAM12-S, enhanced the ability of tumor cells to migrate and invade in vitro and resulted in a higher incidence of local and distant metastasis in vivo. This stimulatory effect of ADAM12-S on migration and invasion was dependent on its catalytic activity. Expression of both ADAM12 isoforms was found to be significantly elevated in human malignant breast tissue. Taken together, our results suggest that ADAM12 overexpression results in increased tumor take, tumor size, and metastasis in vivo. These findings suggest that ADAM12 may represent a potential therapeutic target in breast cancer.

Roy, Roopali; Rodig, Scott; Bielenberg, Diane; Zurakowski, David; Moses, Marsha A.

2011-01-01

101

Deregulation of tumor angiogenesis and blockade of tumor growth in PPAR?-deficient mice  

PubMed Central

The peroxisome proliferator-activated receptor-? (PPAR?) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb?/? mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb?/? mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57Kip2 as a PPAR? target gene and a mediator of the PPAR?-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb?/? mice. Our data point to an unexpected essential role for PPAR? in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

Muller-Brusselbach, Sabine; Komhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jurgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Muller, Rolf

2007-01-01

102

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

SciTech Connect

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

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

2006-02-01

103

Reaction-diffusion model for the growth of avascular tumor.  

PubMed

A nutrient-limited model for avascular cancer growth including cell proliferation, motility, and death is presented. The model qualitatively reproduces commonly observed morphologies for primary tumors, and the simulated patterns are characterized by its gyration radius, total number of cancer cells, and number of cells on tumor periphery. These very distinct morphological patterns follow Gompertz growth curves, but exhibit different scaling laws for their surfaces. Also, the simulated tumors incorporate a spatial structure composed of a central necrotic core, an inner rim of quiescent cells and a narrow outer shell of proliferating cells in agreement with biological data. Finally, our results indicate that the competition for nutrients among normal and cancer cells may be a determining factor in generating papillary tumor morphology. PMID:11863563

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

2002-01-23

104

Paracrine/autocrine growth mechanisms in tumor metastasis.  

PubMed

The successful growth of metastatic tumor cells is due to their responses to local paracrine growth factors and inhibitors and their production and responses to autocrine growth factors. At early stages of metastatic progression, there is a tendency for many common malignancies to metastasize and grow preferentially at particular sites, suggesting that paracrine growth mechanisms may dominate the growth signals affecting metastatic cells. At later stages of metastatic progression, where widespread dissemination to various tissues and organs occurs, autocrine growth mechanisms may dominate the growth signals affecting metastatic cells. The progression of malignant cells to completely autonomous (acrine) states can ultimately occur, and at this stage of metastatic progression cell growth can be completely independent of growth factors or inhibitors. Various strategies have been developed to treat cancer that are based on the responses of malignant cells to growth factor or inhibitor analogs, anti-receptor antibodies, or antibody- or growth factor-toxin conjugates. Since the responses and expression of growth factor receptors can change during malignant progression, the development of cancer treatments using analogs of specific growth inhibitors or antagonists of growth factors, such as monoclonal antibodies or other agents, to block growth signaling mechanisms may only be useful at the early stages of malignant cancer progression before widespread metastasis of acrine cells occurs. PMID:1292754

Nicolson, G L

1992-01-01

105

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

PubMed

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 and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for women with newly diagnosed breast cancer; orthotopic breast tumor grafting is a step toward individualized models for tumor growth, metastasis and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. PMID:22019887

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

2011-10-23

106

Pinning of Tumoral Growth by Enhancement of the Immune Response  

NASA Astrophysics Data System (ADS)

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

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

2004-06-01

107

Semiautomatic growth analysis of multicellular tumor spheroids.  

PubMed

Multicellular tumor spheroids (MCTS) are routinely employed as three-dimensional in vitro models to study tumor biology. Cultivation of MCTS in spinner flasks provides better growing conditions, especially with regard to the availability of nutrients and oxygen, when compared with microtiter plates. The main endpoint of drug response experiments is spheroid size. It is common practice to analyze spheroid size manually with a microscope and an ocular micrometer. This requires removal of some spheroids from the flask, which entails major limitations such as loss of MCTS and the risk of contamination. With this new approach, the authors present an efficient and highly reproducible method to analyze the size of complete MCTS populations in culture containers with transparent, flat bottoms. MCTS sediments are digitally scanned and spheroid volumes are calculated by computerized image analysis. The equipment includes regular office hardware (personal computer, flatbed scanner) and software (Adobe Photoshop, Microsoft Excel, ImageJ). The accuracy and precision of the method were tested using industrial precision steel beads with known diameter. In summary, in comparison with other methods, this approach provides benefits in terms of semiautomation, noninvasiveness, and low costs. PMID:21908797

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

2011-09-09

108

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

PubMed Central

The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin (FN) that promote ?5?1 integrin-dependent FN fibril assembly, matrix stiffness, and tumor growth. Tumor growth and FN fibril assembly was reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in FN fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl, that augmented ?5?1 FN fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of FN fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.

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

2012-01-01

109

Darkness improves growth and delays necrosis in a nonchlorophyllous habituated sugarbeet callus: Biochemical changes  

Microsoft Academic Search

The transfer of light-cultured green normal (N) and white habituated (HNO) sugarbeet callus to darkness reduced the growth\\u000a of N callus and improved growth and delayed necrosis in the HNO callus. The decrease of dry matter of N callus under darkness\\u000a was accompanied by a reduced content of carotenoids and by decreased CO2 fixation, which was compensated by an increased

C. Kevers; B. Bisbis; F. Le Dily; J. P. Billard; C. Huault; Th. Gaspar

1995-01-01

110

Impulsive exponential stabilization of discrete population growth models with time delays  

Microsoft Academic Search

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

Yu Zhang; Jitao Sun

2010-01-01

111

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 Rødbro; I Transbøl

1979-01-01

112

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

113

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

PubMed

Mutations in PIK3CA, the gene encoding the p110? catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110? via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110?-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110? and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of 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, María G; Rexer, Brent N; Balko, Justin M; Sánchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

2013-04-30

114

Ricci Flow and Entropy Model for Avascular Tumor Growth and Decay Control  

Microsoft Academic Search

Prediction and control of cancer invasion is a vital problem in medical science. This paper proposes a modern geometric Ricci-flow and entropy based model for control of avascular multicellular tumor spheroid growth and decay. As a tumor growth\\/decay control tool, a monoclonal antibody therapy is proposed. Keywords: avascular tumor growth and decay, multicellular tumor spheroid, Ricci flow and entropy, nonlinear

Tijana T. Ivancevic

2008-01-01

115

P-selectin deficiency attenuates tumor growth and metastasis.  

PubMed

Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals. PMID:9689079

Kim, Y J; Borsig, L; Varki, N M; Varki, A

1998-08-01

116

P-selectin deficiency attenuates tumor growth and metastasis  

PubMed Central

Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals.

Kim, Young J.; Borsig, Lubor; Varki, Nissi M.; Varki, Ajit

1998-01-01

117

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

118

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

Microsoft Academic Search

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

Nancy Dumont; Carlos L Arteaga

2000-01-01

119

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

PubMed Central

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

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

2005-01-01

120

Mining Brain Tumors and Tracking their Growth Rates  

Microsoft Academic Search

Mining brain tumors and tracking their growth trends in the course of magnetic resonance imaging is an important task that assists medical professionals to describe the appropriate treatment. Nevertheless, applying conventional techniques to carry out this process manually is time-consuming and often unreliable and insufficiently accurate. Automating this process is a challenging task due to the fact of the fractal

Abdel-Halim Elamy; Maidong Hu

2007-01-01

121

Altered tumor cell growth and tumorigenicity in models of microgravity  

NASA Astrophysics Data System (ADS)

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

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

122

The role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and puberty.  

PubMed

Variation in FGFR1, GNRHR, TAC3, and TACR3 was evaluated in 146 Finnish subjects with constitutional delay of growth and puberty. Although one male subject carried a previously undescribed heterozygous deletion (Phe309del) in GNRHR, which segregated with delayed puberty in his family, mutations in the coding regions of FGFR1, GNRHR, TAC3, and TACR3 are not likely to underlie common constitutional delay of growth and puberty. PMID:21292259

Vaaralahti, Kirsi; Wehkalampi, Karoliina; Tommiska, Johanna; Laitinen, Eeva-Maria; Dunkel, Leo; Raivio, Taneli

2011-02-03

123

Lymphangiogenic growth factors as markers of tumor metastasis.  

PubMed

Understanding the complex process of tumor metastasis is a problem which has challenged both clinician and scientist for well over 100 years. Defining molecular markers which reflect the metastatic potential of a tumor has also proved elusive. Recently, members of the vascular endothelial growth factor (VEGF) family of glycoproteins have been demonstrated to be potent mediators of both blood vessel and lymphatic vessel formation in the context of tumor biology. Experimental studies in animal models combined with extensive clinicopathological data provide a compelling case indicating that members of the VEGF family play a key role in the formation of metastases in a broad range of solid tumors. The question of whether VEGF signaling pathways can now serve as therapeutic targets alone, or in combination with other forms of anti-cancer agents, needs to be addressed. PMID:15563315

Stacker, Steven A; Williams, Richard A; Achen, Marc G

124

Ketone body utilization drives tumor growth and metastasis  

PubMed Central

We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes.

Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P.

2012-01-01

125

Ketone body utilization drives tumor growth and metastasis.  

PubMed

We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two-compartment tumor metabolism." Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav-1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco-metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID:23082722

Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

2012-09-19

126

Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.  

PubMed

km23-1 is a dynein light chain that was identified as a TGF? receptor-interacting protein. To investigate whether km23-1 controls human ovarian carcinoma cell (HOCC) growth, we established a tet-off inducible expression system in SKOV-3 cells in which the expression of km23-1 is induced upon doxycycline removal. We found that forced expression of km23-1 inhibited both anchorage-dependent and anchorage-independent growth of SKOV-3 cells. More importantly, induction of km23-1 expression substantially reduced the tumorigenicity of SKOV-3 cells in a xenograft model in vivo. Fluorescence-activated cell sorting analysis of SKOV-3 and IGROV-1 HOCCs demonstrated that the cells were accumulating at G2/M. Phospho-MEK, phospho-ERK and cyclin B1 were elevated, as was the mitotic index, suggesting that km23-1 suppresses HOCCs growth by inducing a mitotic delay. Immunofluorescence analyses demonstrated that the cells were accumulating at prometaphase/metaphase with increases in multipolar and multinucleated cells. Further, although the mitotic spindle assembly checkpoint protein BubR1 was present at the prometaphase kinetochore in Dox+/- cells, it was inappropriately retained at the metaphase kinetochore in Dox- cells. Thus, the mechanism by which high levels of km23-1 suppress ovarian carcinoma growth in vitro and inhibit ovary tumor formation in vivo appears to involve a BubR1-related mitotic delay. PMID:21469138

Pulipati, Nageswara R; Jin, Qunyan; Liu, Xin; Sun, Baodong; Pandey, Manoj K; Huber, Jonathan P; Ding, Wei; Mulder, Kathleen M

2011-04-25

127

The autophagic tumor stroma model of cancer or "battery-operated tumor growth"  

PubMed Central

The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the “Autophagy Paradox.” We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumor Growth.” In this sense, autophagy in the tumor stroma serves as a “battery” to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients—both effectively “starving” cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy by the upregulation of natural, endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a “lethal” aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.

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

2010-01-01

128

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

PubMed

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

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

2010-10-01

129

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

PubMed

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

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

2010-08-24

130

Matrix metalloprotease 1a deficiency suppresses tumor growth and angiogenesis.  

PubMed

Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a(+/+) fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer.Oncogene advance online publication, 27 May 2013; doi:10.1038/onc.2013.157. PMID:23708660

Foley, C J; Fanjul-Fernández, M; Bohm, A; Nguyen, N; Agarwal, A; Austin, K; Koukos, G; Covic, L; López-Otín, C; Kuliopulos, A

2013-05-27

131

Effects of Recombinant Human Growth Hormone on Height and Skeletal Maturation in Growth Hormone-Deficient Children with and without Severe Pretreatment Bone Age Delay  

Microsoft Academic Search

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. Methods: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score ?–2, group 1) and mild to moderate delay (BA Z-score between –2 and 0, group

J. Paul Frindik; Stephen F. Kemp; Judy P. Sy

1999-01-01

132

Vascular endothelial growth factor immunoneutralization in combination with cisplatin reduces EAC tumor growth  

Microsoft Academic Search

In the present study, we evaluated the effects of a neutralizing anti-Vascular Endothelial Growth Factor (VEGF) polyclonal antibody on murine EAC tumor growth both in vitro and in vivo. Furthermore, we investigated if in the presence of effective VEGF blockade, a conventional chemotherapeutic drug Cisplatin could be effective, and if so would there be an additive effect of the combination

Sonali Ghosh; Putul Maity

2006-01-01

133

Blocking Fibroblast Growth Factor Receptor Signaling Inhibits Tumor Growth, Lymphangiogenesis, and Metastasis  

PubMed Central

Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-? (hypoxia-inducible factor-1 ?) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin ?9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread.

Larrieu-Lahargue, Frederic; Welm, Alana L.; Bouchecareilh, Marion; Alitalo, Kari; Li, Dean Y.; Bikfalvi, Andreas; Auguste, Patrick

2012-01-01

134

HDAC6 inhibition restores ciliary expression and decreases tumor growth.  

PubMed

Primary cilia are multisensory organelles recently found to be absent in some tumor cells, but the mechanisms of deciliation and the role of cilia in tumor biology remain unclear. Cholangiocytes, the epithelial cells lining the biliary tree, normally express primary cilia and their interaction with bile components regulates multiple processes, including proliferation and transport. Using cholangiocarcinoma as a model, we found that primary cilia are reduced in cholangiocarcinoma by a mechanism involving histone deacetylase 6 (HDAC6). The experimental deciliation of normal cholangiocyte cells increased the proliferation rate and induced anchorage-independent growth. Furthermore, deciliation induced the activation of mitogen-activated protein kinase and Hedgehog signaling, two important pathways involved in cholangiocarcinoma development. We found that HDAC6 is overexpressed in cholangiocarcinoma and overexpression of HDAC6 in normal cholangiocytes induced deciliation and increased both proliferation and anchorage-independent growth. To evaluate the effect of cilia restoration on tumor cells, we targeted HDAC6 by short hairpin RNA (shRNA) or by the pharmacologic inhibitor, tubastatin-A. Both approaches restored the expression of primary cilia in cholangiocarcinoma cell lines and decreased cell proliferation and anchorage-independent growth. The effects of tubastatin-A were abolished when cholangiocarcinoma cells were rendered unable to regenerate cilia by stable transfection of IFT88-shRNA. Finally, inhibition of HDAC6 by tubastatin-A also induced a significant decrease in tumor growth in a cholangiocarcinoma animal model. Our data support a key role for primary cilia in malignant transformation, provide a plausible mechanism for their involvement, and suggest that restoration of primary cilia in tumor cells by HDAC6 targeting may be a potential therapeutic approach for cholangiocarcinoma. PMID:23370327

Gradilone, Sergio A; Radtke, Brynn N; Bogert, Pamela S; Huang, Bing Q; Gajdos, Gabriella B; LaRusso, Nicholas F

2013-01-31

135

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

136

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

137

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

PubMed Central

Although a variety of diffeomorphic deformable registration methods exist in the literature, application of these methods in the presence of space-occupying lesions is not straightforward. The motivation of this work is spatial normalization of MR images from patients with brain tumors in a common stereotaxic space, aiming to pool data from different patients into a common space in order to perform group analyses. Additionally, transfer of structural and functional information from neuroanatomical brain atlases into the individual patient's space can be achieved via the inverse mapping, for the purpose of segmenting brains and facilitating surgical or radiotherapy treatment planning. A method that estimates the brain tissue loss and replacement by tumor is applied for achieving equivalent image content between an atlas and a patient's scan, based on a biomechanical model of tumor growth. Automated estimation of the parameters modeling brain tissue loss and displacement is performed via optimization of an objective function reflecting feature-based similarity and elastic stretching energy, which is optimized in parallel via APPSPACK (Asynchronous Parallel Pattern Search). The results of the method, applied to 21 brain tumor patients, indicate that the registration accuracy is relatively high in areas around the tumor, as well as in the healthy portion of the brain. Also, the calculated deformation in the vicinity of the tumor is shown to correlate highly with expert-defined visual scores indicating the tumor mass effect, thereby potentially leading to an objective approach to quantification of mass effect, which is commonly used in diagnosis.

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

2009-01-01

138

Basic Fibroblast Growth Factor Treatment Delays Age-related Photoreceptor Degeneration in Fischer 344 Rats  

Microsoft Academic Search

This study was undertaken to investigate the potential of basic fibroblast growth factor (bFGF) to delay photoreceptor cell loss in retinas of Fischer 344 rats which exhibit an age-related peripheral retinopathy. Eight male 16-month-old Fischer 344 rats were injected intravitreally with 2.0 ?g bFGF in the right eye, while the vehicle was injected into the left eye and all rats

NING LIN; WEI FAN; HAROLD J. SHEEDLO; JAMES E. TURNER

1997-01-01

139

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

140

Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma.  

PubMed

Tumor-associated inflammation is a driving force in several adult cancers and intake of low-dose aspirin has proven to reduce cancer incidence. Little is known about tumor-associated inflammation in pediatric neoplasms and no in vivo data exists on the effectiveness of low-dose aspirin on established tumors. The present study employs the transgenic TH-MYCN mouse model for neuroblastoma (NB) to evaluate inflammatory patterns paralleling tumor growth in vivo and low-dose aspirin as a therapeutic option for high-risk NB. Spontaneously arising abdominal tumors were monitored for tumor-associated inflammation ex vivo at various stages of disease and homozygous mice received daily low-dose aspirin (10mg/kg) using oral gavage or no treatment, from 4.5 to 6 weeks of age. Using flow cytometry, a transition from an adaptive immune response predominated by CD8(+) T cell in early neoplastic lesions, towards enrichment in immature cells of the innate immune system, including myeloid-derived suppressor cells, dendritic cells and tumor-associated macrophages, was detected during tumor progression. An M1 to M2 transition of tumor-associated macrophages was demonstrated, paralleled by a deterioration of dendritic cell status. Treatment with low-dose aspirin to mice homozygous for the TH-MYCN transgene significantly reduced the tumor burden (P < 0.01), the presence of tumor-associated cells of the innate immune system (P < 0.01), as well as the intratumoral expression of transforming growth factor-?, thromboxane A2 (P < 0.05) and prostaglandin D2 (P < 0.01). In conclusion, tumor-associated inflammation appears as a potential therapeutic target in NB and low-dose aspirin reduces tumor burden in the TH-MYCN transgenic mouse model of NB, hence warranting further studies on aspirin in high-risk NB. PMID:23349014

Carlson, Lena-Maria; Rasmuson, Agnes; Idborg, Helena; Segerström, Lova; Jakobsson, Per-Johan; Sveinbjörnsson, Baldur; Kogner, Per

2013-01-24

141

Pharmacologic activation of PKM2 slows lung tumor xenograft growth.  

PubMed

Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies. PMID:23720766

Parnell, K Mark; Foulks, Jason M; Nix, Rebecca N; Clifford, Adrianne; Bullough, Jeremy; Luo, Bai; Senina, Anna; Vollmer, David; Liu, Jihua; McCarthy, Virgil; Xu, Yong; Saunders, Michael; Liu, Xiao-Hui; Pearce, Scott; Wright, Kevin; O'Reilly, Marc; McCullar, Michael V; Ho, Koc-Kan; Kanner, Steven B

2013-05-29

142

Inhibition of Chlamydia trachomatis growth by recombinant tumor necrosis factor.  

PubMed Central

Purified human recombinant tumor necrosis factor (rTNF) alpha inhibited the growth of Chlamydia trachomatis (L2/434/Bu) in HEp-2 cell cultures. The inhibition of C. trachomatis yield could be achieved even when the rTNF alpha (200 ng/ml) was added up to 12 h after infection. The effect of rTNF alpha on chlamydial infection was synergistic with that of gamma interferon. Images

Shemer-Avni, Y; Wallach, D; Sarov, I

1988-01-01

143

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

144

Mitochondrial dysfunction in breast cancer cells prevents tumor growth  

PubMed Central

Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients, especially by targeting cancer stem cells. Metformin exerts its protective effects by functioning as a weak “mitochondrial poison,” as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism (OXPHOS). Thus, mitochondrial metabolism must play an essential role in promoting tumor growth. To determine the functional role of “mitochondrial health” in breast cancer pathogenesis, here we used mitochondrial uncoupling proteins (UCPs) to genetically induce mitochondrial dysfunction in either human breast cancer cells (MDA-MB-231) or cancer-associated fibroblasts (hTERT-BJ1 cells). Our results directly show that all three UCP family members (UCP-1/2/3) induce autophagy and mitochondrial dysfunction in human breast cancer cells, which results in significant reductions in tumor growth. Conversely, induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect. More specifically, overexpression of UCP-1 in stromal fibroblasts increases ?-oxidation, ketone body production and the release of ATP-rich vesicles, which “fuels” tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells. Hence, the effects of mitochondrial dysfunction are truly compartment-specific. Thus, we conclude that the beneficial anticancer effects of mitochondrial inhibitors (such as metformin) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment. Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions.

Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lamb, Rebecca; Hulit, James; Howell, Anthony; Gandara, Ricardo; Sartini, Marina; Rubin, Emanuel; Lisanti, Michael P.; Sotgia, Federica

2013-01-01

145

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

146

Inhibition of Early Tumor Growth Requires J18-positive (Natural Killer T) Cells1  

Microsoft Academic Search

The role of natural killer T (NKT) cells in the immune response to tumor cells has been largely unexplored. As a model of adoptive tumor immunotherapy, cells from the draining lymph nodes of mice immunized with a tumor-specific or irrelevant antigen were transferred to naive recipients with established tumor. Inhibition of early tumor growth (day 4) required the transfer of

Trina J. Stewart; Mark J. Smyth; Germain J. P. Fernando; Ian H. Frazer; Graham R. Leggatt

147

Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis  

PubMed Central

ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies.

Milsom, Chloe C.; Yu, Joanne L.; Mackman, Nigel; Micallef, Johann; Anderson, G. Mark; Guha, Abhijit; Rak, Janusz W.

2010-01-01

148

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

NASA Astrophysics Data System (ADS)

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

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

2012-11-01

149

Knockdown of RON receptor kinase delays but does not prevent tumor progression while enhancing HGF/MET signaling in pancreatic cancer cell lines.  

PubMed

In this study, the role of RON (receptor originated from nantes) in tumor progression was further investigated in context with MET expression and activity. RON and MET expressions were not detected in an immortalized normal human pancreas cell line (HPNE), but were co-expressed in five of seven pancreatic ductal adenocarcinoma (PDAC) cell lines (PANC-1, BxPC-3, Capan-2, CFPAC-1 and AsPC-1). RON expression was knocked down by an shRNA approach in two PDAC cell lines (BxPC-3 and CFPAC-1) that co-express MET. Knockdown of RON significantly inhibited cell growth, clonogenicity and macrophage stimulating protein (MSP), RON ligand induced invasion by in vitro assays and significantly inhibited tumor growth (P<0.001) and metastasis (P<0.009) in an orthotopic pancreatic cancer mouse model at week 7. However, by week 9, the mice implanted with RON knockdown cells had developed similar size primary tumors and metastases compared with that seen in the control group at week 7. Western blotting and immunohistochemistry analyses showed that MET remains highly expressed in cells and tumor tissues where RON was knocked down. Moreover, knockdown of RON did not prevent hepatocyte growth factor (HGF) stimulated invasion in in vitro Matrigel assays. Treating cells with MSP induced the transphosphorylation of MET, suggesting that signaling may be modulated by relative levels of RON and MET receptors and their corresponding ligands. To this point, HGF treatment of RON knockdown cells caused an increase in intensity and duration of MET signaling, suggesting that MET signaling may compensate for loss of RON signaling. Treatment of cells with an MET inhibitor, PHA-665752, had minimal effects on inhibiting cell growth but significantly inhibited cell invasion induce by ligands for either MET or RON. These results suggest that HGF/MET signaling may have a more important role in tumor cell invasion and metastasis rather than in tumor cell proliferation. This study indicates that specific inhibition of RON delays but does not prevent progression of PDAC. Moreover, specific signaling may be modulated by the interaction of RON and MET receptors. This dynamic interaction of RON and MET in pancreatic cancer cells suggests that dual targeting of both RON and MET will be preferable to inhibition of either target alone. PMID:24100611

Zhao, S; Cao, L; Freeman, J W

2013-10-07

150

A novel fusicoccin derivative preferentially targets hypoxic tumor cells and inhibits tumor growth in xenografts.  

PubMed

Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1? and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1? and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR- 042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer. PMID:22263802

Kawakami, Koshi; Hattori, Miho; Inoue, Takatsugu; Maruyama, Yuriko; Ohkanda, Junko; Kato, Nobuo; Tongu, Miki; Yamada, Takaya; Akimoto, Miho; Takenaga, Keizo; Sassa, Takeshi; Suzumiy, Junji; Honma, Yoshio

2012-09-01

151

Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns.  

PubMed

Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth. PMID:23325801

Vinall, Jillian; Grunau, Ruth E; Brant, Rollin; Chau, Vann; Poskitt, Kenneth J; Synnes, Anne R; Miller, Steven P

2013-01-16

152

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis  

PubMed Central

Heparan sulfate glycosaminoglycans, present at the cell surface and in the extracellular matrix that surrounds cells, are important mediators of complex biological processes. Furthermore, it is now apparent that cells dynamically regulate the structure of their heparan sulfate “coat” to differentially regulate extracellular signals. In the present study, the importance of sequence information contained within tumor cell-surface heparan sulfate was investigated. Herein, we demonstrate that the heparan sulfate glycosaminoglycan coat present on tumor cells contains bioactive sequences that impinge on tumor-cell growth and metastasis. Importantly, we find that growth promoting as well as growth inhibiting sequences are contained within the polysaccharide coat. Furthermore, we find that the dynamic balance between these distinct polysaccharide populations regulates specific intracellular signal-transduction pathways. This study not only provides a framework for the development of polysaccharide-based anti-cancer molecules but also underscores the importance of understanding a cell's polysaccharide array in addition to its protein complement, to understand how genotype translates to phenotype in this postgenomic age.

Liu, Dongfang; Shriver, Zachary; Venkataraman, Ganesh; El Shabrawi, Yosuf; Sasisekharan, Ram

2002-01-01

153

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

Microsoft Academic Search

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

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

2005-01-01

154

Update of Alpha Fetoprotein Growth-Inhibitory Peptides as Biotherapeutic Agents for Tumor Growth and Metastasis  

Microsoft Academic Search

The present update describes the biological activities of an alpha fetoprotein (AFP)-derived peptide termed the growth-inhibitory peptide (GIP), which is a synthetic 34-amino acid segment produced from the native molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult cells. Even though its mechanism of action has not been completely elucidated,

G. J. Mizejewski; M. Muehlemann; M. Dauphinee

2006-01-01

155

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

PubMed Central

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

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

2013-01-01

156

Reduced Survival of Rectal Cancer Patients With Increased Tumor Epidermal Growth Factor Receptor Levels  

Microsoft Academic Search

PURPOSE: The epidermal growth factor receptor and its various ligands (epidermal growth factor, transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor, heregulin, and betacellulin) have been implicated in growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. Although some studies have investigated levels of epidermal growth factor receptor by radioligand binding

Reinhard Kopp; Elisabeth Rothbauer; Elisabeth Mueller; FriedrichWilhelm Schildberg; Karl-Walter Jauch; Andreas Pfeiffer

2003-01-01

157

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

Microsoft Academic Search

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

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

2002-01-01

158

Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth.  

National Technical Information Service (NTIS)

We will determine the mechanism by which Shh signaling accelerates prostate tumor growth, identify Shh targets in prostate tumor stroma, and test the effect of individual target genes on tumor growth. The purpose of the report is to evaluate the second ye...

A. Shaw W. Bushman

2007-01-01

159

Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function.  

PubMed

There is considerable controversy concerning the importance of tumor-derived angiogenic factors to the neovascularization of solid tumors. Tumor, endothelial, and stromal expression of vascular endothelial growth factor (VEGF) have been hypothesized to be critical for tumor angiogenesis. To determine the relative contribution of tumor versus nontransformed tissue expression of VEGF to tumor growth, we used gene targeting and cre-loxP recombination to generate embryonic stem cell lines in which VEGF can be conditionally deleted. These lines were used to derive mouse embryonic fibroblast lines with null mutations in both alleles of VEGF. Upon immortalization and H-ras transformation, we used these VEGF null fibroblasts to make fibrosarcomas in immunocompromised mice. We report that tumorigenic VEGF expression is critical for ras-mediated tumorigenesis, and the loss of tumorigenic expression causes dramatic decreases in vascular density and vascular permeability and increases in tumor cell apoptosis. PMID:10197634

Grunstein, J; Roberts, W G; Mathieu-Costello, O; Hanahan, D; Johnson, R S

1999-04-01

160

Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.  

PubMed Central

Vascular permeability factor (VPF) is an Mr 40-kD protein that has been purified from the conditioned medium of guinea pig line 10 tumor cells grown in vitro, and increases fluid permeability from blood vessels when injected intradermally. Addition of VPF to cultures of vascular endothelial cells in vitro unexpectedly stimulated cellular proliferation. VPF promoted the growth of new blood vessels when administered into healing rabbit bone grafts or rat corneas. The identity of the growth factor activity with VPF was established in four ways: (a) the molecular weight of the activity in preparative SDS-PAGE was the same as VPF (Mr approximately 40 kD); (b) multiple isoforms (pI greater than or equal to 8) for both VPF and the growth-promoting activity were observed; (c) a single, unique NH2-terminal amino acid sequence was obtained; (d) both growth factor and permeability-enhancing activities were immunoadsorbed using antipeptide IgG that recognized the amino terminus of VPF. Furthermore, 125I-VPF was shown to bind specifically and with high affinity to endothelial cells in vitro and could be chemically cross-linked to a high-molecular weight cell surface receptor, thus demonstrating a mechanism whereby VPF can interact directly with endothelial cells. Unlike other endothelial cell growth factors, VPF did not stimulate [3H]thymidine incorporation or promote growth of other cell types including mouse 3T3 fibroblasts or bovine smooth muscle cells. VPF, therefore, appears to be unique in its ability to specifically promote increased vascular permeability, endothelial cell growth, and angio-genesis. Images

Connolly, D T; Heuvelman, D M; Nelson, R; Olander, J V; Eppley, B L; Delfino, J J; Siegel, N R; Leimgruber, R M; Feder, J

1989-01-01

161

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.

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

2012-01-01

162

In vivo imaging-based mathematical modeling techniques that enhance the understanding of oncogene addiction in relation to tumor growth.  

PubMed

The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma. PMID:23573174

Nwabugwu, Chinyere; Rakhra, Kavya; Felsher, Dean; Paik, David

2013-03-20

163

Chronic stress promotes tumor growth through increased BDNF production and neo-innervation  

Microsoft Academic Search

Background: Activation of the sympathetic nervous system (SNS) in response to chronic biobehavioral stress results in high levels of catecholamines and persistent activation of adrenergic signaling, which promotes tumor growth and progression. However it is unknown how catecholamine levels within the tumor exceed systemic levels in circulation. I hypothesized that neo-innervation of tumors is required for stress-mediated effects on tumor

Julie K Allen

2012-01-01

164

Tumor-host interaction: Analysis of cytokines, growth factors, and tumorinfiltrating lymphocytes in ovarian carcinomas  

Microsoft Academic Search

The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients

Athir J Merogi; Aizen J Marrogi; Rajagopal Ramesh; William R Robinson; Cesar D Fermin; Scott M Freeman

1997-01-01

165

Squalamine Inhibits Angiogenesis and Solid Tumor Growth in Vivo and Perturbs Embryonic Vasculature1  

Microsoft Academic Search

The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cyto- toxic to tumor cells, does not alter mitogen production by tumor

Allen K. Sills; Jon I. Williams; Betty M. Tyler; Darin S. Epstein; Eric P. Sipos; John D. Davis; Michael P. McLane; Simon Pitchford; Kimberly Cheshire; Francis H. Gannon; William A. Kinney; Tessa L. Chao; Mark Donowitz; John Laterra; Michael Zasloff; Henry Brem

166

Notch1 and Notch2 Have Opposite Effects on Embryonal Brain Tumor Growth  

Microsoft Academic Search

The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell

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

2004-01-01

167

VCC-1, a novel chemokine, promotes tumor growth  

SciTech Connect

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

Weinstein, Edward J. [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Head, Richard [Department of Genomics and Biotechnology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Griggs, David W. [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Sun Duo [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Evans, Robert J. [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Swearingen, Michelle L. [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Westlin, Marisa M. [Department of Oncology Pharmacology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States); Mazzarella, Richard [Department of Genomics and Biotechnology, Pfizer Inc., 700 Chesterfield Parkway North, St. Louis, MO 63198 (United States)]. E-mail: richard.a.mazzarella@pfizer.com

2006-11-10

168

T model of growth and its application in systems of tumor-immune dynamics.  

PubMed

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

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

2013-06-01

169

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

PubMed

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

2009-10-05

170

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.

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

2009-01-01

171

Growth of Human Tumor Xenografts Implanted under the Renal Capsule of Normal Immunocompetent Mice  

Microsoft Academic Search

The subrenal capsule technique proved effective in demonstrating that the growth of human tumors in normal, immunocompetent animals for 6 days was quantifiable in ocular micrometer units. Positive growth was demonstrable not only with human tumors that had been established in serial transplantation in athymic nude mouse hosts, but also with primary surgical explants. Growth rates of transplantation-established xenograft systems

Arthur E. Bogden; Paula M. Haskell; Doreen J. LePage; Diane E. Kelton; William R. Cobb; Henry J. Esber

1979-01-01

172

Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice  

Microsoft Academic Search

Growth hormone releasing hormone (GHRH) is known to have multiple anabolic effects and immune-stimulatory effects. Previous studies suggest that treatment with anabolic hormones also has the potential to mitigate the deleterious effects of cancer cachexia in animals. We studied the effects of plasmid-mediated GHRH supplementation on tumor growth and the role of antitumor immune cells with two different human tumor

Amir S Khan; Louis C Smith; Ingrid W Anscombe; Kathleen K Cummings; Melissa A Pope; Ruxandra Draghia-Akli

2005-01-01

173

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

174

Tumor growth, angiogenesis and inflammation in mice lacking receptors for platelet activating factor (PAF)  

Microsoft Academic Search

Tumor growth is associated with angiogenesis and inflammation and the endogenous lipid, platelet activating factor (PAF), is a pro-inflammatory and pro-angiogenic mediator. We therefore measured tumor growth, angiogenesis and inflammation in normal (WT) mice and those lacking the receptor for PAF, through gene deletion (PAFR-KO). Growth of solid tumors derived from colon 26 cells was not altered but that from

M. A. N. D. Ferreira; L. S. Barcelos; M. M. Teixeira; Y. S. Bakhle; S. P. Andrade

2007-01-01

175

Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models  

Microsoft Academic Search

Purpose  New research findings have revealed a key role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis\\u000a in clear cell renal carcinoma (RCC) which is a highly vascularized and treatment-resistant tumor. Sorafenib (BAY 43-9006,\\u000a Nexavar®) is a multi-kinase inhibitor which targets receptor tyrosine and serine\\/threonine kinases involved in tumor progression and\\u000a tumor angiogenesis. The effect of sorafenib on

Yong S. Chang; Jalila Adnane; Pamela A. Trail; Joan Levy; Arris Henderson; Dahai Xue; Elizabeth Bortolon; Marina Ichetovkin; Charles Chen; Angela McNabola; Dean Wilkie; Christopher A. Carter; Ian C. A. Taylor; Mark Lynch; Scott Wilhelm

2007-01-01

176

Bone cancer pain: the effects of the bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis  

Microsoft Academic Search

Patients with metastatic breast, lung or prostate cancer frequently have significant bone cancer pain. In the present report we address, in a single in vivo mouse model, the effects the bisphosphonate alendronate has on bone cancer pain, bone remodeling and tumor growth and necrosis. Following injection and confinement of green fluorescent protein-transfected murine osteolytic tumor cells into the marrow space

Molly A. Sevcik; Nancy M. Luger; David B. Mach; Mary Ann C. Sabino; Christopher M. Peters; Joseph R. Ghilardi; Matthew J. Schwei; Heidi Röhrich; Carmen De Felipe; Michael A. Kuskowski; Patrick W. Mantyh

2004-01-01

177

Perfluorochemical emulsions can increase tumor radiosensitivity  

Microsoft Academic Search

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

B. A. Teicher; C. M. Rose

1984-01-01

178

Epidermal growth factor receptor expression in oligodendroglial tumors.  

PubMed Central

A series of 13 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) was studied for gene amplification and expression of the epidermal growth factor receptor gene (EGFR). EGFR gene amplification was found in only one case of anaplastic oligodendroglioma, which additionally showed a deletion/rearrangement at the 5' end of the gene. Northern blot analysis, however, revealed increases of EGFR mRNA expression relative to non-neoplastic control brain in 6 of 13 oligodendrogliomas and 10 of 18 anaplastic oligodendrogliomas. All cases with increased mRNA expression showed strong immunoreactivity for EGFR protein. Our findings thus indicate that increased expression of EGFR mRNA and protein is common in low-grade and high-grade oligodendroglial tumors and in the vast majority of cases is not caused by gene amplification. Images Figure 1 Figure 2 Figure 3

Reifenberger, J.; Reifenberger, G.; Ichimura, K.; Schmidt, E. E.; Wechsler, W.; Collins, V. P.

1996-01-01

179

Bone metabolism compensates for the delayed growth in small for gestational age neonates  

PubMed Central

The goal of the present study is to investigate the relationship between anthropometric and bone metabolism markers in a sample of neonates and their mothers. A sample of 20 SGA (small for the gestational age), AGA (appropriate for the gestational age) and LGA (large for the gestational age) term neonates and their 20 mothers was analyzed at birth and at exit. Elisa method was used to measure the OPG (Osteoprotegerin), RANK (Receptor activator of nuclear factor-kappaB), RANKL (Receptor activator of nuclear factor-kappaB Ligand), IGF-1 (Insulin-like growth factor 1), IGFBP3 (Insulin-like Growth Factor Binding Protein 3) and Leptin levels. Birth weight and length were positively correlated with RANKL, IGF-1 and IGFBP3 and negatively with the ratio OPG/RANKL. SGA neonates presented lower RANKL values and higher OPG/RANKL ratio while LGA neonates had higher RANK levels than AGA neonates. Positive association was shown between neonatal IGFBP3 and maternal IGF-1 values and between neonatal and maternal RANK values at birth and at exit. These results reveal a remarkable upregulation of OPG/RANKL ratio in SGA neonates, pointing out the role of bone turnover in compensating for the delayed neonatal growth.

Tenta, Roxane; Bourgiezi, Ifigeneia; Aliferis, Evangelos; Papadopoulou, Magdalini; Gounaris, Antonis; Skouroliakou, Maria

2013-01-01

180

Hepatocyte growth factor induces delayed STAT3 phosphorylation through interleukin-6 expression.  

PubMed

Met receptor tyrosine kinase mediates pleiotropic cellular responses following its activation by hepatocyte growth factor or scatter factor (HGF/SF). STAT3 was reported to be one of direct downstream molecules in HGF/SF-Met signaling. In the present study, however, we observed that Tyr705 of STAT3 was phosphorylated from 2 h or 6 h in NIH3T3 and Chang liver cells, respectively, after HGF/SF treatment. Blocking of the phosphorylation by cycloheximide or actinomycin D and the rapid STAT3 phosphorylation with the conditioned medium from HGF/SF-treated NIH3T3 cells suggested that a newly synthesized secretory protein was responsible for the delayed STAT3 phosphorylation. Among the known mediators to induce STAT3 phosphorylation, interleukin-6 (IL-6) mRNA and protein were induced by HGF/SF, and the released IL-6 was accumulated in the conditioned medium after HGF/SF treatment. Furthermore, the neutralizing IL-6 antibody abolished the STAT3 phosphorylation. Treatment with LY294002, a PI3 kinase inhibitor, but not with other signal inhibitors, resulted in the loss of delayed STAT3 phosphorylation by HGF/SF, showing the involvement of PI3 kinase pathway. Collectively, these results demonstrate that HGF/SF-Met signal cascade stimulates IL-6 production via PI3 kinase pathway, leading to STAT3 phosphorylation as a secondary effect. PMID:19071214

Lee, Bok-Soon; Park, Minseon; Cha, Hyun-Young; Lee, Jae-Ho

2008-11-30

181

Transient impairment or delay of urinary trihydroxypregnanone (THS) response to metyrapone in boys with delayed adolescence and in patients with isolated growth hormone deficiency.  

PubMed

Twenty three boys with delayed adolescence (age 15.7 +/- 2.0, bone age 12.4 +/- 2.1 years) were studied. Their cortisol response to insulin was normal. After oral metyrapone (500 mg/m2 by mouth) one to three consecutive 12 h urine samples were collected for analysis of THS. Thirty seven tests with 37 first, 21 second, and 11 third samples were carried out. The results could be divided into two main groups: 25 tests (group A) were subnormal in the first sample, 12 of them with a very weak (40 +/- 8 micrograms/m2/12 h) and 13 with an insufficient (191 +/- 16 micrograms/m2/12 h) THS response. Values in the second and third sample were higher, indicating a delayed response. In 12 tests (group B), the results were normal (1016 +/- 143 micrograms/M2/12 h) in the first and lower in the second and third samples. In three patients with repeated tests, there was improvement with increasing bone age. The THS-responses to metyrapone did not correlate with those of growth hormone, gonadotrophins, and TSH to stimuli. It is concluded that the THS-response to a single dose of metyrapone may be temporarily insufficient or delayed in delayed adolescence. We interpret this finding as showing transiently reduced or slow hypothalamic responsiveness. PMID:7058680

Zachmann, M; Tassinari, D; Sorgo, W; Exner, G U; Kempken, B; Prader, A

1982-02-01

182

Simulation of crack growth governed by delayed fracture mechanism under high-cycle loading  

NASA Astrophysics Data System (ADS)

The surface crack growth that results from the delayed fracture mechanism under sliding contact of two solids which gives rise to the formation of a wear particle is computed. The cyclic loading in the form of repetitions of loading and unloading under such conditions is produced by stresses distributed over widely space spots of real contact, which are passing through the site where the crack is positioned. Every passage produces a cycle or event of one loading and one complete unloading. The problem is to find the number of cycles or events from the beginning of the loading process till the critical event. A method suitable to solving the problem for large number of cycles is presented.

Gotlib, V. A.; Salganik, R. L.; Rapoport, L.

1995-10-01

183

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

184

Inhibition of tumor growth and metastasis in association with modification of immune response by novel organic germanium compounds.  

PubMed

The effects of two novel organic germanium compounds, 1-phenyl-2-carbamoylethylgermanium sesquisulfide (PCAGeS) and 1-phenyl-2-carbamoylethylgermanium sequioxide (PCAGeO), on transplantable murine tumors and immune responses were studied. Both drugs showed low toxicity for mice. In culture, neither substance displayed significant cytotoxicity against murine tumor cells L1210 leukemia, L5178Y lymphoma, or IMC carcinoma. Growth of subcutaneously transplanted IMC carcinoma or Meth-A fibrosarcoma was markedly reduced by oral administration of PCAGeS. PCAGeO exhibited a similar but smaller effect on the tumor growth. Pulmonary metastasis of Lewis lung carcinoma was inhibited by oral or intraperitoneal treatment with PCAGeS. The activity of cyclophosphamide or Adriamycin against L1210 leukemia was significantly potentiated by oral administration of PCAGeS. PCAGeS enhanced the delayed-type hypersensitivity response to sheep red blood cells (SRBC) of mice or restored the response suppressed by ascitic IMC carcinoma, but did not significantly affect the formation of antibody to SRBC. PCAGeO similarly stimulated the DTH reaction. Phagocytic activity of peritoneal macrophages was enhanced by oral treatment of mice with PCAGeS. The results suggest that PCAGeS and PCAGeO display tumor-inhibitory activity by modification of the immune mechanism. PMID:3998767

Sato, I; Yuan, B D; Nishimura, T; Tanaka, N

1985-04-01

185

Establishing Intracranial Brain Tumor Xenografts With Subsequent Analysis of Tumor Growth and Response to Therapy using Bioluminescence Imaging  

PubMed Central

Transplantation models using human brain tumor cells have served an essential function in neuro-oncology research for many years. In the past, the most commonly used procedure for human tumor xenograft establishment consisted of the collection of cells from culture flasks, followed by the subcutaneous injection of the collected cells in immunocompromised mice. Whereas this approach still sees frequent use in many laboratories, there has been a significant shift in emphasis over the past decade towards orthotopic xenograft establishment, which, in the instance of brain tumors, requires tumor cell injection into appropriate neuroanatomical structures. Because intracranial xenograft establishment eliminates the ability to monitor tumor growth through direct measurement, such as by use of calipers, the shift in emphasis towards orthotopic brain tumor xenograft models has necessitated the utilization of non-invasive imaging for assessing tumor burden in host animals. Of the currently available imaging methods, bioluminescence monitoring is generally considered to offer the best combination of sensitivity, expediency, and cost. Here, we will demonstrate procedures for orthotopic brain tumor establishment, and for monitoring tumor growth and response to treatment when testing experimental therapies.

Ozawa, Tomoko; James, C. David

2010-01-01

186

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

NASA Astrophysics Data System (ADS)

In the past years different models have been formulated to explain the growth of gliomas in the brain. The most accepted model is based on a reaction-diffusion equation that describes the growth of the tumor as two separate components- a proliferative component and an invasive component. While many improvements have been made to this basic model, the work exploring the factors that naturally inhibit growth is insufficient. It is known that stress fields affect the growth of normal tissue. Due to the rigid skull surrounding the brain, mechanical stress might be an important factor in inhibiting the growth of gliomas. A realistic model of glioma growth would have to take that inhibitory effect into account. In this work a mathematical model based on the reaction-diffusion equation was used to describe tumor growth, and the affect of mechanical stresses caused by the mass effect of tumor cells was studied. An initial tumor cell concentration with a Gaussian distribution was assumed and tumor growth was simulated for two cases- one where growth was solely governed by the reaction-diffusion equation and second where mechanical stress inhibits growth by affecting the diffusivity. All the simulations were performed using the finite difference method. The results of simulations show that the proposed mechanism of inhibition could have a significant affect on tumor growth predictions. This could have implications for varied applications in the imaging field that use growth models, such as registration and model updated surgery.

Garg, Ishita; Miga, Michael I.

2008-04-01

187

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.

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

2012-01-01

188

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

PubMed

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

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

2011-08-01

189

Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect  

Microsoft Academic Search

Background: The unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, ''aerobic glycolysis'' generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage. Methods\\/Findings:

Yijun Chen; Rob Cairns; Ioanna Papandreou; Albert Koong; Nicholas C. Denko

2009-01-01

190

Preventing Growth of Brain Tumors by Creating a Zone of Resistance  

Microsoft Academic Search

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

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

2008-01-01

191

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

192

Portal vein ligation accelerates tumor growth in ligated, but not contralateral lobes  

PubMed Central

AIM: To investigate the mechanisms of liver growth and atrophy after portal vein ligation (PVL) and its effects on tumor growth. METHODS: Mice were subjected to PVL, partial hepatectomy, or sham surgery. The morphological alterations, activation of transcription factors, and expression of cytokines and growth factors involved in liver regeneration were evaluated. In a separate set of experiments, murine colorectal carcinoma cells were injected via the portal vein and the effect of each operation on liver tumor growth was studied. RESULTS: Liver regeneration after PVL and partial hepatectomy were very similar. In ligated lobes, various cytokines, transcription factors and regulatory factors were significantly upregulated compared to non-ligated lobes after PVL. Atrophy in ligated lobes was a result of early necrosis followed by later apoptosis. Tumor growth was significantly accelerated in ligated compared to non-ligated lobes. CONCLUSION: Tumor growth was accelerated in ligated liver lobes and appeared to be a result of increased growth factor expression.

Sakai, Nozomu; Clarke, Callisia N; Schuster, Rebecca; Blanchard, John; Tevar, Amit D; Edwards, Michael J; Lentsch, Alex B

2010-01-01

193

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

Microsoft Academic Search

Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important

Xin Li; Jinhui Liao; Amy J. Koh; William D. Sadler; Kenneth J. Pienta; Thomas J. Rosol; Laurie K. McCauley

2011-01-01

194

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

National Technical Information Service (NTIS)

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 ...

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

1993-01-01

195

On the probability of random genetic mutations for various types of tumor growth.  

PubMed

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

Tomasetti, Cristian

2012-02-07

196

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

PubMed Central

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

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

2008-01-01

197

Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model  

PubMed Central

Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-?, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor growth and for testing strategies to improve clinical effectiveness.

Oflazoglu, Ezogelin; Elliott, Mark; Takita, Hiroshi; Ferrone, Soldano; Henderson, Robert A; Repasky, Elizabeth A

2007-01-01

198

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

PubMed Central

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

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

2012-01-01

199

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

2013-02-04

200

Are Short Boys with Constitutional Delay of Growth and Puberty Candidates for rGH Therapy according to FDA Recommendations?  

Microsoft Academic Search

Background\\/Aims: According to FDA-approved guidelines, boys whose height predictions fall to 160 cm or less are considered for treatment with recombinant growth hormone (rGH). The aim of this study was to analyze the value of different height prediction methods by accurately identifying those boys with constitutional delay of growth and puberty (CDGP) in whom final height (FH) prognosis was poor

E. Krajewska-Siuda; E. Malecka-Tendera; K. Krajewski-Siuda

2006-01-01

201

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.

202

Effect of Protein Intake on Tumor Growth and Cell Cycle Kinetics  

Microsoft Academic Search

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

Michael H. Torosian

1995-01-01

203

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

2011-10-07

204

Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth.  

PubMed

Mesenchymal stem cells (MSCs) have opposite effects on tumor growth, being able either to favor angiogenesis and tumor initiation or to inhibit progression of established tumors. Factors produced by MSCs within the tumor microenvironment may be relevant for their biological effects. Recent studies demonstrated that microvesicles (MVs) are an integral component of inter-cellular communication within the tumor microenvironment. In the present study, we evaluated whether MVs derived from human bone marrow MSCs may stimulate or inhibit in vitro and in vivo growth of HepG2 hepatoma, Kaposi's sarcoma, and Skov-3 ovarian tumor cell lines. We found that MVs inhibited cell cycle progression in all cell lines and induced apoptosis in HepG2 and Kaposi's cells and necrosis in Skov-3. The observed activation of negative regulators of cell cycle may explain these biological effects. In vivo intra-tumor administration of MVs in established tumors generated by subcutaneous injection of these cell lines in SCID mice significantly inhibited tumor growth. In conclusion, MVs from human MSCs inhibited in vitro cell growth and survival of different tumor cell lines and in vivo progression of established tumors. PMID:23034046

Bruno, Stefania; Collino, Federica; Deregibus, Maria Chiara; Grange, Cristina; Tetta, Ciro; Camussi, Giovanni

2012-11-19

205

Stromal impact on tumor growth and lymphangiogenesis in human carcinoma xenografts  

PubMed Central

Squamous cell carcinomas (SCCs) arising in the oral cavity are associated with poor survival, mainly due to metastatic disease. In contrast, skin SCCs rarely metastasize and are usually curable. To study influence of tongue and skin stroma on cancer growth and induction of lymphangiogenesis, xenograft tumors of human carcinoma cells were established either in tongue or skin of BALB/c nude mice. Two oral and two skin SCC cell lines were used, as well as an endometrial adenocarcinoma cell line. Tongue tumors established from all cell lines were larger than corresponding skin tumors. Peritumoral lymphatic vessel density was up to five times higher in tongue than in corresponding skin tumors, and mRNA level of the lymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C was twice as high in tongue tumors compared with corresponding skin tumors. Contrary to lymphatic vessel density, blood vessel density was higher in skin tumors than in tongue tumors. In a cohort of patient samples, lymphatic vessel density was found to be higher in tongue SCCs compared with skin SCCs, supporting a clinical relevance of our findings. Our results show that the tumor stroma has a profound impact on cancer growth and induction of lymphangiogenesis and angiogenesis. The difference in lymphatic vessel density between tongue and skin tumors may be important in directing metastatic potential of tumors arising in these organs.

Wetting, Hilde Ljones; Rikardsen, Oddveig; Steigen, Sonja E.; Kanapathippillai, Premasany; Grenman, Reidar; Winberg, Jan-Olof; Svineng, Gunbj?rg; Uhlin-Hansen, Lars

2010-01-01

206

Dendritic Cell-Tumor Fusion Vaccine Prevents Tumor Growth in Vivo  

Microsoft Academic Search

Dendritic cells (DCs) are potent antigen presenting cells that are uniquely effective in generating primary immune responses. DCs that are manipulated to present tumor antigens induce antitumor immunity in animal models and preclinical human studies. A myriad of strategies have been developed to load tumor antigen effectively onto DCs. DC-tumor fusion presents a spec- trum of tumor-associated antigens to helper

Gi-Young KIM; Ho-Jin CHAE; Ki-Hyung KIM; Man-Soo YOON; Kyu-Sub LEE; Chang-Min LEE; Dong-Oh MOON; Jun-Sik LEE; Young-Il JEONG; Yung Hyun CHOI; Yeong-Min PARK

2007-01-01

207

Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms  

Microsoft Academic Search

Objectives: Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed

Indraneel Banerjee; Julie A Trueman; Catherine M Hall; David A Price; Leena Patel; Andrew J Whatmore; Joel N Hirschhorn; Andrew P Read; Mark R Palmert; Peter E Clayton

2006-01-01

208

Effects of delayed metamorphosis on larval competence, and postlarval survival and growth of abalone Haliotis discus hannai  

Microsoft Academic Search

The effects of delayed metamorphosis on larval competence, and the postlarval survival and growth of Haliotis discus hannai (H. discus hannai) were examined. Competent larvae were induced to metamorphose at 5, 10, 15, and 19 days after fertilization by the addition of 1 ?M ?-aminobutyric acid (GABA). Larvae in another group were maintained until individuals metamorphosed spontaneously. Metamorphosed individuals (postlarvae)

Hideki Takami; Tomohiko Kawamura; Yoh Yamashita

2002-01-01

209

Inoculated mammary carcinoma-associated fibroblasts: contribution to hormone independent tumor growth  

PubMed Central

Background Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth. Methods Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points. Conclusions Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.

2010-01-01

210

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

PubMed Central

Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage inflammatory protein-2, vascular endothelial growth factor, transforming growth factor-beta and IL-6) was increased. Conclusion These results indicate that BM-MSCs promote tumor growth and suggest that the crosstalk between tumor cells and BM-MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.

2013-01-01

211

Effects of Epigallocatechin-3-gallate (EGCG) on A549 Lung Cancer Tumor Growth and Angiogenesis.  

PubMed

Epigallocatechin 3-gallate (EGCG) has cytotoxic effects in many cancer cells. It has been reported that A549 lung cancer cells are markedly resistant to cell death induced by EGCG. In the present study, the effects of EGCG on A549 lung cancer cell growth and angiogenesis were studied. We found that EGCG dose-dependently suppressed A549 cell growth, while A549 cells were markedly resistant to cell death in vitro. Next we found that EGCG increased endostatin expression and suppressed vascular endothelial growth factor (VEGF) expression. We further studied to determine whether EGCG would suppress A549 tumor growth in nude mouse and angiogenesis. EGCG in drinking water significantly suppressed A549 tumor growth in nude mice. Histological analysis revealed that the number of CD34 positive vessels had a tendency to decrease in the tumor. In sum, EGCG had anti-proliferative effects of A549 on tumor growth and showed a tendency to suppress angiogenesis. PMID:24018658

Sakamoto, Yuhi; Terashita, Nobuhiro; Muraguchi, Takashi; Fukusato, Toshio; Kubota, Shunichiro

2013-09-07

212

Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors  

Microsoft Academic Search

Previously, we have shown that insulin-like growth factor binding protein-7 (IGFBP-7) expression is inversely correlated with\\u000a disease progression in breast cancer and is associated with poor outcome. To further investigate the role of IGFBP-7 in the\\u000a growth and metastatic behavior of breast cancer, primary breast tumors and metastatic tumors derived from the same patients\\u000a were analyzed for IGFBP-7 expression. Immunohistochemical

Y. Amemiya; W. Yang; T. Benatar; S. Nofech-Mozes; A. Yee; H. Kahn; C. Holloway; Arun Seth

2011-01-01

213

Stimulation of tumor growth in adult rats in vivo during an acute fast.  

PubMed

These experiments investigate an increase in tumor growth that occurs in adult rats in vivo during an acute fast. The effects of feeding, fasting, and underfeeding on the growth of Morris hepatomas 5123C and 7288CTC in Buffalo rats and of Walker carcinoma 256 and Jensen sarcoma in Sprague-Dawley rats were studied. Animals were matched for tumor size and growth during a period of ad libitum feeding preceding the fasting or underfeeding. Tumor growth was documented by increased size and incorporation of [methyl-3H]thymidine into tumor DNA. Fasting increased the rate of growth of the tumors 3 to 4 times over that measured in fed rats. This effect began during the first day of fasting and ended abruptly on refeeding. After refeeding tumor growth slowed to the rate in fed rats. Tumors from fed or fasted rats were not different in cellularity or dry weight/g wet weight. A positive growth response in the tumor required lipolysis and ketosis in the host. No stimulation was observed during an acute fast in either immature rats or in mature rats whose weights had been reduced by underfeeding. These animals have small fat stores and show no increase in arterial blood free fatty acid or ketone body concentrations during an acute fast. Finally, underfeeding of adult rats raised the blood concentrations of these nutrients to values that were intermediate between those in fasted and fed rats. Tumor growth rates in these rats were intermediate between those in fasted and fed rats. The results support the proposal that an increase in availability of free fatty acids and/or ketone bodies is the stimulus that increases the rate of tumor growth during an acute fast. PMID:3708579

Sauer, L A; Nagel, W O; Dauchy, R T; Miceli, L A; Austin, J E

1986-07-01

214

T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor  

PubMed Central

The results of this paper are consistent with the hypothesis that progressive growth of the Meth A fibrosarcoma evokes the generation of a T-cell-mediated mechanism of immunosuppression that prevents this highly immunogenic tumor from being rejected by its immunocompetent host. It was shown that it is possible to cause the regression of large, established Meth A tumors by intravenous infusion of tumor- sensitized T cells from immune donors, but only if the tumors are growing in T-cell-deficient recipients. It was also shown that the adoptive T-cell-mediated regression of tumors in such recipients can be prevented by prior infusion of splenic T cells from T-cell-intact, tumor-bearing donors. The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression. Because the presence of suppressor T cells generated in response to the Meth A did not suppress the capacity of Meth A-bearing mice to generate and express immunity against a tumor allograft, it is obvious that they were not in a state of generalized immunosuppression.

1980-01-01

215

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

216

IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts.  

PubMed

Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc (Min/+) mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis. PMID:23764754

Hamilton, Kathryn E; Noubissi, Felicite K; Katti, Prateek S; Hahn, Christopher M; Davey, Sonya R; Lundsmith, Emma T; Klein-Szanto, Andres J; Rhim, Andrew D; Spiegelman, Vladimir S; Rustgi, Anil K

2013-06-12

217

Preclinical development of a novel class of CXCR4 antagonist impairing solid tumors growth and metastases.  

PubMed

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; Ieranò, Caterina; Napolitano, Maria; Riccio, Anna; Polimeno, Maria Neve; Monfregola, Luca; Barbieri, Antonio; Luciano, Antonio; Ciarmiello, Andrea; Arra, Claudio; Castello, Giuseppe; Amodeo, Pietro; Scala, Stefania

2013-09-13

218

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.

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

219

Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro.  

PubMed

Extracts of Viscum album (mistletoe) are widely used as complementary cancer therapies in Europe. The mistletoe lectins have been identified as the main active principle of mistletoe extracts. They have been shown to exhibit cytotoxic effects as well as immunomodulatory activities. The latter is exemplified by induction of cytokine secretion and increased activity of natural killer cells. Recent reports, however, indicated possible tumor growth stimulation by mistletoe extracts. Therefore, the three aqueous mistletoe extracts (Iscador M special, Iscador Qu special and Iscador P) were evaluated for antiproliferative and/or stimulatory effects in a panel of 16 human tumor cell lines in vitro using a cellular proliferation assay. The results show no evidence of stimulation of tumor growth by any of the three Iscador preparations, comprising central nervous system, gastric, non-small cell lung, mammary, prostate, renal and uterine cancer cell lines, as well as cell lines from hematological malignancies and melanomas. On the contrary, Iscador preparations containing a high lectin concentration (Iscador M special and Iscador Qu special) showed antitumor activity in the mammary cancer cell line MAXF 401NL at the 15 microg/ml dose level with a more than 70% growth inhibition compared to untreated control cells. In addition, a slight antitumor activity (growth inhibition 30-70%) was found in three tumor cell lines for Iscador M special and in seven tumor cell lines for Iscador Qu special, respectively. Iscador P, which contains no mistletoe lectin I, showed no antiproliferative activity. PMID:11984083

Maier, Gerhard; Fiebig, Heinz-Herbert

2002-04-01

220

Induction of senescence-associated growth inhibitors in the tumor-suppressive function of retinoids.  

PubMed

Retinoids, physiological regulators of cell growth and differentiation, are used in the treatment or chemoprevention of several malignant diseases. This class of compounds can induce growth arrest or apoptosis in tumor cells. Permanent growth arrest of retinoid-treated cells is often assumed to result from retinoid-induced differentiation. Recent studies in breast carcinoma and neuroblastoma cells demonstrated that retinoids can stop tumor cell growth through the program of senescence rather than differentiation. Retinoid-induced tumor suppression is associated with the induction of multiple intracellular and secreted growth-inhibitory proteins. Most of these proteins were also found to be upregulated in senescent cells. The induction of senescence-associated growth inhibitors appears to be an indirect effect of retinoids. Elucidation of the mechanisms responsible for the induction of growth-inhibitory genes in retinoid-treated cells should help in developing agents that would mimic the antiproliferative effect of retinoids in retinoid-insensitive cancers. PMID:12461777

Roninson, Igor B; Dokmanovic, Milos

2003-01-01

221

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

PubMed Central

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 ?-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; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

2011-01-01

222

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

NSDL National Science Digital Library

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

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

2010-06-18

223

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

NASA Astrophysics Data System (ADS)

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

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

1980-07-01

224

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

PubMed

The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a "lethal" aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia. PMID:21051947

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

2010-11-30

225

Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice.  

PubMed

Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non-tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. PMID:18519694

Dineen, Sean P; Lynn, Kristi D; Holloway, Shane E; Miller, Andrew F; Sullivan, James P; Shames, David S; Beck, Adam W; Barnett, Carlton C; Fleming, Jason B; Brekken, Rolf A

2008-06-01

226

Intussusceptive Microvascular Growth in a Human Colon Adenocarcinoma Xenograft: A Novel Mechanism of Tumor Angiogenesis  

Microsoft Academic Search

Intussusceptive microvascular growth refers to vascular network formation by insertion of interstitial tissue columns, called tissue pillars or posts, into the vascular lumen and subsequent growth of these columns, resulting in partitioning of the vessel lumen. While intussusception has been reported in normal developing organs, its existence in solid tumors has not been previously documented. By observing the growth of

Sybill Patan; Lance L. Munn; Rakesh K. Jain

1996-01-01

227

Enhanced Growth of Primary Tumors in Cancer-Prone Mice after Immunization against the Mutant Region of an Inherited Oncoprotein  

PubMed Central

One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC × C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with Arg12 mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg12 mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitivity to the peptide. Immunization with CFA alone or with a different Arg12 mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg12 mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4+ T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg12 mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene–expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.

Siegel, Christopher T.; Schreiber, Karin; Meredith, Stephen C.; Beck-Engeser, Gabriele B.; Lancki, David W.; Lazarski, Christopher A.; Fu, Yang-Xin; Rowley, Donald A.; Schreiber, Hans

2000-01-01

228

Defined tumor cell-host interactions are necessary for malignant growth.  

PubMed

Analyzing the different steps of malignant growth (primary tumor, metastasizing tumor cells, secondary tumor), one recognizes an intense interaction between normal and malignant cells. Tumor cells not only induce activities of normal cells, which normally are rarely activated, but also they exploit properties of normal cells for their own purposes. The major mechanisms and processes of this "parasitism" are described in more detail and the results are discussed. Tumors cannot grow beyond a certain size without a supply of blood and lymph vessels by the host (angiogenesis). Metastasizing tumor cells cannot leave the vessel (extravasate) in which they are transported without the cooperation of the respective endothelial cells of the host. An appropriate environment formed by the host tissues is essential for the settlement of tumor cells at secondary sites. Historically, these are a few examples that show intense cooperation between host and tumor. More are given in the present contribution. PMID:7948109

Paweletz, N; Boxberger, H J

1994-01-01

229

Napsin A and Thyroid Transcription Factor-1-Positive Cerebellar Tumor with Epidermal Growth Factor Receptor Mutation  

PubMed Central

We present a very rare case of cerebellar metastasis of unknown origin, in which a primary lung adenocarcinoma was diagnosed by pathological examination of a cerebellar metastatic tumor, using immunohistochemical markers and epidermal growth factor receptor (EGFR) mutation of primary lung cancer. A 69-year-old woman was admitted to our hospital because of a hemorrhagic cerebellar tumor and multiple small brain tumors. She underwent cerebellar tumor resection. On pathological examination, the tumor was diagnosed as adenocarcinoma. However, the primary tumor site was unidentifiable even with several imaging inspections. On immunohistochemical analysis, the resected tumor was positive for napsin A and thyroid transcription factor-1. In addition, an EGFR mutation was detected in the tumor. Therefore, primary lung cancer was diagnosed and the patient was started on gefitinib (250 mg/day) therapy.

Kuwata, Taiji; Iwata, Teruo; Iwanami, Takashi

2011-01-01

230

An Analysis of Trends and Growth Factor Receptor Expression of GI Carcinoid Tumors  

PubMed Central

The purpose of our study was twofold: 1) to determine the incidence, patient and tumor characteristics, and outcome of patients with GI carcinoid tumors using the Surveillance, Epidemiology and End Results (SEER) database, and 2) to delineate the expression pattern of growth factor receptors (GFRs) in carcinoid tumors. The SEER database search provided information on patients diagnosed with carcinoid tumors from 1990–2002. Carcinoid tumor sections (n = 46) were stained for the GFRs: epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), vascular endothelial growth factor receptor (VEGFR), and HER-2/neu. Over the 12 year analysis period, 18,180 patients were identified with carcinoid tumors of the foregut, midgut, and hindgut; the incidence of carcinoid tumors increased ~2-fold during this time period. Of the patients with carcinoid tumors, there was a trend of increased expression of VEGF-R and IGF-R, particularly in the foregut and midgut carcinoids. Analysis of the SEER database confirms that the incidence of carcinoid tumors is increasing with an approximate doubling in the number of carcinoid cases from 1990–2002. Furthermore, an increase in VEGF-R and IGF-R expression suggests that GFR inhibitors may be effective adjuvant therapy for carcinoid cancer.

Bowen, Kanika A.; Silva, Scott R.; Johnson, Jessica N.; Doan, Hung Q.; Jackson, Lindsey N.; Gulhati, Pat; Qiu, Suimin; Riall, Taylor S.; Evers, B. Mark

2009-01-01

231

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.

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

2012-01-01

232

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

PubMed Central

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

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

2012-01-01

233

Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed I?B kinase activation.  

PubMed

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; Habelhah, Hasem

2013-03-04

234

MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis.  

PubMed

Mitogen-activated protein kinase kinase kinase 3 (MEKK3) plays an essential role in embryonic angiogenesis, but its role in tumor growth and angiogenesis is unknown. In this study, we further investigated the role of MEKK3 in embryonic angiogenesis, tumor angiogenesis, and angiogenic factor production. We found that endothelial cells from Mekk3-deficient embryos showed defects in cell proliferation, apoptosis, and interactions with myocardium in the heart. We also found that MEKK3 is required for angiopoietin-1 (Ang1)-induced p38 and ERK5 activation. To study the role of MEKK3 in tumor growth and angiogenesis, we established both wild-type and Mekk3-deficient tumor-like embryonic stem cell lines and transplanted them subcutaneously into nude mice to assess their ability to grow and induce tumor angiogenesis. Mekk3-deficient tumors developed and grew similarly as control Mekk3 wild-type tumors and were also capable of inducing tumor angiogenesis. In addition, we found no differences in the production of VEGF in Mekk3-deficient tumors or embryos. Taken together, our results suggest that MEKK3 plays a critical role in Ang1/Tie2 signaling to control endothelial cell proliferation and survival and is required for endothelial cells to interact with the myocardium during early embryonic development. However, MEKK3 is not essential for tumor growth and angiogenesis. PMID:17687003

Deng, Yong; Yang, Jianhua; McCarty, Marya; Su, Bing

2007-08-08

235

Inhibition of Tumor Growth and Angiogenesis by Soluble EphB41  

PubMed Central

Abstract EphB receptors and their ephrinB ligands play a key role in the formation of a regular vascular system. Recent studies have also shown the involvement of Eph/ephrin interactions in malignant tumor progression and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4)-expressing A375 melanoma cells to study the effect of dominant negatively acting sEphB4 on tumor growth and angiogenesis. Soluble EphB4-expressing A375 tumors grown subcutaneously in nude mice show dramatically reduced tumor growth compared to control tumors. The proliferative capacity of sEphB4-expressing cells in monolayer culture is not altered. Yet, sEphB4-expressing A375 cells cannot establish proper cell-cell contacts in three-dimensional spheroids. However, sEphB4 transfectants have reduced proliferation and apoptosis rates when grown in three-dimensional culture in vitro or in subcutaneous tumors in vivo. Analysis of the vascular phenotype of the tumors revealed a reduction of intratumoral microvessel density in sEphB4-expressing tumors. Corresponding to these mouse experiments, a matched pair analysis of EphB4 and ephrinB2 expression in human colon carcinomas revealed significantly upregulated levels of EphB4 expression compared to adjacent normal tissue. Taken together, the data identify dual effects of sEphB4 on the tumor and the vascular compartment that collectively inhibit tumor growth.

Martiny-Baron, Georg; Korff, Thomas; Schaffner, Florence; Esser, Norbert; Eggstein, Stefan; Marme, Dieter; Augustin, Hellmut G

2004-01-01

236

Stimulation of tumor growth in adult rats in vivo during acute streptozotocin-induced diabetes.  

PubMed

The effects of acute diabetes mellitus on the growth of Morris hepatoma 7288CTC and Jensen sarcoma were studied in fed, young (less than 200 g), and adult (greater than 250 g) rats. Animals were matched for tumor size and growth; the rates of tumor growth were the same in fed, young and adult nondiabetic rats. Diabetes was induced by the i.v. injection of streptozotocin (65 mg/kg total body weight) into tumor-bearing rats and changes in arterial blood nutrient concentrations were compared to changes in the rates of tumor growth and DNA synthesis. In young rats acute diabetes did not increase the blood concentrations of the fat store-derived nutrients and did not increase the rate of tumor growth. In adult rats, however, acute diabetes raised the arterial blood free fatty acid, glycerol, triglyceride, and ketone body concentrations to high levels and increased the rate of tumor growth about three times over that observed in untreated rats. Progress curves for the mobilization of host fat stores and for incorporation of [methyl-3H]thymidine into tumor DNA during the onset of diabetes showed that these activities were closely correlated in adult rats. Both processes began to increase 2 to 4 h after streptozotocin treatment, reached an initial peak at 12 to 16 h, decreased to a low point at 18 to 20 h, and then increased again to the new steady state after 23 to 24 h. The results indicate that the rate of tumor growth in rats in vivo is limited by the availability of a substance(s) present in the hyperlipemic blood of adult diabetic rats. The tight relationship between host lipolysis and tumor growth suggests that the substance(s) is derived from host fat stores. PMID:3815372

Sauer, L A; Dauchy, R T

1987-04-01

237

tert-Butyl hydroperoxide, an organic peroxide, causes temporary delay in hair growth in a neonatal rat model  

PubMed Central

Summary tert-Butyl hydroperoxide (tBHP), an organic peroxide, has been shown to cause irreversible damage to keratinocytes in vitro with prolonged administration at high concentrations, and reversible damage with short-term administration at low concentrations. To investigate the effects of tBHP on keratinocytes in vivo, we analysed hair growth in tBHP-treated neonatal rats. Sprague–Dawley and Long–Evans rat pups were injected subcutaneously with tBHP or vehicle once daily for 6 days, and hair growth was monitored. The tBHP-treated rats had a significant delay in hair growth. However, this delay reversed within days, and the hair coats, including hair pigmentation, of tBHP-treated and sham-treated rats were indistinguishable 2 weeks later. Histological analysis and BrdU labelling of S phase cells confirmed the delay in hair-follicle growth and its reversal in tBHP-treated rats. Our results indicated that the changes incurred in hair follicles by short-term use of high-dose oxidants in vivo are temporary and reversible.

Wikramanayake, T. C.; Simon, J.; Mauro, L. M.; Perez, C. I.; Roberts, B.; Elgart, G.; Alvarez-Connelly, E.; Schachner, L. A.; Jimenez, J. J.

2011-01-01

238

Deletion of cyclooxygenase 2 in mouse mammary epithelial cells delays breast cancer onset through augmentation of type 1 immune responses in tumors.  

PubMed

Inhibition of cyclooxygenase (COX) 2, which is associated with >40% of breast cancers, decreases the risk of tumorigenesis and breast cancer recurrence. To study the role of COX-2 in breast cancer, we engineered mice that lack selectively mammary epithelial cell (MEC) COX-2 (COX-2 KO(MEC)). Compared with wild type (WT), MEC from COX-2 KO(MEC) mice expressed >90% less COX-2 messenger RNA (mRNA) and protein and produced 90% less of the dominant pro-oncogenic COX-2 product, prostaglandin (PG) E(2). We confirmed COX-2 as the principle source of PGE(2) in MEC treated with selective COX-2 and COX-1 inhibitors. Tumors were induced in mice using medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene. Breast cancer onset was significantly delayed in COX-2 KO(MEC) compared with WT (P = 0.03), equivalent to the delay following systemic COX-2 inhibition with rofecoxib. Compared with WT, COX-2 KO(MEC) tumors showed increased mRNA for Caspase-3, Ki-67 and common markers for leukocytes (CD45) and macrophages (F4/80). Analysis of multiple markers/cytokines, namely CD86, inducible nitric oxide synthase (iNOS), interleukin-6, tumor necrosis factor ? (TNF?) and Tim-3 indicated a shift toward antitumorigenic type 1 immune responses in COX-2 KO(MEC) tumors. Immunohistochemical analysis confirmed elevated expression of CD45, F4/80 and CD86 in COX-2 KO(MEC) tumors. Concordant with a role for COX-2 in restraining M1 macrophage polarization, CD86 and TNF? expression were offset by exogenous PGE(2) in bone marrow-derived macrophages polarized in vitro to the M1 phenotype. Our data reveal the importance of epithelial COX-2 in tumor promotion and indicate that deletion of epithelial COX-2 may skew tumor immunity toward type 1 responses, coincident with delayed tumor development. PMID:21771729

Markosyan, Nune; Chen, Edward P; Ndong, Victoire N; Yao, Yubing; Sterner, Christopher J; Chodosh, Lewis A; Lawson, John A; Fitzgerald, Garret A; Smyth, Emer M

2011-07-18

239

Initiation of Liver Growth by Tumor Necrosis Factor: Deficient Liver Regeneration in Mice Lacking Type I Tumor Necrosis Factor Receptor  

Microsoft Academic Search

The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected

Yasuhiro Yamada; Irina Kirillova; Jacques J. Peschon; Nelson Fausto

1997-01-01

240

Complete Inhibition of Rhabdomyosarcoma Xenograft Growth and Neovascularization Requires Blockade of Both Tumor and Host Vascular Endothelial Growth Factor  

Microsoft Academic Search

Growth of the human rhabdomyosarcoma A673 cell line in nude mice is substantially reduced but not completely suppressed after systemic administration of the antihuman vascular endothelial growth factor (VEGF) monoclonal antibody (Mab) A.4.6.1. Potentially, such escape might be attributable to incomplete local penetration of the antibody because of a diffusion barrier associated with tumor growth. Alterna- tively, it might reflect

Hans-Peter Gerber; Joe Kowalski; Daniel Sherman; David A. Eberhard; Napoleone Ferrara

2000-01-01

241

Tumor growth in experimental animals: nutritional manipulation and chemotherapeutic response in the rat.  

PubMed Central

The effects of nutritional manipulation on host body weight dynamics, tumor growth patterns and host-tumor responses to chemotherapy were studied in Sprague-Dawley rats with Walker-256 carcinosarcomas. Group I maintained throughout on a regular diet (RD) gained carcass weight steadily. Group II lost carcass weight while fed a protein-free diet (PFD) but rapidly gained weight after switching to RD on day 15. Mean tumor volume increased 105% in Group I from day 15 to 21, 218% in Group II and 77% in Group III (continued on PFD p less than 0.05). From day 21 to day 33 tumor growth patterns were similar in Groups I and II, while mean tumor volume eventually plateaued in Group III. In Study B, Group II animals were given Methotrexate (MTX-20 mg/kg) two days and six days after switching from PFD to RD. The mean change in tumor volume in the MTX-treated rats was 1.31 +/- 0.1 cm3 compared with 8.14 +/- 0.1 cm3 (p less than 0.001) in the saline-treated control rats. MTX did not significantly affect tumor growth patterns in Group III (PFD) rats. In Study A, protein-calorie malnutrition resulted in host carcass weight loss and tumor growth retardation while nutritional repletion restored host carcass weight and stimulated tumor growth. In Study B, MTX was maximally effective in tumor-bearing rats that were switched from PFD to RD demonstrating that nutritional manipulation can improve host nutritional status and increase tumor response to chemotherapy.

Daly, J M; Reynolds, H M; Rowlands, B J; Dudrick, S J; Copeland, E M

1980-01-01

242

Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis.  

PubMed

Intussusceptive microvascular growth refers to vascular network formation by insertion of interstitial tissue columns, called tissue pillars or posts, into the vascular lumen and subsequent growth of these columns, resulting in partitioning of the vessel lumen. While intussusception has been reported in normal developing organs, its existence in solid tumors has not been previously documented. By observing the growth of the human colon adenocarcinoma (LS174T) in vivo for a period of 6 weeks, we demonstrate that intussusception is an important mechanism of tumor angiogenesis. At the leading edge of the tumor, vascular growth was found to occur by both intussusception and endothelial sprouting. In the stabilized regions, intussusception led to network remodeling and occlusion of vascular segments. The formation of some tissue pillars appears to depend on intravascular blood-flow patterns or changes in intravascular shear stress. The rapid vascular remodeling by intussusception could possibly contribute to intermittent blood flow in tumors. PMID:8778579

Patan, S; Munn, L L; Jain, R K

1996-03-01

243

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.

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

2011-01-01

244

Functional analysis of tumor cell growth and clearance in living animals  

NASA Astrophysics Data System (ADS)

Evaluation of antineoplastic therapies would be enhanced by sensitive methods that noninvasively asses both tumor location and neoplastic growth kinetics in living animals. Since light is transmitted through mammalian tissues, it was possible to externally monitor growth and regression of luciferase labeled murine tumor cells engrafted into immunodeficient mice. External quantification of tumor burden revealed the biological impact of the chemotherapeutic agent cyclophosphamide on the kinetics of tumor growth in living animals. Therapeutic activity was apparent but this drug did not eliminate the NIH 3T3 cell signal over the 28 d time course. This novel, noninvasive system allowed sensitive, real time spatiotemporal analyses of neoplastic cell growth and may facilitate rapid optimization of effective therapeutic treatment regimes.

Sweeney, Thomas J.; Mailaender, V.; Tucker, Amanda A.; Olomu, A. B.; Zhang, Weisheng; Negrin, Robert S.; Contag, Christopher H.

1999-07-01

245

Transforming Growth Factor Beta Regulation of Tumor Progression in Metastatic Cancer.  

National Technical Information Service (NTIS)

During the metastatic tumor development, osteoclasts differentiate in the presence of high transforming growth factor beta (TGF-beta) concentrations. We hypothesize that TGF-beta is a survival factor for TGF-beta-induced osteoclasts. We tested our hypothe...

M. J. Oursler

2004-01-01

246

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

Microsoft Academic Search

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

Jill M. Manske; Summer E. Hanson

2005-01-01

247

Analysis, forecasting, and control of three-dimensional tumor growth and treatment.  

PubMed

The main point of this contribution is to show how ideas of control theory, automata theory and computer science can be applied to the field of cancer research. We are stressing the modelling of three-dimensional tumor growth and the simulation of different kinds of tumor therapy (surgery, radiation therapy, chemotherapy). In the future it will be possible to schedule the optimized methods and time of tumor treatment by computer simulation prior to clinical therapy. PMID:6512442

Düchting, W; Vogelsaenger, T

1984-10-01

248

Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect  

Microsoft Academic Search

BackgroundThe unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, “aerobic glycolysis” generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage.Methods\\/FindingsWe carried out

Yijun Chen; Rob Cairns; Ioanna Papandreou; Albert Koong; Nicholas C. Denko; Mikhail V. Blagosklonny

2009-01-01

249

Naftopidil, a selective {alpha}1-adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma.  

PubMed

In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha(1)-adrenoceptor (?(1)-AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G(1) cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective ?(1)-AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and ?(1)-AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G(1) cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells. PMID:21205739

Hori, Yasuhide; Ishii, Kenichiro; Kanda, Hideki; Iwamoto, Yoichi; Nishikawa, Kohei; Soga, Norihito; Kise, Hideaki; Arima, Kiminobu; Sugimura, Yoshiki

2011-01-01

250

Cerebrospinal Fluid (Vascular Endothelial Growth Factor) and Serologic (Recoverin) Tumor Markers for Malignant Glioma  

Microsoft Academic Search

Background: Clinically useful tumor markers have yet to be identified for malignant glioma. We report on two potential novel tumor markers, vascular endothelial growth factor (VEGF) and recoverin (protein A). VEGF is a highly specific endothelial cell activator that induces angiogenesis both in vivo and in vitro. Our study was designed to assess whether VEGF could be measured in the

Prakash Sampath; Charles E. Weaver; Arno Sungarian; Selina Cortez; Lloyd Alderson; Edward G. Stopa

2004-01-01

251

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

Microsoft Academic Search

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

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

2000-01-01

252

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.

253

Preferential growth of metastatic tumors at the pleural surface of mouse lung  

Microsoft Academic Search

In an experimental model of lung metastasis we have observed that more metastatic tumors are located on the pleura of the lung than in the parenchyma. To study possible reasons for this differential pattern we have now related the initial distribution of injected tumor cells to the later location and growth rate of metastases in different regions of the lung

F. W. Orr; L. Young; G. M. King; I. Y. R. Adamson

1988-01-01

254

Increased primary tumor growth in mice null for ?3- or ?3/?5-integrins or selectins  

PubMed Central

Expression of ?v?3- or ?v?5-integrins and selectins is widespread on blood cells and endothelial cells. Here we report that human tumor cells injected s.c. into mice lacking ?3- or ?3/?5-integrins or various selectins show enhanced tumor growth compared with growth in control mice. There was increased angiogenesis in mice lacking ?3-integrins, but no difference in structure of the vessels was observed by histology or by staining for NG2 and smooth muscle actin in pericytes. Bone marrow transplants suggest that the absence of ?3-integrins on bone marrow-derived host cells contributes to the enhanced tumor growth in ?3-null mice, although few, if any, bone marrow-derived endothelial cells were found in the tumor vasculature. Tumor growth also was affected by bone marrow-derived cells in mice lacking any one or all three selectins, implicating both leukocyte and endothelial selectins in tumor suppression. Reduced infiltration of macrophages was observed in tumors grown in mice lacking either ?3-integrins or selectins. These results implicate cells of the innate immune system, macrophages or perhaps natural killer cells, in each case dependent on integrins and selectins, in tumor suppression.

Taverna, Daniela; Moher, Heather; Crowley, Denise; Borsig, Lubor; Varki, Ajit; Hynes, Richard O.

2004-01-01

255

Adiponectin Deficiency Promotes Tumor Growth in Mice by Reducing Macrophage Infiltration  

PubMed Central

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

Sun, Yutong; Lodish, Harvey F.

2010-01-01

256

Diallyl disulfide suppresses the growth of human colon tumor cell xenografts in athymic nude mice.  

PubMed

The present studies examined the anti-proliferative effects of diallyl disulfide (DADS) on the growth of human colon tumor cell line, HCT-15, xenografts in 6-wk-old female NCr nu/nu mice with an initial body weight of 20-22 g. Intraperitoneal injection of 1 mg DADS thrice weekly reduced tumor volume by 69% (P < 0.05) without apparent ill consequences such as altered growth of the host. Providing this quantity of DADS intragastrically also inhibited growth of the HCT-15 tumor. At equivalent DADS dosages, intraperitoneal treatment was proportionately more effective (P < 0.05) in reducing tumor growth than gastric intubation. Tumor inhibition caused by DADS (0.5 mg thrice weekly) was similar to that occurring with 5-fluorouracil (5-FU) treatment (0.5 mg thrice weekly). Combining DADS and 5-FU was no more effective in inhibiting tumor growth than using either compound alone. However, concurrent DADS treatment significantly (P < 0.05) inhibited the depression in leukocyte counts and spleen weight and prevented the elevated plasma urea caused by 5-FU treatment. These data suggest that DADS, a constituent of garlic oil, reduces the toxicity of 5-FU and is an effective antitumorigenic agent against xenografts resulting from an established human colon tumor cell line. PMID:8618131

Sundaram, S G; Milner, J A

1996-05-01

257

A Quantitative Theory of Solid Tumor Growth, Metabolic Rate and Vascularization  

PubMed Central

The relationships between cellular, structural and dynamical properties of tumors have traditionally been studied separately. Here, we construct a quantitative, predictive theory of solid tumor growth, metabolic rate, vascularization and necrosis that integrates the relationships between these properties. To accomplish this, we develop a comprehensive theory that describes the interface and integration of the tumor vascular network and resource supply with the cardiovascular system of the host. Our theory enables a quantitative understanding of how cells, tissues, and vascular networks act together across multiple scales by building on recent theoretical advances in modeling both healthy vasculature and the detailed processes of angiogenesis and tumor growth. The theory explicitly relates tumor vascularization and growth to metabolic rate, and yields extensive predictions for tumor properties, including growth rates, metabolic rates, degree of necrosis, blood flow rates and vessel sizes. Besides these quantitative predictions, we explain how growth rates depend on capillary density and metabolic rate, and why similar tumors grow slower and occur less frequently in larger animals, shedding light on Peto's paradox. Various implications for potential therapeutic strategies and further research are discussed.

Herman, Alexander B.; Savage, Van M.; West, Geoffrey B.

2011-01-01

258

Zinc ligand-disrupted recombinant human Endostatin: Potent inhibition of tumor growth, safety and pharmacokinetic profile  

Microsoft Academic Search

Endostatin, a potent endogenous inhibitor of angiogenesis, inhibits the growth of primary tumors without induction of acquired\\u000a drug resistance in mice. We report that a soluble recombinant human (rh) Endostatin produced with characteristics of the native\\u000a Endostatin, effectively inhibited the growth of primary tumors and pulmonary metastases in a dose-dependent manner. We also\\u000a show that deletion of two of the

B. Kim Lee Sim; William E. Fogler; Xin Hua Zhou; Hong Liang; John W. Madsen; Kieu Luu; Michael S. O'Reilly; Joseph E. Tomaszewski; Anne H. Fortier

1999-01-01

259

Increased primary tumor growth in mice null for 3- or 3\\/5-integrins or selectins  

Microsoft Academic Search

Expression of v3- or v5-integrins and selectins is widespread on blood cells and endothelial cells. Here we report that human tumor cells injected s.c. into mice lacking 3- or 3\\/5-integrins or various selectins show enhanced tumor growth compared with growth in control mice. There was increased angiogenesis in mice lacking 3-integrins, but no difference in structure of the vessels was

Daniela Taverna; Heather Moher; Denise Crowley; Lubor Borsig; Ajit Varki; Richard O. Hynes

2004-01-01

260

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

261

Targeted chemotherapy using a cytotoxic somatostatin conjugate to inhibit tumor growth and metastasis in nude mice.  

PubMed

The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-81 was developed by coupling camptothecin (CPT) to the N-terminus of a SST analog (JF-07-69) using an activated carbamate linker. This conjugate selectively targets somatostatin receptor subtype 2 (SSTR2) and also retains high binding affinity and rapid internalization as well as anti-proliferative activity towards various tumor cells. JF-10-81 was tested for its inhibitory activity against the growth of human tumors which included neuroblastoma (IMR32), pancreatic cancer (CFPAC-1), leukemia (MOLT-4), pancreatic carcinoid (BON) and prostate cancer (PC-3). Both SSTR2 mRNAs and proteins were detected in all these tumor cell lines. The conjugate displayed potent in vivo inhibitory activity, although some of the potency measured in in vitro experiments was lost. JF-10-81 was found to significantly inhibit growth of these SSTR-positive tumors, resulting in 87% tumor reduction in neuroblastoma IMR32 and 97% in leukemia MOLT-4 bearing animals, even inducing regression of CFPAC-1 tumors. SSTR-overexpressing BON tumors were unfortunately relatively CPT-insensitive in vitro, however, JF-10-81 again exhibited in vivo potency presumably by specifically increasing CPT concentrations inside the tumor cells so that the inhibition rate for JF-10-81 was 85%. Also, JF-10-81 was used to treat highly invasive PC-3 tumors where s.c. injections inhibited both tumor growth (almost 60% reduction) and tumor metastasis (over 70%). This conjugate demonstrated its broad and excellent anti-tumor activity by targeting SSTR2-specific tumor tissues, supporting that short peptides and their analogs may be applied as ideal drug-delivery carriers to improve the traditional chemotherapy. PMID:21892324

Sun, Li-Chun; Mackey, L Vienna; Luo, Jing; Fuselier, Joseph A; Coy, David H

2008-08-19

262

tRNAPhe and tRNAPro are the near-ultraviolet molecular targets triggering the growth delay effect  

Microsoft Academic Search

The illumination of Escherichia coli cells with UVA light, 320 nm less than or equal to lambda less than or equal to 380 nm, triggers a transient growth and division delay. The built-in 4-thiouridine chromophore which absorbs light at 340 nm leads to the quantitative 8-13 crosslinking of a number of tRNA species corresponding to 50% of the bulk tRNA

M. O. Blondel; A. Favre

1988-01-01

263

Platelet-Derived Growth Factor-BB, But Not AA, Prevents Delayed Neuronal Death After Forebrain Ischemia in Rats  

Microsoft Academic Search

Our previous studies demonstrated coordinate expression of platelet-derived growth factor (PDGF) -B chain and ?-receptor in neurons at risk in the rat brain with focal ischemia. To clarify a role of the -B chain in the brain further, we examined whether PDGF-A or -B chain protects CA1 pyramidal neurons from delayed neuronal death after forebrain ischemia in rats. Pretreatment with

Koji Iihara; Nobuo Hashimoto; Tetsuya Tsukahara; Masahiro Sakata; Hiroji Yanamoto; Takashi Taniguchi

1997-01-01

264

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

PubMed

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

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

2011-07-04

265

Mesenchymal stem cells promote growth and angiogenesis of tumors in mice.  

PubMed

Though the early integration of mesenchymal stem cells (MSCs) into tumor-associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies. PMID:23085755

Huang, W-H; Chang, M-C; Tsai, K-S; Hung, M-C; Chen, H-L; Hung, S-C

2012-10-22

266

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

PubMed Central

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

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

2011-01-01

267

Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation.  

PubMed

Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP-dependent collagen invasion. In this experimental model, knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. This was coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and suppression of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen. These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors. PMID:20876804

Sugiyama, Nami; Varjosalo, Markku; Meller, Pipsa; Lohi, Jouko; Hyytiäinen, Marko; Kilpinen, Sami; Kallioniemi, Olli; Ingvarsen, Signe; Engelholm, Lars H; Taipale, Jussi; Alitalo, Kari; Keski-Oja, Jorma; Lehti, Kaisa

2010-09-28

268

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

PubMed Central

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

Prabha, Swayam; Sharma, Blanka; Labhasetwar, Vinod

2012-01-01

269

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

Microsoft Academic Search

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

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

2010-01-01

270

Origin of the vasculature supporting growth of primary patient tumor xenografts  

PubMed Central

Background Studies of primary patient tumor xenografts grown in immunodeficient mice have shown that these tumors histologically and genetically closely resemble the original tumors. These patient xenograft models are becoming widely used for therapeutic efficacy studies. Because many therapies are directed at tumor stromal components and because the tumor microenvironment also is known to influence the response of a tumor to therapy, it is important to understand the nature of the stroma and, in particular, the vascular supply of patient xenografts. Methods Patient tumor xenografts were established by implanting undisrupted pieces of patient tumors in SCID mice. For this study, formalin fixed, paraffin embedded specimens from several types of solid tumors were selected and, using species-specific antibodies which react with formalin fixed antigens, we analyzed the species origin of the stroma and blood vessels that supported tumor growth in these models. Additionally, we investigated the kinetics of the vascularization process in a colon tumor and a mesothelioma xenograft. In mice bearing a head and neck xenograft, a perfusion study was performed to compare the functionality of the human and mouse tumor vessels. Results In patient tumors which successfully engrafted, the human stroma and vessels which were engrafted as part of the original tumor did not survive and were no longer detectable at the time of first passage (15–25 weeks). Uniformly, the stroma and vessels supporting the growth of these tumors were of murine origin. The results of the kinetic studies showed that the loss of the human vessels and vascularization by host vessels occurred more rapidly in a colon tumor (by 3 weeks) than in a mesothelioma (by 9 weeks). Finally, the perfusion studies revealed that while mouse vessels in the periphery of the tumor were perfused, those in the central regions were rarely perfused. No vessels of human origin were detected in this model. Conclusions In the tumors we investigated, we found no evidence that the human stromal cells and vessels contained in the original implant either survived or contributed in any substantive way to the growth of these xenografts.

2013-01-01

271

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

PubMed

Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \\mu {\\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ. PMID:23221082

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

272

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.

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

273

Growth inhibition of ovarian tumor-initiating cells by niclosamide.  

PubMed

A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy. PMID:22576131

Yo, Yi-Te; Lin, Ya-Wen; Wang, Yu-Chi; Balch, Curt; Huang, Rui-Lan; Chan, Michael W Y; Sytwu, Huey-Kang; Chen, Chi-Kuan; Chang, Cheng-Chang; Nephew, Kenneth P; Huang, Tim; Yu, Mu-Hsien; Lai, Hung-Cheng

2012-05-10

274

Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma  

PubMed Central

Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of Ror2, a new tumor-associated kinase in RCC cell lines and primary tumors. Ror2 is an orphan receptor tyrosine kinase with physiological expression normally seen in the embryonic kidney. However, in RCC, Ror2 expression correlated with expression of genes involved at the extracellular matrix, including Twist and matrix metalloprotease-2 (MMP2). Expression of MMP2 in RCC cells was suppressed by Ror2 knockdown, placing Ror2 as a mediator of MMP2 regulation in RCC and a potential regulator of extracellular matrix remodeling. The suppression of Ror2 not only inhibited cell migration, but also inhibited anchorage independent growth in soft agar and growth in an orthotopic xenograft model. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.

Wright, Tricia M; Brannon, A Rose; Gordan, John D; Mikels, Amanda J; Mitchell, Cicely; Chen, Shufen; Espinosa, Inigo; van de Rijn, Matt; Pruthi, Raj; Wallen, Eric; Edwards, Lloyd; Nusse, Roel; Rathmell, W Kimryn

2009-01-01

275

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

NASA Astrophysics Data System (ADS)

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

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

2003-11-01

276

Thyroid tumors with a follicular growth pattern: problems in differential diagnosis.  

PubMed

Tumors of the thyroid characterized by a follicular growth pattern constitute the most common type of lesion of this organ encountered by pathologists. The vast majority of such lesions do not pose difficulties for histopathologic interpretation. A subset of these tumors, however, can represent a serious challenge for diagnosis. Thyroid tumors with a follicular growth pattern include a broad range of lesions that range from benign, hyperplastic nodules to follicular adenomas to follicular carcinomas. In addition, other types of tumors belonging in separate diagnostic categories can also present histologically with a follicular growth pattern, including the follicular variant of papillary thyroid carcinoma and medullary carcinoma. The histologic features and diagnostic criteria used for distinguishing among these conditions can often be subtle and subjective. PMID:16831055

Suster, Saul

2006-07-01

277

Pituitary Folliculo-Stellate-Like Cells Stimulate Somatotroic Pituitary Tumor Growth in Nude Mice.  

PubMed

A new cell line (TtT/GF) established from a murine pituitary thyrotropic tumor having characteristics similar to those of pituitary folliculo-stellate cell (FS cell) was implanted into nude mice together with cells from a rat pituitary somatotrophic tumor cell line (MtT/S) to determine whether the former enhances pituitary tumor growth. For as long as 2-3 mo after implantation, MtT/S cells implanted either alone or together with fibroblasts formed either no tumors or only very small tumors in the nude mice. In contrast, all of the nude mice that had received MtT/S cells implanted together with TtT/GF cells developed large tumors. Furthermore, the mice bearing the MtT/S and TtT/GF implants showed a significantly higher body weight and serum growth hormone level than those bearing only MtT/S cells or a combination of MtT/S cells and fibroblasts. The TtT/GF cell line itself had no tumorigenicity during the experimental period. Therefore, the TtT/GF cell line as a model of FS cells enhanced pituitary endocrine cell tumor formation. Additionally, immunocytochemistry showed that TtT/GF cells positive for glial fibrillary acidic protein (GFAP) or S-100 protein were present in the parenchymatous tissue elements or connective tissue surrounding the tumor nests. In the parenchymatous tissue, the TtT/GF cells exhibited a stellate appearance and surrounded neighboring tumor cells with their long cell processes. These results suggest that TtT/GF cells can serve as a model for pituitary FS cells, and are capable of stimulating pituitary tumor growth either by modifying the microenvironment or producing growth factors. PMID:12114691

Koyama, Chiaki; Matsumoto, Hirokazu; Sakai, Takafumi; Wakabayashi, Katsumi; Ito, Akihiro; Couch, Ernest F.; Inoue, Kinji

1995-01-01

278

Anti-VEGF antibody in experimental hepatoblastoma: Suppression of tumor growth and altered angiogenesis  

Microsoft Academic Search

Background: Hepatoblastoma is the most common primary hepatic malignancy of childhood, frequently presenting as advanced disease. Vascular endothelial growth factor (VEGF) is an endothelial mitogen and survival factor critical to growth and angiogenesis in many human cancers. Inhibition of VEGF effectively suppresses tumorigenesis in multiple experimental models. The authors hypothesized that anti-VEGF antibody would alter vascular architecture and impede tumor

Kimberly W. McCrudden; Benjamin Hopkins; Jason Frischer; Anna Novikov; Jianzhong Huang; Angela Kadenhe; Tamara New; Akiko Yokoi; Darrell J. Yamashiro; Jessica J. Kandel; William Middlesworth

2003-01-01

279

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

280

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

Microsoft Academic Search

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

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

2010-01-01

281

The epidermal growth factor receptor–tyrosine kinase: A promising therapeutic target in solid tumors  

Microsoft Academic Search

The overexpression and aberrant function of the epidermal growth factor receptor (EGFR) and its ligands in several human carcinomas have provided a rationale for targeting this signaling network with novel treatment approaches. The epidermal growth factor receptor–tyrosine kinase (EGFR-TK) is a selective target for inhibiting cancer because it is activated in many tumor cells, yet is strictly controlled in normal

Christoph A Ritter; Carlos L Arteaga

2003-01-01

282

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

Microsoft Academic Search

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

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

2000-01-01

283

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice  

PubMed Central

Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelial-derived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-rasG12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-rasG12D–driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell–mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

Santos, Angelica M.; Jung, Jason; Aziz, Nazneen; Kissil, Joseph L.; Pure, Ellen

2009-01-01

284

tRNAPhe and tRNAPro are the near-ultraviolet molecular targets triggering the growth delay effect  

SciTech Connect

The illumination of Escherichia coli cells with UVA light, 320 nm less than or equal to lambda less than or equal to 380 nm, triggers a transient growth and division delay. The built-in 4-thiouridine chromophore which absorbs light at 340 nm leads to the quantitative 8-13 crosslinking of a number of tRNA species corresponding to 50% of the bulk tRNA molecules. Determination of the tRNA acylation level by the various aminoacids shows that only the tRNA species acylated by Phe and Pro are strikingly affected in vivo. Both acylation levels decrease to less than 10% of their initial value during the illumination period, remain stable all along the growth lag and increase concomitantly with cell mass when growth resumes. Hence tRNA(Phe) and tRNA(Pro) are the UVA light molecular targets triggering growth delay and related effects of biological significance such as cell volume reduction, photoprotection and protection against UV mutagenesis (antiphotomutagenesis).

Blondel, M.O.; Favre, A.

1988-02-15

285

Combined effects of X rays, Ro 03-8799, and hyperthermia on growth, necrosis, and cell proliferation in a mouse tumor  

SciTech Connect

A mouse adenocarcinoma was treated with 20 Gy X rays, hyperthermia (30 minutes at 43 degrees C), Ro-03-8799, or a combination of two or three of these agents. Combined treatments increase growth delay in the tumor and this was greatest with the combination of all three modalities. Extensive amounts of necrosis were observed after the combined treatments. This effect was most pronounced after treatment modalities including hyperthermia. On the other hand, the radiation-induced micronucleus formation was more enhanced by the sensitizer than by hyperthermia. After X irradiation and combined treatments with X rays a G2-block was observed in DNA-histograms. Tetraploid cells appeared in large amounts that started DNA synthesis followed by necrosis. From these tumors it was impossible to obtain regular DNA-histograms. Tumor regression is a combined result of reduced cell renewal, increased cytogenetic damage, and development of necrosis.

George, K.C.; Streffer, C.; Pelzer, T.

1989-04-01

286

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

PubMed Central

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

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

2008-01-01

287

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

Microsoft Academic Search

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

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

2010-01-01

288

Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome  

Microsoft Academic Search

PURPOSE: Tumor-specific immunomonitoring is essential to evaluate the efficacy of vaccination against cancer. In this study, we investigated the predictive value of the presence or absence of antigen-specific T cells in biopsies from delayed-type hypersensitivity (DTH) sites. PATIENTS AND METHODS: In our ongoing clinical trials, HLA-A2.1+ melanoma patients were vaccinated with mature dendritic cells (DC) pulsed with melanoma-associated peptides (gp100

I. J. M. de Vries; M. R. Bernsen; W. J. Lesterhuis; N. M. Scharenborg; S. P. Strijk; M. J. P. Gerritsen; D. J. Ruiter; C. G. Figdor; C. J. A. Punt; G. J. Adema

2005-01-01

289

Reinforcement learning based control of tumor growth with chemotherapy  

Microsoft Academic Search

In this paper, optimal drug schedule for patients in progressive cancer phase who take the drug through infusion pump is obtained. An objective of control is reducing tumor cell numbers effectively while minimizing total amount of drug regimen. This is done because of the known serious side effects and major damages resulting from chemotherapy. Chemotherapy brings about weakness of the

Amin Hassani; M. B. Naghibi

2010-01-01

290

Antiangiogenic Therapy of Transgenic Mice Impairs de novo Tumor Growth  

Microsoft Academic Search

Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma

Sareh Parangi; Michael O'Reilly; Gerhard Christofori; Lars Holmgren; Jeffrey Grosfeld; Judah Folkman; Douglas Hanahan

1996-01-01

291

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

292

Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin.  

PubMed

Capsaicin, the pungent ingredient of hot chilli pepper, has been recently shown to induce apoptosis in several cell lines through a not well known mechanism. Here, we investigated the role of the vanilloid capsaicin in the death regulation of the human cancer androgen-resistant cell line PC-3. Capsaicin inhibited the growth of PC-3 with an IC(50) of 20 microM cells and induced cell apoptosis, as assessed by flow cytometry and nuclei staining with DAPI. Capsaicin induced apoptosis in prostate cells by a mechanism involving reactive oxygen species generation, dissipation of the mitochondrial inner transmembrane potential (DeltaPsi(m)) and activation of caspase 3. Capsaicin-induced apoptosis was not reduced by the antagonist capsazepine in a dose range from 0.1 microM to 20 microM, suggesting a receptor-independent mechanism. To study the in vivo effects of capsaicinoids, PC-3 cells were grown as xenografts in nude mice. Subcutaneous injection of either capsaicin or capsazepine (5 mg/kg body weight) in nude mice suppressed PC-3 tumor growth in all tumors investigated and induced apoptosis of tumor cells. Our data show a role for capsaicin against androgen-independent prostate cancer cells in vitro and in vivo and suggest that capsaicin is a promising anti-tumor agent in hormone-refractory prostate cancer, which shows resistance to many chemotherapeutic agents. PMID:16374544

Sánchez, A M; Sánchez, M G; Malagarie-Cazenave, S; Olea, N; Díaz-Laviada, I

2006-01-01

293

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

SciTech Connect

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

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

1991-04-01

294

Modeling tumor growth in a complex evolving confinement using a diffuse domain approach  

NASA Astrophysics Data System (ADS)

Understanding the spatiotemporal evolution of tumor growth represents an essential step towards engineering effective treatment for cancer patients. At the macroscopic scale, various biophysical models describing tumors as continuum fluids have been constructed, particularly on a Cartesian grid, where efficient numerical schemes are available to analyze the model for general tumor behaviors in a relatively unconfined space. For practical problems, however, tumors are often found in a confined sub-domain, which can even be dilated and distorted by the growing tumor within. To study such tumors, we adopt a novel diffuse domain approach that enables us to adapt a model to an evolving sub-domain and formulate the modified problem on a Cartesian grid to utilize existing numerical schemes. To demonstrate this approach, we adapt a diffuse-interface model presented in Wise et al. [2008, Three-dimensional multispecies nonlinear tumor growth - I Model and numerical method, J. Theor. Biol. 253, 524-543] to simulate lymphoma growth in a lymph node structure.

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

2011-11-01

295

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

296

Morphology and growth characteristics of epithelial cells from classic Wilms' tumors.  

PubMed Central

The ability to establish cell cultures representing the epithelial component of Wilms' tumor was determined for 18 cases of classic Wilms' tumors. From these 18 cases only two resulted in the culture of epithelial cells. Although the tumors from both cases were composed of a prominent epithelial component, other classic tumors not producing epithelial cell cultures also possessed appreciable epithelial components. Likewise, heterotransplants of these two primary tumors failed to give rise to epithelial cell cultures, although cultures of the blastemal element were produced. This suggests that Wilms' tumors may be prone to differentiate in different directions at varying times during tumor growth, possibly dependent on local tumor environment. Epithelial cells from these two classic cases were grown in culture in basal medium composed of a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 medium, supplemented with selenium, insulin, transferrin, hydrocortisone, tri-iodothyronine, and epidermal growth factor, on a collagen type I matrix with absorbed fetal calf serum proteins. One of the two cases also required the addition of bovine pituitary extract, ethanolamine, prostaglandin E1, and putrescine for optimum growth. Morphological analysis disclosed that the cultured cells were very similar to normal renal tubular cells in culture, except that the cells displayed little evidence for differentiated active ion transport and tended to grow in a multilayered arrangement. The culture of the epithelial cells from classic Wilms' tumors provides a model system for the study of tumor differentiation and progression. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12

Hazen-Martin, D. J.; Garvin, A. J.; Gansler, T.; Tarnowski, B. I.; Sens, D. A.

1993-01-01

297

Modeling propagation delays in the development of SOMs - a parallel with abnormal brain growth in autism  

Microsoft Academic Search

Brain overgrowth in early developmental stages of children with autism is well documented. This paper explores the possibility that increases in propagation delays of stimuli and the signals triggered by them, resulting from this overgrowth, may be conducive to the development of poorly structured cortical maps, which may in turn be associated with autistic characteristics. We use a framework based

Gerardo Noriega

2008-01-01

298

Amelioration of Delayed Neuronal Death in the Hippocampus by Nerve Growth Factor  

Microsoft Academic Search

death in the CA1 sector of the hippo- campus (delayed neuronal death (DND)) develops several days after transient global cerebral ischemia in rodents. Be- cause NGF plays a potential role in neuronal survival, it was decided to study its effect in DND. We report here that in- traventricular injection of NGF either before or after 5 min forebrain ischemia in

Taku Shigeno; Tatsuo Mima; Kintomo Takakura; David I. Graham; Gunshiro Kato; Yoshihide Hashimoto; Shoei Furukawa

1991-01-01

299

Personality-Targeted Interventions Delay the Growth of Adolescent Drinking and Binge Drinking  

ERIC Educational Resources Information Center

|Background: Personality factors are implicated in the vulnerability to adolescent alcohol misuse. This study examined whether providing personality-targeted interventions in early adolescence can delay drinking and binge drinking in high-risk youth. Methods: A randomised control trial was carried out with 368 adolescents recruited from years 9…

Conrod, Patricia J.; Castellanos, Natalie; Mackie, Clare

2008-01-01

300

Granulocyte Macrophage Colony-Stimulating Factor Inhibits Breast Cancer Growth and Metastasis by Invoking an Anti-Angiogenic Program in Tumor-Educated Macrophages  

Microsoft Academic Search

Tumor-educated macrophages facilitate tumor metastasis and angiogenesis. We discovered that granulocyte macrophage colony-stimulating factor (GM-CSF) blocked macrophages vascular endothelial growth factor (VEGF) activity by produc- ing soluble VEGF receptor-1 (sVEGFR-1) and determined the effect on tumor-associated macrophage behavior and tumor growth. We show GM-CSF treatment of murine mammary tumors slowed tumor growth and slowed metastasis. These tumors had more macrophages,

Tim D. Eubank; Ryan D. Roberts; Mahmood Khan; Jennifer M. Curry; Gerard J. Nuovo; Periannan Kuppusamy; Clay B. Marsh

2009-01-01

301

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

302

Inhibition of tumor growth and metastasis by chronic intravenous infusion of prostaglandin E1.  

PubMed Central

The role of prostaglandins and their synthesis inhibitors in malignant disease is undefined. The following studies were done to determine the effects of continuous intravenous prostaglandin E1 (PGE1) or a prostaglandin synthesis inhibitor, indomethacin, on tumor growth and metastasis in mice bearing Lewis lung carcinoma. Male B6D2F1 mice underwent tumor implantation in the right axilla on day 0. After 10 days of tumor growth, mice underwent intravenous (IV) catheterization and were infused with either PGE1 at 3 micrograms/kg/minute (PG-LOW), PGE1 at 6 micrograms/kg/minute (PG-HIGH), indomethacin (INDO) at 1 microgram/kg/minute, or normal saline (NS). After 10 days of infusion, tumor volume, tumor weight, and the number of metastases greater than 2 mm in diameter were significantly decreased, and tumor doubling time was significantly prolonged in the PG-HIGH group compared to NS controls. None of the other experimental groups showed differences in these parameters. A second experiment with a similar experimental design was done infusing PGE1 at 6 micrograms/kg/minute and at 12 micrograms/kg/minute to determine the maximum dose response of IV PGE1. Again a decrease in tumor volume, tumor weight, and metastatic rates were identified when compared to saline control, but there were no significant difference between the two doses of PGE1.

Ellis, L M; Copeland, E M; Bland, K I; Sitren, H S

1990-01-01

303

Impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1-null mice  

PubMed Central

Despite 2 decades of research, no clear function for annexin A1 (AnxA1) has been established. Using AnxA1-KO mice, we show that tumor growth and metastasis are significantly decreased, whereas rodent survival and tumor necrosis are greatly increased when tumors grow in AnxA1-KO mice. Systems analysis of gene expression in these tumors specifically implicates 2 related vascular functions, angiogenesis and wound healing, in this impairment. Both tumor vascular development and wound healing are greatly retarded in KO tissues. Aortic ring assays reveal induced AnxA1 expression on sprouting endothelial cells of normal mice whereas KO aortas exhibit impaired endothelial cell sprouting that is rescued by adenoviral expression of AnxA1. Key differences in specific gene regulation may define new molecular pathways mediating angiogenesis, including a reset profile of pro- versus anti-angiogenic factors, apparently distinct for physiological versus pathological angiogenesis. These studies establish novel pro-angiogenic functions for AnxA1 in vascular endothelial cell sprouting, wound healing, and tumor growth and metastasis, thereby uncovering a new functional target for repairing damaged tissue and treating diseases such as cancer. They also provide critical new evidence that the tumor stroma and its microenvironment can greatly affect tumor progression and metastasis.

Yi, Ming; Schnitzer, Jan E.

2009-01-01

304

Thymidine Phosphorylase is Angiogenic and Promotes Tumor Growth  

Microsoft Academic Search

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-^3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured

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

1995-01-01

305

CD200-expressing human basal cell carcinoma cells initiate tumor growth  

PubMed Central

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

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

2013-01-01

306

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

PubMed

Bioluminescent imaging (BLI) permits sensitive in vivo detection and quantification of cells specifically engineered to emit visible light. Three stable human tumor cell lines engineered to express luciferase were assessed for their tumorigenicity in subcutaneous, intravenous and spontaneous metastasis models. Bioluminescent PC-3M-luc-C6 human prostate cancer cells were implanted subcutaneously into SCID-beige mice and were monitored for tumor growth and response to 5-FU and mitomycin C treatments. Progressive tumor development and inhibition/regression following drug treatment were observed and quantified in vivo using BLI. Imaging data correlated to standard external caliper measurements of tumor volume, but bioluminescent data permitted earlier detection of tumor growth. In a lung colonization model, bioluminescent A549-luc-C8 human lung cancer cells were injected intravenously and lung metastases were monitored in vivo by whole animal imaging. Anesthetized mice were imaged weekly allowing a temporal assessment of in vivo lung tumor growth. This longitudinal study design permitted an accurate, real-time evaluation of tumor burden in the same animals over time. End-point bioluminescence measured in vivo correlated to total lung weight at necropsy. For a spontaneous metastatic tumor model, bioluminescent HT-29-luc-D6 human colon cancer cells implanted subcutaneously produced metastases to lung and lymph nodes in SCID-beige mice. Both primary tumors and micrometastases were detected by BLI in vivo. Ex vivo imaging of excised lung lobes and lymph nodes confirmed the in vivo signals and indicated a slightly higher frequency of metastasis in some mice. Levels of bioluminescence from in vivo and ex vivo images corresponded to the frequency and size of metastatic lesions in lungs and lymph nodes as subsequently confirmed by histology. In summary, BLI provided rapid, non-invasive monitoring of tumor growth and regression in animals. Its application to traditional oncology animal models offers quantitative and sensitive analysis of tumor growth and metastasis. The ability to temporally assess tumor development and responses to drug therapies in vivo also improves upon current standard animal models that are based on single end point data. PMID:14713107

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

2003-01-01

307

The Scatter Factor\\/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy  

Microsoft Academic Search

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scat- ter factor\\/hepatocyte growth factor (SF\\/HGF) and its tyro- sine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and

Yunqing Li; Bachchu Lal; Sherwin Kwon; Xing Fan; Usha Saldanha; Thomas E. Reznik; Eric B. Kuchner; Charles Eberhart; John Laterra; Roger Abounader

2005-01-01

308

Myeloid Cells in Cancer Progression: Unique Subtypes and Their Roles in Tumor Growth, Vascularity, and Host Immune Suppression  

Microsoft Academic Search

Leukocytic infiltrates, particularly myeloid cells, can stimulate an anti-tumor immune response, but more often they stimulate\\u000a tumor development, including promoting invasion, tumor growth, angiogenesis, and metastasis. Distinct myeloid phenotypes are\\u000a being characterized that have been shown to promote tumor growth, angiogenesis, and metastasis. This review provides an overview\\u000a of myeloid differentiation and spotlights specific pro-tumorogenic myeloid populations and their role

Pampee P. Young; Shidrokh Ardestani; Bin Li

2011-01-01

309

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

PubMed

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

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

2011-03-08

310

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.

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

2012-01-01

311

Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-?B  

PubMed Central

Scope Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of Resveratarol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth. Methods and results Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of SIRT1 and downregulation of NF-kB in EL4 cells. SiRNA-mediated down regulation of SIRT1 in EL4 cells increased the activation of NF-kB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-kB. Conclusion These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-kB, leading to suppression of tumor growth.

Singh, Narendra P.; Singh, Udai P.; Hegde, Venkatesh L.; Guan, Hongbing; Hofseth, Lorne; Nagarkatti, Mitzi; Nagarkatti, Prakash S.

2012-01-01

312

Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts  

PubMed Central

Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) EgfrVelvet/+ or Egfr+/+. To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in EgfrVelvet/+ mice were significantly smaller than tumors in Egfr+/+ mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from EgfrVelvet/+ mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR–interleukin-1 crosstalk.

Bissonnette, Marc

2012-01-01

313

Importance of fibroblast growth factor receptor in neovascularization and tumor escape from antiangiogenic therapy.  

PubMed

Therapeutic inhibition of pathways involved in angiogenesis has become the standard of care in renal cell carcinoma (RCC). Most currently available antiangiogenic agents inhibit the vascular endothelial growth factor (VEGF) pathway. Although these drugs have produced exciting benefits, some tumors do not respond to these agents. In addition most if not all tumors that initially respond will eventually develop resistance. Tumor escape from antiangiogenic therapy may include various signaling pathways that are involved in angiogenesis, including the fibroblast growth factor (FGF) signaling pathway. Emerging preclinical data suggest that FGF and VEGF act distinctly and synergistically to promote tumor vascularization. The current review discusses the role of FGF signaling in resistance to anti-VEGF therapies and outlines potential therapeutic implications. PMID:22382009

Saylor, Philip J; Escudier, Bernard; Michaelson, M Dror

2012-02-28

314

Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer.  

PubMed

Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the mechanisms underlying stromal fibroblast activation and their promotion of tumor growth remain largely unknown in gastric cancer. Here, we show that normal fibroblasts (NFs) from non-cancerous regions of gastric cancer exhibit the traits of CAFs when grown together with gastric cancer cells in vivo. Activation of NFs can be induced by co-culture with gastric cancer cells, while deprivation of hepatocyte growth factor (HGF) using a neutralizing antibody inhibits the activation of NFs. Moreover, we identify HGF as an important factor from CAFs that acts in a paracrine manner to promote tumorigenesis in vitro and in vivo. Taken together, these results suggest that HGF may play a pivotal role in the regulatory circuit between gastric cancer cells and stromal fibroblasts, and neutralization of HGF inhibits both activation and tumor-promoting properties of CAFs. PMID:23402812

Wu, Xiongyan; Chen, Xuehua; Zhou, Quan; Li, Pu; Yu, Beiqin; Li, Jianfang; Qu, Ying; Yan, Jun; Yu, Yingyan; Yan, Min; Zhu, Zhenggang; Liu, Bingya; Su, Liping

2013-02-09

315

All-trans-retinoic acid-induced growth suppression of blastemal Wilms' tumor.  

PubMed

All-trans-retinoic acid (RA) has been used to suppress growth of malignant cells and induce epithelial differentiation. We investigated whether RA had a similar effect on Wilms' tumor, a childhood tumor of the kidney that arises from the undifferentiated metanephric blastema. W13 cells, a cell line derived from a blastemal Wilms' tumor, were exposed to RA (10(-9)-10(-5) M) and its effects on cell proliferation, gene expression, and differentiation were examined. Treatment of W13 cells with RA resulted in a dose-dependent suppression of growth. Changes in expression of selected genes were determined by Northern analysis. After 24 h, there was a marked dose-dependent down-regulation of N-myc mRNA as well as up-regulation of insulin-like growth factor-II (IGF-II) mRNA. [125I]IGF-II ligand blotting of conditioned medium from RA-treated cultures revealed a dramatic alteration in the pattern of expression of insulin-like growth factor binding proteins (IGFBPs). Examination of RA-treated W13 cultures by light and electron microscopy did not reveal appreciable morphological changes. We conclude that RA inhibits growth and alters gene expression of W13 cells without inducing epithelial differentiation. The modulation of expression of IGF-II, IGFBP, and N-myc may play a role in RA-induced growth suppression of Wilms' tumor cells. PMID:9025876

Vincent, T S; Re, G G; Hazen-Martin, D J; Tarnowski, B I; Willingham, M C; Garvin, A J

316

Effect of MUC1 mucin, an anti-adhesion molecule, on tumor cell growth.  

PubMed

MUC1 mucin is expressed in a wide variety of tumors and is considered to function as an anti-adhesion molecule which inhibits cell-to-cell interactions. To reveal the biological significance of this activity in tumor cells, MUC1 cDNA was transfected into EJNIH3T3 cells and human colon cancer cell lines, CHCY1 and DLD1. The in vivo growth rate of MUC1+ (MUC1-transfected) EJNIH3T3, CHCY1 and DLD1 cells in SCID mice was clearly lower than that of MUC1- (mock transfectant) cells. Several in vitro experiments using MUC1+ EJNIH3T3 cells were performed to analyze the mechanisms for the decreased in vivo tumor growth. It was found that (i) the in vitro growth rate of MUC1+ EJNIH3T3 cells was also decreased compared to that of MUC1- cells, (ii)the DNA synthesis of MUC1+ EJNIH3T3 cells after stimulation with either growth factor (fetal calf serum or bombesin) or extracellular matrix (collagen or fibronectin) was lower than that of MUC1- cells, and (iii) MUC1+ EJNIH3T3 cells grew more slowly than MUC1- cells on both collagen- and fibronectin-coated dishes. These data suggest that MUC1 mucin may regulate tumor cell growth through inhibition of cell-to-cell, growth factor-to-receptor and cell-to-matrix interactions. PMID:8641988

Makiguchi, Y; Hinoda, Y; Imai, K

1996-05-01

317

Growth Hormone Treatment of Children with Brain Tumors and Risk of Tumor Recurrence  

Microsoft Academic Search

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891

A. J. SWERDLOW; R. E. REDDINGIUS; C. D. HIGGINS; H. A. SPOUDEAS; K. PHIPPS; Z. QIAO; W. D. J. RYDER; M. BRADA; R. D. HAYWARD; C. G. D. BROOK; P. C. HINDMARSH; S. M. SHALET

2010-01-01

318

Inhibition of Tumor Growth and Angiogenesis by Soluble EphB4  

Microsoft Academic Search

EphB receptors and their ephrinB ligands play a key role in the formation of a regular vascular system. Re- cent studies have also shown the involvement of Eph\\/ephrin interactions in malignant tumor progres- sion and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4) -expressing A375 mela- noma cells to study the effect of dominant negatively acting sEphB4 on tumor growth

Georg Martiny-Baron; Thomas Korff; Florence Schaffner; Norbert Esser; Stefan Eggstein; Dieter Marme ´; Hellmut G. Augustin

2004-01-01

319

Discovery of colon tumor cell growth inhibitory agents through a combinatorial approach  

Microsoft Academic Search

Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitrile were synthesized through one pot reaction of the appropriate acetophenone, aldehyde, ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for their tumor cell growth inhibitory activity against the human HT-29 colon tumor cell line, as well as their PDE3 inhibitory activity. Compound

Ashraf H. Abadi; Dalal A. Abouel-Ella; Jochen Lehmann; Heather N. Tinsley; Bernard D. Gary; Gary A. Piazza; Mohammed A. O. Abdel-Fattah

2010-01-01

320

Ion channels and amino acid transporters support the growth and invasion of primary brain tumors  

Microsoft Academic Search

The malignant growth of glial support cells causes gliomas, highly invasive, primary brain tumors that are largely resistant\\u000a to therapy. Individual tumor cells spread by active cell migration, invading diffusely into the normal brain. This process\\u000a is facilitated by Cl? channels that endow glioma cells with an enhanced ability to quickly adjust their shape and cell volume to fit the

Harald Sontheimer

2004-01-01

321

Coexpression of hepatocyte growth factor and c-met in epithelial odontogenic tumors  

Microsoft Academic Search

Hepatocyte growth factor (HGF) and its receptor, c-met, have been shown to regulate cell proliferation, motility and morphology in a variety of cell types. A significant role of the HGF\\/c-met pathway has been demonstrated in various tumors, however, little is known about the role of HGF\\/c-met pathway in odontogenic tumors. The aim of this study was to characterize the expression

Sopee Poomsawat; Jirapa Punyasingh; Paisarn Vejchapipat; Noppadol Larbcharoensub

322

Integrating kinetic models for Simulating tumor growth in Monte Carlo Simulation of ECT systems  

Microsoft Academic Search

We have developed an integrated framework for linking tumor growth models directly into a Monte Carlo simulation algorithm for positron emission tomography and single-photon emission computed tomography systems. Tumors are approximated either by analytically defined five-dimensional (x,y,z,tgeometry,tactivity) compartments or by compound cellular lattice inserts. Both representation models can be placed into arbitrarily complex tomographic or mathematical phantoms. Various models for

Joerg Peter; Wolfhard Semmler

2004-01-01

323

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.

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

2011-01-01

324

Computer studies of the spatial structure and temporal growth of tumor cells.  

PubMed

In the present paper we attempt to determine the spatial structure and the time behaviour of cell renewal systems, continuing previous studies in which tumor diseases were interpreted as unstable control loops. A computer model wa developed for the two-dimensional cell space, which is described by a set of specifications and growth statements. Selected case studies are then simulated by means of a digital computer (CYBER 76). In the development of this model special emphasis was given to (i) the existence of several cell systems with different mean life spans, growing in competition; (ii) the variability of the mean life spans of a cell and of the initial configuration of cell patterns; (iii) the description of the cell-to-cell interactions; (iv) the perturbation of normal cell growth by tumor cells and their elimination in medicine comparable with a direct irradiation or removal by surgery; (v) the consideration of the loss of tumor cells. The development of this model enables a deeper insight into the structure and function of disturbed cell renewal processes. Systematic studies were made on the influence of the size of a tumor nucleus and the mean life span of a tumor cell on the tumor growth assuming constant cell loss. Furthermore it is possible with this computer model to simulate simple basic cases which are difficult to test in real life. PMID:7412245

Düchting, W; Dehl, G

1980-07-01

325

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

PubMed

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

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

2013-04-17

326

Novel EphB4 Monoclonal Antibodies Modulate Angiogenesis and Inhibit Tumor Growth  

PubMed Central

EphB4 receptor tyrosine kinase and its cognate ligand EphrinB2 regulate induction and maturation of newly forming vessels. Inhibition of their interaction arrests angiogenesis, vessel maturation, and pericyte recruitment. In addition, EphB4 is expressed in the vast majority of epithelial cancers and provides a survival advantage to most. Here, we describe two anti-EphB4 monoclonal antibodies that inhibit tumor angiogenesis and tumor growth by two distinct pathways. MAb131 binds to fibronectin-like domain 1 and induces degradation of human EphB4, but not murine EphB4. MAb131 inhibits human endothelial tube formation in vitro and growth of human tumors expressing EphB4 in vivo. In contrast, MAb47 targets fibronectin-like domain 2 of both human and murine EphB4 and does not alter EphB4 receptor levels, but inhibits angiogenesis and growth of both EphB4-positive and EphB4-negative tumors in a mouse s.c. xenograft model. Combination of MAb47 and bevacizumab enhances the antitumor activity and induces tumor regression. Indeed, humanized antibodies hAb47 and hAb131 showed similar affinity for EphB4 and retained efficacy in the inhibition of primary tumor development and experimental metastasis.

Krasnoperov, Valery; Kumar, S. Ram; Ley, Eric; Li, Xiuqing; Scehnet, Jeffrey; Liu, Ren; Zozulya, Sergey; Gill, Parkash S.

2010-01-01

327

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

PubMed Central

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

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

2011-01-01

328

Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules: a case report.  

PubMed

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC. PMID:24114829

Saito, Masaya; Seo, Yasushi; Yano, Yoshihiko; Uehara, Keiichiro; Hara, Shigeo; Momose, Kenji; Hirano, Hirotaka; Yokozaki, Hiroshi; Yoshida, Masaru; Azuma, Takeshi

329

Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model.  

PubMed

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE(-/-)), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE(-/-) and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE(-/-) mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE(-/-) mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE(-/-) mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased Akt(S473) phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated Akt(S473) phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE(-/-) mice is a favorable setting for mammary tumor growth and metastasis. PMID:22469977

Alikhani, N; Ferguson, R D; Novosyadlyy, R; Gallagher, E J; Scheinman, E J; Yakar, S; LeRoith, D

2012-04-02

330

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

331

Prevention of local tumor growth with paclitaxel- loaded microspheres  

Microsoft Academic Search

Objectives: Lung cancer is associated with a significant rate of locoregional recur- rence after surgical resection, particularly when nonanatomic wedge resections are performed.The primary aimofthis studywas toassessthe feasibility ofamicrosphere drug delivery system to locally deliver chemotherapy and prevent the establishment and growth of lung cancer cells and establish proof of concept for a potential future approach to target occult microscopic

Mark W. Grinstaff; Yolonda L. Colson

332

Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo.  

PubMed

Live animal imaging is becoming an increasingly common technique for accurate and quantitative assessment of tumor burden over time. Bioluminescence imaging systems rely on a bioluminescent signal from tumor cells, typically generated from expression of the firefly luciferase gene. However, previous reports have suggested that either a high level of luciferase or the resultant light reaction produced upon addition of D-luciferin substrate can have a negative influence on tumor cell growth. To address this issue, we designed an expression vector that allows simultaneous fluorescence and luminescence imaging. Using fluorescence activated cell sorting (FACS), we generated clonal cell populations from a human breast cancer (MCF-7) and a mouse melanoma (B16-F10) cell line that stably expressed different levels of luciferase. We then compared the growth capabilities of these clones in vitro by MTT proliferation assay and in vivo by bioluminescence imaging of tumor growth in live mice. Surprisingly, we found that neither the amount of luciferase nor biophotonic activity was sufficient to inhibit tumor cell growth, in vitro or in vivo. These results suggest that luciferase toxicity is not a necessary consideration when designing bioluminescence experiments, and therefore our approach can be used to rapidly generate high levels of luciferase expression for sensitive imaging experiments. PMID:21092230

Tiffen, Jessamy C; Bailey, Charles G; Ng, Cynthia; Rasko, John E J; Holst, Jeff

2010-11-22

333

Molecular chaperones in mammary cancer growth and breast tumor therapy.  

PubMed

Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and progression mediated through their intrinsic molecular chaperone properties. These permit the emergence of new malignant traits through the facilitated accumulation of altered oncoproteins. The elevation of HSP concentrations in mammary carcinoma is at least partially dependent on heat shock transcription factor 1 (HSF1), a protein that responds to unfolded proteins and leads to HSP transcription. HSF1 activation has additional downstream activities, crucial for emergence of the breast cancer phenotype and these include activated cell signaling, HSP-mediated ability to evade apoptosis and senescence and an HSF1-dependent bias in transcriptional activity towards a metastatic phenotype. The HSPs are currently being targeted in breast cancer therapy and effective drugs for Hsp90 have been synthesized and evaluated in clinical trial. Mammary carcinoma cells also contain abundant quantities of HSP–tumor antigen complexes and these complexes are being used to develop effective tumor vaccine approaches that provide personalized therapy for each individual's cancer. PMID:22105880

Calderwood, Stuart K; Gong, Jianlin

2012-04-01

334

Molecular chaperones in mammary cancer growth and breast tumor therapy  

PubMed Central

Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and progression mediated through their intrinsic molecular chaperone properties. These permit the emergence of new malignant traits through the facilitated accumulation of altered oncoproteins. The elevation of HSP concentrations in mammary carcinoma is at least partially dependent on heat shock transcription factor 1 (HSF1), a protein that responds to unfolded proteins and leads to HSP transcription. HSF1 activation has additional downstream activities, crucial for emergence of the breast cancer phenotype and these include activated cell signaling, HSP-mediated ability to evade apoptosis and senescence and an HSF1-dependent bias in transcriptional activity towards a metastatic phenotype. The HSPs are currently being targeted in breast cancer therapy and effective drugs for Hsp90 have been synthesized and evaluated in clinical trial. Mammary carcinoma cells also contain abundant quantities of HSP-tumor antigen complexes and these complexes are being used to develop effective tumor vaccine approaches that provide personalized therapy for each individual’s cancer.

Calderwood, Stuart K; Gong, Jianlin

2011-01-01

335

Acute Ulnar Shortening for Delayed Presentation of Distal Radius Growth Arrest in an Adolescent  

PubMed Central

Distal radius physeal fractures are common in children and adolescents. However, posttraumatic growth arrest is uncommon. The management of posttraumatic growth arrest is dependent on the severity of the deformity and the remaining growth potential of the patient. Various treatment options exist. We present a 17-year-old male with distal radius growth arrest who presented four years after the initial injury. He had a symptomatic 15?mm positive ulnar variance managed with an ulnar shortening osteotomy with the use of the AO mini distractor intraoperatively. To the best of our knowledge, an acute ulnar shortening of 15?mm is the largest reported.

Ellanti, Prasad; Harrington, Paul

2012-01-01

336

Increased mannose 6-phosphate/insulin-like growth factor II receptor and transforming growth factor beta 1 levels during monoterpene-induced regression of mammary tumors.  

PubMed

The monoterpenes represent a potentially new class of breast cancer therapeutic agents. We have shown that d-limonene induces the regression of advanced rat mammary adenocarcinomas. These regressing tumors have an increased cellular concentration of both the mannose-6-phosphate/insulin-like growth factor II receptors and transforming growth factor beta 1. The terpene-induced regression of mammary tumors may result in part from the mitoinhibitory and differentiation properties of active transforming growth factor beta 1. Furthermore, the activation of transforming growth factor beta 1 in these tumors is likely to be facilitated by the increased concentration of the mannose-6-phosphate/insulin-like growth factor II receptors in the mammary tumor cells. Tumors not responding to terpene therapy lacked a rise in the mannose-6-phosphate/insulin-like growth factor II receptor level which may relate to the fact that this gene is hemizygous due to maternal imprinting. PMID:8358708

Jirtle, R L; Haag, J D; Ariazi, E A; Gould, M N

1993-09-01

337

Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice.  

PubMed

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of alphaAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets. PMID:19546305

Kaafarani, Itidal; Fernandez-Sauze, Samantha; Berenguer, Caroline; Chinot, Olivier; Delfino, Christine; Dussert, Christophe; Metellus, Philippe; Boudouresque, Françoise; Mabrouk, Kamel; Grisoli, François; Figarella-Branger, Dominique; Martin, Pierre-Marie; Ouafik, L'Houcine

2009-06-22

338

Pollen Tube Growth and the Intracellular Cytosolic Calcium Gradient Oscillate in Phase while Extracellular Calcium Influx Is Delayed.  

PubMed Central

Ratio images of cytosolic Ca2+ (Ca2+i) in growing, fura-2-dextran-loaded Lilium longiflorum pollen tubes taken at 3- to 5-sec intervals showed that the tip-focused [Ca2+]i gradient oscillates with the same period as growth. Similarly, measurement of the extracellular inward current, using a noninvasive ion-selective vibrating probe, indicated that the tip-directed extracellular Ca2+ (Ca2+o) current also oscillates with the same period as growth. Cross-correlation analysis revealed that whereas the [Ca2+]i gradient oscillates in phase with growth, the influx of Ca2+o lags by ~11 sec. Ion influx thus appears to follow growth, with the effect that the rate of growth at a given point determines the magnitude of the ion influx ~11 sec later. To explain the phase delay in the extracellular inward current, there must be a storage of Ca2+ for which we consider two possibilities: either the inward current represents the refilling of intracellular stores (capacitative calcium entry), or it represents the binding of the ion within the cell wall domain.

Holdaway-Clarke, T. L.; Feijo, J. A.; Hackett, G. R.; Kunkel, J. G.; Hepler, P. K.

1997-01-01

339

Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK  

PubMed Central

Introduction Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear. Methods We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents. Results Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK. Conclusions These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.

2011-01-01

340

Growth retardation and delayed puberty in children and adolescents with juvenile idiopathic arthritis  

Microsoft Academic Search

Juvenile idiopathic arthritis (JIA) is the most common joint disorder in developing children. Juvenile idiopathic arthritis is difficult to diagnose and treat. In some patients, signs and symptoms can be frustratingly inconsistent, contradictory or idiosyncratic. Short stature in patients with JIA is usually due to reduced growth in the lower extremities, and only rarely due to reduced growth in the

Wioleta Um?awska; Anna Prusek-Dudkiewicz

2010-01-01

341

The Tumor Microenvironment Contribution to Development, Growth, Invasion and Metastasis of Head and Neck Squamous Cell Carcinomas  

PubMed Central

Head and neck squamous cell carcinoma (HNSCC) is a complex tissue that contains tumor cells and the surrounding stroma, which is populated by different types of mesenchymal cells and the extracellular matrix (ECM). Collectively, they are referred to as the tumor microenvironment (TME). Recent studies have shown that TME has a more profound influence on the growth and metastasis of HNSCC than was previously appreciated. Because carcinoma-associated fibroblasts (CAFs) are frequently observed in the stroma of the tumor, this review focuses on the potential role of tumor-CAFs interactions in progression of HNSCC. Tumor-CAFs crosstalk enhances the production of growth factors, cytokines, chemokines, matrix metalloproteinases (MMPs), and inflammatory mediators, which eventually facilitates tumor growth. In fact, factors and cells that do not support tumor growth are usually down regulated or mitigated in TME. Therefore TME may determine the fate of the tumors at the site of invasion and metastasis. For tumor cells that survive at these sites, stromal activation may serve to establish a supportive tumor stroma, fostering the outgrowth of the metastatic cells. The concept of tumor-stromal interactions and microenvironmental niche has profound consequences in tumor growth and metastasis and therefore, it's understanding will open up new strategies for the diagnosis, prognosis and therapy of HNSCC.

Koontongkaew, Sittichai

2013-01-01

342

Explosive growth of a renal tumor during active surveillance.  

PubMed

The incidence of small renal masses (? 4 cm) has increased over the past three decades. Partial nephrectomy remains the standard for treatment of such lesions, but increased attention is being given to patients who may benefit from active surveillance, given the low risk of metastatic spread and traditionally slow growth rates. Patients with significant comorbidities and the elderly are often considered optimal candidates for surveillance. We present an 86-year-old female undergoing active surveillance for a 1.4 cm lesion that grew in diameter approximately 0.5 cm per year over 3 years, followed by explosive growth to 7 cm in diameter with a retrohepatic inferior vena cava (IVC) thrombus over the subsequent 13 months. PMID:23587518

Uhlman, Matthew A; Pate, Scott C; Brown, James A

2013-04-01

343

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

2012-08-24

344

Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast cancer cells.  

PubMed

Fibroblast growth factor 8 (FGF-8) is a secreted heparin-binding protein, which has mitogenic and transforming activity. Increased expression of FGF-8 has been found in human breast cancer, and it has a potential autocrine role in its progression. Human FGF-8 is alternatively spliced to generate four protein isoforms (a, b, e, and f). Isoform b has been shown to be the most transforming. In this work, we studied the role of FGF-8b in the growth (in vitro and in vivo) of MCF-7 human breast cancer cells, which proliferate in an estrogen-dependent manner. Constitutive overexpression of FGF-8b in MCF-7 cells down-regulated FGF-8b-binding receptors FGF receptor (FGFR) 1IIIc, FGFR2IIIc, and FGFR4 found to be expressed in these cells. FGF-8b overexpression led to an increase in the anchorage-independent proliferation rate in suspension culture and colony formation in soft agar, when MCF-7 cells were cultured with or without estradiol. FGF-8b also provided an additional growth advantage for cells stimulated with estradiol. In addition, FGF-8b-transfected cells invaded more actively through Matrigel than did control cells. This was possibly due to the increased secretion of matrix metalloproteinase 9. In vivo, FGF-8b-transfected MCF-7 cells formed faster growing tumors than vector-only-transfected cells when xenografted into nude mice. The tumors formed by FGF-8b-transfected cells were more vascular than the tumors formed by vector-only-transfected cells. In conclusion, FGF-8b expression confers a growth advantage to MCF-7 breast carcinoma cells, both in vitro and in vivo. In addition to stimulation of proliferation, this growth advantage probably arises from increased invasion and tumor vascularization induced by FGF-8b. The results suggest that FGF-8b signaling may be an important factor in the regulation of tumorigenesis and progression of human breast cancer. PMID:11358849

Ruohola, J K; Viitanen, T P; Valve, E M; Seppänen, J A; Loponen, N T; Keskitalo, J J; Lakkakorpi, P T; Härkönen, P L

2001-05-15

345

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

PubMed Central

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

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

2010-01-01

346

Image guided personalization of reaction-diffusion type tumor growth models using modified anisotropic eikonal equations.  

PubMed

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 tissue types, geometry of the brain and the directions of white matter fiber tracts improved the spatial accuracy of reaction-diffusion models. The adaptation of the general model to the specific patient cases on the other hand has not been studied thoroughly yet. In this paper, we address this adaptation. We propose a parameter estimation method for reaction-diffusion tumor growth models using time series of medical images. This method estimates the patient specific parameters of the model using the images of the patient taken at successive time instances. The proposed method formulates the evolution of the tumor delineation visible in the images based on the reaction-diffusion dynamics; therefore, it remains consistent with the information available. We perform thorough analysis of the method using synthetic tumors and show important couplings between parameters of the reaction-diffusion model. We show that several parameters can be uniquely identified in the case of fixing one parameter, namely the proliferation rate of tumor cells. Moreover, regardless of the value the proliferation rate is fixed to, the speed of growth of the tumor can be estimated in terms of the model parameters with accuracy. We also show that using the model-based speed, we can simulate the evolution of the tumor for the specific patient case. Finally, we apply our method to two real cases and show promising preliminary results. PMID:19605320

Konukoglu, Ender; Clatz, Olivier; Menze, Bjoern H; Stieltjes, Bram; Weber, Marc-André; Mandonnet, Emmanuel; Delingette, Hervé; Ayache, Nicholas

2009-07-14

347

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

PubMed Central

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

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

2012-01-01

348

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

PubMed

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

2013-09-04

349

SDF-1? mediates wound-promoted tumor growth in a syngeneic orthotopic mouse model of breast cancer.  

PubMed

Increased growth of residual tumors in the proximity of acute surgical wounds has been reported; however, the mechanisms of wound-promoted tumor growth remain unknown. Here, we used a syngeneic, orthotopic mouse model of breast cancer to study mechanisms of wound-promoted tumor growth. Our results demonstrate that exposure of metastatic mouse breast cancer cells (4T1) to SDF-1?, which is increased in wound fluid, results in increased tumor growth. Both, wounding and exposure of 4T1 cells to SDF-1? not only increased tumor growth, but also tumor cell proliferation rate and stromal collagen deposition. Conversely, systemic inhibition of SDF-1? signaling with the small molecule AMD 3100 abolished the effect of wounding, and decreased cell proliferation, collagen deposition, and neoangiogenesis to the levels observed in control animals. Furthermore, using different mouse strains we could demonstrate that the effect of wounding on tumor growth and SDF-1? levels is host dependent and varies between mouse strains. Our results show that wound-promoted tumor growth is mediated by elevated SDF-1? levels and indicate that the effect of acute wounds on tumor growth depends on the predetermined wound response of the host background and its predetermined wound response. PMID:23593347

Stuelten, Christina H; Cervoni-Curet, Frances N; Busch, Johanna I; Sutton, Emily; Webster, Joshua D; Kavalukas, Sandra L; Wakefield, Lalage M; Barbul, Adrian; Niederhuber, John E

2013-04-11

350

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

PubMed

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

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

2007-12-15

351

Amplification and\\/or Overexpression of Platelet-derived Growth Factor Receptors and Epidermal Growth Factor Receptor in Human Glial Tumors  

Microsoft Academic Search

Analysis of genomic organization and expression of platelet-derived growth factor receptors (PDGFR) and epidermal growth factor receptor (EGFR) in human malignant gliomas showed amplification and over- expression of both receptors in distinct subsets of tumors. Amplification of the aPDGFR was detected in 4 of 50 glioblastomas (8%). EGFR was amplified in 9 of the 50 tumors (18%). Western blot analysis

Timothy P. Fleming; Abha Saxena; W. Craig Clark; James T. Robertson; Edward H. Oldfield; Stuart A. Aaronson; Iqbal Unnisa Ali

1992-01-01

352

Delayed white matter growth trajectory in young nonpsychotic siblings of patients with childhood-onset schizophrenia.  

PubMed

CONTEXT Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. OBJECTIVE To study WM growth differences in nonpsychotic siblings of patients with COS. DESIGN Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. SETTING National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). INTERVENTION Magnetic resonance imaging. MAIN OUTCOME MEASURE White matter growth rates. RESULTS We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. CONCLUSIONS In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age. PMID:22945617

Gogtay, Nitin; Hua, Xue; Stidd, Reva; Boyle, Christina P; Lee, Suh; Weisinger, Brian; Chavez, Alex; Giedd, Jay N; Clasen, Liv; Toga, Arthur W; Rapoport, Judith L; Thompson, Paul M

2012-09-01

353

Critical Role of Shp2 in Tumor Growth Involving Regulation of c-Myc  

PubMed Central

Activating mutants of Shp2 protein tyrosine phosphatase, encoded by the PTPN11 gene, are linked to leukemia. In solid tumors, however, PTPN11 mutations occur at low frequencies, while the wild-type Shp2 is activated by protein tyrosine kinases (PTKs) in cancer cells and mediates PTK signaling. Therefore, it is important to address whether the wild-type Shp2 plays a functional role critical for tumor growth. Using shRNAs and a PTP-inactive mutant to inhibit Shp2, we find here that tumor growth of DU145 prostate cancer and H292 lung cancer cells depends on Shp2. Suppression of Shp2 inhibited cell proliferation, decreased c-Myc, and increased p27 expression in cell cultures. In H292 tumor tissues, c-Myc–positive cells coincided with Ki67-positive cells, and smaller tumors from Shp2 knockdown cells had less c-Myc–positive cells and more nuclear p27. Shp2-regulated c-Myc expression was mediated by Src and Erk1/2. Down-regulation of c-Myc reduced cell proliferation, while up-regulation of c-Myc in Shp2 knockdown H292 cells partially rescued the inhibitory effect of Shp2 suppression on cell proliferation. Tyrosine phosphoproteomic analysis of H292 tumor tissues showed that Shp2 could both up-regulate and down-regulate tyrosine phosphorylation on cellular proteins. Among other changes, Shp2 inhibition increased phosphorylation of Src Tyr-530 and Cdk1 Thr-14/Tyr-15 and decreased phosphorylation of Erk1- and Erk2-activating sites in the tumors. Significantly, we found that Shp2 positively regulated Gab1 Tyr-627/Tyr-659 phosphorylation. This finding reveals that Shp2 can autoregulate its own activating signal. Shp2 Tyr-62/Tyr-63 phosphorylation was observed in tumor tissues, indicating that Shp2 is activated in the tumors.

Ren, Yuan; Chen, Zhengming; Chen, Liwei; Fang, Bin; Win-Piazza, Hla; Haura, Eric; Koomen, John M.; Wu, Jie

2010-01-01

354

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

SciTech Connect

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

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

2011-07-15

355

Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth.  

PubMed

Vascular endothelial growth factor (VEGF) is a potent proangiogenic protein that activates VEGF receptor (VEGFR) tyrosine kinases expressed by vascular endothelial cells. We previously showed that one of these receptors, VEGFR-2, has a truncated soluble form (sVEGFR-2) that can be detected in mouse and human plasma. Because activation of VEGFR-2 plays an important role in tumor angiogenesis, clinical interest in monitoring plasma sVEGFR-2 levels in cancer patients has focused on its potential exploitation as a surrogate biomarker for disease progression as well as assessing efficacy/activity of antiangiogenic drugs, particularly those that target VEGF or VEGFR-2. However, no preclinical studies have been done to study sVEGFR-2 during tumor growth or the mechanisms involved in its modulation. Using spontaneously growing tumors and both localized and metastatic human tumor xenografts, we evaluated the relationship between sVEGFR-2 and tumor burden as well as underlying factors governing protein level modulation in vivo. Our results show an inverse relationship between the levels of sVEGFR-2 and tumor size. Furthermore, using various methods of VEGF overexpression in vivo, including cell transfection and adenoviral delivery, we found plasma sVEGFR-2 decreases to be mediated largely by tumor-derived VEGF. Finally, in vitro studies indicate VEGF-mediated sVEGFR-2 modulation is the result of ligand-induced down-regulation of the VEGFR-2 from the cell surface. Taken together, these findings may be pertinent to further clinical exploitation of plasma sVEGFR-2 levels as a surrogate biomarker of VEGF-dependent tumor growth as well as an activity indicator of antiangiogenic drugs that target the VEGFR system. PMID:18199548

Ebos, John M L; Lee, Christina R; Bogdanovic, Elena; Alami, Jennifer; Van Slyke, Paul; Francia, Giulio; Xu, Ping; Mutsaers, Anthony J; Dumont, Daniel J; Kerbel, Robert S

2008-01-15

356

A cellular automata model for avascular solid tumor growth under the effect of therapy  

NASA Astrophysics Data System (ADS)

Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

2009-04-01

357

The Role of the Vascular Phase in Solid Tumor Growth: A Historical Review  

PubMed Central

Abstract Angiogenesis is a biological process by which new capillaries are formed from pre-existing vessels. It occurs in both physiological conditions such as embryo development, cyclically in the female genital system and during wound repair, and pathological conditions, such as arthritis, diabetic retinopathy and tumors. In solid tumor growth, a specific critical turning point is the transition from the avascular to the vascular phase. Having developed an intrinsic vascular network, the neoplastic mass is able to grow indefinitely (unlike all the other forms, tumor angiogenesis is not limited in time) both in situ and at distant sites (metastasis) in so far as an intrinsic vascular network enables its cells to enter the vascular bed and colonize other organs. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells and able to stimulate growth of the host's blood vessels. This review describes its history as traced by the main contributions to the international medical literature and their contents. The specific new paradigm discussed here has been gaining general approval and considerable confirmation, thanks to its possible applications, as recently highlighted by the introduction of anti-angiogenic substances in adjuvant tumor management.

Ribatti, Domenico; Vacca, Angelo; Dammacco, Franco

1999-01-01

358

M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth.  

PubMed

Many cancer cells have increased rates of aerobic glycolysis, a phenomenon termed the Warburg effect. In addition, in tumors there is a predominance of expression of the M2 isoform of pyruvate kinase (PKM2). M2 expression was previously shown to be necessary for aerobic glycolysis and to provide a growth advantage to tumors. We report that knockdown of pyruvate kinase in tumor cells leads to a decrease in the levels of pyruvate kinase activity and an increase in the pyruvate kinase substrate phosphoenolpyruvate. However, lactate production from glucose, although reduced, was not fully inhibited. Furthermore, we are unique in reporting increased serine and glycine biosynthesis from both glucose and glutamine following pyruvate kinase knockdown. Although pyruvate kinase knockdown results in modest impairment of proliferation in vitro, in vivo growth of established xenograft tumors is unaffected by PKM2 absence. Our findings indicate that PKM2 is dispensable for tumor maintenance and growth in vivo, suggesting that other metabolic pathways bypass its function. PMID:23267074

Cortés-Cros, Marta; Hemmerlin, Christelle; Ferretti, Stephane; Zhang, Juan; Gounarides, John S; Yin, Hong; Muller, Alban; Haberkorn, Anne; Chene, Patrick; Sellers, William R; Hofmann, Francesco

2012-12-24

359

Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo  

PubMed Central

AIM: To investigate the anti-tumor effects of paeonol in gastric cancer cell proliferation and apoptosis in vitro and in vivo. METHODS: Murine gastric cancer cell line mouse forestomach carcinoma (MFC) or human gastric cancer cell line SGC-7901 was cultured in the presence or absence of paeonol. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell cycle and apoptosis by flow cytometry and TUNEL staining. Tumor growth after subcutaneous implantation of MFC cells in mice was monitored, and the effects of treatment with paeonol were determined. RESULTS: In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression. CONCLUSION: Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo.

Li, Na; Fan, Lu-Lu; Sun, Guo-Ping; Wan, Xin-An; Wang, Zhang-Gui; Wu, Qiang; Wang, Hua

2010-01-01

360

Elevated growth CO 2 delays drought stress and accelerates recovery of rice leaf photosynthesis  

Microsoft Academic Search

Rising atmospheric carbon dioxide concentration ([CO2]) and predicted changes in rainfall frequency and intensity could have considerable impact on crop growth and yield. Our objective was to assess rice leaf photosynthesis and carbohydrate metabolism in response to decreased soil water availability at elevated growth [CO2]. Rice (Oryza sativa [L.] cv. IR-72) was grown season-long in eight sunlit, controlled-environment chambers at

W. Widodo; Joseph C. V. Vu; Kenneth J. Boote; Jeffrey T. Baker; Leon H. Allen

2003-01-01

361

Transforming growth factor-?1 exhibits delayed gene expression following focal cerebral ischemia  

Microsoft Academic Search

Transforming growth factor-?1 (TGF-?1) is a pleiotropic peptide growth factor. The expression of TGF-?1 mRNA in the focal ischemic cortex of rats was studied by means of Northern hybridization. A moderately low level of constitutively expressed TGF-?1 mRNA was detected following ohm surgery or in the contralateral (nonlschemic) cortex. A significant increase of TGF-?1 mRNA level in the ischemic cortex

Xinkang Wang; Tian-Li Yue; Raymond F. White; Frank C. Barone; Giora Z. Feuerstein

1995-01-01

362

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

PubMed Central

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

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

2013-01-01

363

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

PubMed

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

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

2013-09-12

364

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

PubMed Central

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

Ricard, Clement; Stanchi, Fabio; Rodriguez, Thieric; Amoureux, Marie-Claude; Rougon, Genevieve; Debarbieux, Franck

2013-01-01

365

Tissue Inhibitor of Metalloproteinase-1 Alters the Tumorigenicity of Burkitt's Lymphoma via Divergent Effects on Tumor Growth and Angiogenesis  

PubMed Central

Epstein-Barr virus (EBV)-positive Burkitt’s lymphoma cells and EBV-infected B cells elicit humoral factors that inhibit tumor-induced angiogenesis, resulting in tumor necrosis and regression. Of the chemokine factors identified in association with this growth behavior, none have induced complete tumor regression. We have previously identified tissue inhibitors of metalloproteinase (TIMP)-1 in various B cell lymphoma cell lines. Here we show that induction of TIMP-1 expression in an EBV-negative Burkitt’s lymphoma cell line results in a biphasic, in vivo tumor growth pattern in the nude mouse that is essentially identical to EBV-positive Burkitt’s lymphoma cell lines. The initial effect of TIMP-1 is to enhance tumor growth, consistent with the reported anti-apoptotic effect of TIMP-1 on B cell growth. Tumor necrosis and regression then follow the initial period of rapid, increased tumor growth. Only microscopic foci of residual, proliferating tumor cells are observed on biopsy of the tumor site. This latter effect is mediated by TIMP-1 inhibition of an angiogenic response within the developing tumor mass, as demonstrated by immunostaining and microvessel counts. These findings suggest that TIMP-1 is an important mediator of the in vivo growth properties of EBV-positive Burkitt’s lymphoma.

Guedez, Liliana; McMarlin, Andrew J.; Kingma, Douglas W.; Bennett, Teresa A.; Stetler-Stevenson, Maryalice; Stetler-Stevenson, William G.

2001-01-01

366

Role of SOCS-1 Gene on Melanoma Cell Growth and Tumor Development.  

PubMed

Melanoma is the most aggressive form of skin cancer, and its incidence has increased dramatically over the years. The murine B16F10 melanoma in syngeneic C57Bl/6 mice has been used as a highly aggressive model to investigate tumor development. Presently, we demonstrate in the B16F10-Nex2 subclone that silencing of SOCS-1, a negative regulator of Jak/Stat pathway, leads to reversal of the tumorigenic phenotype and inhibition of melanoma cell metastasis. SOCS-1 silencing with short hairpin RNA affected tumor growth and cell cycle regulation with arrest at the S phase with large-sized nuclei, reduced cell motility, and decreased melanoma cell invasion through Matrigel. A clonogenic assay showed that SOCS-1 acted as a modulator of resistance to anoikis. In addition, downregulation of SOCS-1 decreased the expression of epidermal growth factor receptor (mainly the phosphorylated-R), Ins-R?, and fibroblast growth factor receptor. In vivo, silencing of SOCS-1 inhibited subcutaneous tumor growth and metastatic development in the lungs. Because SOCS-1 is expressed in most melanoma cell lines and bears a relation with tumor invasion, thickness, and stage of disease, the present results on the effects of SOCS-1 silencing in melanoma suggest that this regulating protein can be a target of cancer therapy. PMID:21461173

Scutti, Jorge A Borin; Matsuo, Alisson Leonardo; Pereira, Felipe Valença; Massaoka, Mariana Hiromi; Figueiredo, Carlos Rogério; Moreira, Dayson Friaça; Belizário, José Ernesto; Travassos, Luiz R

2011-04-01

367

Role of SOCS-1 Gene on Melanoma Cell Growth and Tumor Development1  

PubMed Central

Melanoma is the most aggressive form of skin cancer, and its incidence has increased dramatically over the years. The murine B16F10 melanoma in syngeneic C57Bl/6 mice has been used as a highly aggressive model to investigate tumor development. Presently, we demonstrate in the B16F10-Nex2 subclone that silencing of SOCS-1, a negative regulator of Jak/Stat pathway, leads to reversal of the tumorigenic phenotype and inhibition of melanoma cell metastasis. SOCS-1 silencing with short hairpin RNA affected tumor growth and cell cycle regulation with arrest at the S phase with large-sized nuclei, reduced cell motility, and decreased melanoma cell invasion through Matrigel. A clonogenic assay showed that SOCS-1 acted as a modulator of resistance to anoikis. In addition, downregulation of SOCS-1 decreased the expression of epidermal growth factor receptor (mainly the phosphorylated-R), Ins-R?, and fibroblast growth factor receptor. In vivo, silencing of SOCS-1 inhibited subcutaneous tumor growth and metastatic development in the lungs. Because SOCS-1 is expressed in most melanoma cell lines and bears a relation with tumor invasion, thickness, and stage of disease, the present results on the effects of SOCS-1 silencing in melanoma suggest that this regulating protein can be a target of cancer therapy.

Scutti, Jorge A Borin; Matsuo, Alisson Leonardo; Pereira, Felipe Valenca; Massaoka, Mariana Hiromi; Figueiredo, Carlos Rogerio; Moreira, Dayson Friaca; Belizario, Jose Ernesto; Travassos, Luiz R

2011-01-01

368

Effects of laparoscopy on intraperitoneal tumor growth and distant metastases in an animal model  

Microsoft Academic Search

Background and aims: Laparoscopic surgery for colorectal cancer is currently being evaluated in humans. The aim of this study was to examine the effect of laparoscopy on intraperitoneal tumor growth and distant metastases in an animal model. We also examined the effect of combining laparotomy with laparoscopy and on infusing the peritoneal cavity with normal saline solution (NaCl), water, and

Helen R Dorrance; Karin Oien; Patrick J O'Dwyer

1999-01-01

369

In vivo tumor growth inhibition and biodistribution studies of locked nucleic acid (LNA) antisense oligonucleotides  

Microsoft Academic Search

Locked nucleic acids (LNA) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. The LNA oligonucleotides (LNA PO ODNs) are very stable in vitro and in vivo without the need for a phosphorothiolated backbone. In this study we tested the biological fate and the efficacy in tumor growth inhibition of antisense oligonucleotides dir- ected against the gene

Kees Fluiter; Asbroek ten A. L. M. A; Wissel de M. B; Marja E. Jakobs; Margit Wissenbach; H. Olsson; O. Olsen; H. Oerum; F. Baas

2003-01-01

370

The Molecular Mechanisms of Traditional Chinese Medicine ZHENG Syndromes on Pancreatic Tumor Growth  

Microsoft Academic Search

Background: Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. Objective: To evaluate the specific effect of TCM ZHENG on tumor growth

Hai-Yan Dai; Peng Wang; Lan-Yun Feng; Lu-Ming Liu; Zhi-Qiang Meng; Xiao-Yan Zhu; Kun Wang; Yong-Qiang Hua; Yi-Xiang Mao; Lian-Yu Chen; Zhen Chen

2010-01-01

371

The Chemokine CCL2 Increases Prostate Tumor Growth and Bone Metastasis through Macrophage and Osteoclast Recruitment1  

Microsoft Academic Search

CC chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein-1) has been demonstrated to recruit monocytes to tumor sites. Monocytes are capable of being differentiated into tumor-associated macrophages (TAMs) and osteoclasts (OCs). TAMs have been shown to promote tumor growth in several cancer types. Osteo- clasts have also been known to play an important role in cancer bone metastasis.

Kosuke Mizutani; Sudha Sud; Natalie A. McGregor; Gari Martinovski; Brandon T. Rice; Matthew J. Craig; Zachary S. Varsos; Hernan Roca; Kenneth J. Pienta

372

Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy.  

PubMed

We have reported that Escherichia coli K-12 colonizes hypoxic and necrotic tumor regions after intravenous injection into tumor-bearing mice. In this study, we established a novel strategy for cancer therapy using engineered bacteria to enhance the therapeutic effects of radiation. E. coli strain K-12 was engineered to produce cytolysin A (ClyA), and its effects on tumor growth in primary and metastatic tumor models were evaluated. A single treatment with E. coli-expressing ClyA significantly decreased tumor growth rates initially (9 days after treatment); however, the tumors tended to grow thereafter. With only radiotherapy (RT; 21 Gy), the tumor growth rates were retarded, but not the tumor sizes. A combination of therapy with E. coli-expressing ClyA and radiation [a total of 5 x 10(7) colony-forming units (CFU) and 21 Gy] resulted in significant tumor shrinkage and even complete disappearance of tumors in mice with tumors derived from murine CT26 colon cancer. Furthermore, treatment with E. coli-expressing ClyA markedly suppressed metastatic tumor growth and prolonged the survival time in mice. The results described here indicate that therapy with engineered E. coli could significantly improve the results of RT, and could exert a striking inhibitory effect on the development of lung metastasis. PMID:20051939

Jiang, Sheng-Nan; Phan, Thuy X; Nam, Taek-Keun; Nguyen, Vu H; Kim, Hyung-Seok; Bom, Hee-Seung; Choy, Hyon E; Hong, Yeongjin; Min, Jung-Joon

2010-01-05

373

An in vivo mouse reporter gene (human secreted alkaline phosphatase) model to monitor ovarian tumor growth and response to therapeutics  

Microsoft Academic Search

Purpose: Developing new anticancer therapeutic regimens requires the measurement of tumor cell growth in response to treatment. This is often accomplished by injecting immunocompromised mice with cells from cancer tissue or cell lines. After treating the animals, tumor weight or volume is measured. Such methods are complicated by inaccuracies in measuring tumor mass and often animals must be killed to

Eric E. Nilsson; Suzanne D. Westfall; Claudia McDonald; Tiffany Lison; Ingrid Sadler-Riggleman; Michael K. Skinner

2002-01-01

374

Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice.  

PubMed

As the main effector-cell population of the central nervous system, microglia (MG) are considered to play an important immunoregulatory function in a number of pathological conditions such as inflammation, trauma, degenerative disease, and brain tumors. Recent studies, however, have suggested that the anti-neoplastic function of MG may be suppressed in malignant brain tumors. Considering the proposed suppressive role of signal transducers and activators of transcription 3 (Stat3) in antitumor immunity, we evaluated the role of Stat3 inhibition on MG and macrophage (MP) activation and tumor growth in a murine glioma model. N9 MG cells were exposed to GL261 glioma conditioned medium (GL261-CM) and evaluated for Stat3 activity and cytokine expression. Furthermore, the role of Stat3 inhibition on MG and MP activation was studied both in vitro and in vivo. Finally, the effect of Stat3 inhibition on tumor growth was assessed in intracranial GL261 gliomas. GL261-CM increased Stat3 activity in N9 cells in vitro and resulted in overexpression of IL-10 and IL-6, and downregulation of IL1-beta, a pro-inflammatory cytokine. Inhibition of Stat3 by CPA-7 or siRNA reversed glioma-induced cytokine expression profile in N9 cells. Furthermore, inactivation of Stat3 in intracranial GL261 tumors by siRNA resulted in MG/MP activation and tumor growth inhibition. Glioma-induced MG and MP suppression may be mediated thorough Stat3. Inhibition of Stat3 function in tumor MG/MP may result in their activation and can potentially be used as an adjunct immunotherapy approach for gliomas. PMID:19306372

Zhang, Leying; Alizadeh, Darya; Van Handel, Michelle; Kortylewski, Marcin; Yu, Hua; Badie, Behnam

2009-10-01

375

Adenosine A2B receptor blockade slows growth of bladder and breast tumors.  

PubMed

The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluated the effects of intermittent intratumor injection of a nonselective adenosine receptor antagonist, aminophylline (AMO; theophylline ethylenediamine) and, for the first time to our knowledge, a selective A(2B)AR antagonist, ATL801. AMO and ATL801 slowed the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice and reduced by 85% metastasizes of breast cancer cells from mammary fat to lung. Based on experiments with A(2A)AR(-/-) or adenosine A(2B) receptor(-/-) mice, the effect of AMO injection was unexpectedly attributed to A(2B)AR and not to A(2A)AR blockade. AMO and ATL801 significantly increased tumor levels of IFN-? and the IFN-inducible chemokine CXCL10, which is a ligand for CXCR3. This was associated with an increase in activated tumor-infiltrating CXCR3(+) T cells and a decrease in endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3(-/-) mice and RAG1(-/-) mice that lack mature T cells. In RAG1(-/-) mice, A(2B)AR deletion enhanced CD86 expression on CD11b(-) DCs. Bone marrow chimera experiments demonstrated that CXCR3 and A(2B)AR expression on bone marrow cells is required for the antitumor effects of AMO. The data suggest that blockade of A(2B)ARs enhances DC activation and CXCR3-dependent antitumor responses. PMID:22116822

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

2011-11-23

376

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

PubMed Central

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.

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

2012-01-01

377

RNAi Targeting CXCR4 Inhibits Tumor Growth Through Inducing Cell Cycle Arrest and Apoptosis  

PubMed Central

CXC chemokine receptor 4 (CXCR4) is involved in many human malignant tumors and plays an important role in tumor growth and metastasis. To explore the effects of CXCR4 expression on the malignant cells of oral squamous cell carcinoma (OSCC), Tca8113 and SCC-9 cell lines, as well as their xenograft models, of nude mice were used to detect cancer cell proliferation alteration. This study also examined the corresponding molecular mechanism after CXCR4 knockdown using a recombinant lentiviral vector expressing small interference RNA (siRNA) for CXCR4. RNA interference-mediated knockdown of CXCR4 in highly aggressive (Tca8113 and SCC-9) tumor cells significantly inhibited the proliferation of the two cell lines in vitro and in vivo. The expression levels of >1,500 genes involved in cell cycle, apoptosis, and multiple signaling pathways were also altered. These results provide new evidence of CXCR4 as a promising tumor gene therapeutic target.

Yu, Tao; Wu, Yingying; Huang, Yi; Yan, Chaoran; Liu, Ying; Wang, Zongsheng; Wang, Xiaoyi; Wen, Yuming; Wang, Changmei; Li, Longjiang

2012-01-01