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1

Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of tumor growth and tumor angiogenesis of mouse ehrlich ascites tumor in vivo.  

PubMed

A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 3(a-e) were synthesized by nucleophilic substitution reaction of 1-benzhydryl-piperazine with different sulfonyl chlorides and were characterized by 1H NMR, LC/MS, FTIR and elemental analysis. In the present study, the compounds 3(a-e) exhibited in vivo inhibition of Ehrlich ascites tumor (EAT) cell growth and increased the Median Survival Time (MST) and %ILS of EAT bearing mice. Further treatment of derivatives in vivo resulted in reduction of EAT cell number and ascites formation. The efficacy of the derivatives to inhibit the angiogenesis in vivo was evaluated in tumor bearing mice peritoneum and chorio allantoic membrane (CAM) model. The compounds suppressed the blood vessel formation in vivo in mice peritoneum and in CAM. Among the compounds studied, 3e demonstrated highest tumor inhibitory and anti-angiogenic effects against mouse tumor. However, this phenomenon needs detailed investigation. PMID:18782043

Kumar, C S Ananda; Chandru, H; Sharada, A C; Thimmegowda, N R; Prasad, S B Benaka; Kumar, M Karuna; Rangappa, K S

2008-09-01

2

Ornithine alpha-ketoglutarate limits muscle protein breakdown without stimulating tumor growth in rats bearing Yoshida ascites hepatoma.  

PubMed

The growth of the Yoshida ascites hepatoma AH130 (YAH) is associated with early wasting, depletion of intracellular amino acid pools, and a pronounced activation of protein degradation in skeletal muscle of the host animal. Ornithine alpha-ketoglutarate (OKG) is used in the treatment of hypercatabolic states, and it has been suggested that it may improve nitrogen balance through repletion of free amino acid pools and suppression of protein catabolism. In cancer, OKG might similarly improve host nutritional status or stimulate tumor growth if its metabolites are limiting for tumor growth. Enteral supplementation with OKG was investigated in Sprague-Dawley rats bearing YAH. Tumor-bearing rats were compared with ad libitum- and pair-fed controls. Rats received OKG (3.4 to 4.0 g/kg body weight/d) or an equal amount of nitrogen as glycine (n = 8 in each group) for 5 days. Tumor implantation decreased cumulative food intake (-40%), host weight (-6%), skeletal muscle weight, and free amino acid levels in muscle and plasma. Muscle protein balance was estimated in vitro; decreased protein synthesis (-30%) and increased proteolysis (+113%) were observed in epitrochlearis muscles (EPI) of YAH-bearing rats compared with control groups. OKG had no effect on the wet weight (10 +/- 1 g) and nitrogen content of the tumor, or on free amino acid levels in the tumor. In tumor-bearing rats, OKG improved muscle protein balance by reducing breakdown by 33% and overall amino acid release of incubated EPI by 46%. PMID:8028516

Le Bricon, T; Cynober, L; Baracos, V E

1994-07-01

3

Ehrlich ascites tumor cells produce a transforming growth factor-? (TGF?)-like activity but lack receptors with TGF?-binding capacity  

Microsoft Academic Search

Ehrlich ascites tumor cells incorporate [methyl-3H]thymidine into DNA independently of exogenous growth factors or fetal calf serum. Using an acid\\/ethanol extraction procedure we have obtained from these tumor cells a fraction that induces both the proliferation and the formation of cell foci by Swiss 3T3 mouse fibroblasts in the presence of insulin; inhibits the proliferation of Mv1Lu mink lung epithelial

Ana Elexpuru; José Martín-Nieto; Amparo Jiménez; Carmen Gómez; Antonio Villalobo

1997-01-01

4

In vivo growth inhibitory and anti-angiogenic effects of synthetic novel dienone cyclopropoxy curcumin analogs on mouse Ehrlich ascites tumor.  

PubMed

In the present study, four novel dienone cyclopropoxy curcumin analogs 1a-4a were synthesized by nucleophillic substitution reaction with cyclopropyl bromide. The tumor inhibitory and anti-angiogenic effects of the synthetic compounds were studied on mouse Ehrlich ascites tumor (EAT) in vivo. The compounds 1a-4a increased the life span (% ILS) of EAT bearing mice with corresponding significant reduction in ascites volume and cell number and induced apoptotic bodies in EAT cells. Anti-angiogenic studies of the compounds demonstrated significant reduction of microvessel density (MVD) in the peritoneum wall sections of mice and induced avascular zone in CAM model. Our findings demonstrate that the tumor growth inhibitory effects of synthetic dienone cyclopropoxy curcumin analogs 1a-4a could be mediated by promoting apoptosis and inhibiting tumor angiogenesis. However, the compounds need to be explored further to assess its clinical relevance. PMID:17869527

Chandru, H; Sharada, A C; Bettadaiah, B K; Kumar, C S Ananda; Rangappa, K S; Sunila; Jayashree, K

2007-12-15

5

Chylous Ascites Following Surgical Treatment for Wilms Tumor  

Microsoft Academic Search

PurposePostoperative chylous ascites is a rare complication of retroperitoneal surgery that has considerable morbidity. We review the pathogenesis and management of chylous ascites following surgical treatment of Wilms tumor.

ADAM C. WEISER; BRUCE W. LINDGREN; MICHAEL L. RITCHEY; ISRAEL FRANCO

2003-01-01

6

Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-?B signaling activation in CD4+ T cells.  

PubMed

Gastrodia elata Blume (G. elata) is a famous restorative food in East Asia. It can be used as an auxiliary reagent in hepatocellular carcinoma (HCC) treatment. Previous studies unveiled that G. elata exhibited immunomodulatory activities. To explore the active ingredients contributing to its immunomodulatory activities, gastrodin, vanillin, and parishin B were purified from G. elata and their anti-HCC effects were assessed in vivo. Among these compounds, only gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell growth in vivo with low toxicity. Further investigations were designed to explore the effects of gastrodin on the immune system of tumor-bearing mice and potential molecular mechanisms underlying these effects. Our data showed that gastrodin ameliorated tumor cell transplantation-induced activation of endogenous pro-apoptotic pathway in CD4+ T cells and abnormalities in serum cytokine profiles in host animals. These events enhanced cytotoxic activities of natural killer and CD8+ T cells against H22 hepatic cancer cells. Gastrodin administration specifically upregulated mRNA levels of several nuclear factor ?B (NF-?B) responsive genes in CD4+ T cells but not in CD8+ T cells. Chromatin immunoprecipitation assay showed that gastrodin increased the association of NF-?B p65 subunit to the promoter regions of IL-2 and Bcl-2 encoding genes in CD4+ T cells. Our investigations demonstrated that gastrodin is the main active ingredient contributing to the anticancer immunomodulatory properties of G. elata. Promoting NF-?B-mediated gene transcription in CD4+ T cells is implicated in its immunomodulatory activity. PMID:23578476

Shu, Guangwen; Yang, Tianming; Wang, Chaoyuan; Su, Hanwen; Xiang, Meixian

2013-06-15

7

Oscillabolastic model, a new model for oscillatory dynamics, applied to the analysis of Hes1 gene expression and Ehrlich ascites tumor growth.  

PubMed

This paper introduces a new dynamical model, called the oscillabolastic model, to analyze the dynamical behavior of biomedical data when one observes oscillatory behavior. The proposed oscillabolastic model is sufficiently flexible to represent various types of oscillatory behavior. The oscillabolastic model is applied to two sets of data. The first data set deals with the oscillabolastic modeling of Ehrlich ascites tumor cells and the second one is the oscillabolastic modeling of the mean signal intensity of Hes1 gene expression in response to serum stimulation. A generalized oscillabolastic model is also suggested to accommodate cases in which predictor variables other than time are also involved. PMID:22198604

Tabatabai, M A; Eby, W M; Bursac, Z

2012-06-01

8

Ascites  

MedlinePLUS

Portal hypertension - ascites ... pressure in the blood vessels of the liver (portal hypertension) and low levels of a protein called ... include: Clots in the veins of the liver (portal vein thrombosis) Congestive heart failure Pancreatitis Thickening and ...

9

[Conditions for forming ascitic tumors in hybridoma cultivation in vivo].  

PubMed

The conditions of the formation of ascitic cells in BALB/c mice injected with hybridoma cells were studied. All the hybridomas under study, producing monoclonal antibodies to viral antigens, induced the formation of ascitic tumors when introduced into the abdominal cavity of BALB/c mice pretreated with sensitizing agents. In the mice pretreated with pristane hybridoma cells took at a rate of 43-80% and in the mice pretreated with Freund's complete adjuvant, 31-70%. Angara oil and perfume oil, as well as Bayol F, were less effective. The time of the formation of ascites was inversely proportional to the dose of the injected cells, while the volume of ascitic fluid depended rather on the type of hybridoma and not on the dose of the injected cells. The study showed that the use of physiological saline or culture medium without serum for washing the abdominal cavity of mice after withdrawing ascites permitted the additional collection of 2.6-13.7 million hybrid cells, as well as a considerable amount of immunoglobulins. PMID:3751404

Novokhatski?, A S; Malakhova, I V; Ga?damovich, S Ia; Mel'nikova, E E; Sveshnikova, N A

1986-07-01

10

Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor.  

PubMed

Ursolic acid (UA) is a pentacyclic triterpene naturally occurring in many plant foods. In the present study, we investigated anti-cancer activity of UA in vivo in Ehrlich ascites carcinoma (EAC) tumor. 15 × 10(6) EAC cells were implanted intraperitoneally (i.p., ascitic tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received UA i.p. at 25, 50 and 100mg/kg bw for 14 d in ascitic and 100mg/kg bw in solid tumor for 30 d. On day 15, blood samples were collected for hematological assessment of hemoglobin (Hb%), RBCs, WBCs and PCV. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF, iNOS, CD31, caspase-3 and Bax were also performed. UA significantly inhibited tumor growth, cell viability, in both ascites and solid tumor model in vivo (p<0.001). The anti-angiogenic effects were accompanied with decreased VEGF, iNOS, TNF-? and increased IL-12 levels. UA at 100mg/kg bw dose significantly increased SOD and CAT activity (p<0.01). GSH and TBARS were increased as compared to control group (p<0.001). Furthermore, UA increased total RBCs, WBCs as well as Hb% significantly (p<0.05) compared to cyclophosphamide (CP). Histopathological examination of tumor cells in the treated group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. Decreased peritoneal angiogenesis showed the anti-angiogenic potential. UA downregulated VEGF & iNOS expression whereas bax and caspase-3 expressions were upregulated suggesting drug induced tumor cell apoptosis through activating the pro-apoptotic bcl-2 family and caspase-3 and downregulation of VEGF. The present study sheds light on the potent antitumor property of the UA and can be extended further to develop therapeutic protocols for treatment of cancer. PMID:24051192

Saraswati, Sarita; Agrawal, S S; Alhaider, Abdulqader A

2013-11-25

11

[Chronobiological analysis of thyroxine action on cell proliferation in the hypotetraploid strain of Ehrlich's ascitic tumor].  

PubMed

Experiments on white random-bred male mice were made to study the effect of L-thyroxine on cell proliferation of the hypotetraploid strain of Ehrlich's ascites carcinoma. It was shown that prolonged thyroxine administration (during 6 days of carcinoma growth) lead to synchronization of cell proliferation and the maximum values of the mitotic index was found 3 hours earlier then in the control experiments. At the same time thyroxine did not exert any noticeable effect on the average daily magnitudes of the number of DNA-synthesizing cells and did not change the pattern of modulations in the radioactive index. The changes in the mitotic index and radioactive index were asynchronous in control and experimental animals. Analogous results were found for hyperdiploid strain of Ehrlich's ascites tumor. Ploidy of cells did not influence the tipe rhythms of the cell proliferation and its reaction on the action of thyroxine. PMID:2633828

Romanov, Iu A; Stepanenko, V A

1989-11-01

12

Curcumin's effects on sialic acid level and sialidase activity in Ehrlich ascites tumor bearing mice.  

PubMed

In this study, we determined curcumin's anticancer and chemopreventive effects in mice bearing Ehrlich ascites tumor by evaluation of cancer biomarkers, sialic acid level and sialidase activity. Both plasma sialic acid level and sialidase activity increased significantly in the mice group with Ehrlich ascites tumor. When the tumor groups fed with curcumin and fed with sesame oil were compared, sialic acid level and sialidase activity in ascites fluid significantly reduced in the group fed with curcumin in addition to the increases of plasma sialic acid level and sialidase activity. The tumor group fed with curcumin lived twice longer than the one fed with sesame oil. Curcumin as a phenolic compound decreased all these parameters in Ehrlich ascites tumors and lengthened survival by 88% in the mice with tumor. We concluded that curcumin has anticancer activity. PMID:12434997

Ozen, Naile; Uslu, Ezel; Ozen, Metehan; Aydin, Seval; Altug, Tuncay; Belce, Ahmet; Kokoglu, Emine

2002-08-01

13

Anti-MUC1 Monoclonal Antibody (C595) and Docetaxel Markedly Reduce Tumor Burden and Ascites, and Prolong Survival in an in vivo Ovarian Cancer Model  

PubMed Central

MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. We previously reported that anti-MUC1 monoclonal antibody C595 (MAb C595) plus docetaxel (DTX) increased efficacy of DTX alone and caused cultured human epithelial ovarian cancer (EOC) cells to undergo apoptosis. To further study the mechanisms of this combination-mediated apoptosis, we investigated the effectiveness of this combination therapy in vivo in an intraperitoneal (i.p.) EOC mouse model. OVCAR-3 cells were implanted intraperitoneally in female athymic nude mice and allowed to grow tumor and ascites. Mice were then treated with single MAb C595, DTX, combination test (MAb C595 and DTX), combination control (negative MAb IgG3 and DTX) or vehicle control i.p for 3 weeks. Treated mice were killed 4 weeks post-treatment. Ascites volume, tumor weight, CA125 levels from ascites and survival of animals were assessed. The expression of MUC1, CD31, Ki-67, TUNEL and apoptotic proteins in tumor xenografts was evaluated by immunohistochemistry. MAb C595 alone inhibited i.p. tumor growth and ascites production in a dose-dependent manner but did not obviously prevent tumor development. However, combination test significantly reduced ascites volume, tumor growth and metastases, CA125 levels in ascites and improved survival of treated mice compared with single agent-treated mice, combination control or vehicle control-treated mice (P<0.05). The data was in a good agreement with that from cultured cells in vitro. The mechanisms behind the observed effects could be through targeting MUC1 antigens, inhibition of tumor angiogenesis, and induction of apoptosis. Our results suggest that this combination approach can effectively reduce tumor burden and ascites, prolong survival of animals through induction of tumor apoptosis and necrosis, and may provide a potential therapy for advanced metastatic EOC.

Wang, Li; Chen, Hongmin; Pourgholami, Mohammad H.; Beretov, Julia; Hao, Jingli; Chao, Hongtu; Perkins, Alan C.; Kearsley, John H.; Li, Yong

2011-01-01

14

Importance of viability and attachment to an ascites tumor in the release of plasminogen activator.  

PubMed Central

Tumor plasminogen activator (PA) has been alleged to play a role in the growth and metastasis of tumors. Before such a role can be realized, PA first must be released from tumor cells. Having determined intra- and extracellular PA and PA-inhibitor activities in an experimental pancreatic ascites tumor grown in hamsters, the release of PA from these cells was investigated. No PA activity was detected in the suspension medium of freshly isolated tumor cells; inclusion of plasminogen, fibrinogen, or collagen in the medium yielded similar negative results. On the other hand, PA activity was demonstrated to be released in a time-dependent manner from these tumor cells embedded in fibrin clots. Plasminogen activator activity also was not found in the suspension medium of frozen-thawed tumor cells, despite the fact that most of them had breaks on their cell membrane. Unlike freshly isolated tumor cells, PA was not released from frozen-thawed cells embedded in fibrin clots. Full PA activity was demonstrated in frozen-thawed cells treated with Triton X-100, however. Frozen-thawed cells exhibited signs of severe damage, and more than 80% of them failed to exclude trypan blue. Obviously PA is released from viable tumor cells embedded in fibrin clots but not suspended in artificial medium. The PA-release mechanism, not PA itself, is destroyed in cells rendered nonviable by freeze thawing. Images Figure 1 Figure 5 Figure 6 Figure 7

Dong, Q.; Zhou, M.; Subbarao, V.; Ts'ao, C.

1991-01-01

15

In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma.  

PubMed

Adult Swiss albino mice were inoculated intraperitoneally (i.p.) with 10 (6) Ehrlich ascites carcinoma cells. Twenty-four hours later they were given an i.p. injection of 10-60 mg/kg of withaferin A (WA), isolated from the roots of Withania somnifera. The tumor growth and tumor free animal survival were studied for up to 120 days. In another experiment 30 mg/kg WA was injected i.p. to mice at 1, 3 or 5 days after tumor cell injection with or without acute abdominal exposure to 7.5 Gy gamma radiation and the tumor growth and 120-day survival were studied. WA inhibited tumor growth and increased tumor free survival in a dose-dependent manner. The drug ED50 for 120-day survival was approximately 30 mg/kg body wt. Drug treatment before irradiation synergistically increased 120-day even in advanced tumors. A dose of 30 mg/kg seems to be optimum for combination with radiation. PMID:7656229

Devi, P U; Sharada, A C; Solomon, F E

1995-08-16

16

Synergism between propolis and hyperthermal intraperitoneal chemotherapy with cisplatin on ehrlich ascites tumor in mice.  

PubMed

We investigated antitumor, genotoxic, chemopreventive, and immunostimulative effects of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in a mouse-bearing Ehrlich ascites tumor (EAT). Mice were treated with water-soluble derivative of propolis (WSDP) at a dose of 50 mg kg(-1) , 7 and 3 days before implantation of EAT cells, whereas cisplatin (5 or 10 mg kg(-1) ) was injected 3 days after implantation of EAT cells at 37°C and 43°C. The following variables were analyzed: the total number of cells, differential count of the cells present in the peritoneal cavity, functional activity of macrophages, comet assay, and micronucleus assay. The combination of WSDP + CIS 5 mg kg(-1) at 37°C resulted in tumor growth inhibition and increased the survival of mice by additional 115.25%. WSDP with HIPEC increased the survival of mice by additional 160.3% as compared with HIPEC. WSDP reduced cisplatin toxic and genotoxic effect to normal cells without affecting cisplatin cytotoxicity on EAT cells. In addition, WSDP with HIPEC increased the cytotoxic actions of macrophages to tumor cells. Water-soluble derivative of propolis increases macrophage activity and sensitivity of tumor cells to HIPEC and reduces cisplatin toxicity to normal cells. PMID:24136132

Oršoli?, Nada; Car, Nikola; Lisi?i?, Duje; Benkovi?, Vesna; Kneževi?, Anica Horvat; Diki?, Domagoj; Petrik, József

2013-12-01

17

Cytokine profile of Ehrlich ascites tumor treated with Bothrops jararaca venom.  

PubMed Central

We previously demonstrated that Bothrops jararaca venom (BjV) has an antitumor effect on Ehrlich ascites tumor (EAT) cells and induces an increase of polymorphonuclear leukocytes in early stages of tumor growth. It has been reported that this venom presents an important inflammatory effect when inoculated in animal models and in human snakebites, and that cytokine levels have been detected in these cases. To evaluate whether the cytokines can be involved with the suppression of the tumoral growth, we evaluate the cytokine profile in the peritoneal cavity of mice inoculated with EAT cells and treated with BjV. Swiss mice were inoculated with EAT cells by the intraperitoneal route and treated with BjV venom (0.4 mg/kg, intraperitoneally), on the 1st, 4th, 7th, 10th, and 13th day. Mice were evaluated for cytokine levels on the 2nd, 5th, 8th, 11th and 14th day. Analysis was performed using an enzyme-linked immunosorbent assay for interleukin (IL)-1alpha, IL-2, IL4, IL-6, IL-10, IL-13, and tumor necrosis factor-alpha (TNF-alpha) levels in the peritoneal washing supernatant. Results were analyzed statistically by the Kruskal-Wallis and Dunn's tests at the 5% level of significance. We observed that EAT implantation induces IL-6 production on the 11th and 14th days of tumor growth, IL-10 on the 11th day and TNF-alpha on the 14th day. The treatment with BjV suppresses production of these cytokines. In addition, IL-13 was produced by animals that were inoculated only with venom on the 11th and 14th days, and by the group inoculated with EAT cells and treated with venom on the 2nd and 14th days. Furthermore, we suggest that the IL-6 detected in the present study is produced by the EAT cells and the suppression of its production could be associated with the antitumor effect of BjV.

da Silva, Reinaldo J; da Silva, Marcia G; Vilela, Lizia C; Fecchio, Denise

2002-01-01

18

Cell Swelling Activates Phospholipase A 2 in Ehrlich Ascites Tumor Cells  

Microsoft Academic Search

.   Ehrlich ascites tumor cells, loaded with 3H-labeled arachidonic acid and 14C-labeled stearic acid for two hours, were washed and transferred to either isotonic or hypotonic media containing BSA to\\u000a scavenge the labeled fatty acids released from the cells. During the first two minutes of hypo-osmotic exposure the rate of\\u000a 3H-labeled arachidonic acid release is 3.3 times higher than that

S. M. Thoroed; L. Lauritzen; I. H. Lambert; H. S. Hansen; E. K. Hoffmann

1997-01-01

19

The membrane potential of Ehrlich ascites tumor cells microelectrode measurements and their critical evaluation  

Microsoft Academic Search

Summary Intracellular potentials were measured, using a piezoelectric electromechanical transducer to impale Ehrlich ascites tumor cells with capillary microelectrodes. In sodium Ringer's, the potential immediately after the penetration was ?24±7 mV, and decayed to a stable value of about ?8 mV within a few msec. The peak potentials disappeared in potassium Ringer's and reappeared immediately after resuspension in sodium. Ringer's,

U. V. Lassen; A.-M. T. Nielsen; L. Pape; L. O. Simonsen

1971-01-01

20

Ascites analysis by a microfluidic chip allows tumor-cell profiling  

PubMed Central

Ascites tumor cells (ATCs) represent a potentially valuable source of cells for monitoring treatment of ovarian cancer as it would obviate the need for more invasive surgical biopsies. The ability to perform longitudinal testing of ascites in a point-of-care setting could significantly impact clinical trials, drug development, and clinical care. Here, we developed a microfluidic chip platform to enrich ATCs from highly heterogeneous peritoneal fluid and then perform molecular analyses on these cells. We evaluated 85 putative ovarian cancer protein markers and found that nearly two-thirds were either nonspecific for malignant disease or had low abundance. Using four of the most promising markers, we prospectively studied 47 patients (33 ovarian cancer and 14 control). We show that a marker set (ATCdx) can sensitively and specifically map ATC numbers and, through its reliable enrichment, facilitate additional treatment-response measurements related to proliferation, protein translation, or pathway inhibition.

Peterson, Vanessa M.; Castro, Cesar M.; Chung, Jaehoon; Miller, Nathan C.; Ullal, Adeeti V.; Castano, Maria D.; Penson, Richard T.; Lee, Hakho; Birrer, Michael J.; Weissleder, Ralph

2013-01-01

21

Fluorescence-lifetime molecular imaging can detect invisible peritoneal ovarian tumors in bloody ascites.  

PubMed

Blood contamination, such as bloody ascites or hemorrhages during surgery, is a potential hazard for clinical application of fluorescence imaging. In order to overcome this problem, we investigate if fluorescence-lifetime imaging helps to overcome this problem. Samples were prepared at concentrations ranging 0.3-2.4 ?m and mixed with 0-10% of blood. Fluorescence intensities and lifetimes of samples were measured using a time-domain fluorescence imager. Ovarian cancer SHIN3 cells overexpressing the D-galactose receptor were injected into the peritoneal cavity 2.5 weeks before the experiments. Galactosyl serum albumin-rhodamine green (GSA-RhodG), which bound to the D-galactose receptor and was internalized thereafter, was administered intraperitoneally to peritoneal ovarian cancer-bearing mice with various degrees of bloody ascites. In vitro study showed a linear correlation between fluorescence intensity and probe concentration (r(2) > 0.99), whereas the fluorescence lifetime was consistent (range, 3.33 ± 0.15-3.75 ± 0.04 ns). By adding 10% of blood to samples, fluorescence intensities decreased to <1%, while fluorescence lifetimes were consistent. In vivo fluorescence lifetime of GSA-RhodG stained tumors was longer than the autofluorescence lifetime (threshold, 2.87 ns). Tumor lesions under hemorrhagic peritonitis were not depicted using fluorescence intensity imaging; however, fluorescence-lifetime imaging clearly detected tumor lesions by prolonged lifetimes. In conclusion, fluorescence-lifetime imaging with GSA-RhodG depicted ovarian cancer lesions, which were invisible in intensity images, in hemorrhagic ascites. PMID:24479901

Nakajima, Takahito; Sano, Kohei; Sato, Kazuhide; Watanabe, Rira; Harada, Toshiko; Hanaoka, Hirofumi; Choyke, Peter L; Kobayashi, Hisataka

2014-03-01

22

Über die morphologische Wirkung verschiedener Chemotherupeutica auf Degranol-empfindlichen und Degranol-resistenten NK\\/Ly Ascites-Tumor  

Microsoft Academic Search

Im Degranolresistenten NK\\/Ly Ascites-Tumor kommen Zeichen einer Zellschädigung (untergehende Zellen, pathologische Mitosen) unter der Einwirkung vom Brom-Degranol, Dibrommannit und Mannit-Myleran kaum und unter Einwirkung von Stickstofflost, Sarcolysin, Endoxan, Thio-TEPA und Mitomycin C in viel geringerem Ausmaß vor als im Degranol-empfindlichen Tumor.

Éva Gåti

1965-01-01

23

Cholesterol metabolism during the growth of a rat ascites hepatoma (Yoshida AH-130).  

PubMed Central

The metabolism of cholesterol has been investigated in tumour cells, ascitic fluid and blood serum during the growth of an ascites hepatoma (Yoshida AH-130) in the rat. High rates of cholesterol synthesis and elevated free and esterified cholesterol content were observed in tumour cells. During tumour growth, the host animals progressively developed marked changes in the level and distribution of serum cholesterol consisting in an increase of total cholesterol and of a marked reduction of HDL cholesterol (HDL2 subfraction in particular). In agreement with previous observations, these findings indicate that a consistent pattern of altered cholesterol homeostasis develops in relation to normal or neoplastic tissue growth. High synthetic rates and intracellular accumulation of cholesterol are observed in the proliferating cells. Moreover, blood serum cholesterol decreases in the HDL fraction while it increases in LDLs, suggesting that during proliferative processes cholesterol fluxes between tissues and serum lipoproteins are markedly perturbed.

Dessi, S.; Batetta, B.; Anchisi, C.; Pani, P.; Costelli, P.; Tessitore, L.; Baccino, F. M.

1992-01-01

24

Immunomodulatory and anti-tumor effects of Nigella glandulifera freyn and sint seeds on ehrlich ascites carcinoma in mouse model  

PubMed Central

Aim: This study investigated the immunomodulatory and anti-tumor effects of Nigella glandulifera Freyn and Sint seeds (NGS) on Ehrlich ascites carcinoma in a mouse model. Materials and Methods: Kunming mice with transplanted Ehrlich ascites tumor cells (EAC) were treated with NGS by oral administration. On the 11th day after the EAC implant, mouse thymus, liver, spleen and kidney tumors were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Results: The results indicate that NGS treatment leads to an increase in TNF-?, IL-1?, and IL-2 blood serum levels. Absence of viable EAC and presence of necrotic cells were observed in the tumor tissue of the NGS-treated animals. Conclusions: The study results indicated that a water extract of NGS had the highest anti-tumor effect. Moreover, NGS treatment also showed an increase in the immune system activity.

Aikemu, Ainiwaer; Xiaerfuding, Xiadiya; Shiwenhui, Chengyufeng; Abudureyimu, Meiliwan; Maimaitiyiming, Dilinuer

2013-01-01

25

Cellular thiols status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells  

Microsoft Academic Search

Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans, and also breast and prostate cancers in animal models are reduced by green tea, and several mechanisms have been proposed for these effects. In this study the relationship between cellular sulfhydryl (SH) groups and the cytotoxicity of green tea polyphenols in Ehrlich ascites tumor cells

David Opare Kennedy; Miho Matsumoto; Akiko Kojima; Isao Matsui-Yuasa

1999-01-01

26

Involvement of protein tyrosine phosphorylation in the effect of green tea polyphenols on Ehrlich ascites tumor cells in vitro  

Microsoft Academic Search

Green tea extract and its polyphenolic components have been found to possess anticarcinogenic, antimutagenic, antihypertensive and antihepatotoxic effects, and several mechanisms have been proposed for these effects. In this study, the effects of five tea polyphenols, (?)-epigallocatechin-3-gallate (EGCG), (?)-epigallocatechin (EGC), (?) epicatechin-3-gallate (ECG), (?) epicatechin (EC) and (+)-catechin (C), were examined on the viability of Ehrlich ascites tumor cells in

David Opare Kennedy; Satomi Nishimura; Tadayoshi Hasuma; Yoshihisa Yano; Shuzo Otani; Isao Matsui-Yuasa

1998-01-01

27

Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis  

PubMed Central

Background Ascites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promote de novo resistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized. Methods Using human OC cell lines and tissues microarrays of human OC biopsies, we assessed the mechanism by which OC ascites increase Mcl-1 expression using Western blots, chemical inhibitors of ERK and small-inhibitory RNA treatments. Results In the present study, we found that both Mcl-1 mRNA and protein levels were upregulated within 2 h upon treatment of OC cells with ascites obtained from women with advanced OC. In contrast, the expression of other Bcl-2 family antiapoptotic members such as Bcl-2 and Bcl-XL was not affected by ascites. An increase of Mcl-1 expression was consistently observed across different ascites from women with advanced serous OC. The knockdown of Mcl-1 significantly blocked ascites-induced Mcl-1 upregulation and ascites-mediated inhibition of TRAIL-induced apoptosis. Ascites induced a rapid phosphorylation of ERK1/2 and Elk-1 transcription factor. Furthermore, we found that ERK1/2 inhibition or Elk-1 knockdown was sufficient to block ascites-induced Mcl-1 expression. In high grade serous OC, we found a positive correlation between phosphorylated ERK1/2 and Mcl-1 expression. Conclusions These results indicate that ascites-induced ERK1/2/Elk-1 signaling is critical for Mcl-1 expression and for the ascites-mediated attenuation of TRAIL-induced apoptosis. The ERK1/2/Elk-1/Mcl-1 pathway represents a novel mechanism by which ascites induce de novo TRAIL resistance in OC cells.

2012-01-01

28

Human ovarian tumor ascites fluids rapidly and reversibly inhibit T cell receptor-induced NF-?B and NFAT signaling in tumor-associated T cells  

PubMed Central

Human memory T cells present in ovarian tumor ascites fluids fail to respond normally to stimulation via the T cell receptor (TCR). This immunosuppression is manifested by decreases in NF-?B and NFAT activation, IFN-? production, and cell proliferation in response to TCR stimulation with immobilized antibodies to CD3 and CD28. The anergy of the tumor-associated T cells (TATs) is mediated by soluble factors present in ovarian tumor ascites fluids. The non-responsiveness of the T cells is quickly reversed when the cells are assayed in the absence of the ascites fluid, and is rapidly reestablished when a cell-free ascites fluid is added back to the T cells. Based upon the observed normal phosphorylation patterns of the TCR proximal signaling molecules, the inhibition of NF-?B, and NFAT activation in response to TCR stimulation, as well as the ability of the diacylglycerol analog PMA and the ionophore ionomycin to bypass the ascites fluid-induced TCR signaling arrest, the site of the arrest in the activation cascade appears to be at or just upstream of PLC-?. An identical TCR signaling arrest pattern was observed when T cells derived from normal donor peripheral blood were incubated with either malignant or nonmalignant (cirrhotic) ascites fluids. The immunosuppressive activity of ascites fluids reported here suggests that soluble factors acting directly or indirectly upon T cells present within tumors contribute to the anergy that has previously been observed in T cells derived from malignant and nonmalignant inflammatory microenvironments. The soluble immunosuppressive factors represent potential therapeutic targets for ovarian cancer.

Simpson-Abelson, Michelle R.; Loyall, Jenni L.; Lehman, Heather K.; Barnas, Jennifer L.; Minderman, Hans; O'Loughlin, Kieran L.; Wallace, Paul K.; George, Thaddeus C.; Peng, Peng; Kelleher, Raymond J.; Odunsi, Kunle; Bankert, Richard B.

2013-01-01

29

TGF-? blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models  

PubMed Central

Purpose Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of Transforming Growth Factor beta (TGF-?) in tumor progression has been well studied, the role of TGF-? in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-? blockade in the formation of ascites. Experimental Design We used soluble TGF-? Receptor II (sT?RII) to block TGF-? signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate. Results TGF-? blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-? blockade almost completely abolished ascites formation. TGF-? blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF-? blockade prevent ‘abnormalization’ of diaphragm lymphatic vessels and improved ascites drainage. Conclusions TGF-? blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-? blockade as a palliative treatment for symptomatic ascites.

Liao, Shan; Liu, Jieqiong; Lin, Peichun; Shi, Tony; Jain, Rakesh K.; Xu, Lei

2011-01-01

30

Ca2+ Transport by Mitochondria from L1210 Mouse Ascites Tumor Cells  

PubMed Central

Mitochondria isolated from the ascites form of L1210 mouse leukemia cells readily accumulate Ca2+ from the suspending medium and eject H+ during oxidation of succinate in the presence of phosphate and Mg2+, with normal stoichiometry between Ca2+ uptake and electron transport. Ca2+ loads up to 1600 ng-atoms per mg of protein are attained. As is the case in mitochondria from normal tissues, Ca2+ uptake takes precedence over oxidative phosphorylation. However, Ca2+ transport by the L-1210 mitochondria is unusual in other respects, which may possibly have general significance in tumor cells. The apparent affinity of the L1210 mitochondria for Ca2+ in stimulation of oxygen uptake is about 3-fold greater than in normal liver mitochondria; moreover, the maximal rate of Ca2+ transport is also considerably higher. Furthermore, when Ca2+ pulses are added to L1210 mitochondria in the absence of phosphate or other permeant anions, much larger amounts of Ca2+ are bound and H+ ejected per atom of oxygen consumed than in the presence of phosphate; up to 7 Ca2+ ions are bound per pair of electrons passing each energy-conserving site of the electron-transport chain. Such “superstoichiometry” of Ca2+ uptake can be accounted for by two distinct types of respiration-dependent interaction of Ca2+ with the L1210 mitochondria. One is the stimulation of oxygen consumption, which is achieved by relatively low concentrations of Ca2+ (Km ? 8 ?M) and is accompanied by binding of Ca2+ up to 40 ng-atoms per mg of protein. The second process, also dependent on electron transport, is the binding of further Ca2+ from the medium in exchange with previously stored membrane-bound protons, in which the affinity for Ca2+ is much lower (Km ? 120 ?M).

Reynafarje, Baltazar; Lehninger, Albert L.

1973-01-01

31

Case Report: Detection and quantification of tumor cells in peripheral blood and ascitic fluid from a metastatic esophageal cancer patient using the CellSearch ® technology  

PubMed Central

Analysis of ascitic fluid should help to identify and characterize malignant cells in gastrointestinal cancer. However, despite a high specificity, the sensitivity of traditional ascitic fluid cytology remains insufficient, at around 60%. Since 2004 the CellSearch ® technology has shown its advantages in the detection of circulating tumor cells (CTCs) in peripheral blood, which can perform an accurate diagnosis and molecular analysis at the same time. To our knowledge, no previous study has explored the potential utility of this technology for the detection and quantification of tumor cells in ascitic fluid samples. Herein we report a case of metastatic esophageal adenocarcinoma in a 70-year-old man presenting with dysphagia and a large amount of fluid in the peritoneal cavity. Analysis of a peripheral blood sample and ascites sample with the CellSearch ® technology both revealed the presence of putative tumor cells that were positive for epithelial cell adhesion molecule (EpCAM) and cytokeratin (CK) expression. This study confirmed the hematogenous dissemination of esophageal cancer by the detection of circulating tumor cells in the peripheral blood, and is the first to demonstrate that tumor cells can be identified in ascitic fluid by using CellSearch ® technology.

Tu, Qian; Bittencourt, Marcelo De Carvalho; Cai, Huili; Bastien, Claire; Lemarie-Delaunay, Camille; Bene, Marie C; Faure, Gilbert C

2014-01-01

32

Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice.  

PubMed

Cancerous cells secrete alpha-N-acetylgalactosaminidase (NaGalase) into the blood stream, resulting in deglycosylation of serum vitamin D3-binding protein (known as Gc protein), which is a precursor for macrophage activating factor (MAF). Incubation of Gc protein with immobilized beta-galactosidase and sialidase generates the most potent macrophage activating factor (designated GcMAF). Administration of GcMAF to cancer-bearing hosts can bypass the inactivated MAF precursor and act directly on macrophages for efficient activation. Therapeutic effects of GcMAF on Ehrlich ascites tumor-bearing mice were assessed by survival time and serum NaGalase activity, because serum NaGalase activity was proportional to tumor burden. A single administration of GcMAF (100 pg/mouse) to eight mice on the same day after transplantation of the tumor (5 x 10(5) cells) showed a mean survival time of 21 +/- 3 days for seven mice, with one mouse surviving more than 60 days, whereas tumor-bearing controls had a mean survival time of 13 +/- 2 days. Six of the eight mice that received two GcMAF administrations, at Day 0 and Day 4 after transplantation, survived up to 31 +/- 4 days whereas, the remaining two mice survived for more than 60 days. Further, six of the eight mice that received three GcMAF administrations with 4-day intervals showed an extended survival of at least 60 days, and serum NaGalase levels were as low as those of control mice throughout the survival period. The cure with subthreshold GcMAF-treatments (administered once or twice) of tumor-bearing mice appeared to be a consequence of sustained macrophage activation by inflammation resulting from the macrophage-mediated tumoricidal process. Therefore, a protracted macrophage activation induced by a few administrations of minute amounts of GcMAF eradicated the murine ascites tumor. PMID:9893164

Koga, Y; Naraparaju, V R; Yamamoto, N

1999-01-01

33

Monoclonal Antibodies Targeting Tumor Growth  

Cancer.gov

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

34

CHANGES IN THE ELECTRICAL SURFACE CHARGE AND TRANSPLANTATION PROPERTIES OF TA3 ASCITES TUMOR CELLS DURING SHORT-TERM MAINTENANCE IN AN ISOTONIC SALT SOLUTION  

SciTech Connect

TA3 ascites tumor cells maintained in vitro as a dilute suspension in 0.9% NaCl solution (physiological saline) were found to undergo time-dependent degenerative processes leading to alterations in both membrane characteristics and tumor transplantation properties. A 30% decrease in the negative cellular surface charge density occurred within 2 hr. when TA3 cells were incubated in a 0.9% NaCl solution at 23 °C. A similar reduction in negative surface charge density occurred within 0.5 hr. when the medium was maintained at 37 °C. This time-dependent reduction in surface charge was prevented when cellular metabolism was blocked either by maintaining the medium at 4 °C. or by adding 1 mM cyanide ion to a 23 °C medium. TA3 cells incubated as a dilute suspension in 0.9% NaCl solution at 23 °C also exhibited a large 9 time-dependent reduction in proliferative capacity in isogeneic LAF1/J hosts, as indicated by an increase in the tumor dose for 50% mortality (TD50). Lowering the temperature of the medium to 4 °C was observed to slow the onset of the degenerative processes that lead to a decreased transplantability of TA3 cells. The modification in growth properties of TA3 cells maintained in vitro was found to be attributable in part to an alteration in tumor histocompatibility. This effect was demonstrated by comparing the tumor growth kinetics and TD50 values in normal hosts versus hosts that had been immunosuppressed by whole-body irradiation. Following the in vitro maintenance of TA3 cells, nigrosin dye exclusion tests were performed as a means of assessing cell viability. Evidence obtained in this series of experiments indicated that vital staining is an inadequate criterion for judging either the extent of cell membrane damage or the loss of cellular proliferative capacity.

Tenforde, T.S.; Richards, W.R.; Kelly, L.S.

1980-12-01

35

Massive Ascites as the Only Sign of Ovarian Juvenile Granulosa Cell Tumor in an Adolescent: A Case Report and a Review of the Literature  

PubMed Central

Ovarian neoplasms are relatively rare in childhood and adolescence; only 5% to 8% of the cases are of sex cord stromal origin. Granulosa cell tumors are a group of estrogen producing sex cord stromal tumors of the ovary. They occur in 95% of the cases in adults, and only about 5% of the cases, which differ in histologic characteristics, are of juvenile type. A 13-year-old girl is reported who presented with massive abdominal distention and ascites. An abdominopelvic computed tomography scan showed a predominantly cystic mass lesion with septations arising from the left ovary. All tumor markers were normal, but serum inhibin level was increased. The patient underwent mass resection with salpingoophorectomy. Histopathology was compatible with the juvenile granulosa cell tumor. Interestingly, menarche was started in the patient soon after the surgery. To the best of our knowledge, massive ascites as the only clinical manifestation in the juvenile granulosa cell tumor has not reported as yet.

Ashnagar, Azin; Alavi, Samin; Nilipour, Yalda; Azma, Roxana; Falahati, Farahnaz

2013-01-01

36

Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes  

SciTech Connect

The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H/sub 2/ folate reductase was evaluated. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 microM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell. In studies with the Ehrlich ascites tumor accumulation of methotrexate polyglutamates was increased over 5-fold by the addition of 5 mM L-glutamine or L-glutamate and exhibited a positive correlation with the extracellular concentration of methotrexate. When Ehrlich ascites tumor cells were exposed to 10 microM methotrexate and 5 mM L-glutamine intracellular polyglutamates were detected within 10 minutes and their levels increased linearly over 4 hours. As these derivatives accumulated, there was a decline in intracellular methotrexate due at least in part to a replacement of methotrexate on H/sub 2/ folate reductase by polyglutamates and subsequent efflux of the previously bound methotrexate from the cell. When polyglutamate derivatives were in excess of the H/sub 2/ folate reductase binding capacity and extracellular methotrexate removed, methotrexate rapidly exited the cell whereas the majority of its metabolites were retained and eventually saturated the major portion of the enzyme. These studies indicate that (1) intracellular methotrexate is rapidly converted to polygammaglutamyl derivatives, (2) these metabolites effectively compete with methotrexate for binding sites on H/sub 2/ folate reductase, (3) these derivatives are retained within the cell more effectively than methotrexate, and (4) vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells.

Fry, D.W.; Gewirtz, D.A.; Yalowich, J.C.; Goldman, I.D.

1983-01-01

37

Cellular energy dependent agglutination of rat ascites tumor cells mediated by concanavalin A and Ricinus communis agglutinin.  

PubMed

Effect of various metabolic inhibitors on the agglutination of rat ascites tumor cells mediated by concanavalin A and Ricinus communis agglutinin was studied using a quantitative assay method for agglutination in which turbidity of cell suspension is measured. Cell agglutination was inhibited by low temperature, cytochalasin B and inhibitors of energy generating systems without affecting lectin binding, and agglutination was not affected by hydroxyurea, actinomycin D or cycloheximide. The inhibitors of energy generating systems decreased the cellular ATP level and inhibited macromolecular synthesis under the conditions where they inhibited the agglutinations. In contrast, cytochalasin B did not depress the cellular ATP level nor inhibit RNA and protein syntheses. These results suggest that the agglutination is associated with cellular energy dependent processes other than macromolecular synthesis; probably with some cellular surface movements participated by microfilament activity. PMID:1201283

Kaneko, I; Hayatsu, H; Satoh, H; Ukita, T

1975-12-01

38

Chylous ascites  

Microsoft Academic Search

Summary  The present study reports a patient with chylous ascites, edema, and hypoalbuminemia, which had appeared after pelvic surgery and irradiation for adenocarcinoma of the endocervix. The administration of a diet high in fat aggravated the degree of hypoalbuminemia and the extent of the edema. A reduction of the edema and of the ascites, and a rise in serum albumin to

L. Donald Weinstein; Gerard T. Scanlon; Theodore Hersh

1969-01-01

39

Effect of Lawsonia inermis on tumor expression induced by Dalton's lymphoma ascites in Swiss albino mice  

PubMed Central

The purpose of this study was investigating experimentally the possible antitumor effect of ethanol extract of root of Lawsonia inermis against Dalton’s lymphoma ascites (DLA) bearing mice. Mice were administered with L. inermis at a dosage of 180 mg/kg of body weight for 15 days after 24 h of DLA inoculation. The ethanolic root extract of L. inermis reverted the increased number of the WBC count, platelets and lymphocytes and decreased the number of the RBC count, hemoglobin content and monocytes. The effect of root extract of L. inermis also increased the pathophysiological marker enzyme, lipid profile and decreased the enzymic and non enzymic antioxidants. A histopathological result shows the loss of liver hepatocytes and kidney architecture in DLA bearing mice. However, mice treatment with L. inermis extract improves the liver and kidney function and rearranges more or less normal architecture. The present work indicates that the ethanol extract of L. inermis exhibited significant antitumor activity.

Priya, R.; Ilavenil, S.; Kaleeswaran, B.; Srigopalram, S.; Ravikumar, S.

2011-01-01

40

When ascites is not ascites  

Microsoft Academic Search

The case is reported of a patient presenting with ascites and acute renal failure resulting from spontaneous rupture of the urinary bladder, 30 years after the successful initial treatment of childhood rhabdomyosarcoma. The delay in the presentation until the patient began to experience the symptoms due to urinary ascites, the diagnostic dilemma because of the rarity of the condition, and

A Sharma; B Teh; D J R Morgan; D Bell; C Woodhouse

2008-01-01

41

Modifying the response of Ehrlich ascites tumor cells to nitrogen mustard (HN/sub 2/) by vincristine, Ca and liposomes  

SciTech Connect

Though vincristine (0.5mg/kg) has no significant carcinostatic effect on Ehrlich ascites tumor cells, it does modify the carcinostatic effect of HN/sub 2/. Cells treated with 25 ..mu..m HN/sub 2/ in vitro, cold washed, then injected into recipient mice (1 x 10/sup 5/ cells/mouse) yielded 62% 60d mouse survival while cells treated with HN/sub 2/ and vincristine yielded approx. 30% survival. Parallel in vitro experiments using /sup 13/N HN/sub 2/ showed that vincristine did not decrease HN/sub 2/ uptake. Pretreating cells with 0.25 mM Ca before addition of drugs reversed the vincristine inhibition of HN/sub 2/ action. The action of extracellular Ca increased microtubule polymerization, decreasing vincristine action as has been reported for other systems. Cells treated with liposomes made of L(..cap alpha..) dipalmitoylphosphatidyl choline, then with HN/sub 2/ then injected into mice yielded 92% mouse survival. Liposome treatment increased HN/sub 2/ uptake only about 18% while increasing cytostatis approx. 30%. The liposome effect was removed, and cytostatis reduced to approx. 30% mouse survival by vincristine. Cells pretreated with Ca + liposomes restored HN/sub 2/ effectiveness to near that seen with liposomes alone. HN/sub 2/ distribution and tumor cell death are modified by (1) the state of microtubule polymerization and (2) by membrane phospholipid composition.

Ritter, C.; Kutman, R.J.

1986-03-01

42

Concentrated ascites re-infusion therapy for pseudo-Meigs' syndrome complicated by massive ascites in large pedunculated uterine leiomyoma.  

PubMed

Pseudo-Meigs' syndrome accompanied by massive ascites in uterine leiomyoma is rare. We encountered a rare case of a 37-year-old, nulliparous woman with a lower abdominal tumor and severe abdominal distention due to massive ascites. Serum cancer antigen 125 and vascular endothelial growth factor levels were elevated to 1007.9?U/mL and 103?pg/mL, respectively. She was tentatively diagnosed with ovarian cancer. Emergency concentrated ascites re-infusion therapy was performed to improve dyspnea, abdominal pain, and her preoperative respiratory condition. Concentrated ascites re-infusion therapy eliminated dyspnea and abdominal discomfort without decreasing serum albumin levels. The patient underwent laparotomy, which revealed a fist-sized pedunculated uterine leiomyoma arising from the right uterine fundus. Myomectomy was performed. Pseudo-Meigs' syndrome mimics advanced ovarian cancer due to massive ascites and markedly elevated serum cancer antigen 125 and vascular endothelial growth factor levels. Concentrated ascites re-infusion therapy was effective in improving the subjective symptoms of pseudo-Meigs' syndrome and the patient's preoperative condition. PMID:25056475

Yonehara, Yukie; Yanazume, Shintaro; Kamio, Masaki; Togami, Shinichi; Tasaki, Takashi; Douchi, Tsutomu

2014-07-01

43

Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.  

PubMed

Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90. PMID:9187119

Yamamoto, N; Naraparaju, V R

1997-06-01

44

When ascites is not ascites.  

PubMed

The case is reported of a patient presenting with ascites and acute renal failure resulting from spontaneous rupture of the urinary bladder, 30 years after the successful initial treatment of childhood rhabdomyosarcoma. The delay in the presentation until the patient began to experience the symptoms due to urinary ascites, the diagnostic dilemma because of the rarity of the condition, and the possible aetiologies are discussed. PMID:18940952

Sharma, A; Teh, B; Morgan, D J R; Bell, D; Woodhouse, C

2008-09-01

45

Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase.  

PubMed

The observation that Th17 infiltration in ovarian cancer correlates with markedly improved survival has prompted the question of whether ovarian tumor antigen-specific Th17 responses could be stimulated by tumor vaccination. Dendritic cells (DCs) treated with IL-15 and an inhibitor of p38 MAPK signaling (DC(IL-15/p38inhib)) bias T-cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination; however, significant barriers remain. Tumor vaccines, including DC vaccination, usually stimulate immune responses, but the lack of clinical responses in cancer patients has been disappointing. Possible reasons may include an inability of antitumor T cells to migrate into the tumor microenvironment, and an inability of T cells to retain effector function in the face of tumor-associated immune suppression. We found that ovarian tumor antigen-specific CD4(+) T cells induced by DC(IL-15/p38inhib) migrated in response to CXCL12 and CCL22 (both highly expressed in ovarian cancer) and to ascites CD14(+) myeloid cells. Cocultures showed that ascites CD14(+) cells markedly suppressed antigen-specific CD4(+) T responses, but suppression could be alleviated by treatment with anti-IL-10 or inhibition of indoleamine 2,3-dioxygenase. These results suggest that the efficacy of DC vaccination against ovarian cancer may be boosted by agents that inhibit tumor-associated CD14(+) myeloid cell suppression or indoleamine 2,3-dioxygenase activity. PMID:24598451

Goyne, Hannah E; Stone, Pamela J B; Burnett, Alexander F; Cannon, Martin J

2014-04-01

46

Radiotherapeutic Response of Ehrlich Ascites Tumor Cells Perfused in Agarose Gel Threads and Implanted in Mice  

Microsoft Academic Search

Aim: In order to obtain better understanding of radiation-induced alterations in intracellular metabolism, a dynamic and non-invasive experimental model system is required. A serial study in cultured tumor cell line followed by verification in the in vivo samples may be of considerable value for non-invasive prediction and\\/or detection of tumor response to therapy. The present study was undertaken to evaluate

Rakesh Kumar Sharma; Viney Jain

2001-01-01

47

Glucose uptake-stimulatory activity of Tinospora cordifolia stem extracts in Ehrlich ascites tumor cell model system.  

PubMed

Diabetes mellitus is a multifunctional disorder with several causes and multiple consequences. Nutraceuticals play a vital role in ameliorating diabetic condition. The stems of the plant, Tinospora cordifolia (T. cordifolia) are often used in Ayurvedic medicine for the management of diabetes. Earlier studies have shown that T. cordifolia to be a potent antidiabetic plant material by virtue of being rich in nutraceuticals. In the present study we were interested to know if, T. cordifolia stem extracts are able to promote glucose uptake through glucose transporters, 1 (GLUT1) and 3 (GLUT3), which are responsible for basal glucose uptake. Hence, Ehrlich ascites tumor (EAT) cells were chosen as a model which harbours both GLUT1 and GLUT3 and glucose uptake was measured using a fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG). Serially, solvent extracted T. cordifolia stems, especially water, ethanol and methanol extracts showed glucose uptake activity. Uptake was stimulated in a dose dependent manner at dosages of 1-100 ?g. Glucose-stimulating activity does not seem to be solely due to polyphenol content since methanol extract, with high amount of polyphenol content (9.5?±?0.1 g?kg(-1)), did not stimulate higher glucose uptake activity when compared to water extract. PMID:24426067

Joladarashi, Darukeshwara; Chilkunda, Nandini D; Salimath, Paramahans Veerayya

2014-01-01

48

Preparation and characterization of 80 s ribosomes of ascites tumor cells active in polypeptide synthesis  

Microsoft Academic Search

SUMMARY The preparation of tumor ribosomes that are essentially free of polyribosomes and active in polypeptide synthesis is described. Most active preparations were obtained by incubating ribosomal suspensions 20 min under conditions of protein synthesis. After this time, all polysomes had been converted to 80 S particles which could be stimulated to polypeptide synthesis by polyuridylic acid or liver mRNA.

Karl Letnansky

1972-01-01

49

One-way fluxes of alpha-aminoisobutyric acid in Ehrlich ascites tumor cells. Trans effects and effects of sodium and potassium  

PubMed Central

One-way fluxes in the steady state and one-way influxes at zero intracellular concentrations were measured for alpha-aminoisobutyric acid (AIB) in Ehrlich ascites tumor cells at 32 degrees C. The one-way fulxes show trans effects in the concentration of AIB and are dependent on sodium levels. The one-way fluxes for initial influx and for the steady state were fitted with the equations derived for the frequently used two-state carrier model. Estimates of the parameters of these equations were obtained with use of nonlinear least squares. These gave relatively good fits of the flux data and the data on steady-state distribution ratios. The two-state carrier model predicted a trans inhibition of one-way influx and a trans stimulation of one-way efflux. The former phenomenon has been demonstrated for AIB transport in Ehrlich ascites cells and there is evidence, through less firm, for the latter.

1975-01-01

50

The Effect of Diet with Low Protein and Intermittent Lighting on Ascites Induced by Cold Temperatures and Growth Performance in Broilers  

Microsoft Academic Search

In this study we aimed to investigate the effect of intermittent lighting and feed with low protein on ascites induced by cold temperatures and subsequent effect on growth performance of young male and female broiler chickens. A total of 300 male and 300 female broiler chickens aged one day were used for the treatment. Research was conducted as three groups

2006-01-01

51

The role of actin in temperature-dependent gel-sol transformation of extracts of Ehrlich ascites tumor cells  

PubMed Central

Ehrlich ascites tumor cell extracts form a gel when warmed to 25 degrees C at pH 7.0 in sucrose solution, and the gel rapidly becomes a sol when cooled to 0 degrees C. This gel-sol transformation was studied quantitatively by determining the volume or the total protein of pellets of gel obtained by low-speed centrifugation. The gelation depended on nucleotide triphosphates, Mg2+, KCl, and a reducing agent. Gelation was inhibited reversibly by 0.5 microM free Ca2+, and 25--50 ng/ml of either cytochalasin B or D, but it was not affected by 10 mM colchicine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that the gel was composed of six major proteins with mol wt greater than 300,000, 270,000, 89,000, 51,000, 48,000, and 42,000 daltons. The last component was identified as cell actin because it had the same molecular weight as muscle actin and bound with muscle myosin and tropomyosin. The role of actin in gelation was studied by use of actin-inhibitors. Gelation was inhibited by a chemically modified subfragment-1 of myosin, which binds with F-actin even in the presence of ATP, and by bovine pancreatic DNase I, which tightly binds with G- actin. Muscle G-actin neutralized the inhibitory effect of DNase I when added at an equimolar ratio to the latter, and it also restored gelation after its inhibition by DNase I. These findings suggest that gelation depends on actin. However, the extracts showed temperature- dependent, cytochalasin-sensitive, and Ca2+-regulated gelation as did the original extracts when the cell actin in the extracts was replaced by muscle actin, suggesting that components other than cell actin might be responsible for these characteristics of the gelation.

1979-01-01

52

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

PubMed Central

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

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

2014-01-01

53

Nerve growth factor from cobra venom inhibits the growth of Ehrlich tumor in mice.  

PubMed

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

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

2014-03-01

54

Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid.  

PubMed

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

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

1994-11-16

55

Effect of Honey and Eugenol on Ehrlich Ascites and Solid Carcinoma  

PubMed Central

Ehrlich ascites carcinoma is a spontaneous murine mammary adenocarcinoma adapted to ascites form and carried in outbred mice by serial intraperitoneal (i/p) passages. The previous work from our laboratory showed that honey having higher phenolic content was potent in inhibiting colon cancer cell proliferation. In this work, we extended our research to screen the antitumor activity of two selected honey samples and eugenol (one of the phenolic constituents of honey) against murine Ehrlich ascites and solid carcinoma models. Honey containing higher phenolic content was found to significantly inhibit the growth of Ehrlich ascites carcinoma as compared to other samples. When honey containing higher phenolic content was given at 25% (volume/volume) intraperitoneally (i/p), the maximum tumor growth inhibition was found to be 39.98%. However, honey was found to be less potent in inhibiting the growth of Ehrlich solid carcinoma. On the other hand, eugenol at a dose of 100?mg/kg i/p was able to inhibit the growth of Ehrlich ascites by 28.88%. In case of solid carcinoma, eugenol (100?mg/kg; i/p) showed 24.35% tumor growth inhibition. This work will promote the development of honey and eugenol as promising candidates in cancer chemoprevention.

Jaganathan, Saravana Kumar; Mondhe, Dilip; Wani, Z. A.; Pal, Harish C.; Mandal, Mahitosh

2010-01-01

56

Effect of honey and eugenol on Ehrlich ascites and solid carcinoma.  

PubMed

Ehrlich ascites carcinoma is a spontaneous murine mammary adenocarcinoma adapted to ascites form and carried in outbred mice by serial intraperitoneal (i/p) passages. The previous work from our laboratory showed that honey having higher phenolic content was potent in inhibiting colon cancer cell proliferation. In this work, we extended our research to screen the antitumor activity of two selected honey samples and eugenol (one of the phenolic constituents of honey) against murine Ehrlich ascites and solid carcinoma models. Honey containing higher phenolic content was found to significantly inhibit the growth of Ehrlich ascites carcinoma as compared to other samples. When honey containing higher phenolic content was given at 25% (volume/volume) intraperitoneally (i/p), the maximum tumor growth inhibition was found to be 39.98%. However, honey was found to be less potent in inhibiting the growth of Ehrlich solid carcinoma. On the other hand, eugenol at a dose of 100 mg/kg i/p was able to inhibit the growth of Ehrlich ascites by 28.88%. In case of solid carcinoma, eugenol (100 mg/kg; i/p) showed 24.35% tumor growth inhibition. This work will promote the development of honey and eugenol as promising candidates in cancer chemoprevention. PMID:20369055

Jaganathan, Saravana Kumar; Mondhe, Dilip; Wani, Z A; Pal, Harish C; Mandal, Mahitosh

2010-01-01

57

Role of malignant ascites on human mesothelial cells and their gene expression profiles  

PubMed Central

Background Malignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression. Methods Human OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays. Results As compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P?ascites-exposed HPMCs. Stimulation of HPMCs with OC ascites resulted in differential expression of genes mainly associated with the regulation of cell growth and proliferation, cell death, cell cycle and cell assembly and organization, compared to benign peritoneal fluids. Top networks up-regulated by OC ascites included Akt and NF-?B survival pathways whereas vascular endothelial growth factor (VEGF) pathway was down-regulated. Conclusions The results of this study not only provide evidence supporting the importance of the interplay between cancer cells and HPMCs but also define the role that the tumor environment plays in these interactions.

2014-01-01

58

Role of nuclear glycogen synthase and cytoplasmic UDP glucose pyrophosphorylase in the biosynthesis of nuclear glycogen in HD33 Ehrlich-Lettre ascites tumor cells  

PubMed Central

Biochemical and autoradiographic evidence show both glycogen synthesis and the presence of glycogen synthase (UDP glucose [UDPG]: glycogen 4- alpha-D-glucosyltransferase; EC 2.4.1.11) in isolated nuclei of Ehrlich- Lettre mouse ascites tumor cells of the mutant subline HD33. 5 d after tumor transplantation, glycogen (average 5-7 pg/cell) is stored mainly in the cell nuclei. The activity of glycogen synthase in isolated nuclei is 14.5 mU/mg protein. At least half of the total cellular glycogen synthase activity is present in the nuclei. The nuclear glycogen synthase activity exists almost exclusively in its b form. The Km value for (a + b) glycogen synthase is 1 x 10(-3) M UDPG, the activation constant is 5 x 10(-3) M glucose-6-phosphate (Glc-6-P). Light and electron microscopic autoradiographs of isolated nuclei incubated with UDP-[1-3H]glucose show the highest activity of glycogen synthesis not only in the periphery of glycogen deposits but also in interchromatin regions unrelated to detectable glycogen particles. Together with earlier findings on nuclear glycogen synthesis in intact HD33 ascites tumor cells (Zimmermann, H.-P., V. Granzow, and C. Granzow. 1976. J. Ultrastruct. Res. 54:115-123), the results of tests on isolated nuclei suggest a predominantly appositional mode of nuclear glycogen deposition, without participation of the nuclear membrane system. In intact cells, synthesis of UDPG for nuclear glycogen synthesis depends on the activity of the exclusively cytoplasmic UDPG pyrophosphorylase (UTP: alpha-D-glucose-1-phosphate uridylyltransferase; EC 2.7.7.9). However, we conclude that glycogen synthesis is not exclusively a cytoplasmic function and that the mammalian cell nucleus is capable of synthesizing glycogen.

1981-01-01

59

Research of ALA combined with HpD-PDT which induced s180 ascitic tumor cells, death or apoptosis on cytology  

NASA Astrophysics Data System (ADS)

To ascertain the adequate dosage of ALA combined with HpD-PDT which induced tumor cell death or apoptosis on cytology. And to study the different effect of ALA-PDT and HPD-PDT used only. Rat ascitic tumor cells(S180) were randomly divided into several groups and incubated with ALA?20?g/ml ?40?g/ml?80?g/ml ?160?g/ml??HPD?2.5?g/ml?5?g/ml?10?g/ml?and their combination dosages. 630nm light (total output 2W) was delivered to tumor cells at a constant fluence rate: 200mw/cm2 and a constant irradiated time period: 20 minutes. We set 3 groups (no photosensitizers or no irradiation or neither) to be the control groups. We used inversion microscopy to observe the morphological change of tumor cells and flow cytometry technology to detect the death or apoptosis of tumor cells during the experiment. ..

Zhu, Jing; Yan, Min; Zhang, Hui-Guo; Li, Enling; Luo, Hongyu

2005-07-01

60

The impact of the Uighur medicine abnormal savda munziq on antitumor and antioxidant activity in a S180 and Ehrlich ascites carcinoma mouse tumor model  

PubMed Central

Aim: This study was designed to study the antitumor and antioxidant activity of Uighur medicine abnormal savda munziq (ASMq) in the S180 and Ehrlich ascites carcinoma mice tumor model. Materials and Methods: The serum levels of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione-catalase (GSH-PX) were analyzed, and the mice were also subjected to a hypoxia tolerance test. Their climbing ability was also analyzed. Results: The findings of the study revealed that ASMq-treatment leads to an increase in blood serum SOD and GSH-PX levels but a decrease in blood serum MDA levels. Moreover, ASMq-treatment enhanced the survival time of mice maintained under hypoxic conditions and improved their mice climbing ability. Conclusions: The results of this study indicate that ASMq has obvious antitumor and antioxidative effects.

Aikemu, Ainiwaer; Yusup, Abdiryim; Umar, Anwar; Berke, Benedicte; Moore, Nicholas; Upur, Halmurat

2012-01-01

61

A novel pro-apoptotic effector lactaptin inhibits tumor growth in mice models.  

PubMed

Lactaptin, a human milk-derived protein, induces apoptosis in cultured tumor cells. We designed a recombinant analog of lactaptin (RL2) and tested its antitumor activity. The sensitivity of hepatocarcinoma A-1 (HA-1), Lewis lung carcinoma, and Ehrlich carcinoma to RL2 were tested to determine the most reliable in vitro animal model. HA-1 cells, which had the highest sensitivity to RL2, were transplanted into A/Sn mice to investigate RL2 antitumor activity in vivo. Investigation of the molecular effects of RL2 shows that RL2 induces apoptotic transformation of HA-1 cells in vitro: phosphatidylserine translocation from inner side of the lipid bilayer to the outer one and dissipation of the mitochondrial membrane potential. Repetitive injections of RL2 (5-50 mg/kg) for 3-5 days effectively inhibited ascites and solid tumor transplant growth when administered intravenously or intraperitoneally, without obvious side effects. The solid tumor inhibitory effect of RL2 (5 i.v. injections, cumulative dose 125 mg/kg) was comparable with that of cyclophosphamide at a therapeutic dose (5 i.v. injections, cumulative dose 150 mg/kg). In combination therapy with cyclophosphamide, RL2 had an additive antitumor effect for ascites-producing tumors. Histomorphometric analysis indicated a three-fold reduction of spontaneous metastases in the liver of RL2-treated mice with solid tumor transplants in comparison with control animals. Repeated RL2 treatment substantially prolonged the lifespan of mice with intravenously injected tumor cells. Recombinant analog of lactaptin effectively induced apoptosis of tumor cells in vitro and suppressed the growth of sensitive tumors and metastases in vivo. PMID:22968174

Koval, Olga A; Fomin, Alexandr S; Kaledin, Vasily I; Semenov, Dmitry V; Potapenko, Miraslava O; Kuligina, Elena V; Nikolin, Valery P; Nikitenko, Eugeny V; Richter, Vladimir A

2012-12-01

62

Mammalian protein homologous to VAT-1 of Torpedo californica: isolation from Ehrlich ascites tumor cells, biochemical characterization, and organization of its gene.  

PubMed

Recently, interest has focused on the human gene encoding the putative protein homologous to VAT-1, the major protein of the synaptic vesicles of the electric organ of the Pacific electric ray Torpedo californica, after it has been localized on chromosome locus 17q21 in a region encompassing the breast cancer gene BRCA1. Chromosomal instability in this region is implicated in inherited predisposition for breast and ovarian cancer. Here we describe isolation and biochemical characterization of a mammalian 48 kDa protein homologous to the VAT-1 protein of Torpedo californica. This VAT-1 homolog was isolated from a murine breast cancer cell line (Ehrlich ascites tumor) and identified by sequencing of cleavage peptides. The isolated VAT-1 homolog protein displays an ATPase activity and exists in two isoforms with isoelectric points of 5.7 and 5.8. cDNA was prepared from Ehrlich ascites tumor cells, and the murine VAT-1 homolog sequence was amplified by polymerase chain reaction and partially sequenced. The known part of the murine and the human translated sequences share 97% identity. By Northern blots, the size of the VAT-1 homolog mRNA in both murine and human (T47D) breast cancer cells was determined to be 2.8 kb. Based on the presented data, a modified gene structure of the human VAT-1 homolog with an extended exon 1 is proposed. VAT-1 and the mammalian VAT-1 homolog form a subgroup within the protein superfamily of medium-chain dehydrogenases/reductases. PMID:9581869

Hayess, K; Kraft, R; Sachsinger, J; Janke, J; Beckmann, G; Rohde, K; Jandrig, B; Benndorf, R

1998-06-01

63

Establishment of a Human Ovarian Cancer Cell Line Capable of Forming Ascites in Nude Mice and Effects of Tranexamic Acid on Cell Proliferation and Ascites Formation1  

Microsoft Academic Search

The present study was designed to obtain an experimental tumor model as similar as possible to human ovarian cancer which often had a large amount of ascites and to assess the therapeutic value of tranexamic acid. Human tumor cell lines which form ascites in nude mice were established from ascites of patient with serous cystadenocarcinoma of the ovary. Two cloned

Yoshihiro Kikuchi; Isao Kizawa; Keibun Oomori; Munenori Miyauchi; Tsunekazu Kita; Michio Sugita; Yoshio Tenjin; Koichi Kato

64

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

65

Brain tumor epidemiology, growth, and invasion.  

PubMed

This article focuses on the most common primary intracranial neoplasms and the biologic descriptions of their growth and invasion. The proliferative aspects of the different primary brain tumors are discussed, along with recently discovered genetic changes. Because local invasion of primary brain tumors is a key pathologic feature of these tumors, the mechanisms known to influence cell movement are discussed. PMID:2135961

Berens, M E; Rutka, J T; Rosenblum, M L

1990-01-01

66

Effects of Dietary L-carnitine Supplementation on Growth Performance, Organ Weight, Biochemical Parameters and Ascites Susceptibility in Broilers Reared Under Low-temperature Environment  

PubMed Central

The objective of this study was to investigate the effects of L-carnitine on growth performance, organ weight, biochemical parameters of blood, heart and liver, and ascites susceptibility of broilers at different ages reared under a low-temperature environment. A total of 420 1-d-old male Ross 308 broilers were randomly assigned to two dietary treatments with fifteen replicates of fourteen broilers each. Treatment diets consisted of L-carnitine supplementation at levels of 0 and 100 mg/kg. At 11-d of age, low temperature stress was used to increase ascites susceptibility. Blood, heart and liver samples were collected at different ages for analysis of boichemical parameters. The results showed that, there was no significant difference in growth performance with L-carnitine supplementation, but the mortality due to ascites was significantly decreased. Dietary L-carnitine supplementation significantly reduced heart index (HI) and ascites heart index (AHI) on d 21, lung index (LUI) on d 35 and liver index (LI) on d 42. The broilers fed diets containing L-carnitine had significantly lower red blood cell counts (RBC), hemoglobin (HGB) concentration and hematocrit (HCT) on d 42. Dietary L-carnitine supplementation significantly reduced malondialdehyde (MDA) content of heart tissue on d 21 and 35, and significantly increased total superoxide dismutase (T-SOD) and Glutathione peroxidase (GSH-Px) activity of the heart on d 21 and 42. L-carnitine supplementation significantly reduced serum triglyceride (TG) content on d 28 and 35 and serum glucose (GLU) on d 35 and 42, and significantly increased serum total protein (TP) and globulin (GLO) content on d 42. L-carnitine supplementation significantly enhanced liver succinodehydrogenase (SDH), malic dehydrogenase (MDH) and Na+-K+-ATPase activity on d 28, and tended to reduce the lactic acid (LD) level of liver on d 35 (p = 0.06). L-carnitine supplementation significantly reduced serum uric acid (UA) content on d 28, 35 and 42. Based on the current results, it can be concluded that dietary L-carnitine supplementation reduced organ index, red blood cell counts and hematocrit, enhanced antioxidative capacity of the heart, enhanced liver enzymes activity involved in tricarboxylic acid cycle, and reduced serum glucose and triglyceride. Therefore, it is suggested that L-carnitine can potentially reduce susceptibility and mortality due to ascites.

Wang, Y. W.; Ning, D.; Peng, Y. Z.; Guo, Y. M.

2013-01-01

67

Immunostimulatory activities of a low molecular weight antitumoral polysaccharide isolated from Agaricus blazei Murill (LMPAB) in Sarcoma 180 ascitic tumor-bearing mice.  

PubMed

LMPAB is a linear beta-(1-3)-glucan we isolated from polysaccharide extract of Agaricus blazei Murill (AbM). Effects of LMPAB on splenic natural killer (NK) cell activity, splenocyte proliferation, index of spleen and thymus, IFN-gamma expression in spleen and the concentration of IL-12, IL-18 and TNF-alpha in serum of S180 ascitic tumor-bearing mice were detected. The results showed that intraperitoneal injection of LMPAB (100 mg x kg(-1) x d(-1)) significantly increased the thymus index. LMPAB augmented splenic NK cell activity in a dose-dependent manner (50-200 mg x kg(-1) x d(-1)). The concanavalin A (3 microg/ ml) stimulated splenocyte proliferation was significantly enhanced by LMPAB at dosages of 50, 100 or 200 mg x kg(-1) x d(-1). Further studies showed that LMPAB (50, 100 or 200 mg x kg(-1) x d(-1), 14d) significantly increased the production of IL-12, TNF-alpha, IL-18 and the expression IFN-gamma as determined by ELISA and immunohistochemistry, respectively. These results clearly indicate that the anti-tumor effects of LMPAB are closely associated with up-regulation of activity of NK cells, expression of IFN-gamma in spleen and the systemic level of IL-12, IL-18 and TNF-alpha in tumor-bearing mice. PMID:19694186

Niu, Ying-Cai; Liu, Ji-Cheng; Zhao, Xue-Mei; Su, Fu-Qin; Cui, Hong-Xia

2009-07-01

68

Tumor growth in intestinal neobladder  

PubMed Central

The case of a 73 years old man with tumor in intestinal neobladder was presented. Tumor was resected using standard TUR technique. Tumor proved to be benign, follow–up revealed no recurrences. The schedule of lifelong follow–up was proposed.

Gluchowski, Jaroslaw; Weli-Wegbe, James; Blawat, Adam; Kordasz, Janusz

2013-01-01

69

Fibroblast-mediated acceleration of human epithelial tumor growth in vivo.  

PubMed Central

Transformed fibroblasts coinoculated with epithelial cells accelerated the growth and shortened the latency period of human epithelial tumors in athymic mice. Addition of NbF-1 fibroblasts caused epithelial tumors to grow from five marginally tumorigenic or "nontumorigenic" (nontumor-forming) human tumor cell lines or strains: PC-3 (prostate), WH (bladder), MDA-436 (breast), and cells derived from the ascites fluids of patients with metastatic renal pelvic or prostate cancers. Evidence for the human and epithelial nature of these experimental tumors was provided by histologic, immunohistochemical, Southern and dot-blot hybridization, and cytogenetic analyses. Transformed fibroblasts induced predominantly carcinosarcomas, whereas nontumorigenic fibroblasts (NIH 3T3) and lethally irradiated transformed fibroblasts induced exclusively carcinomas. The fibroblast-epithelial interaction appears to occur bidirectionally and does not result from cell fusion. Because coculture experiments in vitro did not demonstrate an increased cell proliferation, it appears that undefined host factors can influence tumor growth. This tumor model may be useful in drug-screening programs and in mechanistic studies of factors regulating human tumor growth and progression. Images

Camps, J L; Chang, S M; Hsu, T C; Freeman, M R; Hong, S J; Zhau, H E; von Eschenbach, A C; Chung, L W

1990-01-01

70

Vital microscopic analysis of polymeric micelle extravasation from tumor vessels: macromolecular delivery according to tumor vascular growth stage.  

PubMed

Particles larger than a specific size have been thought to extravasate from tumor vessels but not from normal vessels. Therefore, various nanoparticles incorporating anticancer drugs have been developed to realize selective drug delivery to solid tumors. However, it is not yet clear whether nanoparticles extravasate readily from all tumor vessels including vessels of microtumors. To answer this question, we synthesized new polymeric micelles labeled with fluorescein isothiocyanate (FITC) and injected them into the tail vein of rats with implanted skinfold transparent chambers. We also analyzed, by means of time-lapse vital microscopy with image analysis, extravasation of FITC micelles from tumor vessels at different stages of growth of Yoshida ascites sarcoma LY80. Polymeric micelles readily leaked from vessels at the interface between normal and tumor tissues and those at the interface between tumor tissues and necrotic areas. The micelles showed negligible extravasation, however, from the vascular network of microtumors less than 1 mm in diameter and did not accumulate in the microtumor. Our results suggest that we must develop a novel therapeutic strategy that can deliver sufficient nanomedicine to microtumors. PMID:19544373

Hori, Katsuyoshi; Nishihara, Masamichi; Yokoyama, Masayuki

2010-01-01

71

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

72

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

Microsoft Academic Search

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

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

2001-01-01

73

Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor.  

PubMed

Tumor necrosis factor (TNF)-? has been proved as an adjuvant therapy for tumor by FDA. However, the effect of chronic TNF-? expression for tumor is still controversial. In this study, we investigated the effect of low-dose TNF-? on tumor growth. We confirmed that low-dose TNF-? promoted angiogenesis of tumor in vivo, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1?, the transcription factor of VEGF, were both upregulated. Our results suggested that low-dose TNF-? was a powerful activator of angiogenesis in tumor and HIF-1?-VEGF pathway seemed to be the most important molecular mechanism. PMID:21740086

Jing, Yingying; Ma, Nannan; Fan, Tingting; Wang, Chenyang; Bu, Xinxin; Jiang, Guocheng; Li, Rong; Gao, Lu; Li, Ding; Wu, Mengchao; Wei, Lixin

2011-08-01

74

ROLE OF CHEMOKINES IN TUMOR GROWTH  

PubMed Central

Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed.

Raman, Dayanidhi; Baugher, Paige J.; Thu, Yee Mon; Richmond, Ann

2007-01-01

75

The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian cancer  

Microsoft Academic Search

BACKGROUND: The production of ascites is a common complication of ovarian cancer. Ascites constitute a unique tumor microenvironment that may affect disease progression. In this context, we recently showed that ovarian cancer ascites may protect tumor cells from TRAIL-induced apoptosis. In this study, we sought to determine whether the prosurvival effect of ascites affects disease-free intervals. METHODS: Peritoneal fluids were

Isabelle Matte; Claudine Rancourt; Alain Piché

2010-01-01

76

Growth factors, tumor promoters, and cancer genes  

SciTech Connect

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

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

1988-01-01

77

Involvement of an arachidonic-acid-dependent pathway in the interferon-beta-mediated expression of C202 gene in Ehrlich-ascites-tumor cells.  

PubMed

We have investigated the signal transduction mechanism of the expression of the C202 gene mediated by interferon beta (IFN-beta) in the murine Ehrlich's ascites tumor cell line. We have shown that treatment of cells with IFN-beta transiently enhances within minutes the release of free arachidonic acid through membrane phospholipase activity. Furthermore, prior treatment with either p-bromophenacyl bromide, an antagonist of both cytosolic and secretory phospholipase A2, or neomycin, which blocks phospholipase C activity, significantly decreased the activation of the murine IFN-beta-inducible gene, C202. Moreover, an increase of the expression of the C202 gene was observed after blocking of both the cyclooxygenase and lipoxygenase pathways. This suggests that further metabolism of arachidonic acid to epoxides via epoxygenase-catalysed pathways may be a mechanism by which second messengers for IFN-beta-mediated effects on C202 gene expression are generated. Taken together, these results indicate that lipids as second messengers may be important mediators in the IFN-beta-based activation of C202 gene expression. PMID:8631372

Toniato, E; Flati, V; Cifone, M G; Del Grosso, E; Roncaioli, P; Cilenti, L; Tessitore, A; Lista, F; Frati, L; Gulino, A; Martinotti, S

1996-01-15

78

Angiogenic and proliferative effects of the cytokine VEGF in Ehrlich ascites tumor cells is inhibited by Glycyrrhiza glabra  

Microsoft Academic Search

Blood vessel plays a crucial role in solid tumor development. It has been suggested that blocking of angiogenesis and the action of the cytokine VEGF could be possible in cancer therapy. In a screen for naturally occurring angiogenic inhibitors, we have identified an extract from the roots of Glycyrrhiza glabra, which has potent antiangiogenic and antitumor activity. The aqueous extract

M. L. Sheela; M. K. Ramakrishna; Bharathi P. Salimath

2006-01-01

79

Super-Rough Dynamics on Tumor Growth  

NASA Astrophysics Data System (ADS)

The growth of a cultivated typical brain tumor is studied in this work. The tumor is analyzed both dynamically and morphologically. We have measured its fractal dimension to be df = 1.21+/-0.05. From its dynamical behavior we determine the scaling critical exponents of this circular symmetry system which are compatible with the linear molecular beam epitaxy universality class. A very important feature of tumor profiles is that they are super-rough, which constitutes the first ( 1+1)-dimensional experiment in literature with super-roughness. The results obtained from the dynamics study make manifest two very surprising features of tumor growth: Its dynamics is mainly due to contour cells and the tendency of an interface cell to duplicate is a function of the local curvature.

Brú, Antonio; Pastor, Juan Manuel; Fernaud, Isabel; Brú, Isabel; Melle, Sonia; Berenguer, Carolina

1998-11-01

80

Characterization of Ascites-Derived Ovarian Tumor Cells from Spontaneously Occurring Ovarian Tumors of the Chicken: Evidence for E-Cadherin Upregulation  

PubMed Central

Ovarian cancer, a highly metastatic disease, is the fifth leading cause of cancer-related deaths in women. Chickens are widely used as a model for human ovarian cancer as they spontaneously develop epithelial ovarian tumors similar to humans. The cellular and molecular biology of chicken ovarian cancer (COVCAR) cells, however, have not been studied. Our objectives were to culture COVCAR cells and to characterize their invasiveness and expression of genes and proteins associated with ovarian cancer. COVCAR cell lines (n?=?13) were successfully maintained in culture for up to19 passages, cryopreserved and found to be viable upon thawing and replating. E-cadherin, cytokeratin and ?-smooth muscle actin were localized in COVCAR cells by immunostaining. COVCAR cells were found to be invasive in extracellular matrix and exhibited anchorage-independent growth forming colonies, acini and tube-like structures in soft agar. Using RT-PCR, COVCAR cells were found to express E-cadherin, N-cadherin, cytokeratin, vimentin, mesothelin, EpCAM, steroidogenic enzymes/proteins, inhibin subunits-?, ?A, ?B, anti-müllerian hormone, estrogen receptor [ER]-?, ER-?, progesterone receptor, androgen receptor, and activin receptors. Quantitative PCR analysis revealed greater N-cadherin, vimentin, and VEGF mRNA levels and lesser cytokeratin mRNA levels in COVCAR cells as compared with normal ovarian surface epithelial (NOSE) cells, which was suggestive of epithelial-mesenchymal transformation. Western blotting analyses revealed significantly greater E-cadherin levels in COVCAR cell lines compared with NOSE cells. Furthermore, cancerous ovaries and COVCAR cell lines expressed higher levels of an E-cadherin cleavage product when compared to normal ovaries and NOSE cells, respectively. Cancerous ovaries were found to express significantly higher ovalbumin levels whereas COVCAR cell lines did not express ovalbumin thus suggesting that the latter did not originate from oviduct. Taken together, COVCAR cell lines are likely to improve our understanding of the cellular and molecular biology of ovarian tumors and its metastasis.

Tiwari, Anupama; Hadley, Jill A.; Hendricks, Gilbert L.; Elkin, Robert G.; Cooper, Timothy; Ramachandran, Ramesh

2013-01-01

81

[Non-cirrhotic ascites: Pathophysiology, diagnosis and etiology].  

PubMed

Ascites, in 20% of cases, is not linked to liver cirrhosis. The pathophysiology is most often different. The understanding of these pathophysiological mechanisms can lead to etiologic diagnosis. The diagnostic approach is mainly based on the biological study of ascites, especially protein concentration and albumin gradient between serum and ascites. In Western countries, tumors and heart diseases are the predominant causes, while developing countries are mainly concerned by infectious diseases, among which tuberculosis is the leading cause. Other uncommon causes must be recognized, as ascites may be the presenting feature of the disease. Their knowledge will facilitate the therapeutic approach. PMID:24406314

Carrier, P; Jacques, J; Debette-Gratien, M; Legros, R; Sarabi, M; Vidal, E; Sautereau, D; Bezanahary, H; Ly, K H; Loustaud-Ratti, V

2014-06-01

82

Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis  

PubMed Central

Claudin-3 (CLDN3) is a tight junction protein that is overexpressed in 90% of ovarian tumors. Previous in vitro studies have indicated that CLDN3 overexpression promotes the migration, invasion, and survival of ovarian cancer cells. Here, we investigated the efficacy of lipidoid-formulated CLDN3 siRNA in 3 different ovarian cancer models. Intratumoral injection of lipidoid/CLDN3 siRNA into OVCAR-3 xenografts resulted in dramatic silencing of CLDN3, significant reduction in cell proliferation, reduction in tumor growth, and a significant increase in the number of apoptotic cells. Intraperitoneal injection of lipidoid-formulated CLDN3 siRNA resulted in a substantial reduction in tumor burden in MISIIR/TAg transgenic mice and mice bearing tumors derived from mouse ovarian surface epithelial cells. Ascites development was reduced in CLDN3 siRNA-treated mice, suggesting the treatment effectively suppressed metastasis. Toxicity was not observed after multiple i.p. injections. Importantly, treatment of mice with nonimmunostimulatory 2?-OMe modified CLDN3 siRNA was as effective in suppressing tumor growth as unmodifed siRNA. These results suggest that lipidoid-formulated CLDN3 siRNA has potential as a therapeutic for ovarian cancer.

Huang, Yu-Hung; Bao, Yunhua; Peng, Weidan; Goldberg, Michael; Love, Kevin; Bumcrot, David A.; Cole, Geoffrey; Langer, Robert; Anderson, Daniel G.; Sawicki, Janet A.

2009-01-01

83

Circulating Fibronectin Controls Tumor Growth12  

PubMed Central

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.

von Au, Anja; Vasel, Matthaeus; Kraft, Sabrina; Sens, Carla; Hackl, Norman; Marx, Alexander; Stroebel, Philipp; Hennenlotter, Jorg; Todenhofer, Tilman; Stenzl, Arnulf; Schott, Sarah; Sinn, Hans-Peter; Wetterwald, Antoinette; Bermejo, Justo Lorenzo; Cecchini, Marco G; Nakchbandi, Inaam A

2013-01-01

84

Contour Instabilities in Early Tumor Growth Models  

NASA Astrophysics Data System (ADS)

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

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

2011-04-01

85

Ascites in poultry  

Microsoft Academic Search

Research on ascites occurring in meat?type chickens reared at moderate and low altitude has shown that the pathogenesis is similar to that of the high altitude disease. Pulmonary hypertension (PH) caused by increased blood flow or increased resistance to flow in the lung results in right ventricular hypertrophy (RVH), valvular insufficiency, increased venous pressure and ascites. The structure of the

Richard J. Julian

1993-01-01

86

Management of refractory ascites.  

PubMed

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, high-dose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction (<90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (<78 mmol/d). Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated paracentesis and improves the quality of life. Several treatments that act at different steps in the pathogenesis of ascites are investigational, and some show promising results. Splanchnic and peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial volume and decrease activation of the renin-angiotensin system with resultant increase in renal sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid mobilization of ascites by significantly decreasing the sympathetic activity and renin-aldosterone levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign, liver transplantation should be considered and incorporated early in the treatment plan. PMID:21192246

Singhal, Shashideep; Baikati, Kiran K; Jabbour, Ibrahim I; Anand, Sury

2012-03-01

87

Endometriosis with massive ascites.  

PubMed

We present 4 cases of endometriosis complicated by massive ascites from our institution and a review of 27 cases from the literature. In most of these patients, the presence of ascites with its related symptoms in association with pelvic masses suggested a neoplastic disease. However, a large proportion of these women had also classical manifestations of endometriosis, e.g., dysmenorrhea, cul-de-sac nodularities, and exacerbation of ascites and other symptoms during the menses. The response to hormonal therapy including GnRH agonists was often unsatisfactory. Repeat recurrences and severe complications required multiple laparotomies and thoracotomies for associated pleural and pulmonary involvement. PMID:9570997

Muneyyirci-Delale, O; Neil, G; Serur, E; Gordon, D; Maiman, M; Sedlis, A

1998-04-01

88

The lymphatic vascular system in liver diseases: its role in ascites formation  

PubMed Central

The lymphatic system is part of the circulatory system and plays a key role in normal vascular function. Its failure plays a crucial role in the development and maintenance of various diseases including liver diseases. Lymphangiogenesis (the growth of lymphatic vessels) and changes in the properties of lymphatic vessels are associated with pathogenesis of tumor metastases, ascites formation, liver fibrosis/cirrhosis and portal hypertension. Despite its significant role in liver diseases and its importance as a potential therapeutic target for those diseases, the lymphatic vascular system of the liver is poorly understood. Therefore, how the lymphatic vascular system in general and lymphangiogenesis in particular are mechanistically related to the pathogenesis and maintenance of liver diseases are largely unknown. This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation.

Chung, Chuhan

2013-01-01

89

The lymphatic vascular system in liver diseases: its role in ascites formation.  

PubMed

The lymphatic system is part of the circulatory system and plays a key role in normal vascular function. Its failure plays a crucial role in the development and maintenance of various diseases including liver diseases. Lymphangiogenesis (the growth of lymphatic vessels) and changes in the properties of lymphatic vessels are associated with pathogenesis of tumor metastases, ascites formation, liver fibrosis/cirrhosis and portal hypertension. Despite its significant role in liver diseases and its importance as a potential therapeutic target for those diseases, the lymphatic vascular system of the liver is poorly understood. Therefore, how the lymphatic vascular system in general and lymphangiogenesis in particular are mechanistically related to the pathogenesis and maintenance of liver diseases are largely unknown. This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation. PMID:23837133

Chung, Chuhan; Iwakiri, Yasuko

2013-06-01

90

Effects of intratumoral injection of I-125 iododeoxyuridine on Ehrlich ascites carcinoma  

SciTech Connect

Intratumoral injection of I-125 iododeoxyuridine (IUdR), saline solution, and oil suspension was investigated using Ehrlich ascites tumors in the thighs of mice. The oil suspension was more effective in tumor growth delay than was the saline solution. Single injection of the oil suspension at the dose of 12.5 microCi resulted in 21.5 days growth delay, whereas 50 microCi of the saline solution resulted in 11.5 days growth delay relative to control growth delay. At 40 days after treatment, higher radioactivities were observed in the tumor and the skin of the mice treated with the oil suspension, which represented the prolongation of I-125 IUdR oil suspension within the tumor. No normal tissue toxicities were observed.

Hong, S.S.; Ford, E.H.; Alfieri, A.A.; Bravo, S. (Univ. of Medicine and Dentistry of New Jersey, Newark (USA))

1989-11-01

91

Congenital chylous ascites  

PubMed Central

Summary Congenital chylous ascites is a rare entity, conditioned by numerous factors and with changing dynamics of the disease. Because of the lack of therapeutic and diagnostic standards, this disease constitutes to be a medical challenge. This article presents current knowledge on pathogenesis, diagnostics and management of this disease, as well as a case of a newborn with primary congenital chylous ascites in the abdominal cavity.

Romanska-Kita, Justyna; Borszewska-Kornacka, Maria Katarzyna; Dobrzanska, Anna; Rudzinska, Iwona; Czech-Kowalska, Justyna; Wawrzoniak, Tomasz

2011-01-01

92

Endometriosis with Massive Ascites  

Microsoft Academic Search

We present 4 cases of endometriosis complicated by massive ascites from our institution and a review of 27 cases from the literature. In most of these patients, the presence of ascites with its related symptoms in association with pelvic masses suggested a neoplastic disease. However, a large proportion of these women had also classical manifestations of endometriosis, e.g., dysmenorrhea, cul-de-sac

Ozgul Muneyyirci-Delale; Gregory Neil; Eli Serur; David Gordon; Mitchell Maiman; Alexander Sedlis

1998-01-01

93

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

94

Malignant ascites: pathophysiology and treatment.  

PubMed

Malignant ascites (MA) accompanies a variety of abdominal and extra-abdominal tumors. It is a primary cause of morbidity and raises several treatment challenges. MA has several symptoms, producing a significant reduction in the patient's quality of life: loss of proteins and electrolyte disorders cause diffuse oedema, while the accumulation of abdominal fluid facilitates sepsis. Treatment options include a multitude of different procedures with limited efficacy and some degree of risk. A Pubmed, Medline, Embase, and Cochrane Library review of medical, interventional and surgical treatments of MA has been performed. Medical therapy, primarily paracentesis and diuretics, are first-line treatments in managing MA. Paracentesis is widely adopted but it is associated with significant patient discomfort and several risks. Diuretic therapy is effective at the very beginning of the disease but efficacy declines with tumor progression. Intraperitoneal chemotherapy, targeted therapy, immunotherapy and radioisotopes are promising medical options but their clinical application is not yet completely elucidated, and further investigations and trials are necessary. Peritoneal-venous shunts are rarely used due to high rates of early mortality and complications. Laparoscopy and hyperthermic intraperitoneal chemotherapy (HIPEC) have been proposed as palliative therapy. Literature on the use of laparoscopic HIPEC in MA includes only reports with small numbers of patients, all showing successful control of ascites. To date, none of the different options has been subjected to evidence-based clinical trials and there are no accepted guidelines for the management of MA. PMID:22460778

Cavazzoni, Emanuel; Bugiantella, Walter; Graziosi, Luigina; Franceschini, Maria Silvia; Donini, Annibale

2013-02-01

95

Essential operating principles for tumor spheroid growth  

PubMed Central

Background Our objective was to discover in silico axioms that are plausible representations of the operating principles realized during characteristic growth of EMT6/Ro mouse mammary tumor spheroids in culture. To reach that objective we engineered and iteratively falsified an agent-based analogue of EMT6 spheroid growth. EMT6 spheroids display consistent and predictable growth characteristics, implying that individual cell behaviors are tightly controlled and regulated. An approach to understanding how individual cell behaviors contribute to system behaviors is to discover a set of principles that enable abstract agents to exhibit closely analogous behaviors using only information available in an agent's immediate environment. We listed key attributes of EMT6 spheroid growth, which became our behavioral targets. Included were the development of a necrotic core surrounded by quiescent and proliferating cells, and growth data at two distinct levels of nutrient. Results We then created an analogue made up of quasi-autonomous software agents and an abstract environment in which they could operate. The system was designed so that upon execution it could mimic EMT6 cells forming spheroids in culture. Each agent used an identical set of axiomatic operating principles. In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation. Conclusion The finalized analogue required nine axioms. We posit that the validated analogue's operating principles are reasonable representations of those utilized by EMT6/Ro cells during tumor spheroid development.

Engelberg, Jesse A; Ropella, Glen EP; Hunt, C Anthony

2008-01-01

96

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.

97

Antitumor activity of methanolic extract of Cassia fistula L. seed against Ehrlich ascites carcinoma.  

PubMed

Effects of methanolic extract (ME) of Cassia fistula seed on the growth of Ehrlich ascites carcinoma (EAC) and on the life span of tumor bearing mice were studied. ME treatment showed an increase of life span, and a decrease in the tumor volume and viable tumor cell count in the EAC tumor hosts. Cytological studies have revealed a reduction in the mitotic activity, and the appearance of membrane blebbing and intracytoplasmic vacuoles in the treated tumor cells. Improvement in the hematological parameters following ME treatment, like hemoglobin content, red blood cell count and bone marrow cell count of the tumor bearing mice have also been observed. The results of the present study suggest that ME of C. fistula seed has an antitumor activity. PMID:10967466

Gupta, M; Mazumder, U K; Rath, N; Mukhopadhyay, D K

2000-09-01

98

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

Microsoft Academic Search

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

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

2006-01-01

99

Pea lectin inhibits growth of Ehrlich ascites carcinoma cells by inducing apoptosis and G2/M cell cycle arrest in vivo in mice.  

PubMed

Pea (Pisum sativum L.) lectin is known to have interesting pharmacological activities and of great interest on biomedical research. In the current research pea lectin was purified followed by ion exchange chromatography on DEAE column and affinity chromatography on glucose-sepharose column. The lectin shown 11.7-84% inhibitory effect against Ehrlich ascites carcinoma (EAC) cells at the concentration range of 8-120 ?g/ml in RPMI 1640 medium as determined by MTT assay. Pea lectin was also shown 63% and 44% growth inhibition against EAC cells in vivo in mice when administered 2.8 mg/kg/day and 1.4 mg/kg/day (i.p.) respectively for five consequent days. When Pea lectin injected into the EAC bearing mice for 10 days its significantly increased the hemoglobin and RBC with the decreased of WBC levels toward the normal. Apoptotic cell morphological change of the treated EAC cells of mice was determined by fluorescence and optical microscope. Interestingly, cell growth inhibition of the lectin was significantly reduced in the presence of caspase inhibitors. Treatment with the lectin caused the cell cycle arrest at G2/M phase of EAC cells which was determined by flow cytometry. The expression of apoptosis-related genes, Bcl-2, Bcl-X and Bax was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR). Intensive increase of Bax gene expression and totally despaired of Bcl-2 and Bcl-X gene expression were observed in the cells treated with Pea lectin for five consecutive days. PMID:23867650

Kabir, Syed Rashel; Nabi, Md Mahamodun; Haque, Ariful; Rokon Uz Zaman; Mahmud, Zahid Hayat; Reza, Md Abu

2013-11-15

100

Chylous ascites following para-aortic lymphadenectomy: a case report  

Microsoft Academic Search

Background. Chylous ascites is an uncommon complication following para-aortic lymph node dissection in the management of gynecologic malignancies. Treatment options are serial paracentesis, medium-chain triglyceride diet, total parenteral nutrition and somatostatin as conservative management and peritoneovenous shunting, and surgical exploration for refractory cases.Case. A 31-year-old female patient developed chylous ascites following para-aortic lymph node dissection for borderline mucinous tumor of

Nurettin Boran; Aylin Pelin Cil; Gokhan Tulunay; Nejat Ozgul; M. Faruk Kose

2004-01-01

101

Serum-ascites albumin gradient in differential diagnosis of ascites.  

PubMed

The present study was aimed to find out causes of ascites based on serum-ascites albumin gradient (SAAG) and to compare the diagnostic accuracy of the serum-ascites albumin gradient, proposed as a new biochemical criterion for the differential diagnosis of ascites and to evaluate the value of serum-ascites albumin gradient in differential diagnosis of ascites. This study includes 50 patients with ascites admitted in Medicine wards of Comilla Medical College Hospital, Comilla during the period of July 2010 to June 2011. Blood was drawn from the antecubital vein and ascetic fluid was obtained by paracentesis at the same time. Determination of the concentrations of albumin in both the serum and the ascitic fluid was carried out simultaneously. Considering SAAG value of ?1.1g/dl is high SAAG and a SAAG value <1.1g/dl is low SAAG. Out of 50 patients, male patients were 36 and female patients were 14. Male and female ratio was 2.5:1. Age range was 21 years to 70 years. Most of the patients fall in age group of 41-50(28%).Among the 50 patients with ascites, cirrhosis of liver accounted for 68%, followed by tubercular peritonitis 12%, nephrotic syndrome 8%, congestive cardiac failure 6%, hepatocellular carcinoma 4% and malignancy related 2%. In this study serum ascites albumin gradient accurately identified the cause of ascites in 97% cases. In contrast the exudate-transudate concept identified only 83% correctly. Serum ascites albumin gradient was found superior to the exudate-transudate concept. So, differential diagnosis of ascites should be based on the serum ascites albumin gradient which is a better distinguishing marker. PMID:24292307

Uddin, M S; Hoque, M I; Islam, M B; Uddin, M K; Haq, I; Mondol, G; Tariquzzaman, M

2013-10-01

102

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

103

Mathematical Modeling of Tumor Cell Growth and Immune System Interactions  

NASA Astrophysics Data System (ADS)

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

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

104

Treatment for Malignant Ascites  

Cancer.gov

In this trial, researchers will randomly assign patients with malignant ascites to receive either octreotide or a placebo once a month for up to two years. The investigators will see whether octreotide can delay, or even eliminate, the need for paracentesis and assess side effects and quality of life of patients undergoing this treatment.

105

Proinvasive properties of ovarian cancer ascites-derived membrane vesicles.  

PubMed

Malignant ovarian ascites are rich in cellular components, membrane-bound vesicles, and soluble proteins. This study focused on the structure of membrane-bound vesicles and their ability to promote invasion in cultured malignant ovarian epithelium. Membrane vesicles were derived from women with stage I-IV malignant ovarian ascites and from nonmalignant gynecologic ascites. Isolated vesicles were characterized by immunofluorescence and Western blot analysis. Using gel zymography for matrix metalloproteinase (MMP) detection and a colorimetric assay for urokinase-type plasminogen activator (uPA) analysis, we analyzed the proteinase activities of MMP-2, MMP-9, and uPA from the prepared vesicles, whole cells isolated from ascites, and the cell-free ultracentrifuged supernatant. The invasiveness of established cultured malignant ovarian epithelium on addition of ascites-derived vesicles was tested using a Matrigel-based invasion assay. Fractionation of malignant ascites revealed that extracellular matrix-degrading proteinases including MMPs and uPA are localized preferentially in membrane vesicles. All malignant vesicles tested, regardless of cancer stage, stimulated invasion. Furthermore, the combination of ovarian cancer cells and membrane vesicles resulted in greater uPA activation than that of cells or vesicles alone. Membrane vesicles from malignant ascites were also found to contain activated MMP-2, MMP-9, and uPA. Our data suggest that vesicle-stimulated proteinase activation leads to increased extracellular matrix degradation, which may facilitate tumor cell invasion and metastasis. PMID:15466198

Graves, Laura E; Ariztia, Edgardo V; Navari, Jason R; Matzel, Heather J; Stack, M Sharon; Fishman, David A

2004-10-01

106

The role of complement in tumor growth.  

PubMed

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

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

2014-01-01

107

TGF-?-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth  

Microsoft Academic Search

Tumor-associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME, including tumor growth factor-? (TGF-?), allow tumors to circumvent host-mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells,

T J Standiford; R Kuick; U Bhan; J Chen; M Newstead; V G Keshamouni

2011-01-01

108

Reproducible growth in tissue culture of retinoblastoma tumor specimens  

Microsoft Academic Search

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

B L Gallie; Wendy Holmes; Robert A. Phillips

1982-01-01

109

Rare cancers yield potential source of tumor growth  

Cancer.gov

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

110

Brick by brick: metabolism and tumor cell growth  

PubMed Central

Summary Tumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the ‘Warburg effect’). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these pathways into focus. In this review, we discuss how tumor cells achieve high rates of nucleotide and fatty acid synthesis, how oncogenes and tumor suppressors influence these activities, and how glutamine metabolism enables macromolecular synthesis in proliferating cells.

DeBerardinis, Ralph J.; Sayed, Nabil; Ditsworth, Dara; Thompson, Craig B.

2008-01-01

111

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

112

Refractory congenital chylous ascites.  

PubMed

Refractory congenital chylous ascites (CCA) is an uncommon clinical condition. Few cases have been described and no gold standard treatment has been defined so far. This report describes a case of refractory CCA in a newborn child which was treated by surgery. Preoperative lower-limb lymphoscintigraphy associated with intraoperative patent blue testing and fibrin glue application were useful in order to provide a successful outcome. PMID:20821276

Melo-Filho, Antônio Aldo; Souza, Ivana Jesus Nogueira; Leite, Christiane Araújo Chaves; Leite, Robério Dias; Colares, João Henrique Freitas; Correia, Júlio Marcus Sousa

2010-11-01

113

Assessing growth and response to therapy in murine tumor models.  

PubMed

Rodent models provide an important means of assessing antitumor activity vs toxicity for new cancer therapies. Tumors are often grown subcutaneously on the flank or back of animals, allowing accurate serial determination of tumor volume with calipers by measuring the tumors in three dimensions. The advantages of assessing tumor volume in subcutaneous tumors must be balanced against the potential artifacts induced by growth of tumor cells in subcutaneous tissue. Various orthotopic models have been developed. However, they are more labor-intensive and generally do not allow accurate assessment of tumor growth and/or response unless investigators have access to small animal cross-sectional imaging. Use of small-animal magnetic resonance imaging (MRI) allows one to assess the growth and response of intracavitary tumors, but the cost and labor-intensive nature of MRI limits its use in drug testing. Another approach to intracavitary solid tumor models is the intravenous injection of tumor cells, which can produce lung, liver, or bone metastases (depending on the cell line used), whereas direct injection of tumor cells into the femur or tibia of mice can cause local growth in bone. Progression of both lung metastases and bone lesions can be assessed by small-animal analog X-ray techniques that are more easily available and less labor-intensive to use, and are proving useful for selected therapeutic and biological studies. PMID:15911989

Reynolds, C Patrick; Sun, Bee-Chun; DeClerck, Yves A; Moats, Rex A

2005-01-01

114

Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models1  

PubMed Central

Abstract The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

Wu, Yingjen Jeffrey; Muldoon, Leslie L.; Dickey, Dana Thomas; Lewin, Seth J.; Varallyay, Csanad G.; Neuwelt, Edward A.

2009-01-01

115

Endothelial cell-derived interleukin-6 regulates tumor growth  

PubMed Central

Background Endothelial cells play a complex role in the pathobiology of cancer. This role is not limited to the making of blood vessels to allow for influx of oxygen and nutrients required for the high metabolic demands of tumor cells. Indeed, it has been recently shown that tumor-associated endothelial cells secrete molecules that enhance tumor cell survival and cancer stem cell self-renewal. The hypothesis underlying this work is that specific disruption of endothelial cell-initiated signaling inhibits tumor growth. Methods Conditioned medium from primary human dermal microvascular endothelial cells (HDMEC) stably transduced with silencing RNA for IL-6 (or controls) was used to evaluate the role of endothelial-derived IL-6 on the activation of key signaling pathways in tumor cells. In addition, these endothelial cells were co-transplanted with tumor cells into immunodefficient mice to determine the impact of endothelial cell-derived IL-6 on tumor growth and angiogenesis. Results We observed that tumor cells adjacent to blood vessels show strong phosphorylation of STAT3, a key mediator of tumor progression. In search for a possible mechanism for the activation of the STAT3 signaling pathway, we observed that silencing interleukin (IL)-6 in tumor-associated endothelial cells inhibited STAT3 phosphorylation in tumor cells. Notably, tumors vascularized with IL-6-silenced endothelial cells showed lower intratumoral microvessel density, lower tumor cell proliferation, and slower growth than tumors vascularized with control endothelial cells. Conclusions Collectively, these results demonstrate that IL-6 secreted by endothelial cells enhance tumor growth, and suggest that cancer patients might benefit from targeted approaches that block signaling events initiated by endothelial cells.

2014-01-01

116

Molecular Profiling and Clinical Outcome of High-Grade Serous Ovarian Cancer Presenting with Low- versus High-Volume Ascites  

PubMed Central

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.

Clarke, Blaise; Virtanen, Carl; Plotkin, Anna; Rosen, Barry; Bernardini, Marcus Q.; Brown, Theodore J.; Murphy, K. Joan

2014-01-01

117

Molecular Profiling and Clinical Outcome of High-Grade Serous Ovarian Cancer Presenting with Low- versus High-Volume Ascites.  

PubMed

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes. PMID:24982872

Feigenberg, Tomer; Clarke, Blaise; Virtanen, Carl; Plotkin, Anna; Letarte, Michelle; Rosen, Barry; Bernardini, Marcus Q; Kollara, Alexandra; Brown, Theodore J; Murphy, K Joan

2014-01-01

118

Vascular Endothelial Growth Factor C-Induced Lymphangiogenesis DecreasesTumor Interstitial Fluid Pressure and Tumor Growth1  

PubMed Central

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

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

2013-01-01

119

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

120

A case of inflammatory ascites.  

PubMed

Case background: Ascites appears mainly as a consequence of portal hypertension in patients with liver cirrhosis, or can be caused by several other causes, such us congestive heart failure, peritoneal malignancy, or tuberculosis. In some cases, ascites can pose a diagnostic challenge for clinicians and in some patients, despite thorough and extensive work-up, the origin of this ascites remains unknown. Case report: In the unusual case hereby reported, a 52-year-old man developed severe ascites in a few weeks, in the absence of known liver disease or congestive hearth failure. We performed laboratory analysis, endoscopic, and imaging investigations, including abdominal contrast-enhanced computed tomography and 18-fluorodeoxyglucose-positron emission tomography. Peritoneal fluid analysis showed exudative fluid without neoplastic cells. A diagnostic laparoscopy with multiple diagnostic biopsies was carried out, but no macroscopic cause of the ascites was found; histopathological examination showed minimal aspects of diffuse and non-specific chronic inflammation. Conclusions: We decided to empirically treat the patient with steroid therapy (methylprednisolone: 0·5 mg/kg/day). Over a period of 6 weeks, his ascites resolved and at 2 months, he was in remission on low-dose methylprednisolone. Our final hypothesis was reactive inflammatory ascites. The literature on ascites and its management has also been reviewed. PMID:24820919

Guidetti, E; Galassi, M; Croci, L; Stagni, B; Crespi, C; Tovoli, F; Bolondi, L

2014-06-01

121

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

PubMed

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

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

2014-07-17

122

Catumaxomab: in malignant ascites.  

PubMed

Catumaxomab is a rat/murine hybrid, trifunctional, bispecific (anti-human epithelial cell adhesion molecule [EpCAM]?×?anti-CD3) monoclonal antibody. Compared with paracentesis alone, paracentesis followed by catumaxomab therapy was associated with significant prolongation of paracentesis-free survival and time to repeat paracentesis in a randomized, open-label, multicentre, pivotal phase II/III trial in patients with recurrent symptomatic malignant ascites due to EpCAM-positive tumours who were resistant to conventional chemotherapy. The benefits of catumaxomab were seen across a broad range of epithelial ovarian and nonovarian cancers, and irrespective of whether or not catumaxomab recipients developed human anti-mouse antibodies. Combining catumaxomab with paracentesis also resulted in more pronounced and prolonged reductions in ascites signs and symptoms and a delayed deterioration in health-related quality of life compared with paracentesis alone. Despite the study not being designed or powered to evaluate overall survival, significant differences favouring the addition of catumaxomab to paracentesis were seen in analyses of the safety population and the subpopulation of patients with gastric cancer. Catumaxomab was generally well tolerated in the pivotal phase II/III trial. The most frequent adverse events attributed to catumaxomab treatment included cytokine-release-related symptoms, which were mostly of mild to moderate severity and manageable with standard symptomatic treatment. PMID:22676343

Frampton, James E

2012-07-01

123

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

124

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

PubMed Central

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

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

2014-01-01

125

Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.  

PubMed

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis. PMID:21415165

Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat

2011-05-01

126

Patient specific tumor growth prediction using multimodal images.  

PubMed

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

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

2014-04-01

127

Bioavailable copper modulates oxidative phosphorylation and growth of tumors  

PubMed Central

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

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

2013-01-01

128

Expression and significance of cyclooxygenase-2 mRNA in benign and malignant ascites  

PubMed Central

AIM: To investigate the mRNA expression of cyclooxygensae-2 (COX-2) in benign and malignant ascites, and to explore the difference in COX-2 mRNA expression among different diseases. METHODS: A total of 36 samples were collected from the Fifth Affiliated Hospital of Sun Yat-Sen University and divided into two experimental groups: benign ascites (n = 21) and malignant ascites (n = 15). Benign ascites included cirrhotic ascites (n = 10) and tuberculous ascites (n = 5). Malignant ascites included oophoroma (n = 7), cancer of colon (n = 5), cancer of the liver (n = 6), gastric cancer (n = 2), and bladder carcinoma (n = 1). The mRNA expression of COX-2 in ascites was examined with reverse transcriptase polymerase chain reaction (RT-PCR) technology, and the positive rate of COX-2 mRNA was compared between different diseases. RESULTS: The positive rate of COX-2 mRNA in malignant ascites was 42.9% (9/21), which was significantly higher than in benign ascites, 6.7% (1/15), difference being significant between these two groups (?2 = 4.051, P = 0.044). The proportion of the positive rate in the malignant ascites was as follows: ovarian cancers 57.1% (4/7), colon cancer 40.0% (2/5), liver cancer 33.3% (2/6), gastric cancer 50.0% (1/2), and bladder cancer 0.00% (0/1). However, there was no significant difference in COX-2 mRNA expression among various tumors with malignant ascites (?2 = 1.614, P = 0.806). Among the benign ascites, COX-2 mRNA levels were different between the tuberculous ascites (0/5) and cirrhotic ascites (1/10), but there was no significant difference (P = 1.000). CONCLUSION: COX-2 mRNA, detected by RT-PCR, is useful in the differential diagnosis of benign and malignant ascites, which also has potential value in the clinical diagnosis of tumors.

Lu, Jing; Li, Xiao-Feng; Kong, Li-Xia; Ma, Lin; Liao, Su-Huan; Jiang, Chang-You

2013-01-01

129

DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency.  

PubMed

Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies. PMID:19664991

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

2009-08-01

130

A tumor growth inhibitory factor and a tumor growth promoting factor isolated from unfertilized ova of shad (Alosa sapidissima).  

PubMed

In the present study, a cytostatic tumor growth inhibitory peptide and a tumor growth promoting peptide with molecular weights of 20,000-30,000 Da have been identified in the supernatant fraction of unfertilized ova from Shad. The factors can be separated by gel chromatography, thus indicating that the factors are individual molecules. Both of the factors are nondialyzable, heat stable, and resistant to trypsin digestion and periodate oxidation. PMID:2930539

Sheid, B; Prat, J C; Gaetjens, E

1989-03-15

131

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

PubMed Central

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

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

2007-01-01

132

[Tlaloc and ascites].  

PubMed

Ascites has been a common pathological sign among prehispanic Mexican people, as a result from hepatic and cardiac ailments. In this sense it represents a significant epidemiological problem. But it also is important because is related to Tlaloc and the rain gods and goddesses. The hidropic body is a symbolic water container and have a special function: serve as a Tlaloc and related gods vehicle to transport the precious liquid. In this paper we analyze the Tlaloc role as water and alimentary substances provider and his capital importance for people survival. We also describe five different plastic ways to represent water in the body, all of them with clear relationships to Tlaloc. PMID:20141653

Viesca-Treviño, Carlos; Macuil-García, Carmen; Monzón-Barranco, Abraham; Rosas-Peña, Jonathan

2009-01-01

133

A multiphase model for three-dimensional tumor growth  

NASA Astrophysics Data System (ADS)

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

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

2013-01-01

134

RGD-Tachyplesin Inhibits Tumor Growth1  

Microsoft Academic Search

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

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

2001-01-01

135

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis  

PubMed Central

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

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

2013-01-01

136

Prognostic significance of computed tomography defined ascites in advanced gastric cancer  

PubMed Central

Purpose The aim of this study was to investigate the clinicopathologic features and prognosis in patients with computed tomography (CT) findings of ascites, with a focus on the correlation with peritoneal carcinomatosis. Methods This study included a total of 157 patients who underwent surgery for advanced gastric cancer from 2003 to 2008 at the Department of Surgery, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea, which were analyzed retrospectively. Results Fourteen patients (8.9%) presented ascites on their CT scan. Among them, 10 patients had peritoneal carcinomatosis, and showed significant difference with CT ascites positive group in the incidence of peritoneal carcinomatosis. The presence of CT ascites was significantly correlated with pathologic T stage, tumor size, histologic type, CT T and N stages, CT peritoneal nodularity and curability of surgery, statistically. The prognosis of CT ascites positive group was much poorer in the total advanced gastric cancer patients (P < 0.001), as well as in patients with pathologic T4 (P = 0.002). Also in patients without peritoneal carcinomatosis, CT ascites positive subgroup tended to have a worse prognosis than CT ascites negative subgroup (P = 0.086). Tumor size, CT T and N stages and the presence of CT peritoneal nodularity and ascites influenced the prognosis significantly; among which, if a tumor size larger than 5 cm, CT T4 stage and the presence of CT ascites were identified as independent prognostic factors. Conclusion The presence of ascites was closely associated with peritoneal metastasis, and was the most significant independent prognostic factor in advanced gastric cancer in the present study.

Cheong, Jin Cheol; Kim, Doo Jin; Park, Jun Ho; Cho, Sung Jin; Choi, Chul Soon; Kim, Joo Seop

2012-01-01

137

TRPV Channels in Tumor Growth and Progression  

Microsoft Academic Search

\\u000a Transient receptor potential (TRP) channels affect several physiological and pathological processes. In particular, TRP channels\\u000a have been recently involved in the triggering of enhanced proliferation, aberrant differentiation, and resistance to apoptotic\\u000a cell death leading to the uncontrolled tumor invasion. About thirty TRPs have been identified to date, and are classified\\u000a in seven different families: TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin),

Giorgio Santoni; Valerio Farfariello; Consuelo Amantini

138

Multicystic mesothelioma--a rare case of ascites: case report.  

PubMed

We present the case of a 37-year-old male, admitted to our clinic with abdominal tenderness, right supraclavicular tumour, and ascites. The presence of ascites was incidentally reported 6 years before, but no other evaluation was done at that moment or during this period. Abdominal ultrasound and CT scan revealed moderate ascites, perivascular adenopathies, and multiple abdominal cystic lesions, while thoracic CT scan revealed the same lesions in mediastinum. Laboratory data were within normal limits, including the tumoral markers, and the tests for hydatid cysts. A biopsy from the right supraclavicular nodule was performed, and based on usual and immunohistochemical stains (calretinin, mesotheline, CK 5/6, CK 7, CK18 diffusely positive in mesothelial cells, and CEA -M, bcl-2 and vimentin negative), suggested the diagnosis of mesothelioma. Based on these results, the diagnosis of "multicystic mesothelioma" was made. The patient was referred for surgery. PMID:18389776

Manuc, M; Lamatic, C; Pop, C; Dobrea, C; Becheanu, G; Grasu, M; Iosif, D; Diculescu, M

2007-01-01

139

Three-Dimensional Multispecies Nonlinear Tumor Growth-II: Tumor Invasion and Angiogenesis  

PubMed Central

We extend the diffuse interface model developed in Wise et al. (2008) to study nonlinear tumor growth in 3D. Extensions include the tracking of multiple viable cell species populations through a continuum diffuse-interface approach, onset and aging of discrete tumor vessels through angiogenesis, and incorporation of individual cell movement using a hybrid continuum-discrete approach. We investigate disease progression as a function of cellular-scale parameters such as proliferation and oxygen/nutrient uptake rates. We find that heterogeneity in the physiologically complex tumor microenvironment, caused by non-uniform distribution of oxygen, cell nutrients, and metabolites, as well as phenotypic changes affecting cellular-scale parameters, can be quantitatively linked to the tumor macro-scale as a mechanism that promotes morphological instability. This instability leads to invasion through tumor infiltration of surrounding healthy tissue. Models that employ a biologically-founded, multiscale approach, as illustrated in this work, could help to quantitatively link the critical effect of heterogeneity in the tumor microenvironment with clinically observed tumor growth and invasion. Using patient tumor-specific parameter values, this approach may provide a predictive tool to characterize the complex in vivo tumor physiological characteristics and clinical response, and thus lead to improved treatment modalities and prognosis.

Frieboes, H.B.; Jin, F.; Chuang, Y.-L.; Wise, S.M.; Lowengrub, J.S.; Cristini, V.

2010-01-01

140

Inhibition of melanoma tumor growth in vivo by survivin targeting  

PubMed Central

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

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

2001-01-01

141

Immunosuppressive drugs and their effect on experimental tumor growth  

Microsoft Academic Search

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

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

1995-01-01

142

From the Cover: Glutamate antagonists limit tumor growth  

NASA Astrophysics Data System (ADS)

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

Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

2001-05-01

143

Pharmacological Inhibition of BMK1 Suppresses Tumor Growth Through PML  

PubMed Central

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

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

2010-01-01

144

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

PubMed

This paper deals with antitumor properties of a fenugreek (Trigonella Foenum Graecum L.) as to the different genesis tumors--the Ca755 mouse mammary carcinoma and the Guerin's carcinoma in rats. Fenugreek powder was shown to inhibit (25-40 %) growth of certain tumors, decrease (27-63%) level of malone dialdehyde in liver, heart and kidney. Consumption of fenugreek was accompanied with decreased polyamines (spermine, spermidine, putrescine) content in tumor tissue. Inclusion of fenugreek to allowance was shown to improve certain blood value. PMID:23534282

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

2012-01-01

145

Optimal control synthesis in therapy of solid tumor growth  

NASA Astrophysics Data System (ADS)

A mathematical model of tumor growth therapy is considered. The total amount of a drug is bounded and fixed. The problem is to choose an optimal therapeutic strategy, i.e., to choose an amount of the drug permanently affecting the tumor that minimizes the number of tumor cells by a given time. The problem is solved by the dynamic programming method. Exact and approximate solutions to the corresponding Hamilton-Jacobi-Bellman equation are found. An error estimate is proved. Numerical results are presented.

Bratus', A. S.; Chumerina, E. S.

2008-06-01

146

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

147

Alpha1-antitrypsin inhibits angiogenesis and tumor growth.  

PubMed

Disturbances of the ratio between angiogenic inducers and inhibitors in tumor microenvironment are the driving force behind angiogenic switch critical for tumor progression. Angiogenic inhibitors may vary depending on organismal age and the tissue of origin. We showed that alpha(1)-antitrypsin (AAT), a serine protease inhibitor (serpin) is an inhibitor of angiogenesis, which induced apoptosis and inhibited chemotaxis of endothelial cells. S- and Z-type mutations that cause abnormal folding and defective serpin activity abrogated AAT antiangiogenic activity. Removal of the C-terminal reactive site loop had no effect on its angiostatic activity. Both native AAT and AAT truncated on C-terminus (AATDelta) inhibited neovascularization in the rat cornea and delayed the growth of subcutaneous tumors in mice. Treatment with native AAT and truncated AATDelta, but not control vehicle reduced tumor microvessel density, while increasing apoptosis within tumor endothelium. Comparative analysis of the human tumors and normal tissues of origin showed correlation between reduced local alpha(1)-antitrypsin expression and more aggressive tumor growth. PMID:15316942

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

2004-12-20

148

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

2011-10-01

149

Molecular Cochaperones: Tumor Growth and Cancer Treatment  

PubMed Central

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

Calderwood, Stuart K.

2013-01-01

150

Antiproliferative and hepatoprotective activity of metabolites from Corynebacterium xerosis against Ehrlich Ascites Carcinoma cells  

PubMed Central

Objective To find out the effective anticancer drugs from bacterial products, petroleum ether extract of Corynebacterium xerosis. Methods Antiproliferative activity of the metabolite has been measured by monitoring the parameters like tumor weight measurement, tumor cell growth inhibition in mice and survival time of tumor bearing mice, etc. Hepatoprotective effect of the metabolites was determined by observing biochemical, hematological parameters. Results It has been found that the petroleum ether extract bacterial metabolite significantly decrease cell growth (78.58%; P<0.01), tumor weight (36.04 %; P<0.01) and increase the life span of tumor bearing mice (69.23%; P<0.01) at dose 100 mg/kg (i.p.) in comparison to those of untreated Ehrlich ascites carcinoma (EAC) bearing mice. The metabolite also alters the depleted hematological parameters like red blood cell, white blood cell, hemoglobin (Hb%), etc. towards normal in tumor bearing mice. Metabolite show no adverse effect on liver functions regarding blood glucose, serum alkaline phosphatases, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase activity and serum billirubin, etc. in normal mice. Histopathological observation of these mice organ does not show any toxic effect on cellular structure. But in the case of EAC bearing untreated mice these hematological and biochemical parameters deteriorate extremely with time whereas petroleum ether extract bacterial metabolite receiving EAC bearing mice nullified the toxicity induced by EAC cells. Conclusion Study results reveal that metabolite possesses significant antiproliferative and hepatoprotective effect against EAC cells.

Islam, Farhadul; Ghosh, Soby; Khanam, Jahan Ara

2014-01-01

151

CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR  

PubMed Central

Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.

Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

2014-01-01

152

Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth  

PubMed Central

Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance of tumors in vivo.

Chen, Jinyun; Chung, Franklin; Yang, Guizhi; Pu, Minying; Gao, Hui; Jiang, Wei; Yin, Hong; Capka, Vladimir; Kasibhatla, Shailaja; Laffitte, Bryan; Jaeger, Savina; Pagliarini, Raymond; Zhou, Wenlai

2013-01-01

153

Tumor models for prostate cancer exemplified by fibroblast growth factor 8-induced tumorigenesis and tumor progression.  

PubMed

Prostate cancer is a very common malignancy among Western males. Although most tumors are indolent and grow slowly, some grow and metastasize aggressively. Because prostate cancer growth is usually androgen-dependent, androgen ablation offers a therapeutic option to treat post-resection tumor recurrence or primarily metastasized prostate cancer. However, patients often relapse after the primary response to androgen ablation therapy, and there is no effective cure for cases of castration-resistant prostate cancer (CRPC). The mechanisms of tumor growth in CRPC are poorly understood. Although the androgen receptors (ARs) remain functional in CRPC, other mechanisms are clearly activated (e.g., disturbed growth factor signaling). Results from our laboratory and others have shown that dysregulation of fibroblast growth factor (FGF) signaling, including FGF receptor 1 (FGFR1) activation and FGF8b overexpression, has an important role in prostate cancer growth and progression. Several experimental models have been developed for prostate tumorigenesis and various stages of tumor progression. These models include genetically engineered mice and rats, as well as induced tumors and xenografts in immunodeficient mice. The latter was created using parental and genetically modified cell lines. All of these models greatly helped to elucidate the roles of different genes in prostate carcinogenesis and tumor progression. Recently, patient-derived xenografts have been studied for possible use in testing individual, specific responses of tumor tissue to different treatment options. Feasible and functional CRPC models for drug responsiveness analysis and the development of effective therapies targeting the FGF signaling pathway and other pathways in prostate cancer are being actively investigated. PMID:24607251

Tuomela, Johanna; Härkönen, Pirkko

2014-03-01

154

Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts.  

PubMed

Among the natural products shown to possess chemopreventive and anticancer properties, curcumin is one of the most potent. In the current study, we investigated the effects of this natural product on the growth of human glioma U-87 cells xenografted into athymic mice. We show here that curcumin administration exerted significant anti-tumor effects on subcutaneous and intracerebral gliomas as demonstrated by the slower tumor growth rate and the increase of animal survival time. While investigating the mechanism of its action in vivo, we observed that curcumin decreased the gelatinolytic activities of matrix metalloproteinase-9. Furthermore, treatment with curcumin inhibited glioma-induced angiogenesis as indicated by the decrease of endothelial cell marker from newly formed vessels and by the diminution of the concentration of hemoglobin in curcumin-treated tumors. We also demonstrate, using an in vitro model of blood-brain barrier, that curcumin can cross the blood-brain barrier to a high level. These are the first results showing that curcumin suppresses tumor growth of gliomas in xenograft models. The mechanisms of the anti-tumor effects of curcumin were related, at least partly, to the inhibition of glioma-induced angiogenesis. PMID:20087857

Perry, Marie-Claude; Demeule, Michel; Régina, Anthony; Moumdjian, Robert; Béliveau, Richard

2010-08-01

155

Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice  

PubMed Central

Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n?6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n?6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n?6 AA and increased D6D activity can lead to enhanced n?6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention.

He, Chengwei; Qu, Xiying; Wan, Jianbo; Rong, Rong; Huang, Lili; Cai, Chun; Zhou, Keyuan; Gu, Yan; Qian, Steven Y.; Kang, Jing X.

2012-01-01

156

Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape  

PubMed Central

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

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

2012-01-01

157

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

158

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

159

Platelet-Derived Growth Factor Production by B16 Melanoma Cells Leads to Increased Pericyte Abundance in Tumors and an Associated Increase in Tumor Growth Rate  

Microsoft Academic Search

Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimu- lation of tumor angiogenesis. In the present study, the B16 mouse mela- noma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or

Masao Furuhashi; Tobias Sjoblom; Alexandra Abramsson; Jens Ellingsen; Patrick Micke; Hong Li; Erika Bergsten-Folestad; Ulf Eriksson; Rainer Heuchel; Christer Betsholtz; Carl-Henrik Heldin; Arne Ostman

160

Sustained Expression of Early Growth Response Protein1 Blocks Angiogenesis and Tumor Growth  

Microsoft Academic Search

Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by

Markus Lucerna; Jiri Pomyje; Diana Mechtcheriakova; Alexandra Kadl; Florian Gruber; Martin Bilban; Yuri Sobanov; Gernot Schabbauer; Johannes Breuss; Oswald Wagner; Markus Bischoff; Matthias Clauss; Erhard Hofer

2006-01-01

161

Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.  

PubMed

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity. PMID:23345334

Wang, Zhihui; Liu, Jin-Qing; Liu, Zhenzhen; Shen, Rulong; Zhang, Guoqiang; Xu, Jianping; Basu, Sujit; Feng, Youmei; Bai, Xue-Feng

2013-03-01

162

Systemic Par-4 inhibits non-autochthonous tumor growth.  

PubMed

The tumor suppressor protein Par-4 (Prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC pro-apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy. PMID:21613819

Zhao, Yanming; Burikhanov, Ravshan; Brandon, Jason; Qiu, Shirley; Shelton, Brent J; Spear, Brett; Bondada, Subbarao; Bryson, Scott; Rangnekar, Vivek M

2011-07-15

163

[Chylous ascites, a revealing sign of peritoneal tuberculosis in an 11-month-old infant].  

PubMed

Chylous ascites is rare in children. We report on a case of chylous ascites in an 1-month-old infant in Togo. The infant had been appropriately vaccinated, had normal growth and psychomotor development, and he was living in a rural area. He had fever that had started 3 months earlier and persisted despite various treatments with antimalarials and antibiotics. Then progressively abdominal pain with abdominal distension developed, while lactescent ascites was discovered after puncture. The patient was referred to the Lomé teaching hospital for advanced management. Intradermic reaction to tuberculin (IRD) was positive (16 mm). Chylous ascites liquid analysis revealed apparently lymphocytic pleocytosis. Culture on special milieu allowed isolation of Mycobacterium tuberculosis. The clinical course was favorable with antituberculosis treatment. Peritoneal tuberculosis should be suspected in endemic areas in the case of a persistent fever with abdominal bloating and effusion, whatever the patient's age and the nature of ascites liquid. PMID:23380033

Azoumah, K-D; Douti, K-N; N'timon, B; Tsolényanu, E; Adjenou, K-E; Bakondé, B; Rédah, D

2013-03-01

164

TGF-?-induced IRAK-M Expression in Tumor Associated Macrophages Regulates Lung Tumor Growth  

PubMed Central

Tumor associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME including TGF-?, allow tumors to circumvent host mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin receptor associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. Here we show that TAMs express significantly higher levels of IRAK-M compared to peritoneal macrophages (PEMs) in a syngeneic mouse model of lung cancer. Subcutaneous implantation of LLC cells in IRAK-M?/? mice resulted in a five-fold reduction in tumor growth, as compared to tumors in wild type animals. Furthermore, compared to WT TAMs, TAMs isolated from IRAK-M?/? mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, IFN-?, and iNOS. Human lung cancer cells induced IRAK-M expression in human PBMCs when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-? pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-?, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF-?-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages.

Standiford, Theodore J.; Kuick, Rork; Bhan, Urvashi; Chen, Jun; Newstead, Michael; Keshamouni, Venkateshwar G.

2010-01-01

165

Fibrosis in immune control of mammary-tumor growth.  

PubMed

In malignancies, an interruption of growth (dormancy) is sometimes observed. In the immunogenic mammary carcinoma MC2, dormancy followed by regression after a period of growth was observed in 18% of s.c. implants in normal mice. Dormant implants removed for histologic examination were invariably found to be completely surrounded by a highly fibrous stroma. Fibrosis was enhanced in immunized mice, and reduced in immuno-deficient mice. Surgical disruption of the fibrous capsule around dormant tumors early (19 +/- 3 days) in the immune response led more frequently to resumed growth, while later (32 +/- 3 days) disruption of the capsule led more frequently to complete regressions. This showed that fibrous capsules that could destroy tumors could also shield them against well-developed systemic immune mechanisms. PMID:1568799

Vaage, J

1992-05-01

166

Precordial low voltage in patients with ascites  

Microsoft Academic Search

Aims Electrocardiographic (ECG) changes in patients with ascites are not well studied. The aim of this study was to evaluate ECG changes in patients with ascites. Methods and results Prospective analysis of patients with ascites who were referred for paracentesis. Three ECGs were recorded before paracentesis. ECG 1 was a standard 12-lead ECG. For ECG 2 the pre- cordial leads

Florim Cuculi; Peiman Jamshidi; Richard Kobza; Martin Rohacek; Paul Erne

167

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. 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

2014-04-24

168

TPX2 regulates tumor growth in human cervical carcinoma cells.  

PubMed

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

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

2014-06-01

169

'Doubling down' on the autophagy pathway to suppress tumor growth.  

PubMed

In this issue of Genes & Development, Wei and colleagues (pp. 1204-1216) use elegant genetic approaches to simultaneously delete the essential autophagy gene FIP200 (FAK family-interacting protein of 200 kDa) and the signaling adaptor p62/SQSTM1 within established murine tumors, which reveals an unexpected synergism between the autophagy pathway and p62 in driving tumor growth. Intriguingly, these observations suggest that the combined targeting of autophagy and p62 may serve as an effective approach to treat specific cancers. PMID:24888584

Leidal, Andrew M; Debnath, Jayanta

2014-06-01

170

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

171

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

PubMed

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

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

2012-05-01

172

Attenuation of tumor growth by honokiol: an evolving role in oncology.  

PubMed

Honokiol may exert significant antineoplastic effects in other systemic tumors besides skin cancers by virtue of modulation of other pathways. For instance, honokiol attenuates tumor growth in mammary malignancies. It mediates its anti-neoplastic role in these tumors by accentuating the phosphorylation of AMPK. As a result, honokiol causes significant mitigation of tumor proliferation and growth. PMID:23337821

Kapoor, S

2012-12-01

173

Stromal Cell–Derived Factor1 Promotes Cell Migration and Tumor Growth of Colorectal Metastasis  

Microsoft Academic Search

In a mouse model of established extrahepatic colo- rectal metastasis, we analyzed whether stromal cell- derived factor (SDF) 1 stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis and tumor growth in vivo, green fluorescent

Otto Kollmar; Kathrin Rupertus; Claudia Scheuer; Bastian Junker; Bettina Tilton; Martin K. Schilling; Michael D. Menger

2007-01-01

174

The role of mechanical forces in tumor growth and therapy.  

PubMed

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

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

2014-07-11

175

The role of mechanical forces in tumor growth and therapy  

PubMed Central

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

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

2014-01-01

176

Natural killer cells: role in local tumor growth and metastasis  

PubMed Central

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

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

2012-01-01

177

Ascites in poultry: recent investigations.  

PubMed

In recent years, ascites research has centred on gaining an increased understanding of pulmonary hypertension syndrome together with the potential role of primary cardiac pathologies. The impact at a cellular level of factors which trigger ascites and substances that protect against it has also been documented. Primary pulmonary hypertension has been induced when birds are exposed to hypoxia during incubation. The conditions experienced during this phase of development may impact on the ability of the bird to regulate its basal metabolic rate through endocrine signals controlled by thyroid activity. The extent of ventilation in the lung influences the ability of the bird to oxygenate haemoglobin. Ventilation/ perfusion mismatches may occur prior to or post-hatching. This factor has been studied extensively using the pulmonary artery/bronchus clamp model. At high altitude, a decreased ventilation/perfusion ratio may occur following the effective increase in physiological dead space due to the lowered oxygen tension at the level of the parabronchi. This explains the mechanism by which ascites is triggered by hypoxia in this particular situation. The effects of ascites are ameliorated by the use of beta agonists and dietary arginine, which act by increasing ventilation and blood flow in the lungs and thus correcting a ventilation/perfusion mismatch. Transient bacterial and viral infections may also influence the induction of pulmonary hypertension. The increases in blood viscosity associated with ascites are most probably a consequence of the condition rather than a cause. A bird may alleviate the effects of pulmonary hypertension by decreasing blood viscosity through inhibition of platelet function, increased erythrocyte deformability and the production of coronary relaxants. Evidence is accumulating that primary cardiac pathology may be associated with a number of ascites cases. Broilers that subsequently develop ascites, exhibit lower heart rates than their normal flock mates. Furthermore, during ascites, hypoxic broilers exhibit bradycardia as opposed to the expected tachycardia. In these cases, a tachycardia induced by feed restriction may protect the bird by raising its cardiac output. Right atrio-ventricular regurgitant flow velocities in chickens are relatively slow compared with similar regurgitant flows induced by pulmonary hypertension in other species. The conduction system in the avian heart is specialized and contains a recurrent bundle branch that innervates the right atrio-ventricular valve, thus initiating active valve closure before right ventricular systole. This predisposes the heart to right ventricular volume overload through a valvular incompetance following a failure of valvular innervation. The resultant elevated diastolic wall stress can trigger the production of angiotensin II and its converting enzyme, which mediate ventricular hypertrophy. Subclinical myocardial damage, irrespective of its cause, can be detected by the presence of troponin T in the blood. Reactive oxygen species may damage cell membranes compromising cellular function in a number of body systems. A positive correlation exists between oxidized glutathione concentrations and right ventricular weight ratio. This indicates a failure to cope with oxidative stress at the level of the respiratory membrane. It is not known if it is possible to modulate levels of antioxidants at this location and hence protect the bird. The final description of the ascites aetiology may lie in the concept of a circuit of events between the cardiac, pulmonary and vascular systems that satisfy the metabolic requirements of the bird. A deficit in one of these systems, at a level that prevents adequate compensation from other components, triggers the pathological cascade that results in the end point of clinical ascites. PMID:16147559

Currie, R J

1999-08-01

178

Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site.  

PubMed

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

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

2009-01-01

179

Suppression of ascites formation and re-accumulation associated with human ovarian cancer by an anti-VPF monoclonal antibody in vivo.  

PubMed

Ascites formation is often observed in ovarian cancer patients. Vascular permeability factor (VPF) may induce ascites formation. We established an animal model of ascites formation and re-accumulation by i.p. transplantation of a human ovarian adenocarcinoma cell line, NOS2, into nude mice. The formation of ascites was observed after 10 days of tumor inoculation and continued for up to 4 weeks. In the ascitic fluid, biologically active VPF was detected. The repeated i.p. administration of an immunoneutralizing monoclonal antibody (MAb) to VPF, MV833, significantly inhibited the formation of ascites throughout the experiments. Re-accumulation of ascites occurred quickly in control mice after aspiration of ascites and these mice died within 20 days. MV833 again inhibited the re-accumulation of ascites and significantly prolonged the life span of mice without any side effect. These results indicate that VPF plays an important role in the accumulation of ascites induced by ovarian cancer and an anti-VPF MAb is a new specific drug to suppress the formation and re-accumulation of ascites. This MAb may contribute to ameliorating quality of life of cancer patients as well as prolong their survival. PMID:10769648

Yukita, A; Asano, M; Okamoto, T; Mizutani, S; Suzuki, H

2000-01-01

180

Inhibitor of growth tumor suppressors in cancer progression  

Microsoft Academic Search

The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis,\\u000a senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression.\\u000a ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with\\u000a histone trimethylated at

Brad Piche; Gang Li

2010-01-01

181

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

182

Triptolide inhibits the growth and metastasis of solid tumors.  

PubMed

Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, was tested for its antitumor properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumor cells at extremely low concentrations (2-10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2-3 weeks inhibited the growth of xenografts formed by four different tumor cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumors that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The antitumor effect of TPL was comparable or superior with that of conventional antitumor drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumor cells that were resistant to Taxol attributable to the overexpression of the multidrug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumor cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new antitumor agent. PMID:12533674

Yang, Shanmin; Chen, Jinguo; Guo, Zhen; Xu, Xue-Ming; Wang, Luping; Pei, Xu-Fang; Yang, Jing; Underhill, Charles B; Zhang, Lurong

2003-01-01

183

Numerical simulation of hypoxic cell regulation in avascular tumor growth  

NASA Astrophysics Data System (ADS)

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

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

2013-04-01

184

3D Multi-Cell Simulation of Tumor Growth and Angiogenesis  

PubMed Central

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

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

2009-01-01

185

Prognostic significance of IL6 and IL8 ascites levels in ovarian cancer patients  

Microsoft Academic Search

Background  The acellular fraction of epithelial ovarian cancer (EOC) ascites promotes de novo resistance of tumor cells and thus supports the idea that tumor cells may survive in the surrounding protective microenvironment\\u000a contributing to disease recurrence. Levels of the pro-inflammatory cytokines IL-6 and IL-8 are elevated in EOC ascites suggesting\\u000a that they could play a role in tumor progression.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We measured

Isabelle Matte; Claudine Rancourt; Alain Piché

2011-01-01

186

Phosphatase Inhibitors Modulate the Growth-regulatory Effects of Human Tumor Necrosis Factor on Tumor and Normal Cells  

Microsoft Academic Search

ABSTRACT Tumor necrosis factor a (TNF-a) has been shown to inhibit the growth of tumor cells and stimulate the growth of certain normal cells in vitro. The mechanism,by which TNF exerts its cell growth-regulatory effects is not known. In this report, we investigated the effects of phosphatase inhibitors on the cell growth-inhibitory effects of TNF on L-929, a highly sensitive

Klara Tot pul. Sudha Agarwal; Bharat B. Aggarwal

187

Effect of Prebiotic on Gut Development and Ascites Incidence of Broilers Reared in a Hypoxic Environment1  

Microsoft Academic Search

Modern broilers have been genetically se- lected for an increased growth rate and improved feed conversion, but they are also more susceptible to ascites. Ascites occurs when there is an imbalance between avail- able oxygen and the oxygen demand of the broiler. We hypothesized that promoting neonatal gut development with a prebiotic, such as Aspergillus meal (Prebiotic-AM), would enhance gut

F. Solis; M. B. Farnell; G. Tellez; J. M. Balog; N. B. Anthony; A. Torres-Rodriguez; S. Higgins; B. M. Hargis; A. M. Donoghue

188

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

PubMed Central

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

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

2013-01-01

189

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

190

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.  

PubMed

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

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

2014-01-01

191

Acacia ferruginea inhibits tumor progression by regulating inflammatory mediators-(TNF-a, iNOS, COX-2, IL-1?, IL-6, IFN-?, IL-2, GM-CSF) and pro-angiogenic growth factor- VEGF.  

PubMed

The aim of the present investigation was to evaluate the effect of A ferruginea extract on Dalton's lymphoma ascites (DLA) induced tumours in BALB/c mice. Experimental animals received A ferruginea extract (10 mg/ kg.b.wt) intraperitoneally for 14 consecutive days after DLA tumor challenge. Treatment with extract significantly increased the life span, total white blood cell (WBC) count and haemoglobin (Hb) content and decreased the level of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (?-GT) and nitric oxide (NO) in DLA bearing ascites tumor models. In addition, administration of extract significantly decreased the tumour volume and body weight in a DLA bearing solid tumor model. The levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-?), interleukin-1 beta (IL-1?), interleukin-6 (IL-6) and granulocyte monocyte-colony stimulating factor (GM-CSF), as well as pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) were elevated in solid tumour controls, but significantly reduced by A ferruginea administration. On the other hand, the extract stimulated the production of interleukin-2 (IL-2) and interferon-gamma (IFN-?) in animals with DLA induced solid tumours. Increase in CD4+ T-cell population suggested strong immunostimulant activity for this extract. GC/MS and LC/MS analysis showed quinone, quinoline, imidazolidine, pyrrolidine, cyclopentenone, thiazole, pyrazole, catechin and coumarin derivatives as major compounds present in the A ferruginea methanolic extract. Thus, the outcome of the present study suggests that A ferruginea extract has immunomodulatory and tumor inhibitory activities and has the potential to be developed as a natural anticancer agent. PMID:23886206

Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

2013-01-01

192

Circulating angiogenic growth factor levels in mice bearing human tumors using Luminex Multiplex technology  

Microsoft Academic Search

Tumor angiogenesis is essential for tumor growth and metastasis formation. Luminex methodology was used to measure the levels of four angiogenic cytokines in cell culture medium and in the plasma of mice bearing human tumors. We obtained plasma and conditioned culture medium from 12 different human tumor cell lines. Tumor necrosis factor-alpha (TNF-f), basic fibroblast growth factor (bFGF), vascular endothelial

Kristan A. Keyes; Larry Mann; Karen Cox; Patti Treadway; Philip Iversen; Yun-Fei Chen; Beverly A. Teicher

2003-01-01

193

DNA Vaccines Designed to Inhibit Tumor Growth by Suppression of Angiogenesis  

Microsoft Academic Search

The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1–2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor’s vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel

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

2004-01-01

194

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

PubMed

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

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

2014-08-15

195

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

PubMed Central

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

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

2014-01-01

196

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

197

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

198

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

Microsoft Academic Search

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

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

2008-01-01

199

Management of ascites with hydrothorax  

SciTech Connect

Hydrothorax occurs in 5.3 percent of ascitic patients. Experience with 22 cases forms the basis of this report. Of the 22 cases, 21 were spontaneous and 1 was due to transdiaphragmatic incision. Usually fluid enters the chest through tiny defects in the diaphragm. These defects are often covered by pleuroperitoneum, but the high abdominal pressure raises a bleb on the superior surface of the diaphragm. Rupture produces hydrothorax. The ascites is often relieved with the onset of the hydrothorax. Blockage of the thoracic duct has produced chylous ascites. The thoracoabdominal communication is immediately confirmed by a scan of the chest and abdomen after intraperitoneal injection of technetium-99 colloid. The rate at which the technetium-99 enters the chest is related to the size of the defect in the diaphragm. A significant transfer should occur within 12 hours. Immediate transfer occurs with large defects. The ruptured blister on the diaphragm forms a one-way valve. Intrathoracic injection does not migrate into the peritoneal cavity. The valvular characteristics of the leak force ascitic fluid into the thorax because the differential pressure between the abdominal and pleural cavities is intensified by inspiration. If tension hydrothorax has occurred, urgent thoracocentesis and paracentesis may be required. A chest tube should not be introduced. The main principle of surgery is to supply a low resistance pathway for the return of fluid to the venous system and to eliminate the diaphragmatic defect by obliteration of the pleural space. A LeVeen peritoneovenous shunt is performed after emptying the abdomen of its fluid load. After completion of the shunt operation, the chest is emptied of fluid, and a sclerosing agent (tetracycline or nitrogen mustard) is injected into the pleural cavity. With this regime, the defect closed or was rendered insignificant in 18 of 22 patients.

LeVeen, H.H.; Piccone, V.A.; Hutto, R.B.

1984-08-01

200

Cirrhotic ascites review: Pathophysiology, diagnosis and management  

PubMed Central

Ascites is a pathologic accumulation of peritoneal fluidcommonly observed in decompensated cirrhotic states.Its causes are multi-factorial, but principally involve significant volume and hormonal dysregulation in the setting of portal hypertension. The diagnosis of ascites is considered in cirrhotic patients given a constellation of clinical and laboratory findings, and ultimately confirmed, with insight into etiology, by imaging and paracentesis procedures. Treatment for ascites is multi-modal including dietary sodium restriction, pharmacologic therapies, diagnostic and therapeutic paracentesis, and in certain cases transjugular intra-hepatic portosystemic shunt. Ascites is associated with numerous complications including spontaneous bacterial peritonitis, hepato-hydrothorax and hepatorenal syndrome. Given the complex nature of ascites and associatedcomplications, it is not surprising that it heralds increased morbidity and mortality in cirrhotic patients and increased cost-utilization upon the health-care system. This review will detail the pathophysiology of cirrhotic ascites, common complications derived from it, and pertinent treatment modalities.

Moore, Christopher M; Van Thiel, David H

2013-01-01

201

Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells.  

PubMed

Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS 40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1-5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS 40 and inhibits metastasis up to 50% in LLC and RLS 40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS 40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-? in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells. PMID:23759588

Mironova, Nadezhda L; Petrushanko, Irina Y; Patutina, Olga A; Sen'kova, Aexandra V; Simonenko, Olga V; Mitkevich, Vladimir A; Markov, Oleg V; Zenkova, Marina A; Makarov, Alexander A

2013-07-01

202

Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells  

PubMed Central

Exogenous ribonucleases are known to inhibit tumor growth via apoptosis induction in tumor cells, allowing to consider them as promising anticancer drugs for clinical application. In this work the antitumor potential of binase was evaluated in vivo and the mechanism of cytotoxic effect of binase on tumor cells was comprehensively studied in vitro. We investigated tumoricidal activity of binase using three murine tumor models of Lewis lung carcinoma (LLC), lymphosarcoma RLS40 and melanoma B-16. We show for the first time that intraperitoneal injection of binase at a dose range 0.1–5 mg/kg results in retardation of primary tumor growth up to 45% in LLC and RLS40 and inhibits metastasis up to 50% in LLC and RLS40 and up to 70% in B-16 melanoma. Binase does not exhibit overall toxic effect and displays a general systemic and immunomodulatory effects. Treatment of RLS40-bearing animals with binase together with polychemotherapy revealed that binase decreases the hepatotoxicity of polychemotherapy while maintaining its antitumor effect. It was demonstrated that the cytotoxic effect of binase is realized via the induction of the intrinsic and extrinsic apoptotic pathways. Activation of intrinsic apoptotic pathway is manifested by a drop of mitochondrial potential, increase in calcium concentration and inhibition of respiratory activity. Subsequent synthesis of TNF-? in the cells under the action of binase triggers extrinsic apoptotic pathway through the binding of TNF with cell-death receptors and activation of caspase 8. Thus binase is a potential anticancer therapeutics inducing apoptosis in cancer cells.

Mironova, Nadezhda L.; Petrushanko, Irina Y.; Patutina, Olga A.; Sen'kova, Aexandra V.; Simonenko, Olga V.; Mitkevich, Vladimir A.; Markov, Oleg V.; Zenkova, Marina A.; Makarov, Alexander A.

2013-01-01

203

Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells  

Microsoft Academic Search

Epidermal growth factor receptor (EGFR) targeting agents such as kinase inhibitors reduce tumor growth and progression. We have previously reported that EGFR is not only expressed by the tumor cells but by the tumor endothelial cells (EC) as well (Amin, D. N., Hida, K., Bielenberg, D. R., Klagsbrun, M., 2006. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but

Dhara N. Amin; Diane R. Bielenberg; Eugene Lifshits; John V. Heymach; Michael Klagsbrun

2008-01-01

204

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 first yea...

A. Shaw W. Bushman

2006-01-01

205

Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C.  

PubMed

Recent studies have revealed that the maturation state of vessels in tumors, in addition to vascularity, is a critical determinant of tumor growth. The role of oxygen-dependent signaling pathways in hypoxia-stimulated angiogenesis is well established, however, little is known about their impact on vessel maturation in tumors. Here, we have studied the function of the cellular oxygen sensor, factor inhibiting HIF-1 (FIH), which controls the activity of hypoxia-inducible factor-1. FIH silencing in mouse LM8 osteosarcoma stimulated angiogenesis but did not influence tumor growth. In contrast, FIH overexpression led to increased pericyte coverage of the tumor vasculature, reduced vessel leakiness and enhanced tumor growth. Vessel maturation was paralleled by up-regulation of platelet-derived growth factor (PDGF)-C in tumors and expression of PDGF receptor-? on pericytes. Ablation of PDGF-C in FIH-overexpressing tumor cells reduced pericyte coverage and tumor growth. Our data suggest that FIH-mediated PDGF-C induction in LM8 osteosarcoma stimulates the recruitment of PDGFR-? positive pericytes to the tumor vasculature, leading to vessel maturation and enhanced tumor growth. PMID:22095574

Kuzmanov, Aleksandar; Wielockx, Ben; Rezaei, Maryam; Kettelhake, Antje; Breier, Georg

2012-09-01

206

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

207

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

208

Preferential Sites of Growth of Human Tumors in Nude Mice following Subcutaneous Transplantation1  

Microsoft Academic Search

The growth characteristics and biological behavior of human tumors transplanted s.c. into two different anatomical regions of nude mice were studied. It was observed that tumors trans planted in the anterior lateral thoracic wall grew faster than did tumors transplanted in the posterior aspect of the trunk. Ante riorly growing tumors, in contrast to the posteriorly transplanted ones, were better

Aikaterini A. Kyriazis; Andreas P. Kyriazis

209

Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis  

PubMed Central

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

Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar

2011-01-01

210

In vivo tumor inhibitory and radiosensitizing effects of an Indian medicinal plant, Plumbago rosea on experimental mouse tumors.  

PubMed

Tumor growth inhibitory and radiosensitizing effects of the alcoholic root extract of P. rosea was studied on experimental mouse tumors, S-180 solid tumor and Ehrlich ascites carcinoma in vivo. Intraperitoneal injection of 50 mg/kg of Plumbago extract (PE) for 10 days starting from 24 hr after intradermal inoculation of S-180 cells in BALB/c mice produced about 16% complete response (CR). The CR% increased with increase in drug dose, to 50% at 100 mg/kg for 10 days. As 100 mg/kg produced toxic side effects, lower doses were used with other treatment modalities, radiation (RT) and hyperthermia (HT). Treatment of 50 mm3 tumor with PE (75 mg/kg) for 10 days with local RT (10 Gy) and/or HT (43 degrees C, 30 min) subadditively increased the CR% and tumor free survival. The combination also significantly reduced the growth rates of uncured tumors. The PE significantly reduced the tumor glutathione content and this effect was markedly enhanced by the combination of the three modalities. PE alone was not very effective in preventing the growth of Ehrlich ascites carcinoma in Swiss mice, though it increased mean survival time and ILS% of the mice. But with radiation it produced a synergistic effect in increasing the tumor inhibition and 120 day animal survival from 10% to 50%. The results demonstrate that though PE may have only a weak antitumor effect, it may be a good candidate for use with radiation to enhance the tumor killing effect. PMID:7959931

Devi, P U; Solomon, F E; Sharada, A C

1994-08-01

211

Human choriocarcinomas: placental growth factor-dependent preclinical tumor models.  

PubMed

Choriocarcinomas are a rare form of cancer that develops in the uterus from tissue which would normally become the placenta. Choriocarcinomas are a trophoblastic gestational disease and have been studied largely to investigate conditions related to pregnancy such as preeclampsia. Choriocarcinomas are highly angiogenic and produce high levels of placental growth factor (PlGF) to promote the development of blood vessels. Upregulation of PlGF expression also occurs during the development of other human malignancies such as breast cancer and melanoma. Both tumor specimens and plasma samples have higher levels of PlGF than normal tissues. Hence, PlGF has emerged as a valid target for anti-angiogenic therapy. The cell lines BeWo, JAR and JEG-3, derived from human choriocarcinomas, were investigated in vitro and in vivo for suitability as PlGF-dependent models. BeWo, JAR and JEG-3 cells were characterized in culture and were implanted into immunodeficient mice to generate subcutaneous tumors. The PlGF and VEGF angiogenic profiles of the choriocarcinoma cells and tumors were investigated by ELISA and by immunohistochemical methods. Double immunofluorescence methods were applied to choriocarcinoma xenograft sections to characterize the cellular components of the blood vessels. sFLT01, a fusion protein that neutralizes PlGF, was assessed in cell culture experiments and xenograft studies. The novel results presented here validate the importance of human choriocarcinoma cell lines and xenografts in further exploring the role of PlGF in tumor angiogenesis, for evaluating PlGF as an anti-angiogenic target, and for developing therapies that may provide clinical benefit. PMID:22075622

Bagley, Rebecca G; Ren, Yi; Kurtzberg, Leslie; Weber, William; Bangari, Dinesh; Brondyk, William; Teicher, Beverly A

2012-02-01

212

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

PubMed Central

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

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

2012-01-01

213

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

214

Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors  

Microsoft Academic Search

Angiogenesis is required for the progres- sion of tumors from a benign to a malig- nant phenotype and for metastasis. Malig- nant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Here it is shown that several tumor types express VEGF receptors (VEGFRs) and that inhibition

Rizwan Masood; Jie Cai; Tong Zheng; D. Lynne Smith; David R. Hinton; Parkash S. Gill

2001-01-01

215

Extracellular Matrix Metalloproteinase Inducer Stimulates Tumor Angiogenesis by Elevating Vascular Endothelial Cell Growth Factor and Matrix Metalloproteinases  

Microsoft Academic Search

Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase in- ducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN

Yi Tang; Marian T. Nakada; Prabakaran Kesavan; Francis McCabe; Hillary Millar; Patricia Rafferty; Peter Bugelski

2005-01-01

216

Chylous ascites due to constrictive pericarditis  

Microsoft Academic Search

Chylous ascites due to constrictive pericarditis is an extremely rare clinical entity, possibly caused by the augmented lymph production and high impedance to lymph drainage due to central venous hypertension. The authors describe a patient with chylous ascites caused by constrictive pericarditis in the absence of lymphatic obstruction. Cardiac catheterization is essential for the confirmation of accurate diagnosis of constrictive

Sema Güneri; Cem Nazli; Ozan Kinay; Onder Kirimli; Cem Mermut; Eyüp Hazan

2000-01-01

217

Treatment of Ascites: Old and New Remedies  

Microsoft Academic Search

Ascites is a common complication of chronic liver disease. Treatment of the underlying liver disease with modalities such as abstinence from alcohol in Laennec’s cirrhosis, phlebotomy in hemochromatosis, copper removal in Wilson’s disease, and steroids in autoimmune liver disease, can improve survival in many patients. In addition, therapy of ascites alleviates the symptoms and improves the quality of life of

Paolo Inturri; Agnese Graziotto; Lorenzo Rossaro

1996-01-01

218

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

219

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

PubMed Central

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

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

2004-01-01

220

Antitumor and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma in vivo.  

PubMed

The antitumor and radiosensitizing effects of withaferin A (WA), a steroidal lactone from Withania somnifera, was studied on Ehrlich ascites carcinoma in vivo. The acute LD50(14) for WA in Swiss mice was approximately 80 mg/kg. Twenty-four hours after i.p. inoculation of 10(6) tumor cells, WA was injected i.p. at different dose fractions (5 or 7.5 mg/kg x 8, 10 mg/kg x 5, 20 or 30 mg/kg x 2) with or without abdominal gamma irradiation (RT, 75. Gy) after the first drug dose. Increase in life span and tumor-free survival were studied up to 120 days. The drug inhibited tumor growth and increased survival, which was dependent on the WA dose per fraction rather than the total dose. Combination of RT with all the drug schedules increased tumor cure and tumor-free survival, the best effect seen after 2 fractions of 30 mg/kg each. In another experiment WA was given as 2 (40 mg/kg x 2), 3 (30 mg/kg x 3) or 4 (20 mg/kg x 4) fractions at 5, 7 or 10 days after tumor inoculation with or without RT after the first drug dose. At 7 and 10 days after inoculation the drug was effective only at 40 mg/kg x 2, but with RT 30 mg/kg x 3 produced an equal effect (20% survival) on 7 day old tumors. PMID:8619948

Sharada, A C; Solomon, F E; Devi, P U; Udupa, N; Srinivasan, K K

1996-01-01

221

Synergistic effects of Endostar combined with ?-elemene on malignant ascites in a mouse model  

PubMed Central

To explore an effective combination therapy for malignant ascites, the therapeutic value of the combination of Endostar, a modified recombinant human endostatin, and ?-elemene, an active component of a traditional Chinese herb, in an H22 mouse malignant ascites model was investigated. The optimal dose combination of Endostar and ?-elemene was determined by evaluating the inhibition of ascites volume and increase in the survival rate of the mice. Other therapeutic effects and the underlying mechanisms were investigated under the optimal dose combination (8 mg/kg Endostar plus 100 mg/kg ?-elemene). The mice were randomly divided into four treatment groups and received intraperitoneal injection once a day for eight days: control (0.9% normal saline), Endostar (8 mg/kg), ?-elemene (100 mg/kg) or optimal dose combination (8 mg/kg Endostar plus 100 mg/kg ?-elemene), respectively. The results of this study revealed that the combination therapy had significant synergistic effects on the inhibition of ascites formation and a deceased number of tumor cells and protein levels in ascites compared with the results of treatment with a single agent. A decreased peritoneal microvascular permeability and reduction in VEGF, MMP-2 and hypoxia inducible factor 1? (HIF1?) was noted in the combination group, when compared with single agent treatment. These studies found that in the ascitic tumor cells, the protein levels of VEGF and MMP-2, as well as levels of VEGF mRNA, were significantly inhibited by the combination therapy. The potentiating effects of the combination of Endostar with ?-elemene suggest that this novel therapy may yield an effective therapy for the treatment of malignant ascites.

JIANG, ZI-YU; QIN, SHU-KUI; YIN, XIAO-JIN; CHEN, YA-LI; ZHU, LIN

2012-01-01

222

Differential remodeling of cadherins and intermediate cytoskeletal filaments influence microenvironment of solid and ascitic sarcoma.  

PubMed

Different forms of sarcoma (solid or ascitic) often pose a critical medical situation for pediatric or adolescent group of patients. To date, predisposed genetic anomalies and related changes in protein expression are thought to be responsible for sarcoma development. However, in spite of genetic abnormality, role of tumor microenvironment is also indispensable for the evolving neoplasm. In our present study, we characterized the deferentially remodeled microenvironment in solid and ascitic tumors by sequential immunohistochemistry and flowcytometric analysis of E-cdaherin, N-cadherin, vimentin, and cytokeratin along with angiogenesis and metastasis. In addition, we considered flowcytometric apoptosis and CD133 positive cancer stem cell analysis. Comparative hemogram was also considered as a part. Our investigation revealed that both types of tumor promoted neovascularization over time with sign of local inflammation. Invasion of neighboring skeletal muscle by solid sarcoma was more frequent than its ascitic counterpart. In contrary, rapid and earlier cadherin switching (E-cadherin to N-cadherin) in ascitic sarcoma made them more aggressive than that of solid sarcoma and helped to early metastasize distant tissue like liver through the hematogenous route. Differential cadherin switching and infidelity of cytokeratin expression in Vimentin positive sarcoma also influenced the behavior of ascitic CD133+ cancer initiating cell pool with respect to CD133+ cells housed in solid sarcoma. Therefore our study concludes that differential cadherin switching program and infidelity of intermediate filaments in part, sharply discriminate the severity and metastatic potentiality of either type of sarcoma accompanying with CD133+ cellular repertoire. Besides, tumor phenotype-based dichotomous cadherin switching program could be exploited as a future drug target to manage decompensated malignant ascitic and solid sarcoma. PMID:23861106

Chaklader, Malay; Pan, Ankita; Law, Aditya; Chattopadhayay, Sukalpa; Chatterjee, Ritam; Law, Sujata

2013-10-01

223

Targeting Gli transcription activation by small molecule suppresses tumor growth.  

PubMed

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy. PMID:23686308

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

2014-04-17

224

Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth.  

PubMed

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

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

2013-12-01

225

Phosphocaveolin-1 Enforces Tumor Growth and Chemoresistance in Rhabdomyosarcoma  

PubMed Central

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

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

2014-01-01

226

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

227

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth.  

PubMed

Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy. PMID:15806170

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

2005-06-01

228

Spontaneous Resolution of Fetal and Neonatal Ascites after Birth  

PubMed Central

Fetal ascites is an uncommon abnormality usually reported in relation to non- immunological causes. The prospect for fetal and neonatal mortality is high, particularly when the ascites develops before 24 weeks of gestation. The diminution of severe fetal ascites without intrauterine management, especially with an uncomplicated neonatal outcome, is unusual. We report a case of isolated fetal ascites detected at 20 weeks' gestation. All investigations carried out were normal. Consecutive ultrasound examination showed ascites at 20 weeks’ gestation. A follow-up ultrasound examination at 6 months of age revealed complete recovery from the ascites. Spontaneous resolution of fetal ascites, with a good prognosis, can occur in cases with an idiopathic aetiology.

Abdellatif, Mohamed; Alsinani, Siham; Al-Balushi, Zenab; Al-Dughaishi, Tamima; Abuanza, Mazen; Al-Riyami, Nihal

2013-01-01

229

Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor.  

PubMed Central

Decorin, a small leucine-rich proteoglycan, is capable of suppressing the growth of various tumor cell lines when expressed ectopically. In this report, we investigated the biochemical mechanism by which decorin inhibits cell cycle progression. In A431 squamous carcinoma cells, decorin proteoglycan or protein core induced a marked growth suppression, when either exogenously added or endogenously produced by a transgene. Decorin caused rapid phosphorylation of the EGF receptor and a concurrent activation of mitogen-activated protein (MAP) kinase signal pathway. This led to a protracted induction of endogenous p21, a potent inhibitor of cyclin-dependent kinases, and ultimate cell cycle arrest. Biglycan, a related proteoglycan, had no effect. Moreover, decorin activated the EGF receptor/MAP kinase/ p21 axis in cell lines of various histogenetic backgrounds. These results provide the first evidence that EGF and decorin converge functionally to regulate the cell cycle through activation of a common pathway which ultimately leads to growth suppression.

Moscatello, D K; Santra, M; Mann, D M; McQuillan, D J; Wong, A J; Iozzo, R V

1998-01-01

230

Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations.  

PubMed

KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations. PMID:21193546

Fischer, Marcus; Yen, Wan-Ching; Kapoun, Ann M; Wang, Min; O'Young, Gilbert; Lewicki, John; Gurney, Austin; Hoey, Timothy

2011-03-01

231

Predicting mechanism of biphasic growth factor action on tumor growth using a multi-species model with feedback control  

PubMed Central

A large number of growth factors and drugs are known to act in a biphasic manner: at lower concentrations they cause increased division of target cells, whereas at higher concentrations the mitogenic effect is inhibited. Often, the molecular details of the mitogenic effect of the growth factor are known, whereas the inhibitory effect is not. Hepatoctyte Growth Factor, HGF, has recently been recognized as a strong mitogen that is present in the microenvironment of solid tumors. Recent evidence suggests that HGF acts in a biphasic manner on tumor growth. We build a multi-species model of HGF action on tumor cells using different hypotheses for high dose-HGF activation of a growth inhibitor and show that the shape of the dose-response curve is directly related to the mechanism of inhibitor activation. We thus hypothesize that the shape of a dose-response curve is informative of the molecular action of the growth factor on the growth inhibitor.

Konstorum, Anna; Sprowl, Stephanie A.; Waterman, Marian L.; Lander, Arthur D.; Lowengrub, John S.

2014-01-01

232

Increased intestinal macromolecular permeability and urine nitrite excretion associated with liver cirrhosis with ascites  

Microsoft Academic Search

AIM: To determine intestinal permeability, the serum tumor necrosis factor (TNF)-? level and urine nitric oxide (NO) metabolites are altered in liver cirrhosis (LC) with or without ascites. METHODS: Fifty-three patients with LC and 26 healthy control subjects were enrolled in the study. The intestinal permeability value is expressed as the percentage of polyethylene glycol (PEG) 400 and 3350 retrieval

Soong Lee; Seung-Cheol Son; Moon-Jong Han; Woo-Jin Kim; Soo-Hyun Kim; Hye-Ran Kim; Woo-Kyu Jeon; Ki-Hong Park; Myung-Geun Shin

2008-01-01

233

/sup 99m/Tc-methylene diphosphonate accumulation in ascitic fluid due to neoplasm  

SciTech Connect

/sup 99m/Tc-methylene diphosphonate (MDP) was found to accumulate in the abdomen in 7 patients with ascites due to a primary tumor of the ovary, testis, stomach, or urethra, leukemia, or lymphoma. This finding should strongly suggest malignancy.

Gordon, L.; Schabel, S.I.; Holland, R.D.; Cooper, J.F.

1981-06-01

234

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

Microsoft Academic Search

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

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

2005-01-01

235

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

PubMed Central

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

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

2007-01-01

236

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

PubMed Central

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

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

2013-01-01

237

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

PubMed

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

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

2014-01-30

238

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

PubMed

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

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

2014-03-01

239

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

PubMed

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

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

2014-07-29

240

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

PubMed Central

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

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

2012-01-01

241

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

PubMed Central

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

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

2013-01-01

242

A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) induces both angiogenesis and an increase in vascular permeability, 2 processes that are considered to be important for both tumor growth and the delivery of drugs to the site of tumors. This study demonstrates that transmembrane expression of tumor necrosis factor (tmTNF) is up-regulated in the endothelium of a murine methylcholan- threne (meth A)-induced sarcoma

Matthias Clauss; Cord Sunderkotter; Baldur Sveinbjornsson; Stefan Hippenstiel; Antje Willuweit; Michael Marino; Elvira Haas; Rolf Seljelid; Peter Scheurich; Norbert Suttorp; Matthias Grell; Werner Risau

2001-01-01

243

Struma Ovarii with Elevated Ca-125 Levels and Ascites Mimicking Advanced Ca Ovary  

PubMed Central

Struma ovarii is uncommon tumor of ovary which can mimic as advanced carcinoma of ovary. Thyroid tissue is relatively frequent constituent of mature ovarian teratoma. Case of struma ovarii masquerading as cancer of ovary in a female aged 63 yrs showing complex large unilateral multilocular adnexal mass with elevated CA 125 (more than 1721 IU/L) and massive ascites mislead treating surgeons for long time. Clinicians were virtually clueless about preoperative diagnosis. Combination of ascites has been seen in one third cases but association with raised CA 125 is rare(only 8-10 cases so far). This case developed hypothyroidism one week after surgery.

Sinha, Navin Kumar

2014-01-01

244

Struma ovarii with elevated ca-125 levels and ascites mimicking advanced ca ovary.  

PubMed

Struma ovarii is uncommon tumor of ovary which can mimic as advanced carcinoma of ovary. Thyroid tissue is relatively frequent constituent of mature ovarian teratoma. Case of struma ovarii masquerading as cancer of ovary in a female aged 63 yrs showing complex large unilateral multilocular adnexal mass with elevated CA 125 (more than 1721 IU/L) and massive ascites mislead treating surgeons for long time. Clinicians were virtually clueless about preoperative diagnosis. Combination of ascites has been seen in one third cases but association with raised CA 125 is rare(only 8-10 cases so far). This case developed hypothyroidism one week after surgery. PMID:24783110

Sinha, Navin Kumar

2014-03-01

245

Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling.  

PubMed

Patients with neurofibromatosis type 1 (NF1), one of the most common genetic disease affecting the nervous system, develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). Studies of human tumors and newly developed transgenic mouse models indicate that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that development of these peripheral nerve sheath tumors involves mutations of multiple tumor suppressor genes. However, it is widely held that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that dysregulated growth factor signaling cooperates with these mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this review, we discussed findings demonstrating that a loss of NF1 tumor suppressor gene function in neoplastic Schwann cells is a key early step in neurofibroma formation and that progression from neurofibroma to MPNST is associated with abnormalities of additional tumor suppressor genes, including p53, INK4A, andp27(kip1). In Part II of this review, we consider evidence that dysregulated signaling by specific growth factors and growth factor receptors promotes the proliferation, migration, and survival of neoplastic Schwann cells in neurofibromas and MPNSTs. PMID:15715079

Carroll, Steven L; Stonecypher, Mark S

2005-01-01

246

Screening and Identification of Biomarkers in Ascites Related to Intrinsic Chemoresistance of Serous Epithelial Ovarian Cancers  

PubMed Central

Objective The ability to predict responses to chemotherapy for serous epithelial ovarian cancer (EOC) would be valuable since intrinsically chemoresistant EOC patients (persistent or recurrent disease within 6 months) gain little benefit from standard chemotherapy. The aim of this study was to screen and identify distinctive biomarkers in ascites of serous EOC associated with intrinsic chemoresistance. Methods Protein samples from ascites of 12 chemosensitive and 7 intrinsically chemoresistant serous EOC patients were analyzed using two-dimensional fluorescence difference in gel electrophoresis (2-D DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Furthermore, the identified proteins were validated by ELISA in ascites samples from 19 chemosensitive and 9 intrinsically chemoresistant EOC patients. Results The number of spots detected in all 2-D DIGE gels ranged from 1523–1711 using DeCyder software analysis. Thirty-four spots were differentially expressed based on the criteria of an average ratio of more than 1.5 and a student t-test P value <0.05. After MALDI-TOF/TOF MS analysis, 11 differentially expressed proteins, including 3 up-regulated and 8 down-regulated proteins, in ascites of chemoresistant tumors were successfully identified. Of the four selected proteins (ceruloplasmin, apoliprotein A-IV, transthyretin and haptoglobin) in ascites tested by ELISA, only ceruloplasmin was present at significantly different levels between the chemoresistant and chemosensitive ascites samples with average concentrations of 192.2 µg/ml and 157.5 µg/ml, respectively (P?=?0.001). Conclusion The significantly up-regulated level of ceruloplasmin in the ascites fluid of intrinsic chemoresistant serous EOC patients suggests its potential as a prognostic biomarker for responses to chemotherapy. This finding prompts further investigation with a larger study in order to validate the clinical utility of ceruloplasmin.

Liu, Jihong; Zheng, Minghui; Feng, Yanling; Hu, Kunhua; Huang, Yongwen; Huang, Qidan

2012-01-01

247

S100A9 Interaction with TLR4 Promotes Tumor Growth  

PubMed Central

By breeding TRAMP mice with S100A9 knock-out (S100A9?/?) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9?/? and TLR4?/?, but not in RAGE?/? animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGF? expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.

Kallberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Bjork, Per; Wikstrom, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

2012-01-01

248

Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner.  

PubMed

Rearrangement of the skin during wound healing depends on plasmin and plasminogen, which serve to degrade fibrin depositions in the provisional matrix and thereby facilitate keratinocyte migration. In the current study, we investigated whether plasmin and plasminogen likewise played a role during the development of skin cancer. To test this, we set up a chemically induced skin tumor model in a cohort of mice and found that skin tumor growth in Plg(-/-) male mice was reduced by 52% compared with wild-type controls. Histological analyses suggested that the growth-restricting effect of plasminogen deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted by superimposing heterozygous fibrinogen deficiency on Plg(-/-) mice. Tumors derived from these Fib(-/+);Plg(-/-) mice displayed a significantly decreased level of tumor thrombosis compared with Plg(-/-) mice. In summary, these data indicate that plasmin-driven fibrinolysis facilitates tumor growth by maintaining patency of the tumor vasculature. PMID:22815383

Hald, Andreas; Eickhardt, Hanne; Maerkedahl, Rasmus Baadsgaard; Feldborg, Christina Winther; Egerod, Kristoffer Lihme; Engelholm, Lars Henning; Laerum, Ole Didrik; Lund, Leif Røge; Rønø, Birgitte

2012-11-01

249

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

PubMed

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

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

2013-12-01

250

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.

251

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

NASA Astrophysics Data System (ADS)

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

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

2014-05-01

252

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

PubMed

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

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

2011-09-15

253

Hyperbolastic modeling of tumor growth with a combined treatment of iodoacetate and dimethylsulphoxide  

PubMed Central

Background An understanding of growth dynamics of tumors is important in understanding progression of cancer and designing appropriate treatment strategies. We perform a comparative study of the hyperbolastic growth models with the Weibull and Gompertz models, which are prevalently used in the field of tumor growth. Methods The hyperbolastic growth models H1, H2, and H3 are applied to growth of solid Ehrlich carcinoma under several different treatments. These are compared with results from Gompertz and Weibull models for the combined treatment. Results The growth dynamics of the solid Ehrlich carcinoma with the combined treatment are studied using models H1, H2, and H3, and the models are highly accurate in representing the growth. The growth dynamics are also compared with the untreated tumor, the tumor treated with only iodoacetate, and the tumor treated with only dimethylsulfoxide, and the combined treatment. Conclusions The hyperbolastic models prove to be effective in representing and analyzing the growth dynamics of the solid Ehrlich carcinoma. These models are more precise than Gompertz and Weibull and show less error for this data set. The precision of H3 allows for its use in a comparative analysis of tumor growth rates between the various treatments.

2010-01-01

254

Pathophysiology and management of pediatric ascites  

Microsoft Academic Search

Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal\\u000a factors. The main pathophysiologic theories of ascites formation include the ‘underfill,’ ‘overflow,’ and peripheral arterial\\u000a vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic\\u000a thread: The body senses a decreased effective arterial blood volume,

Mahmoud Sabri; Miguel Saps; John M. Peters

2003-01-01

255

Chylous Ascites Following Treatment for Gynecologic Malignancies  

Microsoft Academic Search

Background. Chylous ascites is a rare complication following abdominal radiation or para-aortic lymph node dissection in the management of gynecologic malignancies. Treatment options include dietary restriction with addition of medium-chain triglycerides, serial paracenteses, total parenteral nutrition, and somatostatin. Current opinion advocates that surgical exploration and peritoneo-venous shunts be reserved for refractory cases.Cases. Two patients developed chylous ascites, one after completion

Tom P. Manolitsas; Shahab Abdessalam; Jeffrey M. Fowler

2002-01-01

256

Chylous ascites following abdominal aortic surgery  

Microsoft Academic Search

Three patients, two women, one man (mean age 74 years), who had abdominal aortic aneurysms (2) or aortobifemoral surgery (1),\\u000a developed chylous ascites postoperatively. They were studied to determine their clinical course and develop a plan for management\\u000a of this complication. In each patient, the ascites was not manifest until abdominal swelling developed two weeks after operation,\\u000a and the problem

Russell A. Williams; John Vetto; William Quifiones-Baldrich; Frederic S. Bongard; Samuel E. Wilson

1991-01-01

257

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

258

p62/SQSTM1 synergizes with autophagy for tumor growth in vivo.  

PubMed

Autophagy is crucial for cellular homeostasis and plays important roles in tumorigenesis. FIP200 (FAK family-interacting protein of 200 kDa) is an essential autophagy gene required for autophagy induction, functioning in the ULK1-ATG13-FIP200 complex. Our previous studies showed that conditional knockout of FIP200 significantly suppressed mammary tumorigenesis, which was accompanied by accumulation of p62 in tumor cells. However, it is not clear whether FIP200 is also required for maintaining tumor growth and how the increased p62 level affects the growth in autophagy-deficient FIP200-null tumors in vivo. Here, we describe a new system to delete FIP200 in transformed mouse embryonic fibroblasts as well as mammary tumor cells following their transplantation and show that ablation of FIP200 significantly reduced growth of established tumors in vivo. Using similar strategies, we further showed that either p62 knockdown or p62 deficiency in established FIP200-null tumors dramatically impaired tumor growth. The stimulation of tumor growth by p62 accumulation in FIP200-null tumors is associated with the up-regulated activation of the NF-?B pathway by p62. Last, we showed that overexpression of the autophagy master regulator TFEB(S142A) increased the growth of established tumors, which correlated with the increased autophagy of the tumor cells. Together, our studies demonstrate that p62 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy. PMID:24888590

Wei, Huijun; Wang, Chenran; Croce, Carlo M; Guan, Jun-Lin

2014-06-01

259

Antibody-guided irradiation of malignant ascites in ovarian cancer: a new therapeutic method possessing specificity against cancer cells  

SciTech Connect

Immunocytology of ascitic fluid of a patient with ovarian cancer demonstrated reactivity with two tumor-associated monoclonal antibodies, AUA1 and HMFG2. AUA1 radiolabeled with 48.6 mCi /sup 131/I was given intraperitoneally. There was a reduction in the rate of reaccumulation of ascites. Cytology of recurrent ascites revealed reactivity with antibody HMFG2 but not AUA1. The patient was further treated intraperitoneally with 39.0 mCi /sup 131/I-labeled HMFG2. There has been no reaccumulation of ascites. It is concluded that antibody-guided irradiation may be an effective treatment of malignant ascites secondary to ovarian cancer. Furthermore, this case illustrates the specificity of antibody interactions in the mediation of therapeutic effect and the possibility of tumor selection after irradiation with a single monoclonal antibody. If specificity plays a role, all major specificities should be covered by an appropriate panel of radioactively labeled antibodies. It is recommended that for comprehensive therapy of malignant ascites secondary to ovarian cancer, a mixture of antibodies such as HMFG2 and AUA1 should be used.

Epenetos, A.A.; Hooker, G.; Krausz, T.; Snook, D.; Bodmer, W.F.; Taylor-Papadimitriou, J.

1986-09-01

260

[Percutaneous radiofrequency ablation with artificial ascites for hepatocellular carcinoma adjacent to the diaphragm].  

PubMed

Surgical resection is the first-line curative treatment of hepatocellular carcinoma (HCC). However most patients are unable to undergo surgical resection because of advanced tumoral stage, severe liver dysfunction or poor clinical status. Therefore, image-guided tumor ablation techniques have been introduced for the treatment of unresectable HCC. Among them, radiofrequency ablation (RFA) has been demonstrated to be an effective alternative curative therapy. However, local ablative therapy for tumors located close to structures such as the diaphragm or gastrointestinal tract is technically challenging because of the risk of collateral thermal damage to nearby structures or incomplete treatment of the HCC resulting from poor visibility on sonography. The introduction of artificial ascites can separate adjacent organs from the tumor and improve the sonic window. The aim of this study was to evaluate the feasibility, safety and efficacy of RFA with artificial ascites for HCC adjacent to the diaphragm. PMID:21059478

Adán Merino, Luisa; Olveira Martín, Antonio; Pérez Robledo, Juan Pedro; Prieto, Isabel; Gea Rodriguez, Francisco; Castillo Grau, Pilar; Martín Arranz, Eduardo; Alonso Gamarra, Eduardo; Mora Sanz, Pedro

2010-12-01

261

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

PubMed

Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8(+) T-cell responses. Furthermore, we found that IL-17A was produced mainly by V?4 ?? T cells, insofar as depleting V?4 ?? T cells reduced tumor growth, whereas adoptive transfer of V?4 ?? T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing ?? T cells via production of IL-1? and IL-23. Conversely, IL-17A could also enhance production of IL-1? and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among ?? T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. PMID:24525743

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

2014-04-01

262

[The inhibitory effect of intraperitoneal hyperthermic and hypotonic chemotherapy on ascites cancer cells in mice].  

PubMed

To study the effect of inhibition of intraperitoneal hyperthermic hypotonic chemotherapy on the ascites cacer cells, LACA mice were given intraperitoneal injection of H22 cancer cells (2 x 10(7) tumor cell, each mouse). At 24 hours after the cancer injection, intraperitoneal simple hyperthermic (43 C) hypotonic fluid group (I), isotonic fluid group (II), cis-Diamminodichloroplatinum (DDP) group (IV) and hyperthermic hypotonic fluid perfusion combined with DDP group (V) were processed. The results showed that cancer cells in LACA mice peritoneal cavity were seriously damaged, the ascites growing was obviously inhibited, and the survival days of LACA mice were prolonged in all groups; however, the intraperitoneal hyperthermic hypotonic fluid perfusion with DDP group (V) presented greater effect compared with the other groups. This might be a new therapeutic procedure for the prevention and treatment of cancer ascites in the patients with digestive tract malignancies. PMID:7657323

Chen, Z; Peng, D; Tan, J

1995-03-01

263

Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody.  

PubMed

Angiogenesis is essential for successful tumor growth in vivo. There is a hypothesis that tumors secrete a putative tumor angiogenic factor (TAF) to facilitate blood vessel formations. Although several endothelial growth factors have been reported, it remains unclear whether these factors function as TAF in vivo. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is a vascular endothelial mitogen that can increase blood vessel permeability. We have established a cell line (HeLa/v5), which secretes VEGF/VPF, by transfection of human VEGF/VPF cDNA. HeLa/v5 showed higher angiogenic activity, taken/planted ratio and tumor growth rate than the control transformant (HeLa/c), when they were implanted to nude mice. Administration of a polyclonal antibody, which neutralizes the mitogenic activity of VEGF/VPF in vitro, to the tumor implanted nude mice suppressed the in vivo growth of HeLa/v5. Furthermore, all 8 tumor cell lines we tested secrete VEGF/VPF into culture media. Our findings indicate that VEGF/VPF is a tumor angiogenic factor. PMID:7688963

Kondo, S; Asano, M; Suzuki, H

1993-08-16

264

The role of recombinant epidermal growth factor and serotonin in the stimulation of tumor growth in a SCCHN xenograft model  

PubMed Central

One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0 phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0-arresting cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit 562 cells were injected into NMRI-Foxn1nu mice. Treatment was performed with 15 ?g murine or human EGF, or 200 ?g serotonin. The control mice were treated with Lactated Ringer’s solution (5 mice/group). Tumor size was measured on days 4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN tumors.

GEISSLER, CHRISTIN; HAMBEK, MARKUS; ECKARDT, ANNE; ARNOLDNER, CHRISTOPH; DIENSTHUBER, MARC; STOVER, TIMO; WAGENBLAST, JENS

2012-01-01

265

Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization.  

PubMed

Notch signaling plays an important role in vascular development and tumor angiogenesis. It has been shown that disruption of Dll4-triggered Notch signal activation effectively inhibits tumor growth, but this treatment also results in the formation of vascular neoplasms. In this study, we investigate the effects of over-expressing Notch ligand Dll1 in B16 melanoma cells on tumor cell proliferation and tumor growth in vitro and in vivo. Our results showed that over-expression of Dll1 could activate Notch signaling in tumor cells, and promote tumor cell proliferation in vitro. In contrast, growth of Dll1-over-expressing tumors in vivo was reduced, due to abnormal tumor vessel formation. Impaired tumor vasculature enhanced hypoxia and necrosis in tumor tissues, leading to retarded tumor growth. These results suggest that activation of Notch signaling may serve as an anti-angiogenesis strategy in the treatment of malignant tumors. PMID:21752535

Zhang, Jian-Ping; Qin, Hong-Yan; Wang, Li; Liang, Liang; Zhao, Xing-Cheng; Cai, Wei-Xia; Wei, Ya-Ning; Wang, Chun-Mei; Han, Hua

2011-10-28

266

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis.  

PubMed

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

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

2014-09-01

267

Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma.  

PubMed

Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents. PMID:23395639

Blagoev, Krastan B; Wilkerson, Julia; Stein, Wilfred D; Motzer, Robert J; Bates, Susan E; Fojo, A Tito

2013-02-21

268

Block of purinergic P2X7R inhibits tumor growth in a C6 glioma brain tumor animal model.  

PubMed

We examined the expression and pharmacological modulation of the purinergic receptor P2X7R in a C6 glioma model. Intrastriatal injection of C6 cells induced a time-dependent growth of tumor; at 2 weeks postinjection immunohistochemical analysis demonstrated higher levels of P2X7R in glioma-injected versus control vehicle-injected brains. P2X7R immunoreactivity colocalized with tumor cells and microglia, but not endogenous astrocytes. Intravenous administration of the P2X7R antagonist brilliant blue G (BBG) inhibited tumor growth in a spatially dependent manner from the C6 injection site. Treatment with BBG reduced tumor volume by 52% versus that in controls. Double immunostaining indicated that BBG treatment did not alter microgliosis, astrogliosis, or vasculature vessels in C6-injected animals. In vitro, BBG reduced the expression of P2X7R and glioma chemotaxis induced by the P2X7R ligand, 2',3'-O-(4-benzoyl-benzoyl)adenosine triphosphate (BzATP). Immunohistochemical staining of human glioblastoma tissue samples demonstrated greater expression of P2X7R compared to control nontumor samples. These results suggest that the efficacy of BBG in inhibiting tumor growth is primarily mediated by direct actions of the compound on P2X7R in glioma cells and that pharmacological inhibition of this purinergic receptor might serve as a strategy to slow the progression of brain tumors. PMID:21157381

Ryu, Jae K; Jantaratnotai, Nattinee; Serrano-Perez, Maria C; McGeer, Patrick L; McLarnon, James G

2011-01-01

269

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

PubMed Central

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

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

2014-01-01

270

Successful treatment for intractable chylous ascites in a child using a peritoneovenous shunt  

Microsoft Academic Search

Intractable post-operative chylous ascites had been managed successfully using a peritoneovenous shunt (PVshunt). A 4-year-old girl with neuroblastoma originated from the right adrenal gland was admitted to our hospital. Following the preoperative chemotherapy, tumor resection, and lymph node dissection of the abdominal paraaortic region were carried out. Post-operative radiation therapy 9.6 gray to the tumor bed and to the paraaortic

Hiroshi Matsufuji; Takeki Nishio; Ryota Hosoya

2006-01-01

271

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

PubMed

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

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

2013-09-01

272

Reduced tumor growth after low-dose irradiation or immunization against blastic suppressor T cells.  

PubMed Central

Suppressor T cells have been shown to be much more radiosensitive than other lymphoïd cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and other develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

Tilkin, A F; Schaaf-Lafontaine, N; Van Acker, A; Boccadoro, M; Urbain, J

1981-01-01

273

Stromal estrogen receptor-? promotes tumor growth by normalizing an increased angiogenesis.  

PubMed

Estrogens directly promote the growth of breast cancers that express the estrogen receptor ? (ER?). However, the contribution of stromal expression of ER? in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17?-estradiol (E2) impacts the microenvironment and modulates tumor development of ER?-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ER?-deficient mice, showing a critical role of host ER?. Notably, E2 did not accelerate tumor growth when ER? was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ER?-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ER?-negative cancer cells through the activation of stromal ER? (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. PMID:22523036

Péqueux, Christel; Raymond-Letron, Isabelle; Blacher, Silvia; Boudou, Frédéric; Adlanmerini, Marine; Fouque, Marie-José; Rochaix, Philippe; Noël, Agnès; Foidart, Jean-Michel; Krust, Andrée; Chambon, Pierre; Brouchet, Laurent; Arnal, Jean-François; Lenfant, Françoise

2012-06-15

274

Reduced tumor growth after low-dose irradiation or immunization against blastic suppressor T cells  

SciTech Connect

Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

Tilkin, A.F. (Universite Libre de Bruxelles, Belgium); Schaaf-Lafontaine, N.; Van Acker, A.; Boccadoro, M.; Urbain, J.

1981-03-01

275

Reduced Tumor Growth after Low-Dose Irradiation or Immunization against Blastic Suppressor T Cells  

NASA Astrophysics Data System (ADS)

Suppressor T cells have been shown to be much more radiosensitive than other lymphoid cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in mildly irradiated mice. We also attempted to reduce syngeneic tumor growth by raising immunity against suppressor T cells in two different systems. DBA/2 mice were immunized against splenic T cells collected after disappearance of cytotoxicity and then injected with P815 tumor cells. These mice develop a very high primary cytotoxicity against P815 cells. C57BL/6 mice were immunized against blastic suppressor T cells, before injection of T2 tumor cells. Some of these mice reject the tumor and others develop smaller tumors than control mice. These results could be explained by the induction of antiidiotypic activity directed against the immunological receptors of suppressor T lymphocytes, because immunization with blastic suppressor T cells from mice bearing the T2 tumor does not modify the growth of another tumor, T10.

Tilkin, A. F.; Schaaf-Lafontaine, N.; van Acker, A.; Boccadoro, M.; Urbain, J.

1981-03-01

276

Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1-7)  

PubMed Central

Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1–7) agonist or an angiotensin (1–7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1–7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1–7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer.

Abd-Alhaseeb, Mohammad M.; Zaitone, Sawsan A.; Abou-El-Ela, Soad H.; Moustafa, Yasser M.

2014-01-01

277

Olmesartan potentiates the anti-angiogenic effect of sorafenib in mice bearing Ehrlich's ascites carcinoma: role of angiotensin (1-7).  

PubMed

Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1-7) agonist or an angiotensin (1-7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1-7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1-7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer. PMID:24465768

Abd-Alhaseeb, Mohammad M; Zaitone, Sawsan A; Abou-El-Ela, Soad H; Moustafa, Yasser M

2014-01-01

278

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Premna herbacea Roxb. in Ehrlich ascites carcinoma model and Dalton's lymphoma ascites model.  

PubMed

In the present study, the root nodules of Premna herbacea Roxb. (PH) was investigated for its in vitro cytotoxicity and in vivo antitumor activity. Two extracts, aqueous and alcoholic; two fractions of alcoholic extract, ethyl acetate and butanol fractions were screened for their in vitro cytotoxicity by brine shrimp lethality (BSL) assay, trypan blue exclusion assay and MTT assay. Alcoholic extract and its ethyl acetate fraction were found to be the most effective in BSL assay, trypan blue exclusion assay. In vivo antitumor activity was screened in the Ehrlich ascites carcinoma (EAC) model and the Dalton lymphoma ascites (DLA) model. The extracts and the fractions were tested at two dosages (250 and 500 mg/kg) by intraperitoneally (i.p.) route on every alternate day upto 13th day. Cisplatin was used as positive control in both studies in single dose (day 1) 3.5 mg/kg by i.p. route. In EAC model, ascites tumor was induced by inoculating 2.5 million of EAC cells i.p. alcoholic extract at 500 mg/kg was the most effective in elevating MST, reduction in body weight in EAC induced tumor. Only the effective extract i.e., alcoholic extract were studied for hematological and antioxidant parameter. It showed a restoring effect on altered hematological parameters and a significant improvement in biochemical parameters at 250 mg/kg dose of alcoholic extract. These results explain the toxicity of 500 mg/kg might be high. In the Dalton lymphoma ascites (DLA) model, solid tumor was developed by i.m. injection of 1 million DLA cells. Both the extracts and the fractions possessed potent antitumor activity against solid tumor models by significantly reducing the solid tumor weight and volume. PMID:21920724

Dhamija, Isha; Kumar, Nitesh; Manjula, S N; Parihar, Vipan; Setty, M Manjunath; Pai, K S R

2013-03-01

279

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

PubMed

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

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

2011-01-01

280

CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice.  

PubMed

CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4?CD25? Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy. PMID:21537079

Wang, Long; Fan, Jie; Thompson, Linda F; Zhang, Yi; Shin, Tahiro; Curiel, Tyler J; Zhang, Bin

2011-06-01

281

Giant cell tumor of the lumbar spine with intraperitoneal growth: case report and review of literature.  

PubMed

Giant cell tumors of the spine are uncommon. Usually they are benign and solitary, but locally very aggressive. Most of them occur at the sacral spine. There are only 26 reported cases in the literature involving this type of tumor in the lumbar spine, in particular exhibiting an intraperitoneal growth. We present the case of a woman with a primary tumor of the lumbar spine (giant cell tumor) with intraperitoneal growth, the outcome as well as a review of the literature. Furthermore, after reviewing all spinal cases in the literature above the sacral spine, we carefully suggest a management algorithm. PMID:23615800

Munoz-Bendix, C; Cornelius, J F; Bostelmann, R; Gierga, K; Steiger, H J

2013-07-01

282

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

283

Four Cases of Chylous Ascites following Robotic Gynecologic Oncological Surgery.  

PubMed

Chylous ascites is an uncommon form of ascites characterized by milky-appearing fluid caused by blocked or disrupted lymph flow through chyle-transporting vessels. The most common causes of chylous ascites are therapeutic interventions and trauma. In this report, we present four cases of chylous ascites following robot-assisted surgery for endometrial staging and the treatment strategies that we used. After retroperitoneal lymph node dissection, leaving a drain is very useful in diagnosing chylous ascites and observing its resolution; furthermore, the use of octreotide in conjunction with TPN appears to be an efficient treatment modality for chylous ascites and should be considered before any invasive intervention. PMID:24716036

Göçmen, Ahmet; Avc?, Muhittin Eftal; Sanl?kan, Fatih; Uçar, Mustafa Gazi

2014-01-01

284

Four Cases of Chylous Ascites following Robotic Gynecologic Oncological Surgery  

PubMed Central

Chylous ascites is an uncommon form of ascites characterized by milky-appearing fluid caused by blocked or disrupted lymph flow through chyle-transporting vessels. The most common causes of chylous ascites are therapeutic interventions and trauma. In this report, we present four cases of chylous ascites following robot-assisted surgery for endometrial staging and the treatment strategies that we used. After retroperitoneal lymph node dissection, leaving a drain is very useful in diagnosing chylous ascites and observing its resolution; furthermore, the use of octreotide in conjunction with TPN appears to be an efficient treatment modality for chylous ascites and should be considered before any invasive intervention.

Gocmen, Ahmet; Avc?, Muhittin Eftal; Sanl?kan, Fatih; Ucar, Mustafa Gazi

2014-01-01

285

Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth  

Microsoft Academic Search

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

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

2007-01-01

286

Mirk kinase inhibition targets ovarian cancer ascites  

PubMed Central

The Mirk/dyrk1B gene is commonly amplified or upregulated in ovarian cancers, and Mirk is an active kinase in these cancers. Mirk mediates cancer cell survival by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes, possibly through its transcriptional activator functions. Mirk has the unusual property of being most active in quiescent cancer cells because of marked transcriptional downregulation by Akt/mTOR signaling and by MEK/erk signaling in cycling cells. Metastatic ovarian cancer cells form ascites, non-adherent multicellular aggregates floating within the peritoneal fluid. Most ascites cancer cells are in a reversible quiescent, dormant state, suggesting that Mirk might be expressed in these quiescent cells and thus a therapeutic target. The current studies show that ovarian cancer cell line spheroids that mimic ascites cancer spheroids were largely quiescent in G0/G1, and enriched in Mirk and the quiescence proteins, p130/Rb2 and the CDKI p27. Mirk kinase inhibition in spheroids made from established cell lines and in patient-derived ascites cancer cell spheroids reduced spheroid volume, disrupted spheroid structure to single cells, increased apoptosis, and decreased cell numbers. Earlier studies had shown that the mTOR inhibitor RAD001 increased transcription of the Mirk/dyrk1B gene, so treatments combined RAD001 with the most active Mirk kinase inhibitor. The number of ascites cells from 9 patients was reduced a similar amount by cisplatin, Mirk kinase inhibition or RAD001, but reduced substantially more, about 90%, by concurrent treatment with both the Mirk kinase inhibitor EHT5372 and RAD001. Addition of RAD001 increased the amount of toxic ROS induced by Mirk kinase inhibition. Two ascites samples taken one month apart gave similar drug responses, showing reproducibility of the techniques. Thus Mirk/dyrk1B kinase may be a therapeutic target in ovarian cancer ascites.

Deng, Xiaobing; Hu, Jing; Cunningham, Mary J.; Friedman, Eileen

2014-01-01

287

Mice Lacking NCF1 Exhibit Reduced Growth of Implanted Melanoma and Carcinoma Tumors  

PubMed Central

The NADPH oxidase 2 (NOX2) complex is a professional producer of reactive oxygen species (ROS) and is mainly expressed in phagocytes. While the activity of the NOX2 complex is essential for immunity against pathogens and protection against autoimmunity, its role in the development of malignant tumors remains unclear. We compared wild type and Ncf1m1J mutated mice, which lack functional NOX2 complex, in four different tumor models. Ncf1m1J mutated mice developed significantly smaller tumors in two melanoma models in which B16 melanoma cells expressing a hematopoietic growth factor FLT3L or luciferase reporter were used. Ncf1m1J mutated mice developed significantly fewer Lewis Lung Carcinoma (LLC) tumors, but the tumors that did develop, grew at a pace that was similar to the wild type mice. In the spontaneously arising prostate carcinoma model (TRAMP), tumor growth was not affected. The lack of ROS-mediated protection against tumor growth was associated with increased production of immunity-associated cytokines. A significant increase in Th2 associated cytokines was observed in the LLC model. Our present data show that ROS regulate rejection of the antigenic B16-luc and LLC tumors, whereas the data do not support a role for ROS in growth of intrinsically generated tumors.

Kelkka, Tiina; Pizzolla, Angela; Laurila, Juha Petteri; Friman, Tomas; Gustafsson, Renata; Kallberg, Eva; Olsson, Olof; Leanderson, Tomas; Rubin, Kristofer; Salmi, Marko; Jalkanen, Sirpa; Holmdahl, Rikard

2013-01-01

288

Gene Transfer of Thromboxane A2 Synthase and Prostaglandin I2 Synthase Antithetically Altered Tumor Angiogenesis and Tumor Growth1  

Microsoft Academic Search

Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H2, which is immediately con- verted to bioactive prostanoids including PGE2, PGD2, thromboxane (TX)A2 and PGI2. To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA2 synthase cDNA or PGI2 synthase cDNA to colon-26 adenocarci- noma cells and

Prasenohadi Pradono; Ryushi Tazawa; Makoto Maemondo; Masashi Tanaka; Kazuhiro Usui; Yasuo Saijo; Koichi Hagiwara; Toshihiro Nukiwa

289

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

PubMed Central

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

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

2013-01-01

290

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

PubMed Central

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

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

2014-01-01

291

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

292

Restriction of tumor growth in mice by sodium-deficient diet.  

PubMed

Generalized malnutrition results in inhibition of tumorigenesis and tumor growth in experimental animal models. Neither the specific nutrient deficiency nor the mechanism has been definitely elucidated. We have shown previously that dietary sodium deprivation in rapidly growing rats retards protoplasmic growth. This effect was correlated to the extracellular fluid (ECF) volume expansion which is dependent on sodium accumulation. Since solid tumors are composed of a large quantity of ECF (which includes plasma volume) it was postulated that preventing the accumulation of new ECF by means of sodium restriction would influence tumor growth. The present study was designed to determine the effects of salt restriction on tumor growth and to relate these effects to ECF volume. Approximately 10(6) viable B16 melanoma cells were injected into C57BL/6 x DBA/2 F1 and C57 mice. A salt restricted diet (sodium less than 3 microeq/g) was provided ad libitum. The drinking solution was distilled water for the experimental group and 0.45% saline solution for the controls. There was a significant decrease in tumor growth rates during sodium restriction. The total body ECF volume increased when dietary sodium was supplied but did not change during salt restriction. Therefore, the only source for the ECF in the tumor mass was from nontumorous tissue. We conclude that during dietary sodium restriction solid tumor growth is retarded and can proceed only to the extent that ECF is released from cachectic body tissues. PMID:3370641

Fine, B P; Ponzio, N M; Denny, T N; Maher, E; Walters, T R

1988-06-15

293

Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.  

PubMed

Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth. PMID:22593188

Holopainen, Tanja; López-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari

2012-07-15

294

Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model.  

PubMed

Lysosomal cysteine cathepsins contribute to proteolytic events promoting tumor growth and metastasis. Their enzymatic activity, however, is tightly regulated by endogenous inhibitors. To investigate the role of cathepsin inhibitor stefin B (Stfb) in mammary cancer, Stfb null mice were crossed with transgenic polyoma virus middle T oncogene (PyMT) breast cancer mice. We show that ablation of Stfb resulted in reduced size of mammary tumors but did not affect their rate of metastasis. Importantly, decrease in tumor growth was correlated with an increased incidence of dead cell islands detected in tumors of Stfb-deficient mice. Ex vivo analysis of primary PyMT tumor cells revealed no significant effects of ablation of Stfb expression on proliferation, angiogenesis, migration and spontaneous cell death as compared with control cells. However, upon treatment with the lysosomotropic agent Leu-Leu-OMe, cancer cells lacking Stfb exhibited a significantly higher sensitivity to apoptosis. Moreover, Stfb-ablated tumor cells were significantly more prone to cell death under increased oxidative stress. These results indicate an in vivo role for Stfb in protecting cancer cells by promoting their resistance to oxidative stress and to apoptosis induced through the lysosomal pathway. PMID:23955077

Butinar, M; Prebanda, M T; Rajkovi?, J; Jeri?, B; Stoka, V; Peters, C; Reinheckel, T; Krüger, A; Turk, V; Turk, B; Vasiljeva, O

2014-06-26

295

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

Microsoft Academic Search

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

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

2007-01-01

296

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

297

Radiofrequency ablation for hepatocellular carcinoma abutting the diaphragm: the value of artificial ascites.  

PubMed

Ultrasound (US)-guided percutanoeus radiofrequency (RF) ablation is difficult to perform for treating a hepatic tumor abutting the diaphragm due to a poor sonic window and high risk of diaphragmatic thermal injury. RF ablation with assistance of the use of artificial ascites is a simple and safe technique for treating a hepatic dome tumor abutting the diaphragm. One can improve the sonic window and separate the RF ablation zone from the diaphragm by downward displacement of the liver with the use of a simple and inexpensive technique. Dextrose water solution is an ideal fluid due to its nonionic nature. Complications related to the use of artificial ascites including hemoperitoneum are rare. Peritoneal adhesion and tumor location in the bare area are the limitations for the application of this technique. PMID:18463915

Rhim, Hyunchul; Lim, Hyo K

2009-01-01

298

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

299

Neonatal ascites due to lysosomal storage disease.  

PubMed

The clinical and radiographic features of four newborns with lysosomal storage disease (LSD) in whom the dominant presenting clinical feature was ascites are presented. The diseases included infantile Gaucher disease, GM I gangliosidosis, infantile sialidosis, and Salla disease. Abdominal distention due to ascites and hepatosplenomegaly, and hypoplastic lungs were seen in all four infants. In the infant with Gaucher disease, the ribs and long bones were markedly thinned. Varying degrees of coarsening of the trabecular pattern of the bones and thinning of the cortex, and a lack of modeling were seen in all patients. Metaphyseal irregularity was noted in the patients with sialidosis and Salla disease. These skeletal radiographic findings may alert the radiologist to the cause for ascites in these patients, which is obscure. In all four patients, there was a history of perinatal death due to the same disease in a sibling; ascites was present in three of the siblings. The diagnosis was missed at autopsy in each of these siblings, underlining the lack of awareness of LSD as a cause for neonatal ascites. PMID:6414044

Daneman, A; Stringer, D; Reilly, B J

1983-11-01

300

Antitumor activity of galactoxyloglucan-gold nanoparticles against murine ascites and solid carcinoma.  

PubMed

Galactoxyloglucan polysaccharide (PST001), isolated from the seed kernels of Tamarindus indica (Ti), was used both as reducing and capping agent for the preparation of gold nanoparticles (PST-Gold) of 20 nm size. The present study evaluated the anticancer effects of the PST-Gold nanoparticles both in vitro and in vivo. The cytotoxicity was evaluated in the murine cancer cell lines, Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC). Galactoxyloglucan-gold nanoparticles (PST-Gold) not only retained the anticancer effects of PST001, but also showed enhanced cytotoxicity via induction of apoptosis even at lower doses and lesser incubation times. In vivo antitumor activity was tested in DLA and EAC murine ascites and EAC solid-tumor syngeneic mouse models. PST-Gold nanoparticles reduced tumor burden and increased median survival and life span significantly in both tumor models compared to the controls. The PST-Gold nanoparticles were very effective as a chemopreventive agent, showing the best overall response when administered prior to tumor induction. In the case of solid tumors, intratumoral administration of the PST-Gold nanoparticles yielded significant results with regard to survival and increment in lifespan as compared to intraperitoneal mode of drug administration. Further studies in higher animal models and in patients at high-risk for recurrence are warranted to fully explore and develop the potential of PST-Gold nanoconjugates as a chemopreventive and therapeutic anti-cancer agent. PMID:24486833

Joseph, Manu M; Aravind, S R; George, Suraj K; Pillai, K Raveendran; Mini, S; Sreelekha, T T

2014-04-01

301

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

PubMed

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

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

2013-03-01

302

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

PubMed Central

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

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

2006-01-01

303

WT1-Mediated Growth Suppression of Wilms Tumor Cells Expressing a WT1 Splicing Variant  

Microsoft Academic Search

A human Wilms tumor cell line (RM1) was developed to test the tumor suppressor activity of WT1, a zinc finger transcription factor that is expressed in the developing human kidney and is mutationally inactivated in a subset of Wilms tumors. Transfection of each of four wild-type WT1 isoforms suppressed the growth of RM1 cells. The endogenous WT1 transcript in these

Daniel A. Haber; Seon Park; Shyamala Maheswaran; Christoph Englert; Gian G. Re; Debra J. Hazen-Martin; Donald A. Sens; A. Julian Garvin

1993-01-01

304

Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival  

Microsoft Academic Search

We have shown recently that the hyaluronan receptor, CD44, and matrix metalloproteinase 9 (MMP-9) form a complex on the surface\\u000a of TA\\/St mouse mammary carcinoma cells that activates latent transforming growth factor-beta (TGF-?) and is required for tumor\\u000a invasion. Disruption of the CD44\\/MMP-9 complex by expression of soluble CD44 results in the loss of tumor invasiveness and\\u000a abrogates tumor cell

Qin Yu; Ivan Stamenkovic

2004-01-01

305

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

306

Acetyl-11-Keto-?-Boswellic Acid Inhibits Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis  

PubMed Central

The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-?-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg of AKBA) after solid tumors reached about 100 mm3 (n=5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively and suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68 ?mol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mTOR, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.

Pang, Xiufeng; Yi, Zhengfang; Zhang, Xiaoli; Sung, Bokyung; Qu, Weijing; Lian, Xiaoyuan; Aggarwal, Bharat B.; Liu, Mingyao

2009-01-01

307

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

PubMed

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

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

2012-08-23

308

Dietary treatment of chylous ascites in yellow nail syndrome  

Microsoft Academic Search

Chylous ascites has rarely been reported in yellow nail syndrome. A case of chylous ascites in yellow nail syndrome is described which was treated successfully with dietary restriction of fat and supplements of medium chained triglycerides.

W C Tan

1989-01-01

309

V3 versican isoform expression has a dual role in human melanoma tumor growth and metastasis  

Microsoft Academic Search

Versican is a large chondroitin sulfate proteoglycan produced by several tumor cell types, including malignant melanoma, which exists as four different splice variants. The presence of versican in the extracellular matrix plays a role in tumor cell growth, adhesion and migration, which could be altered by altering the ratio between versican isoforms. We have previously shown that overexpression of the

Laia Miquel-Serra; Montserrat Serra; Daniel Hernández; Clelia Domenzain; María José Docampo; Rosa M Rabanal; Inés de Torres; Thomas N Wight; Angels Fabra; Anna Bassols

2006-01-01

310

Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth.  

PubMed

Antimicrobial peptides, such as the cathelicidin LL-37/hCAP-18 and its mouse homolog cathelicidin-related antimicrobial peptide (CRAMP), are important effectors of the innate immune system with direct anti-bacterial activity. Cathelicidin is possibly involved in the regulation of tumor cell growth. The aim of this study was to characterize the role of cathelicidin expressed in non-tumorous cells in a preclinical mouse model of tumor growth. Wild-type and CRAMP-deficient animals were exposed to cigarette smoke (CS) and Lewis lung carcinoma cells were injected to initiate the growth of tumors in the lung. CS exposure significantly increased the proliferation of lung tumors in wild-type mice, but not in CRAMP-deficient mice. CS exposure induced the recruitment of myeloid cell into tumor tissue in a CRAMP-dependent manner. Mice lacking RelA/p65 specifically in myeloid cells showed impaired recruitment of CRAMP-positive cells into the lung. In vitro studies with human cells showed that LL-37/hCAP-18 in macrophages is induced by soluble factors derived from cancer cells. Taken together, these data indicate that cathelicidin expressed from myeloid cells promotes CS-induced lung tumor growth by further recruitment of inflammatory cells. The regulation of cathelicidin expression involves myeloid p65/RelA and soluble factor from tumor cells. PMID:23812430

Li, D; Beisswenger, C; Herr, C; Schmid, R M; Gallo, R L; Han, G; Zakharkina, T; Bals, R

2014-05-22

311

Antigen forks: bispecific reagents that inhibit cell growth by binding selected pairs of tumor antigens  

Microsoft Academic Search

Bispecific antibodies of a new category, termed “antigen forks”, were constructed by crosslinking antibodies that recognized pairs of distinct tumor cell surface antigens. At concentrations of 1–100 nM, several such forks inhibited the growth of human tumor cell lines bearing both relevant antigens. The same cells were not inhibited by unconjugated component antibodies, and the active conjugates did not inhibit

David B. Ring; Sylvia T. Hsieh-Ma; Tim Shi; John Reeder

1994-01-01

312

Estrogen Promotes Growth of Human Thyroid Tumor Cells by Different Molecular Mechanisms  

Microsoft Academic Search

Thyroid tumors are about 3 times more frequent in females than in males. Epidemiological studies suggest that the use of estrogens may contribute to the pathogenesis of thyroid tumors. In a very recent study a direct growth stimulatory effect of 17b-estradiol was dem- onstrated in FRTL-5 rat thyroid cells. In this work the presence of estrogen receptors a and b

DIANA MANOLE; BEATRICE SCHILDKNECHT; BERNADETT GOSNELL; ERIC ADAMS; MICHAEL DERWAHL

2006-01-01

313

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

314

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.

315

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

PubMed Central

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

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

2013-01-01

316

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

317

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

PubMed

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

Fink, Krzysztof; Boraty?ski, Janusz

2012-01-01

318

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

PubMed Central

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

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

2013-01-01

319

Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.  

PubMed

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

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

2013-01-01

320

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

PubMed Central

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

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

2009-01-01

321

Diagnostic value of adenosine deaminase in ascites for tuberculosis ascites: a meta-analysis.  

PubMed

The diagnosis of tuberculosis (TB) ascites using standard diagnostic tools is difficult. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of adenosine deaminase (ADA) levels in ascites for diagnosing TB ascites. A systematic review was performed of English language publications prior to April 2013. Sensitivity, specificity, and other measures of the accuracy of ADA for the diagnosis of TB ascites using ascites fluid were summarized using a random-effects model or a fixed-effects model. Receiver operating characteristic curves were used to summarize overall test performance. Seventeen studies involving 1797 subjects were eligible for the analysis. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under cure of overall analysis were: 0.93, 0.94, 13.55, 0.11, 169.83, and 0.976, respectively; the results of sensitivity analysis of studies that used Giusti method were 0.94, 0.94, 12.99, 0.08, 183.18, and 0.977, respectively. Our results suggest that ADA in the ascites can be a sensitive and specific target and a critical criterion for the diagnosis of TB ascites. PMID:24629577

Tao, Lin; Ning, Hong-Jian; Nie, Hai-Ming; Guo, Xiao-Yun; Qin, Shan-Yu; Jiang, Hai-Xing

2014-05-01

322

Single center experience of cell-free and concentrated ascites reinfusion therapy in malignancy related ascites.  

PubMed

Cell-Free and Concentrated Ascites Reinfusion Therapy (CART) is expected to improve patients' symptoms related to ascites. Use of a patient's own proteins in ascites might reduce the risk of infection. However, several reports have described that reinfusion of concentrated ascites might elevate body temperature. The aim of this study is to examine the safety and efficacy of the CART system performed exclusively on patients with malignancies. In this retrospective cohort observational study, we examined 81 CART processes performed on 24 patients with malignancies. Data were collected from medical records and records during processing of ascites. We investigated the effectiveness and adverse events during the procedures. The amount of ascites processed was 2.6 ± 1.4 L on average. The concentration ratio was 9.31 ± 5.45 on average. We found an increase in the urine volume after the procedure, which was significantly related to the amount of reinfused protein. The body temperature increased by 0.44°C. Systolic blood pressure decreased by 4 mm Hg after paracentesis, but no significant difference was found between the pressure before paracentesis and after reinfusion. In platelet counts, no significant change was observed. After all, no clinically significant adverse event was confirmed during CART procedures. Results show that CART can be performed safely even on patients with malignancy-related ascites and that the procedure might improve diuresis. PMID:24499089

Ito, Tetsuya; Hanafusa, Norio; Fukui, Mieko; Yamamoto, Hiroko; Watanabe, Yasuyuki; Noiri, Eisei; Iwase, Satoru; Miyagawa, Kiyoshi; Fujita, Toshiro; Nangaku, Masaomi

2014-02-01

323

Effects of Cordyceps militaris extract on angiogenesis and tumor growth1  

Microsoft Academic Search

3 R&D Lab of Bulrolife Co, Ltd, Daejeon, Korea ABSTRACT AIM: To evaluate the effects of Cordyceps militaris extract (CME) on angiogenesis and tumor growth. METHODS: Human umbilical vein endothelial cells (HUVEC), HT1080, and B16-F10 cells were used. DNA fragment, angio- genic related gene expressions (MMPs, bFGF, VEGF, etc), capillary tube formation, wound healing in vitro, tumor growth in vivo

Hwa-seung YOO; Jang-woo SHIN; Jung-hyo CHO; Yeon-weol LEE; Sang-yong PARK; Chong-kwan CHO

324

Managing ascites in patients with chronic liver disease.  

PubMed

This article discusses the pathophysiology of ascites, a complication associated with chronic liver disease. The diagnosis and grading of ascites and assessment of patients with the condition are explored. In addition, the nursing and medical management of ascites is discussed, and recommendations for interdisciplinary working and education are suggested. Nursing knowledge of this complication is essential to ensure that patients with ascites are cared for effectively and that their comfort is maximised. PMID:24494916

Fullwood, D; Purushothaman, A

2014-02-01

325

Extensive Loculated Ascites in Hepatic Amyloidosis  

PubMed Central

Context: Amyloidosis is a disease of extracellular deposition of misfolded proteinaceous subunits, which could be systemic or localized disease. Though hepatic amyloidosis was not uncommon in autopsy series, most cases of hepatic amyloidosis were asymptomatic. Ascites, jaundice, portal hypertension, and gastrointestinal bleeding from esophageal varices were reported in literature. Case report: A 42-year-old man with end-stage renal disease on hemodialysis and recent small bowel obstruction presented with chronic abdominal pain. Computed tomography of abdomen and pelvis showed extensive loculated ascites and multiple small bowel loops tethered to adhesions and hepatomegaly. Finally, hepatic venography and liver biopsy confirmed hepatic amyloidosis with portal hypertension. The patient was waiting for liver transplant for definite treatment. Conclusion: We report a rare case of hepatic amyloidosis with prior small bowel obstruction presented with extensive loculated ascites and multiple small bowel loops tethered to adhesions.

Buppajarntham, Saranya; Kue-A-Pai, Pongsathorn

2014-01-01

326

Angiogenesis-independent tumor growth mediated by stem-like cancer cells  

PubMed Central

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Sakariassen, Per ?.; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit B?lge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; ?yan, Anne M.; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G.; Terzis, A. Jorge A.; Bjerkvig, Rolf; Enger, Per ?yvind

2006-01-01

327

Angiogenesis-independent tumor growth mediated by stem-like cancer cells.  

PubMed

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors. PMID:17056721

Sakariassen, Per Ø; Prestegarden, Lars; Wang, Jian; Skaftnesmo, Kai-Ove; Mahesparan, Rupavathana; Molthoff, Carla; Sminia, Peter; Sundlisaeter, Eirik; Misra, Anjan; Tysnes, Berit Bølge; Chekenya, Martha; Peters, Hans; Lende, Gabriel; Kalland, Karl Henning; Øyan, Anne M; Petersen, Kjell; Jonassen, Inge; van der Kogel, Albert; Feuerstein, Burt G; Terzis, A Jorge A; Bjerkvig, Rolf; Enger, Per Øyvind

2006-10-31

328

Preventing Growth of Brain Tumors by Creating a Zone of Resistance  

PubMed Central

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 expression of therapeutic proteins by tumor cells themselves. However, as antitumor proteins are generally lethal to tumor cells, the therapeutic reservoir is rapidly depleted, allowing escape of residual tumor cells. Moreover, it has been difficult to achieve consistent transduction of these highly heterogeneous tumors. In our studies, we found that transduction of normal cells in the brain with an adeno-associated virus (AAV) vector encoding interferon-? (IFN-?) was sufficient to completely prevent tumor growth in orthotopic xenograft models of GBM, even in the contralateral hemisphere. In addition, complete eradication of established tumors was achieved through expression of IFN-? by neurons using a neuronal-restricted promoter. To our knowledge this is the first direct demonstration of the efficacy of targeting gene delivery exclusively to normal brain cells for brain tumor therapy.

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

2010-01-01

329

Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience.  

PubMed

Because interleukin-10 (IL-10) has potent immunosuppressive and anti-inflammatory properties and is produced by some cancers, including melanoma, we hypothesized that its production by tumor cells may contribute to the escape from immune surveillance. To test this hypothesis, we transfected human A375P melanoma cells that do not express IL-10 with the murine IL-10 gene and subsequently analyzed for changes in tumor growth and metastasis in nude mice. Surprisingly, IL-10 gene transfer resulted in a loss of metastasis and significant inhibition of tumor growth. In addition, the growth of other murine or human melanoma cells was also inhibited when they were admixed with IL-10-transfected cells before injection into nude mice. We provide evidence that IL-10 exerts its antitumor and antimetastatic activity by inhibiting angiogenesis in vivo. The in vivo decrease in neovascularization found in IL-10-secreting tumors is most likely due to the ability of IL-10 to downregulate the synthesis of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and matrix metalloproteinase-9 (MMP-9) in tumor-associated macrophages. Other studies have shown that IL-10 inhibits tumor metastasis through a natural killer (NK) cell-dependent mechanism. The inhibitory effects of IL-10 on tumor growth and metastasis were also demonstrated in other tumor models, including breast cancers. Furthermore, administration of rIL-10 into mice resulted in inhibition of tumor metastasis. Because IL-10 has little toxicity when given systemically to human volunteers, its efficacy as an antimetastatic agent should be further explored, both as an independent and in combination with other inhibitors of neovascularization. PMID:10454339

Huang, S; Ullrich, S E; Bar-Eli, M

1999-07-01

330

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

2013-09-12

331

Enhancement of tumor associated antigen expression during the regression phase of xenogenized tumor cell growth in vivo.  

PubMed

Rat fibrosarcoma cells infected with Friend leukemia virus (FV-KMT-17) grow for a short time and then regress spontaneously in syngeneic hosts. This regression was caused by immunological mechanisms, because the tumor cells were renogenized. In this study, we have tried to find out whether tumor-associated antigen (TAA) expression in these xenogenized tumor cells can be modulated by xenogenization. FV-KMT-17 cells (1 x 10(7)), which were subcutaneously transplanted into ten rats, spontaneously regressed after temporary growth. All rats which rejected FV-KMT-17 cells showed strong resistance to rechallenge with KMT-17 (1 x 10(6)) cells. To reveal the chronological modulation of TAA and virus-associated antigen (VAA), a single-cell suspension was obtained from the subcutaneous tumors and expression of these antigens was chronologically measured. TAA, termed CE7 antigen, was examined by anti-CE7 monoclonal antibody (MoAb) and VAA was examined by anti-FK1 MoAb which recognizes the FV env gene product (gp 70). Expression of VAA was not modulated through either the progression or the regression phase, but expression of TAA was strongly enhanced in the regression phase. These results show that enhancement of TAA expression occurs during the regression phase of FV-KMT-17 growth in vivo and that TAA-expressing cells may stimulate anti-tumor immunity, resulting in acquisition of resistance against parental KMT-17 cells. PMID:9216677

Shibata, T; Micallef, M; Chiba, I; Arisue, M; Hosokawa, M; Okada, F; Takeichi, N; Kobayashi, H

1997-01-01

332

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

PubMed Central

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

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

2010-01-01

333

A huge renal cyst mimicking ascites: a case report  

PubMed Central

Background Renal cysts are common in old patients, and usually remain untreated. Giant renal cyst measuring more than 15 cm in diameter and containing more than 1500 mls of serous fluid are rarely seen. We report a case of a 75-year-old man with a giant right renal cyst. Case presentation A 75-year-old man presented with a five years history of suprapubic pain, abdominal distension. He had no urological symptoms. Physical examination revealed a distended abdomen with shifting dullness. Routine hematology, biochemistry, and serum tumor markers were within normal limits. Erroneously diagnosed as ascites on ultrasonographic examination. Abdominal paracentesis of supposed ascites was performed. The diagnosis of giant renal cyst was finally made by Computed tomography (CT) and patient underwent continuous percutaneous catheter drainage with negative pressure, whereby 8 liters of fluid were removed with negative cytology. Subsequent Computed tomography after 6 months revealed disparition of the cysts, and the patient remained asymptomatic. Conclusion Giant renal cysts are uncommon; we conclude that the CT remains the best exam in patients evaluated for giant renal cyst. This to the best of our knowledge is the largest renal cyst in the medical literature. Studies are needed with particular attention to the factors associated with renal cyst enlargement.

2014-01-01

334

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

PubMed

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

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

2013-01-01

335

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

PubMed Central

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

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

2013-01-01

336

Chylous ascites: Treated with total parenteral nutrition and somatostatin  

Microsoft Academic Search

AIM: To determine the effects of total parenteral nutrition and somatostatin on patients with chylous ascites. METHODS: Five patients were diagnosed with chylous ascites on the basis of laboratory findings of ascites sample from Nov 1999 to May 2003. Total parenteral nutrition and somatostatin or its analogue was administered to 4 patients, while the other one only received total parenteral

Qi Huang; Zhi-Wei Jiang; Jun Jiang; Ning Li; Jie-Shou Li

337

Chylous ascites: total parenteral nutrition as primary therapeutic modality  

Microsoft Academic Search

A female infant with Down syndrome and congenital chylous ascites presented at birth with respiratory distress secondary to marked abdominal distension. Total parenteral nutrition (TPN) and paracentesis were the primary therapeutic modality. On hyperalimentation, however, ascites initially recurred, requiring additional paracenteses to improve respiratory distress. The chylous ascites, lymphopenia and hypoalbuminemia were relieved after 10 weeks of TPN administration. We

P. Alliët; C. Young; E. Lebenthal

1992-01-01

338

Umbilical arterial necrotic vasculopathy associated with fetal ascites.  

PubMed

Immune and nonimmune neonatal ascites may be part of hydrops fetalis or may be an isolated finding. However, a significant percentage of nonimmune ascites do not have an identifiable pathogenesis and are considered idiopathic. We report a case of fetal ascites and umbilical arterial necrotic vasculopathy, an association not previously described. PMID:20130389

Rossi, Giuliana; Cosmi, Erich; Trevisanuto, Daniele; Cappellari, Ambra; Andrisani, Alessandra; Visentin, Silvia; Chiarelli, Silvia; Zanardo, Vincenzo

2010-01-01

339

Proinvasive Properties of Ovarian Cancer Ascites-Derived Membrane Vesicles  

Microsoft Academic Search

Malignant ovarian ascites are rich in cellular components, membrane- bound vesicles, and soluble proteins. This study focused on the structure of membrane-bound vesicles and their ability to promote invasion in cultured malignant ovarian epithelium. Membrane vesicles were derived from women with stage I-IV malignant ovarian ascites and from nonma- lignant gynecologic ascites. Isolated vesicles were characterized by immu- nofluorescence and

Laura E. Graves; Edgardo V. Ariztia; Jason R. Navari; Heather J. Matzel; M. Sharon Stack; David A. Fishman

2004-01-01

340

Solid tumor models for the assessment of different treatment modalities: I. Radiation-induced changes in growth rate characteristics of a solid tumor model.  

PubMed Central

A computer program has been developed to quantitatively evaluate changes in tumor growth rates of a solid tumor model (hepatoma 3924A) after a series of radiation doses from 375 R to 3750 R. The computer-derived growth curves are simulated from the volumes of the individual tumors rather than from the mean tumor volume at any specific time point after treatment. The ability to generate data from a family of tumor growth curves permits a more precise evaluation of therapeutic effects on tumors than can be obtained with conventional methods. The quantitative determination of equivalent amounts of radiation needed to produce comparable 5-fluorouracil-induced changes in tumor growth rate has been made. The ability to determine quantitatively radiotherapeutic and chemotherapy equivalents on these solid tumor models has direct implications in regard to our effort to improve the treatment of cancer. At present no specific solid tumor or groups of solid tumors have provided all of the necessary information for clinical utilization in therapeutic scheduling of different forms of cancer treatment. Since solid tumors comprise the majority of human cancer, one of the primary objectives of these studies has been the establishment of a solid tumor model that could serve both as a system for devising improved therapeutic scheduling and for a better understanding of solid tumors.

Looney, W B; Trefil, J S; Schaffner, J C; Kovacs, C J; Hopkins, H A

1975-01-01

341

Chylous Ascites Secondary to Giant Liver Hemangioma  

PubMed Central

Chylous ascites is rare in clinical practice. It is characterized by milky-appearing peritoneal fluid with a triglycerides concentration of >1.25 mmol/l (110 mg/dl). Its pathophysiology is related to a disruption in the normal lymphatic flow. It is more common after trauma (including post surgery), neoplasia or atypical infections such as tuberculosis or filariasis. Other rare medical causes have been reported. The treatment is supportive and focused on correction of the underlying pathology. We report here the first case of chylous ascites caused by giant liver hemangioma and discuss the management of this condition.

Lazarus, Darius L.; Al-Busafi, Said A.; Hilzenrat, Nir

2012-01-01

342

Calcium metabolism in Ehrlich Ascites tumour cells.  

PubMed

Ehrlich ascites tumour cells are able, under the proper experimental conditions, to extrude a substantial amount of Ca2+ from the intracellular space. The Ca2+ extrusion mechanism, probably located at the plasma membrane level, appears to be similar to that found in red blood cells. It is energy-dependent and both respiration and glycolysis are able to drive it. The use of some inhibitors and uncouplers, besides showing that this activity is different from that linked to the mitochondrial Ca2+ pump which acts in the opposite direction, proposes some speculations on the energy compartmentation in the Ehrlich ascites tumour cells. PMID:561619

Cittadini, A; Bossi, D; Rosi, G; Wolf, F; Terranova, T

1977-09-19

343

Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy.  

PubMed

Metastatic melanoma often relapses despite cytotoxic treatment, and hence the understanding of melanoma tumor repopulation is crucial for improving our current therapies. In this study, we aim to define the role of caspase 3 in melanoma tumor growth after cytotoxic therapy. We examined a paradigm-changing hypothesis that dying melanoma cells undergoing apoptosis during cytotoxic treatment activate paracrine signaling events that promote the growth of surviving tumor cells. We propose that caspase 3 has a key role in the initiation of the release of signals from dying cells to stimulate melanoma tumor growth. We created a model for tumor cell repopulation in which a small number of luciferase-labeled, untreated melanoma cells are seeded onto a layer of a larger number of unlabeled, lethally treated melanoma cells. We found that dying melanoma cells significantly stimulate the growth of living melanoma cells in vitro and in vivo. Furthermore, we observed that caspase 3 gene knockdown attenuated the growth-stimulating effect of irradiated, dying cells on living melanoma cell growth. Finally, we showed that caspase 3-mediated dying melanoma cell stimulation of living cell growth involves secreted prostaglandin E2 (PGE2). Our study therefore suggests a counterintuitive strategy to inhibit caspase 3 for therapeutic gain in melanoma treatment. PMID:24434746

Donato, Anne L; Huang, Qian; Liu, Xinjian; Li, Fang; Zimmerman, Mary A; Li, Chuan-Yuan

2014-06-01

344

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

345

IgG2a Monoclonal Antibodies Inhibit Human Tumor Growth through Interaction with Effector Cells  

NASA Astrophysics Data System (ADS)

Monoclonal antibodies of IgG2a isotype specifically inhibited growth of human tumors in nude mice. Twentythree monoclonal antibodies of other isotypes showed no tumoricidal reactivity. Complement depletion of nude mice had no effect on tumor suppression by monoclonal antibody. The role of T and killer cells as mediators of the monoclonal antibody effect in nude mice was virtually excluded. On the other hand, macrophages were strongly incriminated as effector cells because silica treatment of nude mice abolished the tumoricidal effect of monoclonal antibody. IgG2a monoclonal antibody-dependent macrophagemediated cytotoxicity assays with human tumor cells in culture resulted in specific lysis of tumor cells.

Herlyn, Dorothee; Koprowski, Hilary

1982-08-01

346

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

347

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

2012-08-01

348

MHC-mismatched mice liver transplantation promotes tumor growth in liver graft.  

PubMed

Liver transplantation is a final therapeutic option for treatment of hepatic malignancies, but local recurrence remains high after surgery. However, the underlying mechanisms of local tumor recurrence are still unknown. We speculated that immunological status of transplanted liver may contribute to the progress of tumor development. CT-26 tumor cells are injected into graft after allogeneic or syngeneic liver transplantation. The growth pattern of tumor and the co-relationship of regulatory T cell and effector T cells in liver graft were observed and investigated at 3d, 6d, 9d and 15d post-transplantation. The Hepatic Replacement Area of tumor in allogeneic grafts was significantly larger than that in syngeneic grafts. The activation of tumor growth in allografts was due to the dysfunction of effector T cells mediated by regulatory T cells in liver graft. Using nude mice model, we further confirmed that regulatory T cells from allograft significantly weaken the function of effector T cells in vivo. Our data has showed that MHC-mismatched mice liver transplantation can promote tumor growth in liver graft. For the first time, we demonstrated that susceptibility to tumor development in liver graft is due to the down-regulation of effector T cells' function mediated by the regulatory T cells. PMID:24880081

Yan, Sheng; Ding, Yuan; Tian, Yang; Lu, Zhongjie; Wang, Yan; Zhang, Qiyi; Ye, Yufu; Zhou, Lin; Xie, Haiyang; Chen, Hui; Zheng, Minghao; Zheng, Shusen

2014-08-28

349

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

PubMed Central

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

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

2013-01-01

350

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

PubMed Central

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

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

2012-01-01

351

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

PubMed

The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors. PMID:14595012

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

2003-11-11

352

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

PubMed Central

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

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

2003-01-01

353

Establishment and drug sensitivity evaluation of murine ascites hepatocarcinoma cell line with high lymphatic metastatic potential (Hca-P\\/L 6 )  

Microsoft Academic Search

In order to provide a sensitive cell line model for investigating the mechanisms underlying the lymphatic metastasis of tumors\\u000a and the effect of medicine against cells, a new murine ascites hepatocarcinoma cell line with high lymphatic metastatic potential\\u000a (Hca-P\\/L6) was established and the effect of curcumin on biological behavior of Hca-P\\/L6 was observed. Murine ascites hepatocarcinoma cell strain with low

Hongying Zhang; Jianwu Tang; Wenting Zhu; Chunxiu Hu; Guowang Xu

2009-01-01

354

Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas.  

PubMed

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 with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods. PMID:9042797

Merogi, A J; Marrogi, A J; Ramesh, R; Robinson, W R; Fermin, C D; Freeman, S M

1997-03-01

355

Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis  

PubMed Central

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

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

2010-01-01

356

Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth  

PubMed Central

AIM: To study the role of macrophage inflammatory protein (MIP)-2 in liver resection-induced acceleration of tumor growth in a mouse model of hepatic metastasis. METHODS: After a 50% hepatectomy, 1×105 CT26.WT cells were implanted into the left liver lobe of syngeneic balb/c mice (PHx). Additional animals were treated with a monoclonal antibody (MAB452) neutralizing MIP-2 (PHx+mAB). Non-resected and non-mAB-treated mice (Con) served as controls. After 7 d, tumor angiogenesis and microcirculation as well as cell proliferation, tumor growth, and CXCR-2 expression were analyzed using intravital fluorescence microscopy, histology, immunohistochemistry, and flow cytometry. RESULTS: Partial hepatectomy increased (P?tumor cells when compared with non-resected controls, and markedly accelerated (P?tumor growth. Neutralization of MIP-2 by MAB452 treatment significantly (P?tumor growth (P?growth.

Kollmar, Otto; Menger, Michael D; Schilling, Martin K

2006-01-01

357

Expression of P2X7 receptor increases in vivo tumor growth.  

PubMed

The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo. PMID:22505653

Adinolfi, Elena; Raffaghello, Lizzia; Giuliani, Anna Lisa; Cavazzini, Luigi; Capece, Marina; Chiozzi, Paola; Bianchi, Giovanna; Kroemer, Guido; Pistoia, Vito; Di Virgilio, Francesco

2012-06-15

358

Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis  

PubMed Central

It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis, and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi (GSTp1) to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 (DNMT1) mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice.

Henning, Susanne M.; Wang, Piwen; Said, Jonathan; Magyar, Clara; Castor, Brandon; Doan, Ngan; Tosity, Carmen; Moro, Aune; Gao, Kun; Li, Luyi; Heber, David

2011-01-01

359

Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis.  

PubMed

It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice. PMID:22405694

Henning, Susanne M; Wang, Piwen; Said, Jonathan; Magyar, Clara; Castor, Brandon; Doan, Ngan; Tosity, Carmen; Moro, Aune; Gao, Kun; Li, Luyi; Heber, David

2012-11-01

360

Enhanced expression of the ?4-galactosyltransferase 2 gene impairs mammalian tumor growth.  

PubMed

Altered N-glycosylation of membrane proteins is associated with malignant transformation of cells. We found that the expression of the ?4-galactosyltransferase 2 (?4GalT2) gene is decreased markedly during the transformation. Here, we examined whether the tumor growth activity of B16-F10 mouse melanoma cells can be reduced by the enhanced expression of the ?4GalT2 gene. We isolated a clone, B16-?4GalT2, showing its ?4GalT2 transcript 2.5 times higher than a control clone, B16-mock, by transducing its cDNA, and transplanted them subcutaneously into C57BL/6 mice to examine their tumor growth activity. The results showed that the average size of tumors formed with B16-mock cells is 13.1±0.76?mm, whereas that of tumors formed with B16-?4GalT2 cells is 5.1±1.13?mm (P<0.01) 2 weeks after transplantation. Immunohistochemical analyses showed that the apoptosis and the suppression of angiogenesis are induced in the tumors upon transduction of the ?4GalT2 gene. To pursue a clinical usefulness of the ?4GalT2 gene for suppressing human tumor growth, we injected adenoviruses carrying the human ?4GalT2 cDNA into HuH-7 human hepatocellular carcinomas developed in severe combined immunodeficient mice, and observed marked growth retardation of the tumors. The enhancement of the ?4GalT2 gene expression in tumors is one of the promising approaches to suppress human tumor growth. PMID:24903013

Tagawa, M; Shirane, K; Yu, L; Sato, T; Furukawa, S; Mizuguchi, H; Kuji, R; Kawamura, K; Takahashi, N; Kato, K; Hayakawa, S; Sawada, S; Furukawa, K

2014-06-01

361

Cystemustine induces redifferentiation of primary tumors and confers protection against secondary tumor growth in a melanoma murine model.  

PubMed

N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response. PMID:11280801

Demidem, A; Morvan, D; Papon, J; De Latour, M; Madelmont, J C

2001-03-01

362

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

363

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

364

Growth promoting effect of recombinant interleukin I and tumor necrosis factor for human astrocytoma cells  

Microsoft Academic Search

Human IL I has been demonstrated to stimulate the growth of rat astrocytes in vitro. To determine if IL I has a similar growth promoting effect upon human brain cells, two astrocytoma cell lines were tested for their ability to incorporate ³H-thymidine in response to various types of IL I and tumor necrosis factor (TNF). The U373 astrocytoma was found

D. Giulian; C. A. Dinarello; D. C. Brown; L. B. Lachman

1986-01-01

365

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

PubMed

As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis. PMID:24416386

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

2014-01-01

366

Genetic analysis of the growth curve of Rous sarcoma virus-induced tumors in chickens.  

PubMed

White Leghorn chicks homozygous for B19 MHC haplotype were selected for 18 generations on tumor regression after inoculation in the wing web with an SR-D strain of Rous sarcoma virus (RSV) at 4 wk of age. Each chick was assigned a tumor profile index (TPI) based on age at death and size of the tumor. During 18 generations, 2,010 birds were divergently selected on TPI for either progression or regression of the tumor (P and R lines). A Brody growth curve was fitted for each bird. Brody function parameters included the asymptotic tumor volume (A), the factor for increased growth in progression phase (K1), the factor for decreased growth in regression phase (K2), age at maximum volume (Tmax), and maximum volume of the tumor (Vmax). Tumor growth curves were found to be different according to line, sex, and restriction fragment pattern Y complex Rfp-Y MHC haplotype (Yw*15, Yw*16, and Yw*17). Within the P line, birds from the Yw*16 haplotype reached Vmax at an earlier age than Yw*15 and Yw*17, but with a lower Vmax value. Within the R line, tumor growth curves of birds from Yw*16 and Yw*17 haplotypes were similar. Rank correlations between the different parameters and TPI were low (between -0.26 and 0.36). Heritability estimated by the sire component was high for Vmax (0.73). Heritabilities of Tmax and K2 were moderate (0.20 to 0.23 for Tmax and 0.18 to 0.21 for K2) allowing these traits to be used as selection criteria. Heritabilities of A and K1 were lower than 0.12. Modeling the growth curve should contribute to better distinction between progressors and regressors. PMID:15384897

Praharaj, N; Beaumont, C; Dambrine, G; Soubieux, D; Mérat, L; Bouret, D; Luneau, G; Alletru, J-M; Pinard-Van der Laan, M-H; Thoraval, P; Mignon-Grasteau, S

2004-09-01

367

Contributions of Cell Kill and Posttreatment Tumor Growth Rates to the Repopulation of Intracerebral 9L Tumors after Chemotherapy: An MRI Study  

Microsoft Academic Search

The drought of progress in clinical brain tumor therapy provides an impetus for developing new treatments as well as methods for testing therapeutics in animal models. The inability of traditional assays to simultaneously measure tumor size, location, growth kinetics, and cell kill achieved by a treatment complicates the interpretation of therapy experiments in animal models. To address these issues, tumor

Brian D. Ross; Yong-Jie Zhao; Eric R. Neal; Lauren D. Stegman; Matthew Ercolani; Oded Ben-Yoseph; Thomas L. Chenevert

1998-01-01

368

Ephrin-A1 inhibits NSCLC tumor growth via induction of Cdx-2 a tumor suppressor gene  

PubMed Central

Background Tumor formation is a complex process which involves constitutive activation of oncogenes and suppression of tumor suppressor genes. Receptor EphA2 and its ligand ephrin-A1 form an important cell communication system with its functional role in cell-cell interaction and tumor growth. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential. Claudins, the integrated tight junction (TJ) cell-cell adhesion proteins located on the apico-lateral portion of epithelial cells, functions in maintaining cell polarity. There is extensive evidence implicating Eph receptors and ephrins in malignancy, but the mechanisms how these molecular players affect TJ proteins and regulate tumor growth are not clear. In the present study we hypothesized that EphA2 signaling modulates claudin-2 gene expression via induction of cdx-2, a tumor suppressor gene in NSCLC cells. Methods The expression of EphA2, claudin-2 was determined in various NSCLC cell lines by using real-time quantitative polymerase chain reaction and Western blot analysis. The claudin-2 expression was also analyzed by immunofluorescence analysis. EphA2 and erk1/erk2 phosphorylation in ephrin-A1 activated cells was evaluated by Western blot analysis. The cell proliferation and tumor colony formation were determined by WST-1 and 3-D matrigel assays respectively. Results NSCLC cells over expressed receptor EphA2 and claudin-2. Ephrin-A1 treatment significantly down regulated the claudin-2 and EphA2 expression in NSCLC cells. The transient transfection of cells with vector containing ephrin-A1 construct (pcDNA-EFNA1) decreased the expression of claudin-2, EphA2 when compared to empty vector. In addition ephrin-A1 activation increased cdx-2 expression in A549 cells. In contrast over-expression of EphA2 with plasmid pcDNA-EphA2 up regulated claudin-2 mRNA expression and decreased cdx-2 expression. The transient transfection of cells with vector containing cdx-2 construct (pcMV-cdx-2) decreased the expression of claudin-2 in A549 cells. Moreover, silencing the expression of receptor EphA2 by siRNA significantly reduced claudin-2 expression and decreased cell proliferation and tumor formation. Furthermore, silencing cdx-2 gene expression before ephrin-A1 treatment increased claudin-2 expression along with increased cell proliferation and tumor growth in A549 cells. Conclusions Our study suggests that EphA2 signaling up-regulates the expression of the TJ-protein claudin-2 that plays an important role in promoting cell proliferation and tumor growth in NSCLC cells. We conclude that receptor EphA2 activation by ephrin-A1 induces tumor suppressor gene cdx-2 expression which attenuates cell proliferation, tumor growth and thus may be a promising therapeutic target against NSCLC.

2012-01-01

369

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

PubMed

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

Gao, Dingcheng; Mittal, Vivek

2009-08-01

370

Immunohistochemical evidence of association between ghrelin expression and tumor growth in esophageal carcinoma.  

PubMed

Background: Ghrelin, an orexigenic peptide, is primarily produced and secreted by the gastrointestinal tract. As far as we are aware of, there is no evidence of ghrelin expression in esophageal squamous cell carcinoma (ESCC). Materials and Methods: Two hundred and ten patients with ESCC who underwent surgical resection were enrolled in this study. We immunohistochemically investigated ghrelin expression in primary ESCC specimens and analyzed the relationship with clinicopathological factors. Results: High ghrelin expression was observed in 61 patients (29.0%). Depth of tumor invasion and histological differentiation were statistically associated with ghrelin expression. As for depth of tumor invasion, the deeper it was, the higher was the expression of ghrelin. Well-differentiated tumors had a significantly higher proportion of ghrelin-expressing cells than other types. Conclusion: Ghrelin expression correlated with tumor depth and tumor differentiation, suggesting an important role of ghrelin in tumor growth in ESCC. PMID:24922633

Omoto, Itaru; Matsumoto, Masataka; Uchikado, Yasuto; Kita, Yoshiaki; Sakurai, Toshihide; Sasaki, Ken; Setoyama, Tetsuro; Okumura, Hiroshi; Owaki, Tetsuhiro; Ishigami, Sumiya; Natsugoe, Shoji

2014-06-01

371

Ascitic complement system in ovarian cancer  

Microsoft Academic Search

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity.

L Bjørge; J Hakulinen; O K Vintermyr; H Jarva; T S Jensen; O E Iversen; S Meri

2005-01-01

372

Chylous ascites: CT and ultrasound appearance  

Microsoft Academic Search

An unusual but pathognomonic appearance of chylous ascites was observed on computed tomographic (CT) and ultrasound examinations of the abdomen in a patient with AIDS and disseminated tuberculosis. The images showed gradual development of fat-fluid level in the peritoneal collection when the patient maintained a recumbent position. The explanation for this phenomenon is provided together with a brief review of

J. F. Hibbeln; M. D. Wehmueller; A. C. Wilbur

1995-01-01

373

Intractable Ascites following Surgery for Gastric Carcinoma  

Microsoft Academic Search

Over the past 11 years, I have experienced a few patients with intractable ascites after extended radical surgery for gastric carcinomas, which accounted for 1.0% (4 of 394) of all gastric carcinomas resected in our institute. These 4 patients underwent total or subtotal gastrectomy with extended lymphadenectomy, including the lymph nodes of the hepatoduodenal ligament. Histopathologic examination of an intraoperative

Kazuhide Kumagai

1998-01-01

374

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

PubMed Central

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

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

2014-01-01

375

PC Cell-Derived Growth Factor Mediates Tamoxifen Resistance and Promotes Tumor Growth of Human Breast Cancer Cells  

Microsoft Academic Search

PC cell-derived growth factor, also known as progranulin, is an Mr 88,000 growth factor (referred as PCDGF\\/GP88) overexpressed in human breast cancer. Antisense inhibition of PCDGF\\/GP88 expression in MDA- MB-468 cells inhibited tumor formation in nude mice. In estrogen recep- tor-positive cells, PCDGF\\/GP88 was expressed in response to estradiol and shown to mediate its mitogenic effect. Pathologic studies indicated that

Wisit Tangkeangsirisin; Jun Hayashi; Ginette Serrero

2004-01-01

376

Chronic pancreatitis associated with chylous ascites simulating liver cirrhosis.  

PubMed

Purpose. Ascites, esophageal varicose veins, and acute digestive bleeding are unusual in the clinical presentation of chronic pancreatitis; however, these symptoms are frequently observed in patients with liver cirrhosis. Moreover, it is unlikely to observe chylous ascites in both presentations. Method. We report a patient who presented with chronic pancreatitis with splenic vein thrombosis, necrosis of the pancreatic neck and tail, esophageal varicose veins with previous bleeding, and chylous ascites. After partial pancreatectomy, his treatment was based on low-fat oral diet with medium-chain triglycerides with remarkable resolution of the chylous ascites. After 3 years, he presented with decompensated chronic pancreatitis and underwent plexus alcoholization and biliary-enteric deviation with an unremarkable postoperative course. Conclusion. Ascites is rarely associated with chronic pancreatitis, and chylous ascites is even rarer. The treatment of atraumatic chylous ascites is based on resolution of the obstructive causes and should include drainage and a low-fat diet with medium-chain triglycerides. PMID:24363949

Andraus, Wellington; Nacif, Lucas Souto; Araujo, Raphael L C; Buscariolli, Yuri Dos Santos; Salvato, Mayara; D'Albuquerque, Luiz Augusto Carneiro

2013-01-01

377

Spontaneous resolution of fetal and neonatal ascites after birth.  

PubMed

Fetal ascites is an uncommon abnormality usually reported in relation to non- immunological causes. The prospect for fetal and neonatal mortality is high, particularly when the ascites develops before 24 weeks of gestation. The diminution of severe fetal ascites without intrauterine management, especially with an uncomplicated neonatal outcome, is unusual. We report a case of isolated fetal ascites detected at 20 weeks' gestation. All investigations carried out were normal. Consecutive ultrasound examination showed ascites at 20 weeks' gestation. A follow-up ultrasound examination at 6 months of age revealed complete recovery from the ascites. Spontaneous resolution of fetal ascites, with a good prognosis, can occur in cases with an idiopathic aetiology. PMID:23573403

Abdellatif, Mohamed; Alsinani, Siham; Al-Balushi, Zenab; Al-Dughaishi, Tamima; Abuanza, Mazen; Al-Riyami, Nihal

2013-02-01

378

Chronic Pancreatitis Associated with Chylous Ascites Simulating Liver Cirrhosis  

PubMed Central

Purpose. Ascites, esophageal varicose veins, and acute digestive bleeding are unusual in the clinical presentation of chronic pancreatitis; however, these symptoms are frequently observed in patients with liver cirrhosis. Moreover, it is unlikely to observe chylous ascites in both presentations. Method. We report a patient who presented with chronic pancreatitis with splenic vein thrombosis, necrosis of the pancreatic neck and tail, esophageal varicose veins with previous bleeding, and chylous ascites. After partial pancreatectomy, his treatment was based on low-fat oral diet with medium-chain triglycerides with remarkable resolution of the chylous ascites. After 3 years, he presented with decompensated chronic pancreatitis and underwent plexus alcoholization and biliary-enteric deviation with an unremarkable postoperative course. Conclusion. Ascites is rarely associated with chronic pancreatitis, and chylous ascites is even rarer. The treatment of atraumatic chylous ascites is based on resolution of the obstructive causes and should include drainage and a low-fat diet with medium-chain triglycerides.

Nacif, Lucas Souto; Araujo, Raphael L. C.; Buscariolli, Yuri dos Santos; Salvato, Mayara; D'Albuquerque, Luiz Augusto Carneiro

2013-01-01

379

Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth.  

PubMed

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

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

2014-07-01

380

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

381

Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth.  

PubMed

Interleukin-20 (IL-20) is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, little is known about the role of IL-20 in oral cancer. We explored the function of IL-20 in the tumor progression of oral cancer. IL-20 expression levels in tumorous and nontumorous oral tissue specimens from 40 patients with four different stages oral cancer were analyzed with immunohistochemistry (IHC) staining and quantitative real-time PCR (qRT-PCR). Expression of IL-20 and its receptor subunits was higher in clinical oral tumor tissue than in nontumorous oral tissue. The role of IL-20 was examined in two oral cancer cell lines (OC-3 and OEC-M1). In vitro, IL-20 promoted TNF-?, IL-1?, MCP-1, CCR4, and CXCR4 and increased proliferation, migration, reactive oxygen species (ROS) production, and colony formation of oral cancer cells via activated STAT3 and AKT/JNK/ERK signals. To evaluate the therapeutic potential of anti-IL-20 monoclonal antibody 7E for treating oral cancer, an ex vivo tumor growth model was used. In vivo, 7E reduced tumor growth and inflammation in oral cancer cells. In conclusion, IL-20 promoted oral tumor growth, migration, and tumor-associ