scholarly journals Chemokine Expression Is Involved in the Vascular Neogenesis of Ewing Sarcoma: A Preliminary Analysis of the Early Stages of Angiogenesis in a Xenograft Model

2018 ◽  
Vol 22 (1) ◽  
pp. 30-39
Author(s):  
Francisco Giner ◽  
José A López-Guerrero ◽  
Antonio Fernández-Serra ◽  
Isidro Machado ◽  
Empar Mayordomo-Aranda ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Nude Mice ◽  
Ewing Sarcoma ◽  
Xenograft Model ◽  
Bone Cancer ◽  
Mouse Serum ◽  
Early Stages ◽  
Peritumoral Stroma ◽  
Ligand Expression

Background Ewing sarcoma (EWS) is the second most common bone cancer in pediatric patients. Angiogenesis is a major factor for tumor growth and metastasis. Our aim was to carry out a histological, immunohistochemical, and molecular characterization of the neovascularization established between xenotransplanted tumors and the host during the initial phases of growth in nude mice in three angiogenesis experiments (ES2, ES3, and ES4). Methods The original human EWS were implanted subcutaneously on the backs of three nude mice. Tumor pieces 3 mm–4 mm in size from early passages of Nu432, Nu495, and Nu471 were also implanted subcutaneously on the backs of three sets (ES2, ES3, and ES4) of athymic Balb-c nude mice (n = 14 each). The animals were sacrificed at 24, 48, and 96 hours and at 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularization experiments). Results We observed histological, ultrastructural, and immunohistochemical changes in the xenografted tumor at different times after implantation. Chemokine ligand expression peaked twice, once during the first 48 hours and again in the second week. We observed that tumor cells in contact with murine peritumoral stroma presented higher expression of chemokine ligands as well as more tumor cells around the capillary vessels. Mouse serum vascular endothelial growth factor levels peaked twice, once in the first hours and then in the second week after tumor implantation. Conclusion Chemokines and other angiogenic factors may be relevant in the angiogenic mechanism during tumor growth. This model provides information on the early stages of the angiogenic process and could be a useful tool in researching anti-angiogenic drugs for new therapeutic strategies in EWS.

scholarly journals Compression-induced dedifferentiation of adipocytes promotes tumor progression

2020 ◽  
Vol 6 (4) ◽  
pp. eaax5611 ◽  
Author(s):  
Yiwei Li ◽  
Angelo S. Mao ◽  
Bo Ri Seo ◽  
Xing Zhao ◽  
Satish Kumar Gupta ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Tumor Cells ◽  
De Novo ◽  
Xenograft Model ◽  
Mammary Adenocarcinoma ◽  
Transcriptome Profile ◽  
Self Renewal

Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.

scholarly journals Chinese Formula Ganji Fang Inhibits Tumor Growth Through Regulating Cell Mitosis by Reducing ARPP-19 Expression in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Chunlei Zhang ◽  
Kaiyue Tang ◽  
Lili Yang ◽  
Yang Liu ◽  
Yifan Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Survival Time ◽  
Nude Mice ◽  
Tumor Volume ◽  
Xenograft Model ◽  
The Body ◽  
Proliferation Index ◽  
Mouse Xenograft Model ◽  
Liver And Kidney

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with high rate of mortality worldwide. Rare effective treatment is available for HCC patients especially at advanced stage. Ganji Fang (GJF), one formula of traditional Chinese medicine (TCM), has shown therapeutic effect on HCC in clinical application. This study aims at evaluating the anti-HCC effect and safety of GJF treatment, as well as exploring the potential underlying molecular mechanism by using HCC mouse model. Methods: HepG2 cells were subcutaneously injected into the upper flank of male BALB/c nude mice to establish the HCC Xenograft model. Mice were randomly assigned to three groups, treated respectively with high (GJF-H group) or low dose (GJF-L group) of GJF or vehicle (Control group) via gavage. The tumor volume was detected dynamically. Four weeks later, the weight and proliferation activity of tumors were measured. Western blot and immunohistochemistry were used to detect the expression of cAMP-regulated phosphoprotein 19 (ARPP-19) and the regulated molecules. H&E staining of tissue section of liver and kidney was used to assess the toxicity of the formula. Foe investigation of survival time, SMMC 7721 cells were injected subcutaneously to the BALB/c-nude mice. The tumor-bearing mice were allocated into two groups (Control and GJF-H) and treated as above description. The death number of mice was recorded and the survival time was analyzed.Results: Compared with control, the body weight and activity of GJF-treated mice were improved obviously. No toxic change was observed in tissues of liver and kidney. The tumor volume and weight was significantly down-regulated by GJF dose-dependently. The mice with GJF treatment showed the tendency of prolonging survival time. The proliferation index and PCNA expression in the tumor of GJF group were lower than in control. Furthermore, GJF down-regulated levels of ARPP-19 and phospho-(Ser) CDKs substrates, up-regulated level of inactivated cyclin division cycle 2 (Cdc2). Conclusion: GJF can effectively inhibit tumor growth of HCC and improve the general condition of the nude mouse xenograft model. The mechanism of inhibiting tumor growth is partially related to down-regulating ARPP-19 to inhibit mitosis and cell proliferation of HCC.

scholarly journals Ultrasound-Targeted Microbubble Destruction Enhances Inhibitory Effect of Apatinib on Angiogenesis in Triple Negative Breast Carcinoma Xenografts

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dengke Hong ◽  
Jiajia Yang ◽  
Jingjing Guo ◽  
Yu Zhang ◽  
Zhikui Chen
Keyword(s):  
Body Weight ◽  
Tumor Growth ◽  
Nude Mice ◽  
Triple Negative ◽  
Good Condition ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Blood Parameters ◽  
Model Control ◽  
Growth Inhibiting

Ultrasound-targeted microbubble destruction (UTMD) has been proven as an effective technique to assist drugs to cross the vascular wall and cell membrane. This study was aimed at evaluating the synergistic antiangiogenic and growth-inhibiting effects of apatinib (APA) and UTMD on the triple negative breast cancer (TNBC). The TNBC xenograft model was established in nude mice ( n = 40 ) which were then randomly divided into the APA plus UTMD (APA-U) group, UTMD group, APA group, and model control (M) group ( n = 10 per group). Corresponding treatment was done once daily for 14 consecutive days. The general condition and body weight of tumor-bearing nude mice were monitored. Routine blood test and detection of liver and kidney function were done after treatments. The tumor size and microcirculation were examined by two-dimensional ultrasonography (2DUS) and contrast-enhanced ultrasonography (CEUS), respectively. Then, the tumor tissues were harvested for the detection of vascular endothelial growth factor (VEGF) by immunohistochemistry and for CD31-PAS double staining to assess microvessel density (MVD) and heterogeneous vascular positivity rate. After treatments, the tumor growth and angiogenesis were significantly inhibited in the APA group and the APA-U group, and these effects were more obvious in the APA-U group. The tumor volume, CEUS parameters, VEGF expression, and MVD in the APA-U group were significantly lower than those in the APA group ( P < 0.05 ), while there were no marked differences in the heterogeneous vascular positivity rate, body weight, and blood parameters between the two groups ( P > 0.05 ). In the UTMD group, the tumor growth and angiogenesis were not significantly inhibited, and all the parameters were similar to those in the M group ( P > 0.05 ). During the experiment, all mice survived and generally had good condition. In conclusion, APA combined with UTMD may exert synergistic antiangiogenic and growth-inhibiting effects on the TNBC and not increase the heterogeneous vasculature and the severity of APA-related systemic side effects.

The effect of lncRNA HOTAIR on chemoresistance of ovarian cancer through regulation of HOXA7

2018 ◽  
Vol 399 (5) ◽  
pp. 485-497 ◽  
Author(s):  
Siwei Liu ◽  
Huajiang Lei ◽  
Fangyuan Luo ◽  
Yilin Li ◽  
Lan Xie
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Nude Mice ◽  
Tumor Development ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Qrt Pcr

AbstractThis study aimed at investigating the biological functions of long non-coding RNAs (lncRNAs) hox transcript antisense intergenic RNA (HOTAIR) in resistant ovarian cancer cells, exploring the regulation effect of HOTAIR onHOXA7, and investigating their influence on the chemosensitivity of ovarian cancer cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied for the verification of HOTAIR expression in resistant and sensitive groups. How HOTAIR downregulation affected cell proliferation, migration and invasion, and apoptosis were determined using the MTT assay and the colony formation assay, the Transwell assay and flow cytometry analysis, respectively. Immunohistochemistry was used to inspect the protein expression of HOXA7 in resistant and sensitive ovarian cancer tissues. The regulation relationship between HOTAIR andHOXA7was investigated by qRT-PCR and Western blot. The effect of HOTAIR andHOXA7on tumor growth was confirmed by the tumor xenograft model of nude mice. By knocking downHOXA7, HOTAIR downregulation restrained the ovarian cancer deterioration in functional experiments. Silencing of HOTAIR andHOXA7could effectively inhibit tumor growth and increase chemosensitivity of ovarian tumors in nude mice. Downregulation of HOTAIR negatively affected the survival and activity of resistant ovarian cancer cells, and suppressed the expression ofHOXA7. Silencing of HOTAIR andHOXA7could increase the chemosensitivity of ovarian cancer cells, thus suppressing tumor development.

Antagonist Anti-CD40 Monoclonal Antibody, CHIR-12.12, Inhibits Growth of a Rituximab-Resistant NHL Xenograft Model and Achieves Synergistic Activity When Combined with Ineffective Rituximab.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3281-3281 ◽  
Author(s):  
Li Long ◽  
Xia Tong ◽  
Montesa Patawaran ◽  
Lea Aukerman ◽  
Julie Klinger ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
B Cell ◽  
Tumor Cells ◽  
Xenograft Model ◽  
Synergistic Activity ◽  
B Cell Malignancies ◽  
Hodgkin's Lymphomas ◽  
Anti Tumor Activity

Abstract CD40 and CD20 are expressed in several B-cell malignancies and represent attractive targets for therapeutic intervention. The anti-CD20 monoclonal antibody, rituximab, is an approved drug for the treatment of non-Hodgkin’s lymphomas. however, the existence of patients with rituximab-resistant disease limits its clinical utility. We have previously reported that the novel, highly potent, fully human antagonistic anti-CD40 monoclonal antibody, CHIR-12.12, generated from XenoMouse® mice (Abgenix, Inc) has greater anti-tumor activity than rituximab in both rituximab-responsive and rituximab-resistant human NHL models. In this study, we evaluated the potential therapeutic application of combining CHIR-12.12 and rituximab for the treatment of NHL. Namalwa is a Burkitt’s lymphoma cell line that gives rise to aggressive rituximab-resistant tumors when implanted in nude mice. Direct treatment of these tumor cells with CHIR-12.12 or rituximab in culture does not affect cell growth when compared to treatment with an isotype control antibody. Although Namalwa cells express more CD20 than CD40 (average of 10,059 CD20 and 3,138 CD40 molecules per cell respectively, P=0.05), when tested for in vitro ADCC killing using human NK cells as effectors, CHIR-12.12 mediated stronger target cell lysis than rituximab (31.43% vs. 14.15%, P<0.0001). Adding CHIR-12.12 and rituximab together did not enhance the in vitro ADCC killing. When CHIR-12.12 and rituximab were tested in a subcutaneous Namalwa xenograft model, CHIR-12.12 alone caused 60% tumor growth inhibition (P=0.028) whereas rituximab alone at 10 and 20 mg/kg did not inhibit Namalwa tumor growth. When tumor-bearing mice were administered rituximab at 10 mg/kg plus CHIR-12.12 at 5 or 10 mg/kg, synergistic anti-tumor activity was observed in a CHIR-12.12 dose-dependent manner. The mean tumor volume reduction in combination groups is 77% with CHIR-12.12 at 5 mg/kg (P=0.0037) and 83% with CHIR-12.12 at 10 mg/kg (P=0.0018), respectively. The potential interaction between CD40 and CD20 molecules was evaluated in vitro by treating the tumor cells with CHIR-12.12 and assessing the change in CD20 expression and vice versa. The result showed no augmentation of one antigen expression by treating the tumor cells with the other antibody. The mechanism of anti-tumor synergy observed in this combination is under evaluation. Taken together, these data suggest that the combination therapy with anti-CD40 CHIR-12.12 and rituximab has the potential to improve patient outcome in B-cell malignancies co-expressing CD20 and CD40 antigens and support the further development of CHIR-12.12 antibody for treatment of B-cell malignancies.

Effect of anamorelin/ONO-7643, a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19577-e19577
Author(s):  
Robert Northrup ◽  
Ken Kuroda ◽  
Elizabeth Manning Duus ◽  
Sheri Routt Barnes ◽  
Tim Wiley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Food Consumption ◽  
Nude Mice ◽  
Receptor Agonist ◽  
Xenograft Model ◽  
Ghrelin Receptor ◽  
Mouse Xenograft Model ◽  
Ghrelin Receptor Agonist

e19577 Background: Anamorelin/ONO-7643 is an orally-active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related cachexia/anorexia. It displays both anabolic and orexigenic properties via its ghrelin and growth hormone (GH) secretagogue activity. However, increasing GH and insulin-like growth factor-1 (IGF-1) in cancer patients raises potential concerns of stimulating tumor growth. In this study, we investigated the effect of ghrelin and Anamorelin/ONO-7643 on tumor growth in a NSCLC xenograft model. Methods: On Day 1 (D1), 21 days after implanting A549 tumors, female nude mice were sorted into six groups (n=15/group) and administered ghrelin (2 mg/kg i.p.), Anamorelin/ONO-7643 (3, 10, or 30 mg/kg p.o.) or vehicles (saline i.p. or de-ionized water p.o.) for 28 days, starting on D3. Tumor growth, body weight, and food consumption were monitored. Mice used to assess plasma levels of murine GH (mGH) and IGF-1 (mIGF-1) were sorted into three groups (n=21/group) and treated for 28 days with ghrelin, the high dose of Anamorelin/ONO-7643 or vehicle (de-ionized water p.o.). Results: After 28 days of treatment, there was no difference in median tumor volumes (D30 values: 1008, 936, 1080, 666 and 847 mm3 for vehicle, ghrelin and Anamorelin/ONO-7643 at 3, 10 and 30 mg/kg, respectively). Ghrelin significantly increased mGH compared to controls, while Anamorelin/ONO-7643 modestly increased mGH. Peak mIGF-1 levels were slightly higher in animals given ghrelin or Anamorelin/ONO-7643 compared to vehicle, although not significantly. Anamorelin/ONO-7643 at 10 and 30 mg/kg/day showed a statistically significant (p<0.01) increase in body weight from D1 to D30 compared to control animals, with no change in food consumption. Ghrelin treatment had no effect on body weight or food consumption. Conclusions: Anamorelin/ONO-7643 or ghrelin treatment for 28 days had no effect on tumor growth in A549 tumor-bearing nude mice, despite increased mGH and a trend of increased mIGF-1. Anamorelin/ONO-7643 also significantly increased body weight at 10 and 30 mg/kg/day. These results support using ghrelin receptor agonist-based treatments in managing NSCLC-related cachexia/anorexia.

Intratumoral exposure levels of pentaglutamated pemetrexed following treatment with LEAF-1401 and pemetrexed.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3524-3524
Author(s):  
Gwangseong Kim ◽  
Angelique Nyinawabera ◽  
Zhenghong (Hannah) Xu ◽  
Jason DeFuria ◽  
Alvin Sezibera ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Xenograft Model ◽  
Fold Increase ◽  
Drug Candidate ◽  
Tumor Growth Inhibition ◽  
Intracellular Enzyme ◽  
Exposure Levels

3524 Background: The activity of pemetrexed is highly dependent on the intracellular enzyme folypolyglutamate synthase (FPGS) which adds glutamates to pemetrexed and yields very potent pemetrexed polyglutamates. Pemetrexed pentaglutamate (tetraglutamated pemetrexed) is 80-fold more potent than pemetrexed in inhibiting thymidylate synthase. Yet it is a poor drug candidate because it cannot readily cross the negatively charged cell membrane due to its own negative charge. We are developing LEAF-1401, a novel nanoliposomal encapsulation of gamma L-pentaglutamated pemetrexed. Because liposomes can readily be taken up by tumor cells, for its anti-tumor effect, LEAF-1401 can directly deliver pentaglutamated pemetrexed into tumor cells, bypassing the need for transmembrane folate carriers and FPGS which are both downregulated in resistant tumors. Methods: To measure drug levels in tumor, blood and various tissues (biodistribution), in vivo testing of LEAF-1401 and pemetrexed was conducted in a CT-26 murine colorectal carcinoma xenograft model. Animals were treated with a single dose of either LEAF-1401 (80mg/kg; equivalent to 32 mg/kg pemetrexed) or pemetrexed (118mg/kg). Tumor growth inhibition and clinical assessments were conducted. Animals were sacrificed: 5 mice per timepoint in each group and tumor, blood, liver, spleen and other tissues were harvested. Pentaglutamated pemetrexed levels were quantitatively analyzed by LC/MS/MS. Results: Compared to pemetrexed, LEAF-1401 treatment resulted in a 19-fold increase in exposure levels of pentaglutamated pemetrexed in the tumor and significant tumor growth inhibition. Plasma levels of pentaglutamated pemetrexed were high with LEAF-1401, but undetectable with pemetrexed. Like other liposomes, LEAF-1401 also resulted in accumulation of pentaglutamated pemetrexed in the liver and spleen (See Table below). Treatment appeared to be generally well tolerated. Conclusions: LEAF-1401, given at approximately a quarter of the equivalent pemetrexed dose, resulted in a 19-fold increase in pentaglutamate pemetrexed in tumor tissue compared to regular pemetrexed. LEAF-1401 represents a promising new class of novel nanoliposomal antifolates, that enhance the intratumoral delivery of potent polyglutamate antifolates, and improve antitumor activity while retaining an acceptable safety profile. [Table: see text]

scholarly journals Inhibition of Tumor Growth of Human Hepatocellular Carcinoma HepG2 Cells in a Nude Mouse Xenograft Model by the Total Flavonoids fromArachniodes exilis

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Huimin Li ◽  
Dengzhao Jiang ◽  
Lei Zhang ◽  
Jiazhong Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Nude Mice ◽  
Hepg2 Cells ◽  
Xenograft Model ◽  
Human Hepatocellular Carcinoma ◽  
Total Flavonoids ◽  
Tumor Growth Model ◽  
Mouse Xenograft Model

A tumor growth model of human hepatocellular carcinoma HepG2 cells in nude mice was employed to investigate the antitumor activity of the total flavonoids extracted fromArachniodes exilis(TFAE)in vivo. Several biochemical assays including hematoxylin-eosin (HE) staining, immunohistochemistry, and Western blot were performed to elucidate the mechanism of action of total flavonoids extracted fromArachniodes exilis(TFAE). The results showed that TFAE effectively inhibited the tumor growth of hepatocellular carcinoma in nude mice and had no significant effect on body weight, blood system, and functions of liver and kidney. Expression levels of proapoptotic proteins Bax and cleaved caspase-3 remarkably increased while the expressions of Bcl-2, HIF-1α, and VEGF were suppressed by TFAE. These results suggested that the antitumor potential of TFEA was implied by the apoptosis of tumor cells and the inhibition of angiogenesis in tumor tissue.

Translational assessment of the efficacy of CPI-613 against pancreatic cancer in animal models versus patients with stage IV disease.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3075-3075 ◽  
Author(s):  
Avi S. Retter
Keyword(s):  
Pancreatic Cancer ◽  
Animal Models ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Pancreatic Tumor ◽  
Xenograft Model ◽  
Stage Iv ◽  
Tumor Xenograft ◽  
Mitochondrial Enzymes ◽  
Stage Iv Disease

3075 Background: CPI-613 is a novel agent that selectively targets the altered mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and autophagia. Results assessing clinical efficacy of CPI-613 translated from animal tumor xenograft models to patients with stage IV pancreatic cancer are presented. Methods: Efficacy of CPI-613 was tested in mice with pancreatic tumor xenografts generated by inoculation of BxPC-3 human pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 mg/m2), when used in combination with gemcitabine (1,000 mg/m2), was assessed in patients with stage IV pancreatic cancer. Results: In the animal pancreatic tumor xenograft model (n=10/grp), CPI-613 (25 mg/kg, IV, 1x weekly for 4 weeks) suppressed tumor growth by ~100%, when compared to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 weeks), suppressed tumor growth by only ~50%. Median overall survival in tumor-bearing mice treated with CPI-613 was ~240 days, which was significantly longer than those with gemcitabine or vehicle treatments (~65 and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer (Table), the CPI-613+gemcitabine combination was well-tolerated. In those without prior chemotherapy before participating in the clinical trial (first three patients in the table), the CPI-613+gemcitabine combination prolonged survival that correlated with the dose of CPI-613. Conclusions: CPI-613 exhibits efficacy against pancreatic cancer in animal models, which is translational to patients with stage IV disease. [Table: see text]

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