scholarly journals Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Young Sun Choi ◽  
Hyeonha Jang ◽  
Biki Gupta ◽  
Ji-Hak Jeong ◽  
Yun Ge ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Protein C ◽  
Immune Cell ◽  
Tumor Regression ◽  
Tumor Vasculature ◽  
Growth Factor Signaling ◽  
Antitumor Effects ◽  
Cancer Models

Abstract Background Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities. Methods Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett’s multiple comparison test. Results PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in Gα13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway. Conclusions Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy.

Synergistic antitumor effects of liposomal honokiol combined with adriamycin in breast cancer models

2008 ◽  
Vol 22 (8) ◽  
pp. 1125-1132 ◽  
Author(s):  
Wenli Hou ◽  
Lijuan Chen ◽  
Guangli Yang ◽  
Hang Zhou ◽  
Qiqi Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Effects ◽  
Cancer Models

scholarly journals TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models

2015 ◽  
Vol 5 (5) ◽  
pp. e1123369 ◽  
Author(s):  
Myriam Lamrani ◽  
Nejia Sassi ◽  
Catherine Paul ◽  
Nadhir Yousfi ◽  
Jean-Luc Boucher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Regression ◽  
Ros Production ◽  
Induce Tumor Regression ◽  
Cancer Models

scholarly journals Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

2016 ◽  
Vol 113 (16) ◽  
pp. 4476-4481 ◽  
Author(s):  
Jonas Kloepper ◽  
Lars Riedemann ◽  
Zohreh Amoozgar ◽  
Giorgio Seano ◽  
Katharina Susek ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Cell ◽  
Tumor Vasculature ◽  
Prolonged Survival ◽  
Growth And Survival ◽  
Anti Vegf ◽  
Tumor Immune Microenvironment ◽  
M1 Phenotype ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Azurin, highly potent and selective anticancer agent for breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13106-13106
Author(s):  
T. Yamada ◽  
R. Mehta ◽  
D. Majumdar ◽  
A. M. Chakrabarty ◽  
T. K. Das Gupta
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Volume ◽  
Tumor Regression ◽  
Treated Group ◽  
Redox Protein ◽  
The Mean ◽  
The Difference ◽  
Mcf 7

13106 Background: The use of live or attenuated pathogenic bacteria in the treatment of cancer dates back to the late nineteen hundreds when William B. Coley first reported that inducing Streptococcal infection resulted in tumor regression. However, the hazards of using live bacteria are obvious. Similarly, the results of using attenuated bacteria have been spotty and enthusiasm for it has waxed and waned. Recently, we have shown that redox protein azurin (14 kDa) secreted by an opportunistic pathogen, Pseudomonas aeruginosa, is not only cytotoxic to cancer cells in vitro but also produces tumor regression in athymic mice without producing any toxicity (PNAS, 99, 14098–14103, 2002; Science’s STKE, 158, tw416, 2002). Methods: In this study, we show the effect of 1mg/kg of azurin injected i.p. starting 72 hours after inoculation of 5x107 MCF-7 breast cancer cells in estradiol pretreated nude mice for 28 days (n = 20, control = 10, azurin-treated = 10). Results: Univariate analysis of the data showed the difference in tumor growth rates between control animals and azurin-treated animals was significant. For instance, 22 days after the start of treatment, the mean tumor volume in azurin-treated animals was only 22% of the mean tumor volume in the control mice (i.e., 0.0267 cm3 + 0.124 cm3 respectively, P = 0.0179 Kruskal-Wallis test). At the end of the experiment on the 29th day there was a reduction in the tumor volume by 85% in the treated group. We used a multivariate model, where the tumor growth over time was taken to be exponential with coefficients that were subject specific mixed effect (For control, tumor volumes = exp (−4.23 + 0.06 time) while for the treated group it was tumor volume = exp (−4.23 + 0.03 time)). The difference is statistically significant (P = 0.0456). Taken together, this in vivo data shows azurin exerts an inhibitory effect in the growth and progression of MCF-7 tumor xenotransplants. During the 28 days of treatment, treated animals did not show any sign of toxicity. Conclusions: Bacterial redox protein azurin can be explored as a novel therapeutic agent for treatment of breast cancer. Recently, we have prepared a truncated version of azurin which has 28 amino acids. It appers that this chemically synthesized peptide (2.8 kDa) has similar properties as azurin. No significant financial relationships to disclose.

scholarly journals Simple and effective bacterial-based intratumoral cancer immunotherapy

2021 ◽  
Vol 9 (9) ◽  
pp. e002688
Author(s):  
Christina S E Carroll ◽  
Erin R Andrew ◽  
Laeeq Malik ◽  
Kathryn F Elliott ◽  
Moira Brennan ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Human Cancer ◽  
Intratumoral Injection ◽  
Ct Scans ◽  
Antitumor Effects ◽  
Wide Range

BackgroundWe describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.MethodsEfficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.ResultsSignificantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.ConclusionOur data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.

The Zn(S-pr-thiosal)2 complex attenuates murine breast cancer growth by inducing apoptosis and G1/S cell cycle arrest

2020 ◽  
Vol 12 (10) ◽  
pp. 897-914
Author(s):  
Sasa Benazic ◽  
Zana Besser Silconi ◽  
Andra Jevtovic ◽  
Milena Jurisevic ◽  
Jelena Milovanovic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Cyclin D3 ◽  
Antitumor Effects ◽  
Cycle Arrest ◽  
4T1 Cells

Aim: We investigated the antitumor effects of zinc(II) complex with S-propyl thiosalicylic acid [Zn( S-pr-thiosal)2] in 4T1 murine breast cancer model. Results: The Zn( S-pr-thiosal)2 complex reduced primary tumor growth in vivo and induced tumor cell apoptosis. The Zn( S-pr-thiosal)2 complex disrupted the balance between pro- and antiapoptotic Bcl-2 family members in 4T1 cells and induced G1/S cell cycle arrest. The Zn( S-pr-thiosal)2 complex increased the percentage of p16, p21 and p27 positive 4T1 cells. There was a significantly decrease in expression of STAT3 and its targets c-Myc and cyclin D3 in 4T1 cells treated with the Zn( S-pr-thiosal)2 complex thus contributing to G1/S cell cycle arrest and/or apoptosis. Conclusion: Our data suggest that the Zn( S-pr-thiosal)2 complex restricted tumor growth through induction of mitochondrial-driven apoptosis and suppression of cell cycle progression.

Humanized mice (humice) carrying patient-derived xenograft (PDX) as a platform to develop immunotherapy in bladder cancer (BCa).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 381-381 ◽  
Author(s):  
Chong-xian Pan ◽  
Wei Shi ◽  
Ai-Hong Ma ◽  
Hongyong Zhang ◽  
Primo Lara ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Immune Cell ◽  
Tumor Regression ◽  
Genetic Alterations ◽  
Therapeutic Modality ◽  
Whole Body ◽  
Flow Cytometry Analysis ◽  
Nsg Mice ◽  
Human Immune

381 Background: Immunotherapy with anti-programmed cell death 1 (PD1) or PD ligand 1 (PD-L1) antibody has emerged as a promising therapeutic modality, but has a response rate of approximately 20% in BCa. There are various drawbacks associated with current animal models. The objective of this study is to establish and characterize humice carrying PDXs in which both the immune cells and BCa cells are derived from humans. Methods: NOD-scid IL2Rgammanull or NSG, mice received CD34+ hematopoietic progenitor cells (HPC) cells i.v. after whole body radiation. PDXs were established through direct implantation of human BCa clinical specimens into NSG mice. Immune cell subpopulations were analyzed through flow cytometry analysis. Humice carrying HLA-unmatched PDXs were treated with an anti-PD1 antibody pemborlizumab (pembro) or in combination with a BKT/ITK inhibitor ibrutinib to determine the anti-tumor efficacy and toxicity. Results: PDXs retained the morphology fidelity and 92-97% of genetic alterations of parental patient cancers. Of the first 8 PDXs tested, 3 had high PD-L1 ( > 10 FPKM) as determined by RNA-seq which was further confirmed with flow cytometry analysis. Major human immune cell sub-populations were reconstituted in humice. No xenograft versus host disease was observed before pembro treatment. In humice with HPC donor 6466, pembro significantly inhibited tumor growth (p = 0.0016 at Day 29) of PDX BL293, but had no effect in another PDX BL440 with the same HPC donor 6466, or with the same PDX BL293 but with a different HPC donor 912. In another set of humice (HPC donor 710) carrying PDX BL293, pembro alone inhibited tumor growth. However, addition of ibrutinib did not potentiate the efficacy of pembro, but increased toxicity. Tumor regression with pembro treatment was associated with decrease of CD4+PD1+, CD8+PD1+ cells at peripheral blood and increased CD45+ and CD8+ cells in PDXs. Conclusions: Humice carrying PDXs reconstitute with human immune system, and can potentially be used to screen for effective immunotherapeutic agents or combinations, and to study resistant mechanisms.

Abstract A112: Combined targeting of HER2 and HER3 inhibits tumor growth in both trastuzumab-sensitive and trastuzumab-resistant breast cancer models.

2013 ◽  
Author(s):  
Philipp Steiner ◽  
Leslie Wetzel ◽  
Kevin Schifferli ◽  
Raymond Rothstein ◽  
Ravinder Tammali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Models
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