Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model

2016 ◽  
Vol 372 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Manal Amoury ◽  
Katharina Kolberg ◽  
Anh-Tuan Pham ◽  
Dmitrij Hristodorov ◽  
Radoslav Mladenov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fusion Protein ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Protein Targeting ◽  
Granzyme B ◽  
Tumor Model ◽  
Mouse Tumor ◽  
Mouse Tumor Model

scholarly journals 845 A colony stimulating factor 1 receptor-blocking bifunctional protein simultaneously targets tumor-associated macrophages and exhausted T cells for the treatment of triple-negative breast cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A886-A886
Author(s):  
Pandelakis Koni ◽  
Hung-Kai Chen ◽  
Yao-Wen Chang ◽  
Huey-Wen Hsiao ◽  
Chih-Lun Hsiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Fusion Protein ◽  
Tumor Immunity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Model ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

BackgroundTumor-associated macrophages (TAMs) are a significantly-poor prognostic factor for patients with triple-negative breast cancer (TNBC). The tumor microenvironment of TNBC features highly-infiltrating TAMs that contribute to tumor progression and metastasis. Therefore, TAM-targeted immunotherapies are recognized as a potential approach for treating TNBC. However, depleting TAMs alone by use of monoclonal antibodies against colony-stimulating factor 1 receptor (CSF1R) was insufficient to cause substantial tumor control. Recent studies revealed that interleukin-10 (IL-10) can directly activate terminally-exhausted CD8+ T cells to boost anti-tumor activity. We set forth to investigate whether a combination of anti-CSF1R antibody with a half-life-extended IL-10-Fc fusion protein (IL-10-Fc) may enhance anti-tumor immunity, and whether synergistic effects could be achieved with bifunctional antibody forms.MethodsAntibodies and recombinant proteins were produced in-house. In vitro CSF1R activity was evaluated by Western blot analysis of CSF1-mediated CSF1R phosphorylation and monocyte proliferation assays. In vitro IL10 activity was evaluated by MC/9 cell proliferation and CD8 T cell activation assays. 4T1 mouse breast tumor studies were performed at the National Yang Ming Chiao Tung University (Taiwan). Other tumor model studies employed the services of Crownbio (China). Methods of RNAseq analysis of 4T1 tumor masses included Cibersort, gene set enrichment analysis (GSEA) and immune gene signature score analysis.ResultsCo-treatment with a recombinant human IL-10-Fc protein significantly improved the anti-tumor efficacy of anti-mouse CSF1R antibody in a mouse CT26 colon tumor model. It was then hypothesized that a better synergistic effect could be achieved by a bifunctional anti-mouse CSF1R-IL-10 fusion protein (anti-mCSF1R-IL-10), to allow targeted-delivery of IL-10 to CSF1R-positive-TAM-rich tumor microenvironments. Indeed, anti-mCSF1R-IL-10 showed greatly increased anti-tumor efficacy in both EMT-6 and 4T1 mouse models of breast cancer. Consistent with the in vivo efficacy, gene expression profiling revealed an enhanced intratumoral interferon-gamma signature by treatment with anti-mCSF1R-IL-10 as compared to either anti-mCSF1R or IL-10-Fc alone. An anti-human CSF1R-IL-10 (hCSF1R-IL-10) was also constructed using a newly-produced anti-human CSF1R antibody and tested in cell-based functional assays, demonstrating that anti-hCSF1R-IL-10 could both inhibit CSF1-dependent cell growth and activate tumor-infiltrating T cells isolated from tumor biopsies of triple-negative breast cancer patients. Further validation of this bifunctional form will be presented.ConclusionsOur findings provide a potential strategy for simultaneously targeting TAM and exhausted T cells to potentiate anti-tumor immunity for treatment of triple-negative breast cancer.Ethics ApprovalThe studies were approved by the institutional animal care and use committee of National Yang Ming Chiao Tung University; approval numbers 1081025 and 109060.

The Impact of Antioxidants from the Diet on Breast Cancer Cells Monitored by Raman Microspectroscopy

2018 ◽  
Vol 16 (2) ◽  
pp. 127-137
Author(s):  
Paula Sofia Coutinho Medeiros ◽  
Ana Lúcia Marques Batista de Carvalho ◽  
Cristina Ruano ◽  
Juan Carlos Otero ◽  
Maria Paula Matos Marques
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Breast Adenocarcinoma ◽  
Coumaric Acid ◽  
Human Breast ◽  
The Impact

Background: The impact of the ubiquitous dietary phenolic compound p-coumaric acid on human breast cancer cells was assessed, through a multidisciplinary approach: Combined biological assays for cytotoxicity evaluation and biochemical profiling by Raman microspectroscopic analysis in cells. </P><P> Methods: Para-coumaric acid was shown to exert in vitro chemoprotective and antitumor activities, depending on the concentration and cell line probed: a significant anti-invasive ability was detected for the triple-negative MDA-MB-231 cells, while a high pro-oxidant effect was found for the estrogen- dependent MCF-7 cells. A striking cell selectivity was obtained, with a more noticeable outcome on the triple-negative MDA-MB-231 cell line. Results: The main impact on the cellular biochemical profile was verified to be on proteins and lipids, thus justifying the compound´s anti-invasive effect and chemoprotective ability. Conclusion: p-Coumaric acid was thus shown to be a promising chemoprotective/chemotherapeutic agent, particularly against the low prognosis triple-negative human breast adenocarcinoma.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

scholarly journals Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro

BMC Cancer ◽  
2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Susanne Schüler-Toprak ◽  
Julia Häring ◽  
Elisabeth C. Inwald ◽  
Christoph Moehle ◽  
Olaf Ortmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Estrogen Receptor Β

Identification of a rhodium(iii) complex as a Wee1 inhibitor againstTP53-mutated triple-negative breast cancer cells

2018 ◽  
Vol 54 (20) ◽  
pp. 2463-2466 ◽  
Author(s):  
Guan-Jun Yang ◽  
Hai-Jing Zhong ◽  
Chung-Nga Ko ◽  
Suk-Yu Wong ◽  
Kasipandi Vellaisamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

The rhodium(iii) complex1was identified as a potent Wee1 inhibitorin vitroandin cellulo.

scholarly journals Breast Cancer Cells in Microgravity: New Aspects for Cancer Research

2020 ◽  
Vol 21 (19) ◽  
pp. 7345 ◽  
Author(s):  
Mohamed Zakaria Nassef ◽  
Daniela Melnik ◽  
Sascha Kopp ◽  
Jayashree Sahana ◽  
Manfred Infanger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Tumor Model ◽  
Cancer Drug ◽  
Cancer Therapies

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an “unsolved problem of the last century”, breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

Synergistic effect of granzyme B-azurin fusion protein on breast cancer cells

2019 ◽  
Vol 46 (3) ◽  
pp. 3129-3140 ◽  
Author(s):  
Nafiseh Paydarnia ◽  
Shahryar Khoshtinat Nikkhoi ◽  
Azita Fakhravar ◽  
Mohsen Mehdiabdol ◽  
Hedieh Heydarzadeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Synergistic Effect ◽  
Fusion Protein ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Granzyme B

Design, synthesis, and anti-proliferative evaluation of 1H-1,2,3-triazole grafted tetrahydro-β-carboline-chalcone/ferrocenylchalcone conjugates in estrogen responsive and triple negative breast cancer cells

2020 ◽  
Vol 44 (26) ◽  
pp. 11137-11147 ◽  
Author(s):  
Bharvi Sharma ◽  
Liang Gu ◽  
Ruvesh Pascal Pillay ◽  
Nosipho Cele ◽  
Paul Awolade ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Design Synthesis ◽  
Mcf 7

A series of 1H-1,2,3 triazole grafted tetrahydro-β-carboline-chalcone/ferrocenylchalcone conjugates were synthesized and in vitro evaluated against estrogen responsive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells.

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