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Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma
Thesis (PhD (Medical Immunology))--University of Pretoria, 2023.
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University of Pretoria
2023
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| _version_ | 1867613506629533696 |
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| access_status_str | Open Access |
| author2 | Ambele, Melvin |
| author_browse | Ambele, Melvin |
| author_facet | Ambele, Melvin |
| collection | Thesis |
| dc_rights_str_mv | © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Medical Immunology))--University of Pretoria, 2023. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/91939 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:14.131Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/91939 Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma Ambele, Melvin kimberlypeta23@gmail.com Pepper, Michael Sean Durandt, Chrisna Peta, Kimberly Thando UCTD Breast cancer Mesenchymal stem/stromal cells 2-methoxyestradiol Tumour microenvironment Metastasis Tumour progression Macrophages Cytokines Health sciences theses SDG-03 SDG-03: Good health and well-being Thesis (PhD (Medical Immunology))--University of Pretoria, 2023. Breast cancer (BC) is the most prevalent cancer in females and the leading cause of cancer deaths. Treatment options include mastectomy, chemotherapy, and radiotherapy. While these treatments can improve 5-year survival rates and reduce recurrence risk, they also affect healthy cells and not are effective for metastatic BC. To address these limitations, alternative therapies targeting only cancerous cells such as mesenchymal stromal/stem cell (MSC) therapy and a novel chemotherapeutic agent, 2-methoxyestradiol (2-ME), have been explored. MSCs have the ability to “home” to the tumour microenvironment (TME) and either promote or suppress tumour progression. Previous studies resulted in inconsistent results because of varied experimental designs including xenograft models that yielded conflicting results due to cross-species variations, limiting their interpretation. To overcome this, an isogenic mouse model of spontaneous BC was utilized to investigate the effect of MSCs on BC development. MSCs isolated from FVB/N mouse adipose tissue (mASC) were administered to heterozygous FVB/N-Tg(MMTV-PyVT)634Mul/J female mice that develop palpable mammary tumours. While no significant change in mammary tumour mass and volume was observed with mASC treatment, necrosis in lung lesions increased. Also, there was reduced number of CD163+ M2 macrophages and increased CD3+ T cells in the lungs but not mammary tumours in treatment group. Vegfr1, cd105 and mtdh were downregulated in the lungs suggesting an anti-tumour effect, potentially due to the presence of trapped mASCs. Overall, 13 of the measured cytokines were higher in the mASC treated group. These findings indicate that mASCs have an anti-tumour effect on pulmonary metastatic BC. The effect of 2-ME, a compound known for its anti-proliferative and anti-angiogenic properties, on the different stages of BC tumour development, is still unknown and was therefore investigated. The effects of 2-ME treatment on early- and late-stage BC were compared. While 2-ME treatment of early-stage BC led to reduced tumour necrosis with increased mass and volume of mammary tumours, a greater number of necrotic lesions and CD163 macrophages were observed in pulmonary metastatic tumours. Conversely, 2-ME treatment of late-stage BC inhibited tumour growth, increased CD3+ T cells and induced tumour necrosis. However, survival rates were not improved. Cytokine measurements of v early-stage BC indicated that 2-ME may have a pro-rumour effect. These findings suggest that 2-ME treatment has an antitumour effect on late-stage BC but does not enhance survival while no significant benefits were observed with 2-ME treatment of early-stage BC. Interestingly, 2-ME treatment before the appearance of palpable tumours resulted in a significant increase in tumour mass. This pro-tumour activity was accompanied by lower numbers of CD3+ T cells in the TME and elevated levels of the pro-inflammatory cytokine interleukin (IL)-1β. However, 2-ME treatment also led to fewer CD163+ macrophages in the TME, increased tumour necrosis, increased IL-10, and reduced IL-6 and IL-27 levels. This suggests that 2-ME may promote tumour development at the onset and early stages of BC development. In summary, BC is a complex disease with various stages, including tumour initiation, growth, progression and metastasis, and treatment effectiveness varies according to cancer stage. While mASCs show promise in treating pulmonary metastatic BC, 2-ME demonstrates an antitumour effect in late-stage BC but lacks efficacy in early-stage BC. Understanding the diverse responses to these treatments is crucial for developing targeted therapies that can effectively combat BC at different stages of progression. South African Medical Research Council Self-Initiated Research Grant (grant no. A1A982) National Research Foundation Competitive Support for Unrated Researchers (grant no. 114044) South African Medical Research Council University Flagship Project (SAMRC-RFA-UFSP-01-2013/STEM CELLS) Institute for Cellular and Molecular Medicine of the University of Pretoria. SAMRC Extramural Unit for Stem Cell Research and Therapy. Immunology PhD (Medical Immunology) Unrestricted 2023-08-16T09:44:51Z 2023-08-16T09:44:51Z 2023-09-08 2023 Thesis * S2023 http://hdl.handle.net/2263/91939 DOI: https://doi.org/10.25403/UPresearchdata.23961129.v1 10.25403/UPresearchdata.23961129 en © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD Breast cancer Mesenchymal stem/stromal cells 2-methoxyestradiol Tumour microenvironment Metastasis Tumour progression Macrophages Cytokines Health sciences theses SDG-03 SDG-03: Good health and well-being Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title | Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title_full | Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title_fullStr | Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title_full_unstemmed | Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title_short | Influence of mesenchymal stromal cells and 2-methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| title_sort | influence of mesenchymal stromal cells and 2 methoxyestradiol in a murine model of spontaneous mammary carcinoma |
| topic | UCTD Breast cancer Mesenchymal stem/stromal cells 2-methoxyestradiol Tumour microenvironment Metastasis Tumour progression Macrophages Cytokines Health sciences theses SDG-03 SDG-03: Good health and well-being |
| url | http://hdl.handle.net/2263/91939 |