An immunoregulatory role for complement receptors in murine models of breast cancer
The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Multidisciplinary Digital Publishing Institute
2021
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| Online Access: | http://psasir.upm.edu.my/id/eprint/95856/ |
| _version_ | 1848862236535160832 |
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| author | Md Akhir, Fazrena Nadia Mohd Noor, Mohd Hezmee Weng, Keith Kit Leong Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E Nga, Jenny Ting Fung McGirr, Crystal E Shiels, Ian A. Mills, Paul C. Woodruff, Trent Rolfe, Barbara |
| author_facet | Md Akhir, Fazrena Nadia Mohd Noor, Mohd Hezmee Weng, Keith Kit Leong Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E Nga, Jenny Ting Fung McGirr, Crystal E Shiels, Ian A. Mills, Paul C. Woodruff, Trent Rolfe, Barbara |
| author_sort | Md Akhir, Fazrena Nadia |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment. |
| first_indexed | 2025-11-15T13:13:49Z |
| format | Article |
| id | upm-95856 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-15T13:13:49Z |
| publishDate | 2021 |
| publisher | Multidisciplinary Digital Publishing Institute |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-958562023-03-29T03:58:14Z http://psasir.upm.edu.my/id/eprint/95856/ An immunoregulatory role for complement receptors in murine models of breast cancer Md Akhir, Fazrena Nadia Mohd Noor, Mohd Hezmee Weng, Keith Kit Leong Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E Nga, Jenny Ting Fung McGirr, Crystal E Shiels, Ian A. Mills, Paul C. Woodruff, Trent Rolfe, Barbara The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment. Multidisciplinary Digital Publishing Institute 2021 Article PeerReviewed Md Akhir, Fazrena Nadia and Mohd Noor, Mohd Hezmee and Weng, Keith Kit Leong and Nabizadeh, Jamileh A. and Manthey, Helga D. and Sonderegger, Stefan E and Nga, Jenny Ting Fung and McGirr, Crystal E and Shiels, Ian A. and Mills, Paul C. and Woodruff, Trent and Rolfe, Barbara (2021) An immunoregulatory role for complement receptors in murine models of breast cancer. Antibodies, 10 (1). art. no. 2. pp. 1-12. ISSN 2073-4468 https://www.mdpi.com/2073-4468/10/1/2 10.3390/antib10010002 |
| spellingShingle | Md Akhir, Fazrena Nadia Mohd Noor, Mohd Hezmee Weng, Keith Kit Leong Nabizadeh, Jamileh A. Manthey, Helga D. Sonderegger, Stefan E Nga, Jenny Ting Fung McGirr, Crystal E Shiels, Ian A. Mills, Paul C. Woodruff, Trent Rolfe, Barbara An immunoregulatory role for complement receptors in murine models of breast cancer |
| title | An immunoregulatory role for complement receptors in murine models of breast cancer |
| title_full | An immunoregulatory role for complement receptors in murine models of breast cancer |
| title_fullStr | An immunoregulatory role for complement receptors in murine models of breast cancer |
| title_full_unstemmed | An immunoregulatory role for complement receptors in murine models of breast cancer |
| title_short | An immunoregulatory role for complement receptors in murine models of breast cancer |
| title_sort | immunoregulatory role for complement receptors in murine models of breast cancer |
| url | http://psasir.upm.edu.my/id/eprint/95856/ http://psasir.upm.edu.my/id/eprint/95856/ http://psasir.upm.edu.my/id/eprint/95856/ |