Supplementation of Spirulina (= Arthrospira) Platensis Induces Immunosuppression through Increasing T-regulatory Cells in a Syngeneic Mouse Model of Breast Cancer
Hemavathy Subramaiam1*, Wan-Loy Chu2, Ammu Kutty Radhakrishnan3, Srikumar Chakravarthi4, Kanga Rani Selvaduray5 and Yih-Yih Kok6
1School of Medicine, International Medical University, Malaysia
2School of Postgraduate Studies, International Medical University, Malaysia
3Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Malaysia
4SEGi University, Jalan Teknologi, Taman Sains Selangor, Selangor Darul Ehsan, Malaysia
5Product Development and Advisory Services Division, Malaysia
6School of Health Sciences, International Medical University, Malaysia
*Corresponding Author: Hemavathy Subramaiam, School of Medicine, International Medical University, Malaysia.
August 10, 2023; Published: September 19, 2023
Spirulina (= Arthrospira) platensis has been reported to have several health-enhancing activities. To date, the anticancer and immunomodulatory effects of Spirulina platensis against breast cancer (BC) in an experimental model have not been fully explored. The aim of this study was to assess the anticancer and immunomodulatory effects of Spirulina (= Arthrospira) platensis against BC in a syngeneic mouse model of BC using two approaches (1) simultaneous treatment and (2) early treatment models. The simultaneous treatment model evaluated the effect of feeding Spirulina at the time of tumor induction to investigate if this can inhibit tumor growth and metastasis. The aim of the early treatment model was to study if feeding the mice with Spirulina daily for two weeks prior to tumor induction can prevent the onset, growth and spread of the BC. In both models, the total duration of Spirulina supplementation was 28 days. There were no differences in body weight (p > 0.05) and tumor volume (p > 0.05) between the simultaneous and early treatments. However, a marked increase (p < 0.05) in the T-regulatory (Treg) population was observed in mice from the simultaneous treatment groups compared to control animals. The findings suggest that Spirulina feeding may induce an immunosuppressive environment in the tumor-induced animal, which may work through increasing their Treg populations, thereby suppressing the host’s immune response to the tumor.
Keywords: Breast Cancer; Spirulina, Immunomodulatory; T-regulatory (Treg) Cells; Metastasis
- Stingl J and Caldas C. “Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis”. Nature Reviews Cancer10 (2007): 791-799.
- Martelotto LG., et al. “Breast cancer intra-tumor heterogeneity”. Breast Cancer Research3 (2014): 210.
- Malhotra GK., et al. “Histological, molecular and functional subtypes of breast cancers”. Cancer Biology and Therapy 10 (2014): 955-960.
- International Agency for Research on Cancer, Globocan (2018).
- Pike MC., et al. “'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer”. Nature 5920 (1983): 767-770.
- Hunter DJ., et al. “A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer”. Nature Genetics 7 (2007): 870-874.
- Talmadge JE., et al. “AACR centennial series: the biology of cancer metastasis: historical perspective”. Cancer Research 14 (2010): 5649-5669.
- Weigelt B., et al. “Breast cancer metastasis: markers and models”. Nature Reviews Cancer8 (2005): 591-602.
- Lee YT. “Breast carcinoma: pattern of metastasis at autopsy”. Journal of Surgical Oncology3 (1983): 175-180.
- Fidler IJ., et al. “The biology of cancer invasion and metastasis”. Advances in Cancer Research 28 (1978): 149-250.
- Poste G and Fidler IJ. “The pathogenesis of cancer metastasis”. Nature5743 (1980): 139-146.
- Janeway CAJr and Medzhitov R. “Innate immune recognition”. Annual Review of Immunology 20 (2002): 197216.
- Jacobsen PB., et al. “Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates”. Journal of Pain and Symptom Management4 (1999): 233-242.
- Byrne J., et al. “Early menopause in longterm survivors of cancer during adolescence”. American Journal of Obstetrics and Gynecology 3 (1992): 788-793.
- Fisher B., et al. “Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer”. Journal of the National Cancer Institute22 (1997): 1673-1682.
- Goodwin PJ., et al. “Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis”. Journal of Clinical Oncology 1 (1999): 120-129.
- Shapiro CL., et al. “Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients”. Journal of Clinical Oncology11 (1998): 3493-3501.
- Belay A. “The Potential Application of Spirulina (Arthrospira) as a Nutritional and Therapeutic supplement in Health Management”. The Journal of The American Nutraceutical Association2 (2002).
- Sapp J. “The prokaryote-eukaryote dichotomy: meanings and mythology”. Microbiology and Molecular Biology Reviews 2 (2005): 292-305.
- Deng R and Chow TJ. “Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina”. Cardiovascular Therapeutics 28 (2010): 33-45.
- Kay RA. “Microalgae as food and supplement”. Critical Reviews in Food Science and Nutrition6 (1991): 555-573.
- Belay A., et al. “Current knowledge on potential health benefits of Spirulina”. Journal of Applied Phycology 5 (1993): 235-241.
- Mao TK., et al. “Effect of spirulina on the secretion of cytokines from peripheral blood mononuclear cells”. Journal of Medicinal Food3 (2000): 135-140.
- Jiang L., et al. “C-Phycocyanin exerts anti-cancer effects via the MAPK signaling pathway in MDA-MB-231 cells”. Cancer Cell International 18 (2018): 12,0180511-5. eCollection 2018.
- Sannasimuthu A., et al. “Design and characterization of a novel Arthrospira platensis glutathione oxido-reductase-derived antioxidant peptide GM15 and its potent anti-cancer activity via caspase-9 mediated apoptosis in oral cancer cells”. Free Radical Biology and Medicine 135 (2019): 198-209.
- Chen YH., et al. “Well-tolerated Spirulina extract inhibits influenza virus replication and reduces virus-induced mortality”. Scientific Report 6 (2016): 24253.
- Lee J., et al. “Spirulina Extract Enhanced a Protective Effect in Type 1 Diabetes by Anti-Apoptosis and Anti-ROS Production”. Nutrients12 (2017): 10.3390/nu9121363.
- Lima FAV., et al. “Neuroprotective Activities of Spirulina platensis in the 6-OHDA Model of Parkinson's Disease Are Related to Its Anti-Inflammatory Effects”. Neurochemistry Research12 (2017): 3390-400.
- Lobner M., et al. “Enhancement of human adaptive immune responses by administration of a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis”. Journal of Medicinal Food2 (2008): 313-322.
- Chu WL., et al. “Effect of Spirulina (Arthrospira) supplementation on the immune response to tetanus toxoid vaccination in a mouse model”. Journal of Diet3 (2013): 229-240.
- El-Deeb NM., et al. “Arthrospira platensis-Mediated Green Biosynthesis of Silver Nano-particles as Breast Cancer Controlling Agent: In Vitro and In Vivo Safety Approaches”. Applied Biochemistry and Biotechnology 5 (2022): 2183-2203.
- Chen T and Wong YS. “In vitro antioxidant and antiproliferative activities of selenium-containing phycocyanin from selenium-enriched Spirulina platensis”. Journal of Agricultural and Food Chemistry 12 (2008): 4352-4358.
- Heinrich M., et al. “Best Practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines”. Frontiers in Pharmacology 13 (2022): 953205.
- Selvaduray KR., et al. “Palm tocotrienols inhibit proliferation of murine mammary cancer cells and induce expression of interleukin-24 mRNA”. Journal of Interferon and Cytokine Research 12 (2013): 909-916.
- Tomayko MM and Reynolds CP. “Determination of subcutaneous tumor size in athymic (nude) mice”. Cancer Chemotherapy and Pharmacology3 (1989): 148-154.
- Hayashi O., et al. “Enhancement of antibody production in mice by dietary Spirulina platensis”. Journal of Nutritional Science and Vitaminology (Tokyo)5 (1994): 431-441.
- Abdul Hafid SR., et al. “Palm Tocotrienol-Adjuvanted Dendritic Cells Decrease Expression of the SATB1 Gene in Murine Breast Cancer Cells and Tissues”. Vaccines (Basel)4 (2019): 10.
- Abdul Hafid SR., et al. “Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.” PLoS One 9 (2013): e74753.
- Ouhtit A., et al. “Chemoprevention of rat mammary carcinogenesis by spirulina”. American Journal of Pathology1 (2014): 296303.
- Kefayat A., et al. “Spirulina extract enriched for Braun-type lipoprotein (Immulina (R)) for inhibition of 4T1 breast tumors' growth and metastasis”. Phytotherapy Research2 (2020): 368-378.
- Yogianti F., et al. “Inhibitory effects of dietary Spirulina platensis on UVB-induced skin inflammatory responses and carcinogenesis”. Journal of Investigative Dermatology10 (2014): 2610-2619.
- Dasgupta T., et al. “Chemomodulation of carcinogen metabolising enzymes, antioxidant profiles and skin and forestomach papillomagenesis by Spirulina platensis”. Molecular and Cellular Biochemistry1-2 (2001): 27-38.
- Barakat W., et al. “Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice”. Advances in Pharmacological and Pharmaceutical Sciences 2015 (2015): 132873.
- Riva C and Oreal H. “Selenium-enriched Arthrospira platensis potentiates docetaxel, oxaliplatin and topotecan anticancer activity in epithelial tumors”. Journal of Applied Phycology 28 (2016): 3371–3377.
- Hirahashi T., et al. “Activation of the human innate immune system by Spirulina: augmentation of interferon production and NK cytotoxicity by oral administration of hot water extract of Spirulina platensis”. International Immunopharmacology4 (2002): 423-434.
- Smyth MJ., et al. “Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity”. Advances in Immunology 90 (2006): 1-50.
- Subramaiam H., et al. “Evaluating Anticancer and Immunomodulatory Effects of Spirulina (Arthrospira) platensis and Gamma-Tocotrienol Supplementation in a Syngeneic Mouse Model of Breast Cancer”. Nutrients 7 (2021).
- Zhang B. “CD73: a novel target for cancer immunotherapy”. Cancer Research16 (2010): 6407-6411.
- Bates GJ., et al. “Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse”. Journal of Clinical Oncology34 (2006): 5373-5380.
- Sasada T., et al. “CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression”. Cancer5 (2003): 1089-1099.
- Curiel TJ., et al. “Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival”. Nature Medicine9 (2004): 942-949.
- Woo EY., et al. “Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation”. Journal of Immunology9 (2002): 4272-4276.
- Flammiger A., et al. “High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer”. European Journal of Cancer6 (2013): 1273-1279.
- Tao H., et al. “Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells”. Lung Cancer 1 (2012): 95-101.
- Facciabene A., et al. “T-regulatory cells: key players in tumor immune escape and angiogenesis”. Cancer Research 9 (2012): 2162-2171.
- Katsuno Y., et al. “TGF-beta signaling and epithelial-mesenchymal transition in cancer progression”. Current Opinion in Oncology1 (2013): 76-84.
- Sato E., et al. “Intraepithelial CD8+ tumorinfiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer”. Proceedings of the National Academy of Sciences of the United States of America51 (2005): 18538-18543.
- Hess KR., et al. “Metastatic patterns in adenocarcinoma”. Cancer 7 (2006): 1624-1633.
- Mishima T., et al. “Inhibition of tumor invasion and metastasis by calcium spirulan (Ca-SP), a novel sulfated polysaccharide derived from a blue-green alga, Spirulina platensis”. Clinical and Experimental Metastasis6 (1998): 541-550.
- Tao K., et al. “Imagable 4T1 model for the study of late stage breast cancer”. BMC Cancer 8 (2008): 228,2407-8-228.
- Ouhtit A., et al. “In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver”. American Journal of Pathology6 (2007): 20339.