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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
Published on: December 19, 2019
Cell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice
Mohammed Naseemuddin1, Aneeqa Iqbal, Tahseen H Nasti
1Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, AL 35294-0019, USA.
Abstract:
Toll-like receptors (TLRs) activate signals that are critically involved in the initiation of adaptive immune responses and many tumorigenic chemicals have been associated with activation of those pathways. To determine the role of TLR-4 (TLR4) in mammary carcinogenesis, we subjected TLR4 deficient and wild type (WT) mice to oral gavage with carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice. Moreover, there was higher incidence of regulatory T cells in TLR4 deficient mice than WT mice. Similarly, various markers of angiogenesis [matrix metalloproteinases (MMP)-2 and MMP-9, CD31 and vascular endothelial growth factor] were highly expressed in tumors from TLR4 deficient mice than WT mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell-mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.
Insights
Toll-like receptor 4 (TLR4) deficiency exacerbates mammary tumors induced by DMBA. Lack of TLR4 impairs anti-tumor immunity, promoting tumor growth and angiogenesis in mice.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Toll-like receptors (TLRs) are crucial for initiating adaptive immune responses.
- Tumorigenic chemicals can activate TLR pathways, influencing cancer development.
- The specific role of TLR-4 (TLR4) in mammary carcinogenesis requires further investigation.
Purpose of the Study:
- To elucidate the role of TLR4 in mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA).
- To compare tumor development and immune responses in TLR4-deficient versus wild-type (WT) mice exposed to DMBA.
Main Methods:
- Mice genetically deficient in TLR4 and WT mice were administered DMBA via oral gavage.
- Tumor incidence and immune cell populations (T cells, CD11c+ cells) were analyzed.
- Levels of cytokines (IL-17, IFN-γ, IL-12, IL-23) and angiogenesis markers (MMP-2, MMP-9, CD31, VEGF) were quantified.
Main Results:
- TLR4-deficient mice exhibited a higher incidence of mammary tumors compared to WT mice.
- TLR4 deficiency led to increased IL-17 and decreased IFN-γ production by T cells.
- CD11c+ cells from TLR4-deficient mice produced more IL-23, while WT mice had higher IL-12.
- Increased regulatory T cells and elevated angiogenesis markers were observed in tumors from TLR4-deficient mice.
Conclusions:
- TLR4 plays a protective role in preventing DMBA-induced mouse mammary tumorigenesis.
- Targeting TLR4 or modulating the cell-mediated immune response could be a strategy for mammary tumor prevention.
