Induksi Metastasis Limfonodus oleh DMBA Topikal pada Model Mencit C3H/HeJ dengan Karsinoma Sel Skuamosa
DOI:
https://doi.org/10.55606/klinik.v5i2.6491Keywords:
DMBA, Metastasis, Mice, Squamous Cell Carcinoma, Topical ApplicationAbstract
7,12-Dimethylbenz(a)anthracene (DMBA) is an environmental carcinogen. Topical application of DMBA in mice induces skin tumors with 100% incidence, and approximately 40% progress to squamous cell carcinoma (SCC), which carries a high risk of metastasis. To evaluate lymph node metastasis in SCC following topical administration of 0.125% DMBA. This research was conducted as a laboratory experimental study A total of 200 µl of 0.125% DMBA was applied topically to the dorsal skin of C3H/HeJ mice three times a week for 10 weeks. All mice with SCC showed metastatic deposits in the lymph nodes, characterized by anaplastic cells with hyperchromatic nuclei and a 1:1 nucleus-to-cytoplasm ratio. Significant differences in follicular area were found between the malignant DMBA group and the vehicle (mean difference 0.26; P<0.001), distilled water (0.25; P<0.001), and between the benign DMBA group and both vehicle (0.28; P<0.001) and distilled water (0.27; P < 0.001). No significant differences were observed between the malignant and benign DMBA groups (P = 0.767), or between vehicle and distilled water (P = 0.884). Topical application of 0.125% DMBA for 10 weeks is associated with lymph node metastasis in SCC, which can be identified through histological observation of tumor cell deposits and follicular hyperplasia in lymph nodes.
References
Ariany, D., Rahman, A., Rachmawati, N. M., Hermawati, L., & Irawati, N. B. U. (2025). Studi histopatologi pengaruh pemberian DMBA secara topikal pada organ hati mencit C3H/HEJ. Medika Tadulako: Jurnal Ilmiah Kedokteran Fakultas Kedokteran, 10(1 SE-), 66–71.
As’ad, M. (2018). Efek pemberian 7,12-dimethylbenz(a)anthracene (DMBA) secara topikal terhadap gambaran histopatologi jaringan kulit pada mencit strain C3H/HeJ. Universitas Islam Negeri Syarif Hidayatullah Jakarta.
Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., Vonderheide, R. H., Pittet, M. J., Jain, R. K., Zou, W., Howcroft, T. K., Woodhouse, E. C., Weinberg, R. A., & Krummel, M. F. (2018). Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine, 24(5), 541–550. https://doi.org/10.1038/s41591-018-0014-x
Boogaard, H., Patton, A. P., Atkinson, R. W., Brook, J. R., Chang, H. H., Crouse, D. L., Fussell, J. C., Hoek, G., Hoffmann, B., Kappeler, R., Kutlar Joss, M., Ondras, M., Sagiv, S. K., Samoli, E., Shaikh, R., Smargiassi, A., Szpiro, A. A., Van Vliet, E. D. S., Vienneau, D., … Forastiere, F. (2022). Long-term exposure to traffic-related air pollution and selected health outcomes: A systematic review and meta-analysis. Environment International, 164, 107262. https://doi.org/https://doi.org/10.1016/j.envint.2022.107262
Chen, X.-W., & Zhou, S.-F. (2015). NF-κB axis, and tumorigenesis. Drug Design, Development and Therapy, 9, 2941–2946.
Corrêa Rassele, A., Oliveira Almeida, I., Garschagen Gava, M., Bronhara Pimentel, P. A., Giuliano, A., Ruiz Sueiro, F. A., Rodrigues de Oliveira, A., Barboza de Nardi, A., & Dos Santos Horta, R. (2025). Immunohistochemical expression of vascular endothelial growth factor (VEGF) in primary canine mast cell tumors and related regional lymph node metastasis. Animals: An Open Access Journal from MDPI, 15(2). https://doi.org/10.3390/ani15020283
Delclaux, I., Ventre, K. S., Jones, D., & Lund, A. W. (2024). The tumor-draining lymph node as a reservoir for systemic immune surveillance. Trends in Cancer, 10(1), 28–37. https://doi.org/10.1016/j.trecan.2023.09.006
Dongre, A., & Weinberg, R. A. (2019). New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nature Reviews Molecular Cell Biology, 20(2), 69–84. https://doi.org/10.1038/s41580-018-0080-4
Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A., & Fares, Y. (2020). Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduction and Targeted Therapy, 5(1), 28. https://doi.org/10.1038/s41392-020-0134-x
Grimmig, T., Moench, R., Kreckel, J., Haack, S., Rueckert, F., Rehder, R., Tripathi, S., Ribas, C., Chandraker, A., Germer, C. T., Gasser, M., & Waaga-Gasser, A. M. (2016). Toll-like receptor 2, 4, and 9 signaling promotes autoregulatory tumor cell growth and VEGF/PDGF expression in human pancreatic cancer. International Journal of Molecular Sciences, 17(12), 2060. https://doi.org/10.3390/ijms17122060
Jahan, T., Saleh, A. A., & Anwar, S. (2024). Association of cytokine IL-17, IL-4, IL-6, and IL-12 gene polymorphisms in rheumatoid arthritis patients in a tertiary care hospital in Bangladesh. International Journal of Rheumatology, 2024, 3728179. https://doi.org/10.1155/2024/3728179
Kim, K.-H., Jahan, S. A., Kabir, E., & Brown, R. J. C. (2013). A review of airborne polycyclic aromatic hydrocarbons (PAHs) and their human health effects. Environment International, 60, 71–80. https://doi.org/https://doi.org/10.1016/j.envint.2013.07.019
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging biological principles of metastasis. Cell, 168(4), 670–691. https://doi.org/10.1016/j.cell.2016.11.037
Li, H., & Brakebusch, C. (2021). Chapter 7 - Analyzing skin tumor development in mice by the DMBA/TPA model. In L. Galluzzi & A. B. T.-M. in C. B. Buqué (Eds.), Carcinogen-driven mouse models of oncogenesis (Vol. 163, pp. 113–121). Academic Press. https://doi.org/https://doi.org/10.1016/bs.mcb.2020.08.004
Li, J., Yang, F., Wei, F., & Ren, X. (2017). The role of toll-like receptor 4 in tumor microenvironment. Oncotarget, 8(39). https://doi.org/10.18632/oncotarget.19105
Li, T., Liu, T., Zhao, Z., Xu, X., Zhan, S., Zhou, S., Jiang, N., Zhu, W., Sun, R., Wei, F., Feng, B., Guo, H., & Yang, R. (2022). The lymph node microenvironment may invigorate cancer cells with enhanced metastatic capacities. Frontiers in Oncology, 12, 816506. https://doi.org/10.3389/fonc.2022.816506
Li, W., Tanikawa, T., Kryczek, I., Xia, H., Li, G., Wu, K., Wei, S., Zhao, L., Vatan, L., Wen, B., Shu, P., Sun, D., Kleer, C., Wicha, M., Sabel, M., Tao, K., Wang, G., & Zou, W. (2018). Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metabolism, 28(1), 87–103.e6. https://doi.org/10.1016/j.cmet.2018.04.022
Loo, W. T. Y., Cheung, M. N. B., & Loo, P. C. (2025). Meta-analysis: 7,12-dimethylbenz[a]anthracene (DMBA) induces diverse types of breast carcinoma in rat models: A systematic review of tumor histopathology and pathogenesis. Oncogene, 12, 13.
Luo, D., Zhu, C., & Jing, J. (2025). Bergapten exhibits antitumor effects on DMBA-induced oral squamous cell carcinoma via anti-inflammatory and apoptotic activities in hamsters by inhibiting NF-κB and PI3K/Akt/mTOR pathways. Naunyn-Schmiedeberg's Archives of Pharmacology. https://doi.org/10.1007/s00210-025-04405-3
Manna, D., Akhtar, S., Maiti, P., Mondal, S., Kumar Mandal, T., & Ghosh, R. (2020). Anticancer activity of a 1,4-dihydropyridine in DMBA-induced mouse skin tumor model. Anti-Cancer Drugs, 31(4), 394–402. https://doi.org/10.1097/CAD.0000000000000887
Naseemuddin, M., Iqbal, A., Nasti, T. H., Ghandhi, J. L., Kapadia, A. D., & Yusuf, N. (2012). Cell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice. International Journal of Cancer, 130(4), 765–774. https://doi.org/10.1002/ijc.26100
Neagu, M., Caruntu, C., Constantin, C., Boda, D., Zurac, S., Spandidos, D. A., & Tsatsakis, A. M. (2016). Chemically induced skin carcinogenesis: Updates in experimental models (Review). Oncology Reports, 35(5), 2516–2528. https://doi.org/10.3892/or.2016.4683
Owen, J. L., Gunja-Smith, Z., & Lopez, D. M. (2001). MMP-9 production by T cells from mammary tumor bearers is upregulated by tumor-derived VEGF. Breast Cancer Research, 3(1), A46. https://doi.org/10.1186/bcr373
Quail, D. F., & Joyce, J. A. (2017). The microenvironmental landscape of brain tumors. Cancer Cell, 31(3), 326–341. https://doi.org/10.1016/j.ccell.2017.02.009
Samburova, V., Connolly, J., Gyawali, M., Yatavelli, R. L. N., Watts, A. C., Chakrabarty, R. K., Zielinska, B., Moosmüller, H., & Khlystov, A. (2016). Polycyclic aromatic hydrocarbons in biomass-burning emissions and their contribution to light absorption and aerosol toxicity. Science of The Total Environment, 568, 391–401. https://doi.org/https://doi.org/10.1016/j.scitotenv.2016.06.026
Snarskaya, E. S., Pylev, L. N., Akhunzyanov, A. A., & Kuznetсova, E. V. (2017). Experimental Basosquamous Carcinoma Model in Rats. BioNanoScience, 7(2), 423–427. https://doi.org/10.1007/s12668-016-0380-0
Sun, Y., Ma, Y., & Wang, H. (2025). Chemopreventive role of β-caryophyllene in DMBA-induced skin cancer: Modulation of apoptotic pathways and PI3K/Akt signaling in Swiss albino mice. Advances in Clinical and Experimental Medicine, 34(9), 1541–1552.
Thomas, G., Tuk, B., Song, J.-Y., Truong, H., Gerritsen, H. C., de Gruijl, F. R., & Sterenborg, H. J. C. M. (2016). Studying skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice using chronic 7,12-dimethylbenz(a)anthracene topical applications to develop a useful experimental skin cancer model. Laboratory Animals, 51(1), 24–35. https://doi.org/10.1177/0023677216637305
Torres-Cabala, C., Li-Ning-Tapia, E., & Hwu, W.-J. (2020). Pathology-based biomarkers useful for clinical decisions in melanoma. Archives of Medical Research, 51(8), 827–838. https://doi.org/10.1016/j.arcmed.2020.09.008
Vähätupa, M., Pemmari, T., Junttila, I., Pesu, M., & Järvinen, T. A. H. (2019). Chemical-induced skin carcinogenesis model using dimethylbenz[a]anthracene and 12-O-tetradecanoyl phorbol-13-acetate (DMBA-TPA). JoVE, 154, e60445. https://doi.org/10.3791/60445
Wang, Z., Xiao, Y., Huang, A., Zhang, L., & Luo, H. (2025). Attenuation of brucine action on DMBA/TPA-induced skin cancer by PI3K/Akt/mTOR signaling. Journal of Molecular Histology, 56(4), 1–14. https://doi.org/10.1007/s10735-025-10524-1
Wi, K., Hwang, S. Y., Kim, Y. G., Lee, S. I., Lee, C. J., Bang, G., … Lee, M. H. (2025). Costunolide inhibits the progression of TPA-induced cell transformation and DMBA/TPA-induced skin carcinogenesis by regulation of AKT-mediated signaling. Cancer Cell International, 25(1), 106. https://doi.org/10.1186/s12935-025-03742-w
Xia, Y., Huang, C., Zhong, M., Zhong, H., Ruan, R., Xiong, J., Yao, Y., Zhou, J., & Deng, J. (2025). Targeting HGF/c-MET signaling to regulate the tumor microenvironment: Implications for counteracting tumor immune evasion. Cell Communication and Signaling: CCS, 23(1), 46. https://doi.org/10.1186/s12964-025-02033-1
Zotta, A., Toller-Kawahisa, J., Palsson-McDermott, E. M., O’Carroll, S. M., Henry, Ó. C., Day, E. A., McGettrick, A. F., Ward, R. W., Ryan, D. G., Watson, M. A., Brand, M. D., Runtsch, M. C., Maitz, K., Lueger, A., Kargl, J., Miljkovic, J. L., Lavelle, E. C., & O’Neill, L. A. J. (2025). Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion. Science Advances, 11(4), eadq7307. https://doi.org/10.1126/sciadv.adq7307
Zulfa, H. A., Bebi, N., Irawati, U., Hermawati, L., & Diana, W. A. (n.d.). Literature review: The role of pyruvate kinase M2 in aerobic glycolysis of cancer cells: Mechanisms and potential inhibitor (1–9).
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Jurnal Ilmiah Kedokteran dan Kesehatan
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
