Xinye Zhang
ABSTRACT
Monocytes/macrophages are critical inflammatory components predominantly recruited to tumor tissue to facilitate tumor metastasis. However, the underlying regulatory mechanisms remain largely unclear. In the study, we show that tumor-secreted soluble factors are capable of activating monocytes to produce higher level of proinflammatory cytokine tumor necrosis factor alpha (TNF-α), which in turn functions on tumor cells to increase the expression hepatocyte growth factor (HGF) and c-Met in liver cancer cell line HepG2 cells. TNF-α is also able to induce epithelial-mesenchymal transition (EMT) in HepG2 cells, as displayed by the reduced E-Cadherin expression and increased amount of Vimentin, N-Cadherin, transcription factor SNAI1, and SNAI2, but not Twist. Furthermore, we demonstrated that TNF-α possesses the capability of promoting the migration of HepG2 cells, which can be partially impaired by blocking c-Met signaling pathway. Collectively, these data reveal that TNF-α derived from tumor activated monocytes is leading to the upregulation of HGF and c-Met, whose interaction is able to synergistically switch on the activation of HGF-c-Met signaling pathway to foster the EMT. Thus, enhanced secretion of TNF-α in monocytes may represent a novel mechanism linking the innate response to metastasis in human hepatocellular carcinoma, which provides novel strategy for anti-tumor therapy.
- Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA. Cancer J. Clin. (2020). doi:10.3322/caac.21590Google Scholar
- Valastyan, S. & Weinberg, R. A. Tumor metastasis: Molecular insights and evolving paradigms. Cell (2011). doi:10.1016/j.cell.2011.09.024Google Scholar
- Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine (2013). doi:10.1038/nm.3394Google Scholar
- Kitamura, T., Qian, B. Z. & Pollard, J. W. Immune cell promotion of metastasis. Nature Reviews Immunology (2015). doi:10.1038/nri3789Google Scholar
- Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell (2000). doi: 10.1016/S0092-8674(00)81683-9Google Scholar
- Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell (2011). doi:10.1016/j.cell.2011.02.013Google Scholar
- Diepenbruck, M. & Christofori, G. Epithelial-mesenchymal transition (EMT) and metastasis: Yes, no, maybe? Current Opinion in Cell Biology (2016). doi:10.1016/j.ceb.2016.06.002Google Scholar
- Song, W., Mazzieri, R., Yang, T. & Gobe, G. C. Translational significance for tumor metastasis of tumor-associated macrophages and epithelial-mesenchymal transition. Frontiers in Immunology (2017). doi:10.3389/fimmu.2017.01106Google Scholar
- Suarez-Carmona, M., Lesage, J., Cataldo, D. & Gilles, C. EMT and inflammation: inseparable actors of cancer progression. Molecular Oncology (2017). doi: 10.1002/1878-0261.12095Google Scholar
- Kuang, D. M. et al. Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood (2007). doi: 10.1182/blood-2007-01-068031Google Scholar
- Sato, Y. et al. Epithelial-mesenchymal transition induced by transforming growth factor-β1/snail activation aggravates invasive growth of cholangiocarcinoma. Am. J. Pathol. (2010). doi: 10.2353/ajpath.2010.090747Google Scholar
- Sun, B., Liu, R., Xiao, Z. D. & Zhu, X. C-MET protects breast cancer cells from apoptosis induced by sodium butyrate. PLoS One (2012). doi:10.1371/journal.pone.0030143Google Scholar
- Mali, A. V., Joshi, A. A., Hegde, M. V. & Kadam, S. S. Enterolactone suppresses proliferation, migration and metastasis of MDA-MB-231 breast cancer cells through inhibition of uPA induced plasmin activation and MMPs-Mediated ECM remodeling. Asian Pacific J. Cancer Prev. (2017). doi: 10.22034/APJCP.2017.18.4.905Google Scholar
- Figueras, A. et al. ARole forCXCR4in peritonealandhematogenous ovarian cancer dissemination. Mol. Cancer Ther. (2018). doi: 10.1158/1535-7163.MCT-17-0643Google Scholar
- Kroepil, F. et al. Down-Regulation of CDH1 Is Associated with Expression of SNAI1 in Colorectal Adenomas. PLoS One (2012). doi:10.1371/journal.pone.0046665Google Scholar
- Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nature Reviews Molecular Cell Biology (2003). doi:10.1038/nrm1261Google Scholar
- Qian, B. Z. & Pollard, J. W. Macrophage Diversity Enhances Tumor Progression and Metastasis. Cell (2010). doi:10.1016/j.cell.2010.03.014Google Scholar
- Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889--896 (2010).Google ScholarCross Ref
- Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, Inflammation, and Cancer. Cell (2010). doi:10.1016/j.cell.2010.01.025Google Scholar
- Chen, D. P. et al. Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma. Autophagy (2018). doi:10.1080/15548627.2018.1474994Google Scholar
- Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Reviews Cancer (2009). doi:10.1038/nrc2618Google Scholar
- Noy, R. & Pollard, J. W. Tumor-Associated Macrophages: From Mechanisms to Therapy. Immunity (2014). doi:10.1016/j.immuni.2014.06.010Google Scholar
- Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Reviews Cancer (2004). doi:10.1038/nrc1256Google Scholar
- Su, S. et al. A Positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell (2014). doi:10.1016/j.ccr.2014.03.021Google Scholar
Index Terms
- Activated Monocyte-derived TNF-α Upregulates HGF/c-Met to Trigger EMT of Hepatoma Cells
Recommendations
Preliminary Exploration on Effects ff Monocyte/Macrophage on Proliferation, Cell Death, and Migration ff Liver Cancer
ICBBT '21: Proceedings of the 2021 13th International Conference on Bioinformatics and Biomedical TechnologyHepatocellular Carcinoma (HCC) is one of the lethal cancers worldwide with an increased death rate annually. The development of HCC is dependent on both the accumulation of somatic mutations in tumour cells and the interaction with the non-tumour cells ...
Integrative Computational Identifications of the Signaling Pathway Network Related to TNF-alpha Stimulus in Vascular Endothelial Cells
IJCBS '09: Proceedings of the 2009 International Joint Conference on Bioinformatics, Systems Biology and Intelligent ComputingIntegrating multiple datasets becomes essential for systematically understanding complex biological processes. Here, we presented a new method to identify and annotate the downstream pathways related to TNF-alpha (TNF) stimulus in vascular endothelial ...
Integrative computational modeling to unravel novel potential biomarkers in hepatocellular carcinoma
AbstractHepatocellular carcinoma (HCC) is a major health problem around the world. The management of this disease is complicated by the lack of noninvasive diagnostic tools and the few treatment options available. Better clinical outcomes can ...
Highlights- We analyze publicly available transcriptomics data from HCC tumor and non-tumor biopsies.
Comments