Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer-associated fibroblasts of TSCC
Pengfei Ba
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorMingcai Xu
Department of Reproductive Medicine, Weihai second municipal hospital Affiliated to Qingdao University, Weihai, China
Search for more papers by this authorMiao Yu
Department of Stomatology, Weifang People’s Hospital, Weifang, China
Search for more papers by this authorLinxia Li
Department of Stomatology, Affiliated Hospital of Jining Medical University, Jining, China
Search for more papers by this authorXiaoyu Duan
National Engineering Laboratory, WeGo Group Co., Ltd, Weihai, China
Search for more papers by this authorShuyan Lv
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorGuo Fu
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorJianbo Yang
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorPishan Yang
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Search for more papers by this authorCorresponding Author
Chengzhe Yang
Department of Oral and Maxillofacial Surgery, Institute of Stomatology, Qilu Hospital, Shandong University, Jinan, China
Correspondence
Chengzhe Yang, Department of Oral and Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, 107 West Wen Hua Road, Jinan, Shandong 250012, China.
Email: [email protected]
Qinfeng Sun, Department of Periodontology, School of Stomatology, Shandong University, 44-1 Wenhuaxi Road, Jinan, Shandong 250012, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qinfeng Sun
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Correspondence
Chengzhe Yang, Department of Oral and Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, 107 West Wen Hua Road, Jinan, Shandong 250012, China.
Email: [email protected]
Qinfeng Sun, Department of Periodontology, School of Stomatology, Shandong University, 44-1 Wenhuaxi Road, Jinan, Shandong 250012, China.
Email: [email protected]
Search for more papers by this authorPengfei Ba
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorMingcai Xu
Department of Reproductive Medicine, Weihai second municipal hospital Affiliated to Qingdao University, Weihai, China
Search for more papers by this authorMiao Yu
Department of Stomatology, Weifang People’s Hospital, Weifang, China
Search for more papers by this authorLinxia Li
Department of Stomatology, Affiliated Hospital of Jining Medical University, Jining, China
Search for more papers by this authorXiaoyu Duan
National Engineering Laboratory, WeGo Group Co., Ltd, Weihai, China
Search for more papers by this authorShuyan Lv
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorGuo Fu
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorJianbo Yang
Department of Periodontology, Weihai Stomatological Hospital, Weihai, China
Search for more papers by this authorPishan Yang
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Search for more papers by this authorCorresponding Author
Chengzhe Yang
Department of Oral and Maxillofacial Surgery, Institute of Stomatology, Qilu Hospital, Shandong University, Jinan, China
Correspondence
Chengzhe Yang, Department of Oral and Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, 107 West Wen Hua Road, Jinan, Shandong 250012, China.
Email: [email protected]
Qinfeng Sun, Department of Periodontology, School of Stomatology, Shandong University, 44-1 Wenhuaxi Road, Jinan, Shandong 250012, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qinfeng Sun
Department of Periodontology, School of Stomatology, Shandong University, Jinan, China
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China
Correspondence
Chengzhe Yang, Department of Oral and Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, 107 West Wen Hua Road, Jinan, Shandong 250012, China.
Email: [email protected]
Qinfeng Sun, Department of Periodontology, School of Stomatology, Shandong University, 44-1 Wenhuaxi Road, Jinan, Shandong 250012, China.
Email: [email protected]
Search for more papers by this authorAbstract
Cancer-associated fibroblasts (CAFs) are “activated” fibroblasts in the tumor microenvironment (TME) and play a vital role in all steps of cancer development. Increasing evidence focusing on the function of CAFs suggests that CAFs are candidate therapeutic targets and that drugs targeting the modification of CAFs would suppress tumor progression and be beneficial to tumor treatment and prevention. In the present study, we found that curcumin reversed the phenotype of CAFs to that of peri-tumor fibroblast (PTF)-like cells by downregulating the expression of α-SMA (a special marker for CAFs) and inhibiting the secretion of pro-carcinogenic cytokines, including transforming growth factor-β1 (TGF-β1), matrix metalloproteinases 2 (MMP2), and stromal cell-derived factor-1 (SDF-1). We further demonstrated that the conditioned medium (CM) derived from CAFs promoted the proliferation of Cal27, and this effect was confirmed by the xenograft model. More importantly, we found that curcumin blocked the CAF-mediated enhancement of Cal27 proliferation in vitro and in vivo. In conclusion, our data suggest that curcumin reverses cell phenotype from CAF to PTF-like cells and suppresses the CAF-mediated proliferation and tumorigenicity of Cal27 by inhibiting TSCC CAFs.
CONFLICT OF INTEREST
The authors have declared that they have no competing interests.
REFERENCES
- Al-Ansari, M. M., & Aboussekhra, A. (2014). Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes. PLoS One, 9(3), e90907. https://doi.org/10.1371/journal.pone.0090907
- Alkhader, E., Roberts, C. J., Rosli, R., Yuen, K. H., Seow, E. K., Lee, Y. Z., & Billa, N. (2018). Pharmacokinetic and anti-colon cancer properties of curcumin-containing chitosan-pectinate composite nanoparticles. Journal of Biomaterials Science. Polymer Edition, 29(18), 2281–2298. https://doi.org/10.1080/09205063.2018.1541500
- Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A. B., & Aggarwal, B. B. (2008). Curcumin and cancer: An "old-age" disease with an "age-old" solution. Cancer Letters, 267(1), 133–164. https://doi.org/10.1016/j.canlet.2008.03.025
- Ba, P., Zhang, X., Yu, M., Li, L., Duan, X., Wang, M., … Sun, Q. (2019). Cancer associated fibroblasts are distinguishable from peri-tumor fibroblasts by biological characteristics in TSCC. Oncology Letters, 18(3), 2484–2490. https://doi.org/10.3892/ol.2019.10556
- Bimonte, S., Barbieri, A., Leongito, M., Piccirillo, M., Giudice, A., Pivonello, C., … Izzo, F. (2016). Curcumin AntiCancer Studies in Pancreatic Cancer. Nutrients, 8(7), 433. https://doi.org/10.3390/nu8070433
- Dourado, R. C., Porto, L. P. A., Leitao, A., Cerqueira, P. S. G., Dos Santos, J. N., Ramalho, L. M. P., & Xavier, F. C. A. (2018). Immunohistochemical Characterization of Cancer-associated Fibroblasts in Oral Squamous Cell Carcinoma. Applied Immunohistochemistry & Molecular Morphology, 26(9), 640–647. https://doi.org/10.1097/pai.0000000000000486
- Elmusrati, A. A., Pilborough, A. E., Khurram, S. A., & Lambert, D. W. (2017). Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma. British Journal of Cancer, 117(6), 867–875. https://doi.org/10.1038/bjc.2017.239
- Graizel, D., Zlotogorski-Hurvitz, A., Tsesis, I., Rosen, E., Kedem, R., & Vered, M. (2020). Oral cancer-associated fibroblasts predict poor survival: Systematic review and meta-analysis. Oral Diseases, 26(4): 733-744. https://doi.org/10.1111/odi.13140
- Hanley, C. J., Mellone, M., Ford, K., Thirdborough, S. M., Mellows, T., Frampton, S. J., … Thomas, G. J. (2018). Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. JNCI: Journal of the National Cancer Institute, 110(1), 109–120. https://doi.org/10.1093/jnci/djx121
- Hanna, E., Quick, J., & Libutti, S. K. (2009). The tumour microenvironment: A novel target for cancer therapy. Oral Diseases, 15(1), 8–17. https://doi.org/10.1111/j.1601-0825.2008.01471.x
- Hassanalilou, T., Ghavamzadeh, S., & Khalili, L. (2019). Curcumin and gastric cancer: A review on mechanisms of action. J Gastrointest Cancer, 50(2), 185–192. https://doi.org/10.1007/s12029-018-00186-6
- Hendrayani, S. F., Al-Khalaf, H. H., & Aboussekhra, A. J. N. (2013). Curcumin Triggers p16-dependent senescence in active breast cancer-associated fibroblasts and suppresses their paracrine procarcinogenic effects. Neoplasia, 15(6), 631,IN611–640,IN611. https://doi.org/10.1593/neo.13478
- Houthuijzen, J. M., & Jonkers, J. (2018). Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer and Metastasis Reviews, 37(4), 577–597. https://doi.org/10.1007/s10555-018-9768-3
- Jung, J. G., & Le, A. (2018). Targeting metabolic cross talk between cancer cells and cancer-associated fibroblasts. Advances in Experimental Medicine and Biology, 1063, 167–178. https://doi.org/10.1007/978-3-319-77736-8_12
- Kalluri, R. (2003). Angiogenesis: basement membranes: structure, assembly and role in tumour angiogenesis. Nature Reviews Cancer, 3(6), 422–433. https://doi.org/10.1038/nrc1094
- Karagiannis, G. S., Poutahidis, T., Erdman, S. E., Kirsch, R., Riddell, R. H., & Diamandis, E. P. (2012). Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Molecular Cancer Research, 10(11), 1403–1418. https://doi.org/10.1158/1541-7786.MCR-12-0307
- Kim, D. J., Dunleavey, J. M., Xiao, L., Ollila, D. W., Troester, M. A., Otey, C. A., … Dudley, A. C. (2018). Suppression of TGFbeta-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition. British Journal of Cancer, 118(10), 1359–1368. https://doi.org/10.1038/s41416-018-0072-3
- Li, H., Fan, X., & Houghton, J. (2007). Tumor microenvironment: The role of the tumor stroma in cancer. Journal of Cellular Biochemistry, 101(4), 805–815. https://doi.org/10.1002/jcb.21159
- Liao, J. K., Zhou, B., Zhuang, X. M., Zhuang, P. L., Zhang, D. M., & Chen, W. L. (2018). Cancer-associated fibroblasts confer cisplatin resistance of tongue cancer via autophagy activation. Biomedicine & Pharmacotherapy, 97, 1341–1348. https://doi.org/10.1016/j.biopha.2017.11.024
- Lin, N. N., Wang, P., Zhao, D., Zhang, F. J., Yang, K., & Chen, R. (2017). Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. Journal of Oral Pathology and Medicine, 46(1), 21–30. https://doi.org/10.1111/jop.12452
- Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., … Weinberg, R. A. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3), 335–348. https://doi.org/10.1016/j.cell.2005.02.034
- Rowley, D. R. (2008). Reactive stroma and evolution of tumors: Integration of transforming growth factor-β, connective tissue growth factor, and fibroblast growth factor-2 activities. Transforming Growth Factor-β in Cancer Therapy 8, (pp. 475–505). https://doi.org/10.1007/978-1-59745-293-9_30
- Shiga, K., Hara, M., Nagasaki, T., Sato, T., Takahashi, H., & Takeyama, H. (2015). Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel), 7(4), 2443–2458. https://doi.org/10.3390/cancers7040902
- Sobral, L. M., Bufalino, A., Lopes, M. A., Graner, E., Salo, T., & Coletta, R. D. (2011). Myofibroblasts in the stroma of oral cancer promote tumorigenesis via secretion of activin A. Oral Oncology, 47(9), 840–846. https://doi.org/10.1016/j.oraloncology.2011.06.011
- Teng, F., Tian, W.-Y., Wang, Y.-M., Zhang, Y.-F., Guo, F., Zhao, J., … Xue, F.-X. (2016). Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. Journal of Hematology & Oncology, 9, 8–8. https://doi.org/10.1186/s13045-015-0231-4
- Tuxhorn, J. A., Ayala, G. E., Smith, M. J., Smith, V. C., Dang, T. D., & Rowley, D. R. (2002). Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling. Clinical Cancer Research, 8(9), 2912–2923.
- Vallianou, N. G., Evangelopoulos, A., Schizas, N., & Kazazis, C. (2015). Potential anticancer properties and mechanisms of action of curcumin. Anticancer Research, 35(2), 645–651.
- Vaughn, C. J. (2012). Drugs and lactation database: LactMed. Journal of Electronic Resources in Medical Libraries, 9(4), 272–277. https://doi.org/10.1080/15424065.2012.735134
10.1080/15424065.2012.735134 Google Scholar
- Wan Mohd Tajuddin, W. N. B., Lajis, N. H., Abas, F., Othman, I., & Naidu, R. (2019). Mechanistic understanding of Curcumin's therapeutic effects in lung cancer. Nutrients, 11(12), 2989. https://doi.org/10.3390/nu11122989
- Wang, Q., Qu, C., Xie, F., Chen, L., Liu, L., Liang, X., … Meng, Z. (2017). Curcumin suppresses epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells by inhibiting cancer-associated fibroblasts. Am J Cancer Res, 7(1), 125–133.
- Wu, X., Tao, P., Zhou, Q., Li, J., Yu, Z., Wang, X., … Su, L. (2017). IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget, 8(13), 20741–20750. https://doi.org/10.18632/oncotarget.15119
- Xouri, G., & Christian, S. (2010). Origin and function of tumor stroma fibroblasts. Seminars in Cell & Developmental Biology, 21(1), 40–46. https://doi.org/10.1016/j.semcdb.2009.11.017
- Yang, F., Strand, D. W., & Rowley, D. R. (2008). Fibroblast growth factor-2 mediates transforming growth factor-beta action in prostate cancer reactive stroma. Oncogene, 27(4), 450–459. https://doi.org/10.1038/sj.onc.1210663
- Zhao, Z., Xiong, S., Wang, R., Li, Y., Wang, X., Wang, Y., … Cheng, B. (2019). Peri-tumor fibroblasts promote tumorigenesis and metastasis of hepatocellular carcinoma via Interleukin6/STAT3 signaling pathway. Cancer Management and Research, 11, 2889–2901. https://doi.org/10.2147/CMAR.S192263
