Jen-Hwey Chiu1,2,3, Ling-Ming Tseng4,5, Yi-Fang Tsai4,5, Chi-Cheng Huang4,6, Yen-Shu Lin4, Chih-Yi Hsu7,8, Ching-Po Huang9, Chun-Yu Liu4,10. 1. Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. II, Shipai Rd, Taipei, 112, Taiwan, ROC. chiujh@ym.edu.tw. 2. Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC. chiujh@ym.edu.tw. 3. Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. chiujh@ym.edu.tw. 4. Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. II, Shipai Rd, Taipei, 112, Taiwan, ROC. 5. Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. 6. Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan, ROC. 7. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. 8. School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. 9. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. 10. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
Abstract
BACKGROUND: The aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC). METHODS: Using human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (ΔIL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), ΔIL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-β1 as well as anoikis resistance. The Kaplan-Meier's method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS). RESULTS: Our results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the ΔIL-17A group, there was an increase in necrosis area, a decrease in tumor CD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-β1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine 4T1 cell lines. Kaplan-Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients. CONCLUSION: We conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.
BACKGROUND: The aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC). METHODS: Using human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (ΔIL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), ΔIL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-β1 as well as anoikis resistance. The Kaplan-Meier's method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS). RESULTS: Our results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the ΔIL-17A group, there was an increase in necrosis area, a decrease in tumorCD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-β1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine4T1 cell lines. Kaplan-Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients. CONCLUSION: We conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.
Authors: Joseph Antoine Salvator Fabre; Jérôme Giustinniani; Christian Garbar; Yacine Merrouche; Frank Antonicelli; Armand Bensussan Journal: Int J Mol Sci Date: 2018-12-04 Impact factor: 5.923
Authors: Nicholas R Hum; Aimy Sebastian; Kelly A Martin; Naiomy D Rios-Arce; Sean F Gilmore; David M Gravano; Elizabeth K Wheeler; Matthew A Coleman; Gabriela G Loots Journal: Front Oncol Date: 2022-07-18 Impact factor: 5.738