Animal experimental study on the inhibition of breast cancer growth by <i>in vivo</i> transplantation of T lymphocytes secreting EphrinAl-Caspase-3_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Bin ¹ , ZHANG Qin ¹ ,  LI Zhuang ¹ , ZHANG Bensi ² , LI Yanjiao ² , HUANG Yu ²

1. Department of Surgery, The Affiliated Hospital of Dali University/Clinical Medical College of Dali University, Dali, Yunnan 671000, P. R. China;
2. Department of Anatomy, Basic Medical College of Dali University, Dali, Yunnan 671000, P. R. China;

Corresponding author：

LI Zhuang, Email: li_zhuang126@126.com

Keywords：

breast cancer; EphrinAl-Caspase-3; T lymphocytes; animal experiment

DOI：

10.7507/1007-9424.201811027

Video：

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Objective To investigate the inhibitory effect of T lymphocyte transplantation of EphrinAl-Caspase-3 on the growth of breast cancer.Methods Six-week-old BALB/c nude mice were used to inoculate breast cancer cells to construct a nude mouse model of breast cancer. They were randomly divided into 3 groups according to random number table: PBS group received intratumoral injection of 10 μL PBS, and negative control group received intratumoral injection of 1×10⁶ T lymphocytes uninfected with adenovirus, 1×10⁶ EphrinAl-Caspase3-T lymphocytes were injected intratumorally into the infected group, and the tumors size (0, 3, 6, 9, 12 and 15 d) were measured with vernier calipers every 3 days until end of experiment. The content of EphrinAl-Caspase-3 in the tissues of the nude mice was measured. The presence of T lymphocytes expressing green fluorescent protein and the ratio of Caspase-3-positive and Ki-67-positive cell were observed by pathological examination.Results On the day 0 and day 3, there were no significant difference in tumor volume between the 3 groups (P>0.05). On the 6^th day and later, the difference between the infected group and the PBS group/negative control group were statistically significant (P<0.05), but there were no significant difference in tumor volume between the PBS group and negative control group at each time point (P>0.05). The presence of scattered green fluorescent protein-labeled EphrinAl-Caspase-3-T lymphocytes was observed in the tumor tissues of the infected group, while the presence of green fluorescent protein were not detected in the PBS group and the negative control group. In the infected cells, ratio of Caspase-3-positive cell was up-regulated and ratio of Ki-67-positive cell was down-regulated. The expression of EphrinAl-Caspase-3 could be detected on the 3^rd day in the infected group, and at the peak on the 6-day, then the amount of secretion gradually decreased. The expression of EphrinAl-Caspase-3 were not detected in the PBS group and the negative control group at each time point.Conclusion EphrinAl-Caspase-3 can significantly inhibit the growth of breast cancer cells and promote apoptosis.

Citation： ZHAO Bin, ZHANG Qin, LI Zhuang, ZHANG Bensi, LI Yanjiao, HUANG Yu. Animal experimental study on the inhibition of breast cancer growth by in vivo transplantation of T lymphocytes secreting EphrinAl-Caspase-3. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(3): 288-293. doi: 10.7507/1007-9424.201811027 Copy

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2.	Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell, 2007, 11(3): 259-273.
3.	Allred DC, Harvey JM, Berardo M, et al. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol, 1998, 11(2): 155-168.
4.	Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A, 2001, 98(19): 10869-10874.
5.	Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res, 2010, 12(5): R68.
6.	Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol, 2009, 27(8): 1160-1167.
7.	Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature, 2000, 406(6797): 747-752.
8.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
9.	Holen I, Speirs V, Morrissey B, et al. In vivo models in breast cancer research: progress, challenges and future directions. Dis Model Mech, 2017, 10(4): 359-371.
10.	Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst, 2001, 93(13): 979-989.
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12.	Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res, 2008, 14(1): 14-24.
13.	Bovelli D, Plataniotis G, Roila F, et al. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol, 2010, 21 Suppl 5: v277-v282.
14.	Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol, 2009, 53(24): 2231-2247.
15.	Bowles EJ, Wellman R, Feigelson HS, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst, 2012, 104(17): 1293-1305.
16.	Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med, 2005, 353(16): 1673-1684.
17.	de Azambuja E, Cardoso F, Meirsman L, et al. The new generation of breast cancer clinical trials: the right drug for the right target. Bull Cancer, 2008, 95(3): 352-357.
18.	Figueroa-Magalhães MC, Jelovac D, Connolly R, et al. Treatment of HER2-positive breast cancer. Breast, 2014, 23(2): 128-136.
19.	Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer, 2007, 7(5): 332-344.
20.	Brantley-Sieders D, Schmidt S, Parker M, et al. Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des, 2004, 10(27): 3431-3442.
21.	Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev, 2004, 15(6): 419-433.
22.	Zelinski DP, Zantek ND, Stewart JC, et al. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res, 2001, 61(5): 2301-2306.
23.	Nakopoulou L, Alexandrou P, Stefanaki K, et al. Immuno- histochemical expression of caspase-3 as an adverse indicator of the clinical outcome in human breast cancer. Pathobiology, 2001, 69(5): 266-273.
24.	Pu X, Storr SJ, Zhang Y, et al. Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival. Apoptosis, 2017, 22(3): 357-368.
25.	Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med, 2016, 13(4): 496-504.

1. Allred DC, Wu Y, Mao S, et al. Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution. Clin Cancer Res, 2008, 14(2): 370-378.
2. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell, 2007, 11(3): 259-273.
3. Allred DC, Harvey JM, Berardo M, et al. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol, 1998, 11(2): 155-168.
4. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A, 2001, 98(19): 10869-10874.
5. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res, 2010, 12(5): R68.
6. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol, 2009, 27(8): 1160-1167.
7. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature, 2000, 406(6797): 747-752.
8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
9. Holen I, Speirs V, Morrissey B, et al. In vivo models in breast cancer research: progress, challenges and future directions. Dis Model Mech, 2017, 10(4): 359-371.
10. Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst, 2001, 93(13): 979-989.
11. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 2005, 365(9472): 1687-1717.
12. Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res, 2008, 14(1): 14-24.
13. Bovelli D, Plataniotis G, Roila F, et al. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol, 2010, 21 Suppl 5: v277-v282.
14. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol, 2009, 53(24): 2231-2247.
15. Bowles EJ, Wellman R, Feigelson HS, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst, 2012, 104(17): 1293-1305.
16. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med, 2005, 353(16): 1673-1684.
17. de Azambuja E, Cardoso F, Meirsman L, et al. The new generation of breast cancer clinical trials: the right drug for the right target. Bull Cancer, 2008, 95(3): 352-357.
18. Figueroa-Magalhães MC, Jelovac D, Connolly R, et al. Treatment of HER2-positive breast cancer. Breast, 2014, 23(2): 128-136.
19. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer, 2007, 7(5): 332-344.
20. Brantley-Sieders D, Schmidt S, Parker M, et al. Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des, 2004, 10(27): 3431-3442.
21. Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev, 2004, 15(6): 419-433.
22. Zelinski DP, Zantek ND, Stewart JC, et al. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res, 2001, 61(5): 2301-2306.
23. Nakopoulou L, Alexandrou P, Stefanaki K, et al. Immuno- histochemical expression of caspase-3 as an adverse indicator of the clinical outcome in human breast cancer. Pathobiology, 2001, 69(5): 266-273.
24. Pu X, Storr SJ, Zhang Y, et al. Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival. Apoptosis, 2017, 22(3): 357-368.
25. Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med, 2016, 13(4): 496-504.

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Animal experimental study on the inhibition of breast cancer growth by in vivo transplantation of T lymphocytes secreting EphrinAl-Caspase-3

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