Expressions and clinical significance of forkhead box protein 3 and adenosine 2a receptor ingastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SHA Suoyou ^1,2 , SHI Linsen ¹ , SHAO Yong ¹ ,  ZHU Xiaocheng ¹

1. Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P. R. China;
2. Graduate School of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P. R. China;

Corresponding author：

ZHU Xiaocheng, Email: zhuxccf@163.com

Keywords：

gastric cancer; forkhead box protein 3; adenosine 2a receptor; regulatory T cells

DOI：

10.7507/1007-9424.201706118

Video：

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Objective To compare the difference in the expressions of forkhead box protein 3 (FoxP3) and adenosine 2a receptor (A2aR) in gastric cancer tissues and its adjacent tissues, and to investigate the relationship between the elevated expression of FoxP3/A2aR and clinicopathological features in gastric cancer. Methods Gastric cancer tissues and their adjacent tissues from 52 patients with gastric cancer were collected, who underwent surgery in the Affiliated Hospital of Xuzhou Medical University from July 2015 to November 2016, immunohistochemical staining was used to detect the expressions of FoxP3 and A2aR. Results ① The high-expression rate of FoxP3 in gastric cancer tissues was 69.2% (36/52), which was higher than that of adjacent tissues (11.5%, 6/52), P<0.001. The high-expression rate of A2aR in gastric cancer tissues was 69.2% (36/52), which was higher than that of adjacent tissues (25.0%, 13/52),P<0.001. ② The expression of FoxP3 was positively correlated with the expression of A2aR in gastric cancer tissues (r=0.76, P<0.05). ③ In gastric cancer tissues, high-expressions of FoxP3 and A2aR were not related to gender, age, diameter of tumor, tumor location, degree of differentiation, gross type, and histological type (P>0.05), but both associated with TNM stage, T stage, number of lymph node metastasis, and distant metastasis (P<0.05), the high-expression rates of FoxP3 and A2aR in patients with stage Ⅲ+Ⅳ were higher than those of patients with stage Ⅰ+Ⅱ, the high-expression rates of FoxP3 and A2aR in patients with stage T3+T4 were higher than those of patients with stage T1+T2, the high-expression rates of FoxP3 and A2aR in patients with distant metastasis were higher than those of patients without distant metastasis, and the high-expression rates of FoxP3 and A2aR increased gradually with the increase in the number of lymph node metastasis. Conclusion There are high expressions of FoxP3 and A2aR in gastric cancer tissues, and both of them may play important role in promoting the occurrence and development of gastric cancer.

Citation： SHA Suoyou, SHI Linsen, SHAO Yong, ZHU Xiaocheng. Expressions and clinical significance of forkhead box protein 3 and adenosine 2a receptor ingastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(11): 1347-1352. doi: 10.7507/1007-9424.201706118 Copy

1.	Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer, 2008, 44(13): 1875-1882.
2.	Murthy KS. Signaling for contraction and relaxation in smooth muscle of the gut. Annu Rev Physiol, 2006, 68: 345-374.
3.	Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J, 2015, 13: 265-272.
4.	Sitkovsky MV, Hatfield S, Abbott R, et al. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res, 2014, 2(7): 598-605.
5.	Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol, 2016, 29: 90-96.
6.	Ohta A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol, 2016, 7: 109.
7.	Whiteside TL, Mandapathil M, Schuler P. The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem, 2011, 18(34): 5217-5223.
8.	Wittekind C, Oberschmid B. Gastrointestinal tumors : New N classification of the UICC. Chirurg, 2010, 81(2): 95-98, 100-102.
9.	柴立勋, 孙克林, 郭黎平. 等. 食管鳞癌中Ezrin和CD44-v6的表达及其临床意义. 中华肿瘤杂志, 2007, 29(9): 685-688.
10.	Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010, 127(12): 2893-2917.
11.	魏小丽, 徐瑞华. 胃癌免疫治疗的进展. 中华胃肠外科杂志, 2016, 19(2): 225-232.
12.	Kershaw MH, Westwood JA, Slaney CY, et al. Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunology, 2014, 3(5): e16.
13.	Zarganes-Tzitzikas T, Konstantinidou M, Gao Y, et al. Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015). Expert Opin Ther Pat, 2016, 26(9): 973-977.
14.	Weinmann H. Cancer immunotherapy: selected targets and small-molecule modulators. Chem Med Chem, 2016, 11(5): 450-466.
15.	Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001, 27(1): 68-73.
16.	Sun J, Han ZB, Liao W, et al. Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4⁺CD25⁺ Forkhead Boxp3 (FOXP3)⁺ regulatory T cells and balancing anti- and pro-inflammatory factors. Cell Physiol Biochem, 2011, 27(5): 587-596.
17.	Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, 299(5609): 1057-1061.
18.	Lukashev D, Sitkovsky M, Ohta A. From "Hellstrom Paradox" to anti-adenosinergic cancer immunotherapy. Purinergic Signal, 2007, 3(1-2): 129-134.
19.	Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med, 2007, 204(6): 1257-1265.
20.	Schuler PJ, Harasymczuk M, Schilling B, et al. Separation of human CD4⁺CD39⁺ T cells by magnetic beads reveals two phenotypically and functionally different subsets. J Immunol Methods, 2011, 369(1-2): 59-68.
21.	Estrela AB, Abraham WR. Adenosine in the inflamed gut: a Janus faced compound. Curr Med Chem, 2011, 18(18): 2791-2815.
22.	Wehbi VL, Taskén K. Molecular Mechanisms for cAMP-Mediated Immunoregulation in T cells - role of anchored protein kinase A signaling units. Front Immunol, 2016, 7: 222.
23.	Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A, 2006, 103(35): 13132-13137.
24.	Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell, 2016, 30(3): 391-403.
25.	Dahan R, Ravetch JV. Co-targeting of adenosine signaling pathways for immunotherapy: potentiation by fc receptor engagement. Cancer Cell, 2016, 30(3): 369-371.
26.	Hay CM, Sult E, Huang Q, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology, 2016, 5(8): e1208875.

1. Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer, 2008, 44(13): 1875-1882.
2. Murthy KS. Signaling for contraction and relaxation in smooth muscle of the gut. Annu Rev Physiol, 2006, 68: 345-374.
3. Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J, 2015, 13: 265-272.
4. Sitkovsky MV, Hatfield S, Abbott R, et al. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res, 2014, 2(7): 598-605.
5. Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol, 2016, 29: 90-96.
6. Ohta A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol, 2016, 7: 109.
7. Whiteside TL, Mandapathil M, Schuler P. The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem, 2011, 18(34): 5217-5223.
8. Wittekind C, Oberschmid B. Gastrointestinal tumors : New N classification of the UICC. Chirurg, 2010, 81(2): 95-98, 100-102.
9. 柴立勋, 孙克林, 郭黎平. 等. 食管鳞癌中Ezrin和CD44-v6的表达及其临床意义. 中华肿瘤杂志, 2007, 29(9): 685-688.
10. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010, 127(12): 2893-2917.
11. 魏小丽, 徐瑞华. 胃癌免疫治疗的进展. 中华胃肠外科杂志, 2016, 19(2): 225-232.
12. Kershaw MH, Westwood JA, Slaney CY, et al. Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunology, 2014, 3(5): e16.
13. Zarganes-Tzitzikas T, Konstantinidou M, Gao Y, et al. Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015). Expert Opin Ther Pat, 2016, 26(9): 973-977.
14. Weinmann H. Cancer immunotherapy: selected targets and small-molecule modulators. Chem Med Chem, 2016, 11(5): 450-466.
15. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001, 27(1): 68-73.
16. Sun J, Han ZB, Liao W, et al. Intrapulmonary delivery of human umbilical cord mesenchymal stem cells attenuates acute lung injury by expanding CD4⁺CD25⁺ Forkhead Boxp3 (FOXP3)⁺ regulatory T cells and balancing anti- and pro-inflammatory factors. Cell Physiol Biochem, 2011, 27(5): 587-596.
17. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, 299(5609): 1057-1061.
18. Lukashev D, Sitkovsky M, Ohta A. From "Hellstrom Paradox" to anti-adenosinergic cancer immunotherapy. Purinergic Signal, 2007, 3(1-2): 129-134.
19. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med, 2007, 204(6): 1257-1265.
20. Schuler PJ, Harasymczuk M, Schilling B, et al. Separation of human CD4⁺CD39⁺ T cells by magnetic beads reveals two phenotypically and functionally different subsets. J Immunol Methods, 2011, 369(1-2): 59-68.
21. Estrela AB, Abraham WR. Adenosine in the inflamed gut: a Janus faced compound. Curr Med Chem, 2011, 18(18): 2791-2815.
22. Wehbi VL, Taskén K. Molecular Mechanisms for cAMP-Mediated Immunoregulation in T cells - role of anchored protein kinase A signaling units. Front Immunol, 2016, 7: 222.
23. Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A, 2006, 103(35): 13132-13137.
24. Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell, 2016, 30(3): 391-403.
25. Dahan R, Ravetch JV. Co-targeting of adenosine signaling pathways for immunotherapy: potentiation by fc receptor engagement. Cancer Cell, 2016, 30(3): 369-371.
26. Hay CM, Sult E, Huang Q, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology, 2016, 5(8): e1208875.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressions and clinical significance of forkhead box protein 3 and adenosine 2a receptor ingastric cancer

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