Research progress of growth differentiation factor 15 in digestive tumor_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

TAN Qingyuan , DENG Lihui ,  XIA Qing

Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

XIA Qing, Email: xiaqing@medmail.com.cn

Keywords：

growth differentiation factor 15; biomarker; digestive tumor

DOI：

10.7507/1007-9424.201712079

Video：

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Objective To have more insight into roles of growth differentiation factor-15 (GDF15) in digestive tumor. Method The basic and clinical studies on the GDF15 in the digestive tumors published were searched in the databases for summarizing the latest advances on this issue. Results The GDF15, a novel member of transforming growth factor-β superfamily, played the diverse roles in the progress of the various diseases. The increasing number of evidence indicated that the GDF15 was associated with the diagnosis and prognostication of the digestive tumors, eg: colorectal cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, and might serve as a potential biomarker and therapeutic target for the multiple digestive tumors. Conclusions Current basic and clinical studies provide some evidences that GDF15 plays a role in digestive tumors. Further studies are needed to elucidate its roles and molecular mechanisms in different stages of diseases.

Citation： TAN Qingyuan, DENG Lihui, XIA Qing. Research progress of growth differentiation factor 15 in digestive tumor. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(7): 873-877. doi: 10.7507/1007-9424.201712079 Copy

1.	Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev, 2013, 24(4): 373-384.
2.	Lindahl B. The story of growth differentiation factor 15: another piece of the puzzle. Clin Chem, 2013, 59(11): 1550-1552.
3.	Aw Yong KM, Zeng Y, Vindivich D, et al. Morphological effects on expression of growth differentiation factor 15 (GDF15), a marker of metastasis. J Cell Physiol, 2014, 229(3): 362-373.
4.	Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
5.	国家消化系统疾病临床医学研究中心, 中华医学会消化内镜学分会, 中国医师协会消化医师分会. 中国巴雷特食管及其早期腺癌筛查与诊治共识(2017, 万宁). 中华内科杂志, 2017, 56(9): 701-711.
6.	Duggan SP, Behan FM, Kirca M, et al. An integrative genomic approach in oesophageal cells identifies TRB3 as a bile acid responsive gene, downregulated in Barrett’s oesophagus, which regulates NF-kappaB activation and cytokine levels. Carcinogenesis, 2010, 31(5): 936-945.
7.	Fisher OM, Levert-Mignon AJ, Lord SJ, et al. MIC-1/GDF15 in Barrett’s oesophagus and oesophageal adenocarcinoma. Br J Cancer, 2015, 112(8): 1384-1391.
8.	Wang XB, Jiang XR, Yu XY, et al. Macrophage inhibitory factor 1 acts as a potential biomarker in patients with esophageal squamous cell carcinoma and is a target for antibody-based therapy. Cancer Sci, 2014, 105(2): 176-185.
9.	Skipworth RJ, Deans DA, Tan BH, et al. Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer. Br J Cancer, 2010, 102(4): 665-672.
10.	国家消化系统疾病临床医学研究中心, 中华医学会内镜学分会(CSDE, Chinese Society of Digestive Endoscopy), 中华医学会健康管理学分会, 等. 中国早期胃癌筛查流程专家共识意见(草案)(2017 年, 上海). 中华健康管理学杂志, 2018, 12(1): 8-14.
11.	Colucci R, Antonioli L, Bernardini N, et al. Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing. J Pharmacol Exp Ther, 2012, 342(1): 140-149.
12.	Li YL, Cui W, Gao F, et al. Downregulation of growth differentiation factor-15 in trichostatin A-induced apoptosis could play a role in progression of gastric cancer. Int J Clin Exp Pathol, 2015, 8(7): 8136-8142.
13.	Han M, Dai D, Yousafzai NA, et al. CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer. Oncotarget, 2017, 8(61): 103557-103567.
14.	Lu L, Ma GQ, Liu XD, et al. Correlation between GDF15, MMP7 and gastric cancer and its prognosis. Eur Rev Med Pharmacol Sci, 2017, 21(3): 535-541.
15.	Blanco-Calvo M, Tarrío N, Reboredo M, et al. Circulating levels of GDF15, MMP7 and miR-200c as a poor prognostic signature in gastric cancer. Future Oncol, 2014, 10(7): 1187-1202.
16.	国家卫生计生委医政医管局, 中华医学会肿瘤学分会. 中国结直肠癌诊疗规范(2017 年版). 中华胃肠外科杂志, 2018, 21(1): 92-106.
17.	Choi HJ, Do KH, Park JH, et al. Early epithelial restitution by nonsteroidal anti-inflammatory drug-activated gene 1 counteracts intestinal ulcerative injuries. J Immunol, 2016, 197(4): 1415-1424.
18.	Baek SJ, Okazaki R, Lee SH, et al. Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia. Gastroenterology, 2006, 131(5): 1553-1560.
19.	Brown DA, Hance KW, Rogers CJ, et al. Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15): a potential screening tool for the prevention of colon cancer? Cancer Epidemiol Biomarkers Prev, 2012, 21(2): 337-346.
20.	Lee J, Fricke F, Warnken U, et al. Reconstitution of TGFBR2-mediated signaling causes upregulation of GDF-15 in HCT116 colorectal cancer cells. PLoS One, 2015, 10(6): e0131506.
21.	Li C, Wang J, Kong J, et al. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget, 2016, 7(1): 860-872.
22.	Danta M, Barber DA, Zhang HP, et al. Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia. Aliment Pharmacol Ther, 2017, 46(3): 347-354.
23.	Chen H, Qian J, Werner S, et al. Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer. Clin Epidemiol, 2017, 9: 517-526.
24.	Li C, Wang X, Casal I, et al. Growth differentiation factor 15 is a promising diagnostic and prognostic biomarker in colorectal cancer. J Cell Mol Med, 2016, 20(8): 1420-1426.
25.	Wang J, Li W, Wang Y, et al. The H6D genetic variation of GDF15 is associated with genesis, progress and prognosis in colorectal cancer. Pathol Res Pract, 2015, 211(11): 845-850.
26.	Mehta RS, Chong DQ, Song M, et al. Association between plasma levels of macrophage inhibitory cytokine-1 before diagnosis of colorectal cancer and mortality. Gastroenterology, 2015, 149(3): 614-622.
27.	Mehta RS, Song M, Bezawada N, et al. A prospective study of macrophage inhibitory cytokine-1 (MIC-1/GDF15) and risk of colorectal cancer. J Natl Cancer Inst, 2014, 106(4): dju016.
28.	Wang X, Yang Z, Tian H, et al. Circulating MIC-1/GDF15 is a complementary screening biomarker with CEA and correlates with liver metastasis and poor survival in colorectal cancer. Oncotarget, 2017, 8(15): 24892-24901.
29.	中华人民共和国卫生和计划生育委员会医政医管局. 原发性肝癌诊疗规范(2017 年版). 中华消化外科杂志, 2017, 16(7): 705-720.
30.	Hsiao EC, Koniaris LG, Zimmers-Koniaris T, et al. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol, 2000, 20(10): 3742-3751.
31.	Si Y, Liu X, Cheng M, et al. Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS One, 2011, 6(5): e19967.
32.	Zimmers TA, Jin X, Gutierrez JC, et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol, 2008, 134(7): 753-759.
33.	Chung HK, Kim JT, Kim HW, et al. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep, 2017, 7(1): 17238.
34.	Koo BK, Um SH, Seo DS, et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int, 2018, 38(4): 695-705.
35.	Krawczyk M, Zimmermann S, Hess G, et al. Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. PLoS One, 2017, 12(3): e0173506.
36.	Lee ES, Kim SH, Kim HJ, et al. Growth differentiation factor 15 predicts chronic liver disease severity. Gut Liver, 2017, 11(2): 276-282.
37.	Liu X, Chi X, Gong Q, et al. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS One, 2015, 10(5): e0127518.
38.	中国抗癌协会. 远端胆管癌规范化诊治专家共识(2017). 中华肝胆外科杂志, 2018, 24(1): 1-8.
39.	Subbannayya T, Leal-Rojas P, Barbhuiya MA, et al. Macrophage migration inhibitory factor—a therapeutic target in gallbladder cancer. BMC Cancer, 2015, 15: 843.
40.	Koopmann J, Buckhaults P, Brown DA, et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res, 2004, 10(7): 2386-2392.
41.	Koniaris LG. Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J Gastrointest Surg, 2003, 7(7): 901-905.
42.	Ji H, Lu HW, Li YM, et al. Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15. Mol Med Rep, 2015, 12(3): 3841-3848.
43.	Wang X, Li Y, Tian H, et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer, 2014, 14: 578.
44.	Kaur S, Chakraborty S, Baine MJ, et al. Potentials of plasma NGAL and MIC-1 as biomarker(s) in the diagnosis of lethal pancreatic cancer. PLoS One, 2013, 8(2): e55171.
45.	Montes AF, Villarroel PG, Ayerbes MV, et al. Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis. J Cancer Res Ther, 2017, 13(2): 240-245.
46.	Mohamed AA, Soliman H, Ismail M, et al. Evaluation of circulating ADH and MIC-1 as diagnostic markers in Egyptian patients with pancreatic cancer. Pancreatology, 2015, 15(1): 34-39.
47.	Kaur S, Baine MJ, Guha S, et al. NGAL, MIC-1, and CA19-9 in pancreatic juice: pathobiologic implications in diagnosing benign and malignant disease of the pancreas. Pancreas, 2013, 42(3): 494-501.
48.	Loosen SH, Neumann UP, Trautwein C, et al. Current and future biomarkers for pancreatic adenocarcinoma. Tumour Biol, 2017, 39(6): 1010428317692231.
49.	Torres C, Perales S, Alejandre MJ, et al. Serum cytokine profile in patients with pancreatic cancer. Pancreas, 2014, 43(7): 1042-1049.

1. Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev, 2013, 24(4): 373-384.
2. Lindahl B. The story of growth differentiation factor 15: another piece of the puzzle. Clin Chem, 2013, 59(11): 1550-1552.
3. Aw Yong KM, Zeng Y, Vindivich D, et al. Morphological effects on expression of growth differentiation factor 15 (GDF15), a marker of metastasis. J Cell Physiol, 2014, 229(3): 362-373.
4. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
5. 国家消化系统疾病临床医学研究中心, 中华医学会消化内镜学分会, 中国医师协会消化医师分会. 中国巴雷特食管及其早期腺癌筛查与诊治共识(2017, 万宁). 中华内科杂志, 2017, 56(9): 701-711.
6. Duggan SP, Behan FM, Kirca M, et al. An integrative genomic approach in oesophageal cells identifies TRB3 as a bile acid responsive gene, downregulated in Barrett’s oesophagus, which regulates NF-kappaB activation and cytokine levels. Carcinogenesis, 2010, 31(5): 936-945.
7. Fisher OM, Levert-Mignon AJ, Lord SJ, et al. MIC-1/GDF15 in Barrett’s oesophagus and oesophageal adenocarcinoma. Br J Cancer, 2015, 112(8): 1384-1391.
8. Wang XB, Jiang XR, Yu XY, et al. Macrophage inhibitory factor 1 acts as a potential biomarker in patients with esophageal squamous cell carcinoma and is a target for antibody-based therapy. Cancer Sci, 2014, 105(2): 176-185.
9. Skipworth RJ, Deans DA, Tan BH, et al. Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer. Br J Cancer, 2010, 102(4): 665-672.
10. 国家消化系统疾病临床医学研究中心, 中华医学会内镜学分会(CSDE, Chinese Society of Digestive Endoscopy), 中华医学会健康管理学分会, 等. 中国早期胃癌筛查流程专家共识意见(草案)(2017 年, 上海). 中华健康管理学杂志, 2018, 12(1): 8-14.
11. Colucci R, Antonioli L, Bernardini N, et al. Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing. J Pharmacol Exp Ther, 2012, 342(1): 140-149.
12. Li YL, Cui W, Gao F, et al. Downregulation of growth differentiation factor-15 in trichostatin A-induced apoptosis could play a role in progression of gastric cancer. Int J Clin Exp Pathol, 2015, 8(7): 8136-8142.
13. Han M, Dai D, Yousafzai NA, et al. CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer. Oncotarget, 2017, 8(61): 103557-103567.
14. Lu L, Ma GQ, Liu XD, et al. Correlation between GDF15, MMP7 and gastric cancer and its prognosis. Eur Rev Med Pharmacol Sci, 2017, 21(3): 535-541.
15. Blanco-Calvo M, Tarrío N, Reboredo M, et al. Circulating levels of GDF15, MMP7 and miR-200c as a poor prognostic signature in gastric cancer. Future Oncol, 2014, 10(7): 1187-1202.
16. 国家卫生计生委医政医管局, 中华医学会肿瘤学分会. 中国结直肠癌诊疗规范(2017 年版). 中华胃肠外科杂志, 2018, 21(1): 92-106.
17. Choi HJ, Do KH, Park JH, et al. Early epithelial restitution by nonsteroidal anti-inflammatory drug-activated gene 1 counteracts intestinal ulcerative injuries. J Immunol, 2016, 197(4): 1415-1424.
18. Baek SJ, Okazaki R, Lee SH, et al. Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia. Gastroenterology, 2006, 131(5): 1553-1560.
19. Brown DA, Hance KW, Rogers CJ, et al. Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15): a potential screening tool for the prevention of colon cancer? Cancer Epidemiol Biomarkers Prev, 2012, 21(2): 337-346.
20. Lee J, Fricke F, Warnken U, et al. Reconstitution of TGFBR2-mediated signaling causes upregulation of GDF-15 in HCT116 colorectal cancer cells. PLoS One, 2015, 10(6): e0131506.
21. Li C, Wang J, Kong J, et al. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget, 2016, 7(1): 860-872.
22. Danta M, Barber DA, Zhang HP, et al. Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia. Aliment Pharmacol Ther, 2017, 46(3): 347-354.
23. Chen H, Qian J, Werner S, et al. Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer. Clin Epidemiol, 2017, 9: 517-526.
24. Li C, Wang X, Casal I, et al. Growth differentiation factor 15 is a promising diagnostic and prognostic biomarker in colorectal cancer. J Cell Mol Med, 2016, 20(8): 1420-1426.
25. Wang J, Li W, Wang Y, et al. The H6D genetic variation of GDF15 is associated with genesis, progress and prognosis in colorectal cancer. Pathol Res Pract, 2015, 211(11): 845-850.
26. Mehta RS, Chong DQ, Song M, et al. Association between plasma levels of macrophage inhibitory cytokine-1 before diagnosis of colorectal cancer and mortality. Gastroenterology, 2015, 149(3): 614-622.
27. Mehta RS, Song M, Bezawada N, et al. A prospective study of macrophage inhibitory cytokine-1 (MIC-1/GDF15) and risk of colorectal cancer. J Natl Cancer Inst, 2014, 106(4): dju016.
28. Wang X, Yang Z, Tian H, et al. Circulating MIC-1/GDF15 is a complementary screening biomarker with CEA and correlates with liver metastasis and poor survival in colorectal cancer. Oncotarget, 2017, 8(15): 24892-24901.
29. 中华人民共和国卫生和计划生育委员会医政医管局. 原发性肝癌诊疗规范(2017 年版). 中华消化外科杂志, 2017, 16(7): 705-720.
30. Hsiao EC, Koniaris LG, Zimmers-Koniaris T, et al. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol, 2000, 20(10): 3742-3751.
31. Si Y, Liu X, Cheng M, et al. Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes. PLoS One, 2011, 6(5): e19967.
32. 　Zimmers TA, Jin X, Gutierrez JC, et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol, 2008, 134(7): 753-759.
33. Chung HK, Kim JT, Kim HW, et al. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep, 2017, 7(1): 17238.
34. Koo BK, Um SH, Seo DS, et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int, 2018, 38(4): 695-705.
35. Krawczyk M, Zimmermann S, Hess G, et al. Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. PLoS One, 2017, 12(3): e0173506.
36. Lee ES, Kim SH, Kim HJ, et al. Growth differentiation factor 15 predicts chronic liver disease severity. Gut Liver, 2017, 11(2): 276-282.
37. Liu X, Chi X, Gong Q, et al. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS One, 2015, 10(5): e0127518.
38. 中国抗癌协会. 远端胆管癌规范化诊治专家共识(2017). 中华肝胆外科杂志, 2018, 24(1): 1-8.
39. Subbannayya T, Leal-Rojas P, Barbhuiya MA, et al. Macrophage migration inhibitory factor—a therapeutic target in gallbladder cancer. BMC Cancer, 2015, 15: 843.
40. Koopmann J, Buckhaults P, Brown DA, et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res, 2004, 10(7): 2386-2392.
41. Koniaris LG. Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J Gastrointest Surg, 2003, 7(7): 901-905.
42. Ji H, Lu HW, Li YM, et al. Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15. Mol Med Rep, 2015, 12(3): 3841-3848.
43. Wang X, Li Y, Tian H, et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma. BMC Cancer, 2014, 14: 578.
44. Kaur S, Chakraborty S, Baine MJ, et al. Potentials of plasma NGAL and MIC-1 as biomarker(s) in the diagnosis of lethal pancreatic cancer. PLoS One, 2013, 8(2): e55171.
45. Montes AF, Villarroel PG, Ayerbes MV, et al. Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis. J Cancer Res Ther, 2017, 13(2): 240-245.
46. Mohamed AA, Soliman H, Ismail M, et al. Evaluation of circulating ADH and MIC-1 as diagnostic markers in Egyptian patients with pancreatic cancer. Pancreatology, 2015, 15(1): 34-39.
47. Kaur S, Baine MJ, Guha S, et al. NGAL, MIC-1, and CA19-9 in pancreatic juice: pathobiologic implications in diagnosing benign and malignant disease of the pancreas. Pancreas, 2013, 42(3): 494-501.
48. Loosen SH, Neumann UP, Trautwein C, et al. Current and future biomarkers for pancreatic adenocarcinoma. Tumour Biol, 2017, 39(6): 1010428317692231.
49. Torres C, Perales S, Alejandre MJ, et al. Serum cytokine profile in patients with pancreatic cancer. Pancreas, 2014, 43(7): 1042-1049.

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Research progress of growth differentiation factor 15 in digestive tumor

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