The possible apoptosis mechanism of activated pancreatic stellate cells in pancreatic ductal adenocarcinoma targeted by ProAgio_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHENG Wanming ¹ , WU Xinglang ² , YOU Haibo ³ ,  GONG Jianping ²

1. Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital of Yubei District, Chongqing 401120, P. R. China;
2. Department of Hepatobiliary Surgery, The Second Afﬁliated Hospital of Chongqing Medical University. Chongqing 400010, P. R. China;
3. Department of Hepatobiliary Surgery, People’s Hospital of Changshou, Chongqing 401220, P. R. China;

Corresponding author：

GONG Jianping, Email: gongjianping11@126.com

Keywords：

ProAgio; integrin; pancreatic stellate cell; tumor microenvironment; tumor metabolism; pancreatic ductal adenocarcinoma; review

DOI：

10.7507/1007-9424.201908032

Video：

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Objective To summarize the relationship between integrins, tumor metabolism, and tumor cells with pancreatic stellate cells in the tumor microenvironment, in order to provide targets and ideas for the treatment of pancreatic ductal adenocarcinoma.Method To review the literatures on pancreatic stellate cells, integrins, and amino acid metabolism as therapeutic targets for pancreatic ductal adenocarcinoma in the domestic and overseas.Results The drug research for pancreatic ductal adenocarcinoma was currently under vigorous development, but remain in the animal and clinical test stage. As a new therapeutic protein, ProAgio could inhibit the expression of integrin αvβ3, activation and secretion of pancreatic stellate cells, and alanine metabolism in the microenvironment of pancreatic ductal adenocarcinoma, so as to achieve the dual effects of anti-fibrosis and anti-tumor.Conclusions The roles of activated pancreatic stellate cells, ProAgio, integrin αvβ3, and alanine metabolism in pancreatic ductal adenocarcinoma have been partially elucidated, but the specific mechanism still needs further investigation and may become a completely new therapeutic target someday.

Citation： ZHENG Wanming, WU Xinglang, YOU Haibo, GONG Jianping. The possible apoptosis mechanism of activated pancreatic stellate cells in pancreatic ductal adenocarcinoma targeted by ProAgio. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(5): 619-623. doi: 10.7507/1007-9424.201908032 Copy

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3.	Du L, Wang-Gillam A. Trends in neoadjuvant approaches in pancreatic cancer. J Natl Compr Canc Netw, 2017, 15(8): 1070-1077.
4.	Apte MV, Xu Z, Pothula S, et al. Pancreatic cancer: the microenvironment needs attention too! Pancreatology, 2015, 15(4 Suppl): S32-S38.
5.	Schnittert J, Bansal R, Prakash J. Targeting pancreatic stellate cells in cancer. Trends Cancer, 2019, 5(2): 128-142.
6.	Apte MV, Park S, Phillips PA, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas, 2004, 29(3): 179-187.
7.	崔立华, 李彩霞, 卓玉珍, 等. 胰腺星状细胞在胰腺导管腺癌中的作用. 中国中西医结合外科杂志, 2018, 24(4): 516-518.
8.	Watari N, Hotta Y, Mabuchi Y. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn, 1982, 58(4-6): 837-858.
9.	Ferdek PE, Jakubowska MA. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflugers Arch, 2017, 469(9): 1039-1050.
10.	Xue R, Jia K, Wang J, et al. A rising star in pancreatic diseases: pancreatic stellate cells. Front Physiol, 2018, 9: 754.
11.	Zhang Z, Zhao S, Yao Z, et al. Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell. Redox Biol, 2017, 11: 322-334.
12.	Erkan M, Adler G, Apte MV, et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut, 2012, 61(2): 172-178.
13.	Fu Y, Liu S, Zeng S, et al. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol Cancer, 2018, 17(1): 62.
14.	Apte MV, Wilson JS, Lugea A, et al. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology, 2013, 144(6): 1210-1219.
15.	Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: novel therapeutic targets. Cytokine Growth Factor Rev, 2019, 48: 11-23.
16.	Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res, 2008, 68(3): 918-926.
17.	Diab M, Azmi A, Mohammad R, et al. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother, 2019, 20(5): 535-546.
18.	Zhan HX, Zhou B, Cheng YG, et al. Crosstalk between stromal cells and cancer cells in pancreatic cancer: new insights into stromal biology. Cancer Lett, 2017, 392: 83-93.
19.	Schneiderhan W, Diaz F, Fundel M, et al. Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci, 2007, 120(Pt 3): 512-519.
20.	Yang XP, Liu SL, Xu JF, et al. Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor/c-Met/survivin regulated by P53/P21. Exp Cell Res, 2017, 357(1): 79-87.
21.	Karnevi E, Rosendahl AH, Hilmersson KS, et al. Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: adding a third dimension in vitro. Exp Cell Res, 2016, 346(2): 206-215.
22.	Kiss K, Baghy K, Spisák S, et al. Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells. PLoS One, 2015, 10(5): e0128059.
23.	Wu Q, Tian Y, Zhang J, et al. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget, 2017, 8(60): 102721-102738.
24.	Moir JA, Mann J, White SA. The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol, 2015, 24(3): 232-238.
25.	Endo S, Nakata K, Sagara A, et al. Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells. Pancreatology, 2017, 17(6): 990-996.
26.	Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab, 2016, 23(1): 27-47.
27.	Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530.
28.	Sousa CM, Biancur DE, Wang X, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 2016, 536(7617): 479-483.
29.	Horwitz AR. The origins of the molecular era of adhesion research. Nat Rev Mol Cell Biol, 2012, 13(12): 805-811.
30.	Anderson LR, Owens TW, Naylor MJ. Structural and mechanical functions of integrins. Biophys Rev, 2014, 6(2): 203-213.
31.	Mas-Moruno C, Fraioli R, Rechenmacher F, et al. αvβ3- or α5β1-integrin-selective peptidomimetics for surface coating. Angew Chem Int Ed Engl, 2016, 55(25): 7048-7067.
32.	Schittenhelm J, Klein A, Tatagiba MS, et al. Comparing the expression of integrins αvβ3, αvβ5, αvβ6, αvβ8, fibronectin and fibrinogen in human brain metastases and their corresponding primary tumors. Int J Clin Exp Pathol, 2013, 6(12): 2719-2732.
33.	Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol, 2012, 3: 344.
34.	Ulmasov B, Neuschwander-Tetri BA, Lai J, et al. Inhibitors of Arg-Gly-Asp-binding integrins reduce development of pancreatic fibrosis in mice. Cell Mol Gastroenterol Hepatol, 2016, 2(4): 499-518.
35.	Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal, 2019, 12(570): eaav5183.
36.	戴明权, 金海晓, 严小军. 整合素 αvβ3 结构与激活及其肿瘤靶向药物的研究进展. 生物学杂志, 2018, 35(4): 81-85, 93.
37.	Hosotani R, Kawaguchi M, Masui T, et al. Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas, 2002, 25(2): e30-e35.
38.	Marchán S, Pérez-Torras S, Vidal A, et al. Dual effects of β3 integrin subunit expression on human pancreatic cancer models. Anal Cell Pathol (Amst), 2010, 33(5): 191-205.
39.	Lei XF, Fu W, Kim-Kaneyama JR, et al. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice. J Hepatol, 2016, 64(1): 110-117.
40.	Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol, 2014, 60(5): 1090-1096.
41.	Zhou X, Murphy FR, Gehdu N, et al. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem, 2004, 279(23): 23996-24006.
42.	Hersey P, Sosman J, O’Day S, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage Ⅳ metastatic melanoma. Cancer, 2010, 116(6): 1526-1534.
43.	Lombardi G, Pambuku A, Bellu L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol, 2017, 111: 94-102.
44.	Turaga RC, Yin L, Yang JJ, et al. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site. Nat Commun, 2016, 7: 11675.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
2. Kumar V, Abbas AK, Aster JC, et al. Robbins basic pathology. 10^th. Amsterdam, the Netherlands: Elsevier, 2018: 935.
3. Du L, Wang-Gillam A. Trends in neoadjuvant approaches in pancreatic cancer. J Natl Compr Canc Netw, 2017, 15(8): 1070-1077.
4. Apte MV, Xu Z, Pothula S, et al. Pancreatic cancer: the microenvironment needs attention too! Pancreatology, 2015, 15(4 Suppl): S32-S38.
5. Schnittert J, Bansal R, Prakash J. Targeting pancreatic stellate cells in cancer. Trends Cancer, 2019, 5(2): 128-142.
6. Apte MV, Park S, Phillips PA, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas, 2004, 29(3): 179-187.
7. 崔立华, 李彩霞, 卓玉珍, 等. 胰腺星状细胞在胰腺导管腺癌中的作用. 中国中西医结合外科杂志, 2018, 24(4): 516-518.
8. Watari N, Hotta Y, Mabuchi Y. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn, 1982, 58(4-6): 837-858.
9. Ferdek PE, Jakubowska MA. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflugers Arch, 2017, 469(9): 1039-1050.
10. Xue R, Jia K, Wang J, et al. A rising star in pancreatic diseases: pancreatic stellate cells. Front Physiol, 2018, 9: 754.
11. Zhang Z, Zhao S, Yao Z, et al. Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell. Redox Biol, 2017, 11: 322-334.
12. Erkan M, Adler G, Apte MV, et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut, 2012, 61(2): 172-178.
13. Fu Y, Liu S, Zeng S, et al. The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma. Mol Cancer, 2018, 17(1): 62.
14. Apte MV, Wilson JS, Lugea A, et al. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology, 2013, 144(6): 1210-1219.
15. Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: novel therapeutic targets. Cytokine Growth Factor Rev, 2019, 48: 11-23.
16. Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res, 2008, 68(3): 918-926.
17. Diab M, Azmi A, Mohammad R, et al. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother, 2019, 20(5): 535-546.
18. Zhan HX, Zhou B, Cheng YG, et al. Crosstalk between stromal cells and cancer cells in pancreatic cancer: new insights into stromal biology. Cancer Lett, 2017, 392: 83-93.
19. Schneiderhan W, Diaz F, Fundel M, et al. Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci, 2007, 120(Pt 3): 512-519.
20. Yang XP, Liu SL, Xu JF, et al. Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor/c-Met/survivin regulated by P53/P21. Exp Cell Res, 2017, 357(1): 79-87.
21. Karnevi E, Rosendahl AH, Hilmersson KS, et al. Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: adding a third dimension in vitro. Exp Cell Res, 2016, 346(2): 206-215.
22. Kiss K, Baghy K, Spisák S, et al. Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells. PLoS One, 2015, 10(5): e0128059.
23. Wu Q, Tian Y, Zhang J, et al. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget, 2017, 8(60): 102721-102738.
24. Moir JA, Mann J, White SA. The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol, 2015, 24(3): 232-238.
25. Endo S, Nakata K, Sagara A, et al. Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells. Pancreatology, 2017, 17(6): 990-996.
26. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab, 2016, 23(1): 27-47.
27. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530.
28. Sousa CM, Biancur DE, Wang X, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 2016, 536(7617): 479-483.
29. Horwitz AR. The origins of the molecular era of adhesion research. Nat Rev Mol Cell Biol, 2012, 13(12): 805-811.
30. Anderson LR, Owens TW, Naylor MJ. Structural and mechanical functions of integrins. Biophys Rev, 2014, 6(2): 203-213.
31. Mas-Moruno C, Fraioli R, Rechenmacher F, et al. αvβ3- or α5β1-integrin-selective peptidomimetics for surface coating. Angew Chem Int Ed Engl, 2016, 55(25): 7048-7067.
32. Schittenhelm J, Klein A, Tatagiba MS, et al. Comparing the expression of integrins αvβ3, αvβ5, αvβ6, αvβ8, fibronectin and fibrinogen in human brain metastases and their corresponding primary tumors. Int J Clin Exp Pathol, 2013, 6(12): 2719-2732.
33. Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol, 2012, 3: 344.
34. Ulmasov B, Neuschwander-Tetri BA, Lai J, et al. Inhibitors of Arg-Gly-Asp-binding integrins reduce development of pancreatic fibrosis in mice. Cell Mol Gastroenterol Hepatol, 2016, 2(4): 499-518.
35. Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal, 2019, 12(570): eaav5183.
36. 戴明权, 金海晓, 严小军. 整合素 αvβ3 结构与激活及其肿瘤靶向药物的研究进展. 生物学杂志, 2018, 35(4): 81-85, 93.
37. Hosotani R, Kawaguchi M, Masui T, et al. Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas, 2002, 25(2): e30-e35.
38. Marchán S, Pérez-Torras S, Vidal A, et al. Dual effects of β3 integrin subunit expression on human pancreatic cancer models. Anal Cell Pathol (Amst), 2010, 33(5): 191-205.
39. Lei XF, Fu W, Kim-Kaneyama JR, et al. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice. J Hepatol, 2016, 64(1): 110-117.
40. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol, 2014, 60(5): 1090-1096.
41. Zhou X, Murphy FR, Gehdu N, et al. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem, 2004, 279(23): 23996-24006.
42. Hersey P, Sosman J, O’Day S, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage Ⅳ metastatic melanoma. Cancer, 2010, 116(6): 1526-1534.
43. Lombardi G, Pambuku A, Bellu L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol, 2017, 111: 94-102.
44. Turaga RC, Yin L, Yang JJ, et al. Rational design of a protein that binds integrin αvβ3 outside the ligand binding site. Nat Commun, 2016, 7: 11675.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The possible apoptosis mechanism of activated pancreatic stellate cells in pancreatic ductal adenocarcinoma targeted by ProAgio

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