Progress in Role of Notch Signaling Pathway in Pancreas Development and Pancreatic Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DU Xiao , ZHAO Yupei.

Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, ChinaCorresponding Author: ZHAO Yu-pei, E-mail: zhao8028@263.net;

Corresponding author：

Keywords：

Pancreas development; Pancreatic cancer; Notch signaling pathway; Progress

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Objective 　To investigate the role of Notch signaling pathway in pancreas development and pancreatic cancer.
Methods 　The related literatures were reviewed and analyzed.
Results　 Notch signaling played a role early in development by maintaining pancreatic epithelial cells in a progenitor state and delaying their differentiation until timely appropriate. Notch signaling was reactivated in the initiation and progression of pancreatic cancer.
Conclusion 　Notch signaling pathway plays an important role in the pancreas development. Sustained Notch signaling activity promotes the progression of pancreatic cancer, and may be one of major factors in the initiation of pancreatic cancer.

Citation： DU Xiao,ZHAO Yupei.. Progress in Role of Notch Signaling Pathway in Pancreas Development and Pancreatic Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(10): 1109-1112. doi: Copy

1.	Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008 [J]. CA Cancer J Clin, 2008; 58(2): 71-96.　.
2.	Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis [J]. Nature, 2004; 432(7015): 324-331.　.
3.	Bailey JM, Singh PK, Hollingsworth MA. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins [J]. J Cell Biochem, 2007; 102(4): 829-839.　.
4.	Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer [J]. FEBS Lett, 2006; 580(12): 2860-2868.　.
5.	Habbe N, Shi G, Meguid RA, et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice [J]. Proc Natl Acad Sci USA, 2008; 105(48): 18913-18918.　.
6.	Zhu L, Shi G, Schmidt CM, et al. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia [J]. Am J Pathol, 2007; 171(1): 263-273.　.
7.	Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer [J]. Clin Cancer Res, 2009; 15(7): 2291-2301.　.
8.	Morgan TH. The theory of the gene [J]. Am Nat, 1917; LI(609): 513-544.　.
9.	Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes [J]. Cell Mol Life Sci, 2009; 66(10): 1631-1646.　.
10.	Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling-a structural and biochemical perspective [J]. J Cell Sci, 2008; 121(Pt 19): 3109-3119.　.
11.	Kolev V, Kacer D, Trifonova R, et al. The intracellular domain of Notch ligand Delta1 induces cell growth arrest [J]. FEBS Lett, 2005; 579(25): 5798-5802.　.
12.	Lewis J, Hanisch A, Holder M. Notch signaling, the segmentation clock, and the patterning of vertebrate somites [J]. J Biol, 2009; 8(4): 44-50.　.
13.	Blaumueller CM, Qi H, Zagouras P, et al. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane [J]. Cell, 1997; 90(2): 281-291.　.
14.	Edbauer D, Winkler E, Regula JT, et al. Reconstitution of gamma-secretase activity [J]. Nat Cell Biol, 2003; 5(5): 486-488.　.
15.	Matsuno K, Eastman D, Mitsiades T, et al. Human deltex is a conserved regulator of Notch signalling [J]. Nat Genet, 1998; 19(1): 74-78.　.
16.	Yamamoto N, Yamamoto S, Inagaki F, et al. Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor [J]. J Biol Chem, 2001; 276(48): 45031-45040.　.
17.	Hori K, Fostier M, Ito M, et al. Drosophila deltex mediates suppressor of Hairless-independent and late-endosomal activation of Notch signaling [J]. Development, 2004; 131(22): 5527-5537.　.
18.	Kiaris H, Politi K, Grimm LM, et al. Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium [J]. Am J Pathol, 2004; 165(2): 695-705.　.
19.	Liu WH, Lai MZ. Deltex regulates T-cell activation by targeted degradation of active MEKK1 [J]. Mol Cell Biol, 2005; 25(4): 1367-1378.　.
20.	Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells [J]. J Biol Chem, 2004; 279(4): 2937-2944.　.
21.	Edlund H. Pancreatic organogenesis-developmental mechanisms and implications for therapy [J]. Nat Rev Genet, 2002; 3(7): 524-532.　.
22.	Murtaugh LC. Pancreas and beta-cell development: from the actual to the possible [J]. Development, 2007; 134(3): 427-438.　.
23.	Lammert E, Brown J, Melton DA. Notch gene expression during pancreatic organogenesis [J]. Mech Dev, 2000; 94(1-2): 199-203.　.
24.	Jensen JN, Cameron E, Garay MV, et al. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration [J]. Gastroenterology, 2005; 128(3): 728-741.　.
25.	Fujikura J, Hosoda K, Iwakura H, et al. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas [J]. Cell Metab, 2006; 3(1): 59-65.　.
26.	Nakhai H, Siveke JT, Klein B, et al. Conditional ablation of Notch signaling in pancreatic development [J]. Development, 2008; 135(16): 2757-2765.　.
27.	Murtaugh LC, Stanger BZ, Kwan KM, et al. Notch signaling controls multiple steps of pancreatic differentiation [J]. Proc Natl Acad Sci USA, 2003; 100(25): 14920-14925.　.
28.	Hald J, Hjorth JP, German MS, et al. Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development [J]. Dev Biol, 2003; 260(2): 426-437.　.
29.	Siveke JT, Lubeseder-Martellato C, Lee M, et al. Notch signaling is required for exocrine regeneration after acute pancreatitis [J]. Gastroenterology, 2008; 134(2): 544-555.　.
30.	Pasca di Magliano M, Sekine S, Ermilov A, et al. Hedgehog/Ras interactions regulate early stages of pancreatic cancer [J]. Genes Dev, 2006; 20(22): 3161-3173.　.
31.	Strobel O, Dor Y, Alsina J, et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia [J]. Gastroenterology, 2007; 133(6): 1999-2009.　.
32.	Bhanot U, Khntop R, Hasel C, et al. Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis [J]. J Pathol, 2008; 214(3): 312-319.　.
33.	Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis [J]. Cancer Cell, 2003; 3(6): 565-576.　.
34.	Büchler P, Gazdhar A, Schubert M, et al. The Notch signaling pathway is related to neurovascular progression of pancreatic cancer [J]. Ann Surg, 2005; 242(6): 791-800.　.
35.	De La O JP, Emerson LL, Goodman JL, et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia [J]. Proc Natl Acad Sci USA, 2008; 105(48): 18907-18912.　.
36.	Sawey ET, Johnson JA, Crawford HC. Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway [J]. Proc Natl Acad Sci USA, 2007; 104(49): 19327-19332.　.
37.	Guerra C, Schuhmacher AJ, Caamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice [J]. Cancer Cell, 2007; 11(3): 291-302.　.
38.	梁珊, 杨竹林. 慢性胰腺炎与胰腺癌相互关系的研究进展 [J]. 肝胆胰外科杂志, 2006; 18(3): 197-198, 201. 　.
39.	Plentz R, Park JS, Rhim AD, et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma [J]. Gastroenterology, 2009; 136(5): 1741-1749.

1. 　Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008 [J]. CA Cancer J Clin, 2008; 58(2): 71-96.　.
2. 　Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis [J]. Nature, 2004; 432(7015): 324-331.　.
3. 　Bailey JM, Singh PK, Hollingsworth MA. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins [J]. J Cell Biochem, 2007; 102(4): 829-839.　.
4. 　Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer [J]. FEBS Lett, 2006; 580(12): 2860-2868.　.
5. 　Habbe N, Shi G, Meguid RA, et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice [J]. Proc Natl Acad Sci USA, 2008; 105(48): 18913-18918.　.
6. 　Zhu L, Shi G, Schmidt CM, et al. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia [J]. Am J Pathol, 2007; 171(1): 263-273.　.
7. 　Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer [J]. Clin Cancer Res, 2009; 15(7): 2291-2301.　.
8. 　Morgan TH. The theory of the gene [J]. Am Nat, 1917; LI(609): 513-544.　.
9. 　Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes [J]. Cell Mol Life Sci, 2009; 66(10): 1631-1646.　.
10. 　Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling-a structural and biochemical perspective [J]. J Cell Sci, 2008; 121(Pt 19): 3109-3119.　.
11. 　Kolev V, Kacer D, Trifonova R, et al. The intracellular domain of Notch ligand Delta1 induces cell growth arrest [J]. FEBS Lett, 2005; 579(25): 5798-5802.　.
12. 　Lewis J, Hanisch A, Holder M. Notch signaling, the segmentation clock, and the patterning of vertebrate somites [J]. J Biol, 2009; 8(4): 44-50.　.
13. 　Blaumueller CM, Qi H, Zagouras P, et al. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane [J]. Cell, 1997; 90(2): 281-291.　.
14. 　Edbauer D, Winkler E, Regula JT, et al. Reconstitution of gamma-secretase activity [J]. Nat Cell Biol, 2003; 5(5): 486-488.　.
15. 　Matsuno K, Eastman D, Mitsiades T, et al. Human deltex is a conserved regulator of Notch signalling [J]. Nat Genet, 1998; 19(1): 74-78.　.
16. 　Yamamoto N, Yamamoto S, Inagaki F, et al. Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor [J]. J Biol Chem, 2001; 276(48): 45031-45040.　.
17. 　Hori K, Fostier M, Ito M, et al. Drosophila deltex mediates suppressor of Hairless-independent and late-endosomal activation of Notch signaling [J]. Development, 2004; 131(22): 5527-5537.　.
18. 　Kiaris H, Politi K, Grimm LM, et al. Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium [J]. Am J Pathol, 2004; 165(2): 695-705.　.
19. 　Liu WH, Lai MZ. Deltex regulates T-cell activation by targeted degradation of active MEKK1 [J]. Mol Cell Biol, 2005; 25(4): 1367-1378.　.
20. 　Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells [J]. J Biol Chem, 2004; 279(4): 2937-2944.　.
21. 　Edlund H. Pancreatic organogenesis-developmental mechanisms and implications for therapy [J]. Nat Rev Genet, 2002; 3(7): 524-532.　.
22. 　Murtaugh LC. Pancreas and beta-cell development: from the actual to the possible [J]. Development, 2007; 134(3): 427-438.　.
23. 　Lammert E, Brown J, Melton DA. Notch gene expression during pancreatic organogenesis [J]. Mech Dev, 2000; 94(1-2): 199-203.　.
24. 　Jensen JN, Cameron E, Garay MV, et al. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration [J]. Gastroenterology, 2005; 128(3): 728-741.　.
25. 　Fujikura J, Hosoda K, Iwakura H, et al. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas [J]. Cell Metab, 2006; 3(1): 59-65.　.
26. 　Nakhai H, Siveke JT, Klein B, et al. Conditional ablation of Notch signaling in pancreatic development [J]. Development, 2008; 135(16): 2757-2765.　.
27. 　Murtaugh LC, Stanger BZ, Kwan KM, et al. Notch signaling controls multiple steps of pancreatic differentiation [J]. Proc Natl Acad Sci USA, 2003; 100(25): 14920-14925.　.
28. 　Hald J, Hjorth JP, German MS, et al. Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development [J]. Dev Biol, 2003; 260(2): 426-437.　.
29. 　Siveke JT, Lubeseder-Martellato C, Lee M, et al. Notch signaling is required for exocrine regeneration after acute pancreatitis [J]. Gastroenterology, 2008; 134(2): 544-555.　.
30. 　Pasca di Magliano M, Sekine S, Ermilov A, et al. Hedgehog/Ras interactions regulate early stages of pancreatic cancer [J]. Genes Dev, 2006; 20(22): 3161-3173.　.
31. 　Strobel O, Dor Y, Alsina J, et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia [J]. Gastroenterology, 2007; 133(6): 1999-2009.　.
32. 　Bhanot U, Khntop R, Hasel C, et al. Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis [J]. J Pathol, 2008; 214(3): 312-319.　.
33. 　Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis [J]. Cancer Cell, 2003; 3(6): 565-576.　.
34. 　Büchler P, Gazdhar A, Schubert M, et al. The Notch signaling pathway is related to neurovascular progression of pancreatic cancer [J]. Ann Surg, 2005; 242(6): 791-800.　.
35. 　De La O JP, Emerson LL, Goodman JL, et al. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia [J]. Proc Natl Acad Sci USA, 2008; 105(48): 18907-18912.　.
36. 　Sawey ET, Johnson JA, Crawford HC. Matrix metalloproteinase 7 controls pancreatic acinar cell transdifferentiation by activating the Notch signaling pathway [J]. Proc Natl Acad Sci USA, 2007; 104(49): 19327-19332.　.
37. 　Guerra C, Schuhmacher AJ, Caamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice [J]. Cancer Cell, 2007; 11(3): 291-302.　.
38. 　梁珊, 杨竹林. 慢性胰腺炎与胰腺癌相互关系的研究进展 [J]. 肝胆胰外科杂志, 2006; 18(3): 197-198, 201. 　.
39. 　Plentz R, Park JS, Rhim AD, et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma [J]. Gastroenterology, 2009; 136(5): 1741-1749.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress in Role of Notch Signaling Pathway in Pancreas Development and Pancreatic Cancer

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