When developmental signaling pathways go wrong and their impact on pancreatic cancer development

Current Opinion in Gastroenterology

Volumn 21, Issue 5, 2005, Pages 555-560

  Lomberk, Gwen ^a   Fernandez Zapico, Martin E ^a   Urrutia, Raul ^a,b  

^a MAYO CLINIC   (United States)

^b ST MARY S HOSPITAL   (United States)

Author keywords

Hedgehog; Notch; Pancreas development; Pancreatic cancer

Indexed keywords

COMPLEMENTARY DNA; CYCLOOXYGENASE 2 INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; SONIC HEDGEHOG PROTEIN;

CARCINOGENESIS; CELL CYCLE G1 PHASE; CELL CYCLE S PHASE; CELL DIFFERENTIATION; DNA MICROARRAY; DNA REPAIR; GENE TARGETING; HUMAN; NONHUMAN; PANCREAS CANCER; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION;

HUMANS; PANCREATIC NEOPLASMS; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION;

EID: 23944515739     PISSN: 02671379     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mog.0000175462.38153.f7     Document Type: Review

References (32)

1. Fernandez-Zapico M, Urrutia R. Molecular pathways of pancreatic carcinogenesis. Drug Discovery Today. Disease Mechanisms 2004; 1:247-252. This review focuses on the previously known signaling pathways that control cell growth, differentiation, and migration that are altered in pancreatic cancer. This discussion includes both tumor suppressor and oncogenic pathways.
2. Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66:649-661.
3. Weinmaster G, Roberts VJ, Lemke G. Notch2: a second mammalian Notch gene. Development 1992; 116:931-941.
4. Lardelli M, Dahlstrand J, Lendahl U. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev 1994; 46:123-136.
5. Uyttendaele H, Marazzi G, Wu G, et al. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 1996; 122:2251-2259.
6. Pires-daSilva A, Sommer RJ. The evolution of signalling pathways in animal development. Nat Rev Genet 2003; 4:39-49.
7. Jarriault S, Brou C, Logeat F, et al. Signalling downstream of activated mammalian Notch. Nature 1995; 377:355-358.
8. De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398:518-522.
9. Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature 1999; 400:877-881.
10. Esni F, Ghosh B, Biankin AV, et al. Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 2004; 131:4213-4224. The authors demonstrated that activated Notch and its target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. They used lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds to find that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf 1-P48 expression. Ectopic Notch activation also was shown to delay acinar cell differentiation in the developing zebrafish pancreas. Overall, this paper defines a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.
11. Apelqvist A, Ahlgren U, Edlund H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 1997; 7:801-804.
12. Pear WS, Aster JC. T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling. Curr Opin Hematol 2004; 11:426-433.
13. Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer. Semin Cancer Biol 2004; 14:357-364.
14. Pahlman S, Stockhausen MT, Fredlund E, Axelson H. Notch signaling in neuroblastoma. Semin Cancer Biol 2004; 14:365-373.
15. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol 2004; 14:341-347.
16. Callahan R, Egan SE. Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia 2004; 9:145-163.
17. Sancho E, Batlle E, Clevers H. Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 2004; 20:695-723.
18. Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science 2005; 307:1904-1909.
19. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003; 3:565-576.
20. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15:3059-3087.
21. Ruiz i Altaba A. Sanchez P, Dahmane N: Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2002; 2:361-372.
22. Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422:313-317. Epub 2003 Mar 2005.
23. Thayer SP, Magliano MPD, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425:851-856.
24. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of smoothened. Nature 2002; 418:892-897.
25. Alcedo J, Noll M. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Biol Chem 1997; 378:583-590.
26. Nybakken K, Perrimon N. Hedgehog signal transduction: recent findings. Curr Opin Genet Dev 2002; 12:503-511.
27. Kawahira H, Ma NH, Tzanakakis ES, et al. Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development 2003; 130:4871-4879.
28. Kawahira H, Scheel DW, Smith SB, et al. Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev Biol 2005; 280:111-121. The authors demonstrated the requirement of tight control over Hedgehog pathway activity throughout embryonic development to ensure proper pancreas organogenesis. This is shown through ectopic activation of the Hedgehog pathway midway through pancreas development by expression of either Shh or lhh under the control of the human Pax4-promoter. Both transgenic lines display similar defects of the pancreas, suggesting that regulation of the overall level of Hedgehog activity is critical for proper development of this organ. The paper provides a clear demonstration of the connection between Hedgehog signaling and mesenchymal compared with epithelial tissue differentiation, in such a manner that pathway activation impairs the formation of epithelial progenitors.
29. Berman DM, Karhadkar SS, Maltra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425:846-850.
30. Prasad NB, Biankin AV, Fukushima N, et al. Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 2005; 65:1619-1626. The authors used cDNA microarrays containing 15 000 transcripts to identify 49 genes that were differentially expressed in microdissected early PanIN lesions (PanIN-1B/2) compared with microdissected normal duct epithelium. A particular cluster of extrapancreatic foregut markers, including pepsinogen C, MUC6, KLF4, and TFF1, were found to be upregulated in PanIN. Upon transfection of immortalized human pancreatic ductal cells with Gli1, an effector of the Hedgehog pathway, similar upregulation of the majority of foregut markers seen in early PanIN lesions was observed. This paper provides evidence that PanIN development may involve Hedgehog and has the ability to transdifferentiate pancreatic ductular cells into gastric epithelium.
31. Kayed H, Kleeff J, Keleg S, et al. Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int J Cancer 2004; 110:668-676.
32. Kayed H, Kleeff J, Keleg S, et al. Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis. J Endocrinol 2003; 178:467-478.