KEGG   PATHWAY: ko05212Help
Entry
ko05212                     Pathway                                

Name
Pancreatic cancer
Description
Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
Class
Human Diseases; Cancers: Specific types
BRITE hierarchy
Pathway map
ko05212  Pancreatic cancer
ko05212

Ortholog table
Disease
H00019  Pancreatic cancer
Orthology
K07827  GTPase KRas
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K05729  Rho guanine nucleotide exchange factor 6
K04392  Ras-related C3 botulinum toxin substrate 1
K07860  Ras-related C3 botulinum toxin substrate 2
K07861  Ras-related C3 botulinum toxin substrate 3
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K02158  Bcl-2-antagonist of cell death
K04570  Bcl-2-like 1 (apoptosis regulator Bcl-X)
K04399  caspase 9 [EC:3.4.22.62]
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K08732  ral guanine nucleotide dissociation stimulator
K07834  Ras-related protein Ral-A
K07835  Ras-related protein Ral-B
K08773  RalA-binding protein 1
K04393  cell division control protein 42
K08774  transforming growth factor, alpha
K04357  epidermal growth factor
K04361  epidermal growth factor receptor [EC:2.7.10.1]
K05083  receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K04688  ribosomal protein S6 kinase beta [EC:2.7.11.1]
K11217  Janus kinase 1 [EC:2.7.10.2]
K04692  signal transducer and activator of transcription 3
K11220  signal transducer and activator of transcription 1
K05448  vascular endothelial growth factor A
K06621  cyclin-dependent kinase inhibitor 2A
K02089  cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  cyclin-dependent kinase 6 [EC:2.7.11.22]
K04503  G1/S-specific cyclin-D1
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K04451  tumor protein p53
K06625  cyclin-dependent kinase inhibitor 1A
K04402  growth arrest and DNA-damage-inducible protein
K02159  apoptosis regulator BAX
K14021  Bcl-2 homologous antagonist/killer
K10140  DNA damage-binding protein 2
K03511  DNA polymerase kappa [EC:2.7.7.7]
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K04388  TGF-beta receptor type-2 [EC:2.7.11.30]
K04500  mothers against decapentaplegic homolog 2/3
K04501  mothers against decapentaplegic homolog 4
K08775  breast cancer 2 susceptibility protein
K04482  DNA repair protein RAD51
Compound
C00416  Phosphatidate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Von Hoff D, Evans D, Hruban R (ed).
  Title
Pancreatic cancer
  Journal
Jones and Bartlett publishers (2005)
Reference
(Japanese)
  Authors
Niitsu Y, Yokota J (ed).
  Title
[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)
  Journal
Nankodo (1999)
Reference
  Authors
Bardeesy N, DePinho RA.
  Title
Pancreatic cancer biology and genetics.
  Journal
Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949
Reference
  Authors
Bardeesy N, Sharpless NE, DePinho RA, Merlino G.
  Title
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
  Journal
Semin Cancer Biol 11:201-18 (2001)
DOI:10.1006/scbi.2000.0371
Reference
  Authors
Cowgill SM, Muscarella P.
  Title
The genetics of pancreatic cancer.
  Journal
Am J Surg 186:279-86 (2003)
DOI:10.1016/S0002-9610(03)00226-5
Reference
  Authors
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.
  Title
Genetics and biology of pancreatic ductal adenocarcinoma.
  Journal
Genes Dev 20:1218-49 (2006)
DOI:10.1101/gad.1415606
Reference
  Authors
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ.
  Title
Understanding Ras: 'it ain't over 'til it's over'.
  Journal
Trends Cell Biol 10:147-54 (2000)
DOI:10.1016/S0962-8924(00)01740-2
Reference
  Authors
Holbro T, Civenni G, Hynes NE.
  Title
The ErbB receptors and their role in cancer progression.
  Journal
Exp Cell Res 284:99-110 (2003)
DOI:10.1016/S0014-4827(02)00099-X
Reference
  Authors
Marmor MD, Skaria KB, Yarden Y.
  Title
Signal transduction and oncogenesis by ErbB/HER receptors.
  Journal
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
DOI:10.1016/j.ijrobp.2003.06.002
Reference
  Authors
DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW.
  Title
Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
  Journal
Oncogene 22:7781-95 (2003)
DOI:10.1038/sj.onc.1206966
Reference
  Authors
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K.
  Title
Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.
  Journal
Oncogene 22:319-29 (2003)
DOI:10.1038/sj.onc.1206122
Reference
  Authors
Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M, Tanaka M.
  Title
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.
  Journal
Cancer Lett 201:107-16 (2003)
DOI:10.1016/S0304-3835(03)00482-8
Reference
  Authors
Schmid RM.
  Title
Genetic basis of pancreatic cancer.
  Journal
Best Pract Res Clin Gastroenterol 16:421-33 (2002)
DOI:10.1053/bega.2002.0316
Reference
  Authors
Elliott RL, Blobe GC.
  Title
Role of transforming growth factor Beta in human cancer.
  Journal
J Clin Oncol 23:2078-93 (2005)
DOI:10.1200/JCO.2005.02.047
Reference
  Authors
Rudkin TM, Foulkes WD.
  Title
BRCA2: breaks, mistakes and failed separations.
  Journal
Trends Mol Med 11:145-8 (2005)
DOI:10.1016/j.molmed.2005.02.003
Reference
  Authors
Venkitaraman AR.
  Title
Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
  Journal
J Cell Sci 114:3591-8 (2001)
Reference
  Authors
Chang Z, Li Z, Wang X, Kang Y, Yuan Y, Niu J, Wang H, Chatterjee D, Fleming JB, Li M, Abbruzzese JL, Chiao PJ
  Title
Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
  Journal
Clin Cancer Res 19:549-59 (2013)
DOI:10.1158/1078-0432.CCR-12-0032
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