KEGG PATHWAY: ko05212

PATHWAY: ko05212

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; Cancer: specific types

Pathway map

ko05212

Pancreatic cancer

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

K01115

phospholipase D1/2 [EC:3.1.4.4]

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

K23605

mothers against decapentaplegic homolog 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

Authors

Niitsu Y, Yokota J (ed).

Title

[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)

Journal

Nankodo (1999)

Reference

PMID:12459728

Authors

Bardeesy N, DePinho RA.

Title

Pancreatic cancer biology and genetics.

Journal

Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949

Reference

PMID:11407945

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

PMID:12946833

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

PMID:16702400

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

PMID:10740269

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

PMID:12648469

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

PMID:14967450

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

PMID:14586404

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

PMID:12545153

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

PMID:14580692

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

PMID:12079267

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

PMID:15774796