KEGG PATHWAY: hsa05210

PATHWAY: hsa05210

Entry

hsa05210                    Pathway

Name

Colorectal cancer - Homo sapiens (human)

Description

Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).

Class

Human Diseases; Cancer: specific types

Pathway map

hsa05210

Colorectal cancer

Network

Element

N00012

Mutation-activated KRAS/NRAS to ERK signaling pathway

N00032

Mutation-activated KRAS/NRAS to PI3K signaling pathway

N00041

EGFR-overexpression to RAS-ERK signaling pathway

N00042

EGFR-overexpression to PI3K signaling pathway

N00057

Mutation-inactivated APC to Wnt signaling pathway

N00058

Mutation-activated CTNNB1 to Wnt signaling pathway

N00064

Mutation-inactivated TGFBR2 to TGF-beta signaling pathway

N00065

Mutation-inactivated SMAD2 to TGF-beta signaling pathway

N00099

Mutation-inactivated BAX to apoptotic pathway

N00102

Loss of DCC to DCC-apoptotic pathway

N00104

Mutation-activated KRAS to RalGDS signaling pathway

N00115

Mutation-inactivated TP53 to transcription

N00230

TGFA-overexpression to RAS-ERK signaling pathway

N00232

TGFA-overexpression to PI3K signaling pathway

N00276

EGF-overexpression to RAS-ERK signaling pathway

N00278

EREG-overexpression to RAS-ERK signaling pathway

N00280

AREG-overexpression to RAS-ERK signaling pathway

N00281

EGF-overexpression to PI3K signaling pathway

N00283

EREG-overexpression to PI3K signaling pathway

N00285

AREG-overexpression to PI3K signaling pathway

Disease

H00020

Colorectal cancer

Drug

D10137

Regorafenib hydrate (JAN)

D10138

Regorafenib (USAN/INN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

2932	GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]

8312	AXIN1; axin 1 [KO:K02157]

8313	AXIN2; axin 2 [KO:K04385]

1499	CTNNB1; catenin beta 1 [KO:K02105]

324	APC; APC regulator of WNT signaling pathway [KO:K02085]

10297

APC2; APC regulator of WNT signaling pathway 2 [KO:K02085]

6932	TCF7; transcription factor 7 [KO:K02620]

83439

TCF7L1; transcription factor 7 like 1 [KO:K04490]

6934	TCF7L2; transcription factor 7 like 2 [KO:K04491]

51176

LEF1; lymphoid enhancer binding factor 1 [KO:K04492]

332	BIRC5; baculoviral IAP repeat containing 5 [KO:K08731]

4609	MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]

595	CCND1; cyclin D1 [KO:K04503]

3845	KRAS; KRAS proto-oncogene, GTPase [KO:K07827]

5290	PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]

5293	PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]

5291	PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]

5295	PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]

5296	PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]

8503	PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]

207	AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]

208	AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]

10000

AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]

572	BAD; BCL2 associated agonist of cell death [KO:K02158]

842	CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]

369	ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]

673	BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]

5894	RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]

5604	MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]

5605	MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]

5594	MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

5595	MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

3725	JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]

2353	FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]

5900	RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]

5898	RALA; RAS like proto-oncogene A [KO:K07834]

5899	RALB; RAS like proto-oncogene B [KO:K07835]

5879	RAC1; Rac family small GTPase 1 [KO:K04392]

5880	RAC2; Rac family small GTPase 2 [KO:K07860]

5881	RAC3; Rac family small GTPase 3 [KO:K07861]

387	RHOA; ras homolog family member A [KO:K04513]

5599	MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]

5602	MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]

5601	MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]

1630	DCC; DCC netrin 1 receptor [KO:K06765]

836	CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]

26060

APPL1; adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 [KO:K08733]

7040	TGFB1; transforming growth factor beta 1 [KO:K13375]

7042	TGFB2; transforming growth factor beta 2 [KO:K13376]

7043	TGFB3; transforming growth factor beta 3 [KO:K13377]

7046	TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]

7048	TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]

4087	SMAD2; SMAD family member 2 [KO:K04500]

4088	SMAD3; SMAD family member 3 [KO:K23605]

4089	SMAD4; SMAD family member 4 [KO:K04501]

4292	MLH1; mutL homolog 1 [KO:K08734]

4436	MSH2; mutS homolog 2 [KO:K08735]

4437	MSH3; mutS homolog 3 [KO:K08736]

2956	MSH6; mutS homolog 6 [KO:K08737]

581	BAX; BCL2 associated X, apoptosis regulator [KO:K02159]

5366	PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]

10018

BCL2L11; BCL2 like 11 [KO:K16341]

27113

BBC3; BCL2 binding component 3 [KO:K10132]

596	BCL2; BCL2 apoptosis regulator [KO:K02161]

54205

CYCS; cytochrome c, somatic [KO:K08738]

7157	TP53; tumor protein p53 [KO:K04451]

1026	CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]

1647	GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]

4616	GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]

10912

GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]

578	BAK1; BCL2 antagonist/killer 1 [KO:K14021]

1643	DDB2; damage specific DNA binding protein 2 [KO:K10140]

51426

POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]

1950	EGF; epidermal growth factor [KO:K04357]

7039	TGFA; transforming growth factor alpha [KO:K08774]

2069	EREG; epiregulin [KO:K09784]

374	AREG; amphiregulin [KO:K09782]

1956	EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]

2885	GRB2; growth factor receptor bound protein 2 [KO:K04364]

6654	SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]

6655	SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]

3265	HRAS; HRas proto-oncogene, GTPase [KO:K02833]

4893	NRAS; NRAS proto-oncogene, GTPase [KO:K07828]

2475	MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]

6198	RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]

6199	RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]

Compound

C05981

Phosphatidylinositol-3,4,5-trisphosphate

Reference

PMID:15000146

Authors

Grady WM.

Title

Genomic instability and colon cancer.

Journal

Cancer Metastasis Rev 23:11-27 (2004)
DOI:10.1023/A:1025861527711

Reference

PMID:16555243

Authors

Soreide K, Janssen EA, Soiland H, Korner H, Baak JP.

Title

Microsatellite instability in colorectal cancer.

Journal

Br J Surg 93:395-406 (2006)
DOI:10.1002/bjs.5328

Reference

PMID:11078609

Authors

Anwar S, Hall C, White J, Deakin M, Farrell W, Elder JB.

Title

Hereditary non-polyposis colorectal cancer: an updated review.

Journal

Eur J Surg Oncol 26:635-45 (2000)
DOI:10.1053/ejso.2000.0974

Reference

PMID:16699851

Authors

Takayama T, Miyanishi K, Hayashi T, Sato Y, Niitsu Y.

Title

Colorectal cancer: genetics of development and metastasis.

Journal

J Gastroenterol 41:185-92 (2006)
DOI:10.1007/s00535-006-1801-6

Reference

PMID:12621137

Authors

Lynch HT, de la Chapelle A.

Title

Hereditary colorectal cancer.

Journal

N Engl J Med 348:919-32 (2003)
DOI:10.1056/NEJMra012242

Reference

PMID:12951588

Authors

Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C.

Title

The significance of unstable chromosomes in colorectal cancer.

Journal

Nat Rev Cancer 3:695-701 (2003)
DOI:10.1038/nrc1165

Reference

PMID:10505543

Authors

Behrens J.

Title

Cadherins and catenins: role in signal transduction and tumor progression.

Journal

Cancer Metastasis Rev 18:15-30 (1999)
DOI:10.1023/A:1006200102166

Reference

PMID:16042571

Authors

Behrens J.

Title

The role of the Wnt signalling pathway in colorectal tumorigenesis.

Journal

Biochem Soc Trans 33:672-5 (2005)
DOI:10.1042/BST0330672

Reference

PMID:15349822

Authors

Behrens J, Lustig B.

Title

The Wnt connection to tumorigenesis.

Journal

Int J Dev Biol 48:477-87 (2004)
DOI:10.1387/ijdb.041815jb

Reference

PMID:9196022

Authors

Polakis P.

Title

The adenomatous polyposis coli (APC) tumor suppressor.

Journal

Biochim Biophys Acta 1332:F127-47 (1997)
DOI:10.1016/S0304-419X(97)00008-5

Reference

PMID:12737309

Authors

Janssen KP.

Title

Murine models of colorectal cancer: studying the role of oncogenic K-ras.

Journal

Cell Mol Life Sci 60:495-506 (2003)
DOI:10.1007/s000180300041

Reference

PMID:11459867

Authors

Adjei AA.

Title

Blocking oncogenic Ras signaling for cancer therapy.

Journal

J Natl Cancer Inst 93:1062-74 (2001)
DOI:10.1093/jnci/93.14.1062

Reference

PMID:15573119

Authors

Arakawa H.

Title

Netrin-1 and its receptors in tumorigenesis.

Journal

Nat Rev Cancer 4:978-87 (2004)
DOI:10.1038/nrc1504

Reference

PMID:15310786

Authors

Mehlen P, Fearon ER.

Title

Role of the dependence receptor DCC in colorectal cancer pathogenesis.

Journal

J Clin Oncol 22:3420-8 (2004)
DOI:10.1200/JCO.2004.02.019

Reference

PMID:11223406

Authors

Peltomaki P.

Title

DNA mismatch repair and cancer.

Journal

Mutat Res 488:77-85 (2001)
DOI:10.1016/S1383-5742(00)00058-2

Reference

PMID:15711891

Authors

Li F, Cao Y, Townsend CM Jr, Ko TC.

Title

TGF-beta signaling in colon cancer cells.

Journal

World J Surg 29:306-11 (2005)
DOI:10.1007/s00268-004-7813-6

Reference

PMID:11170304

Authors

Roman C, Saha D, Beauchamp R.

Title

TGF-beta and colorectal carcinogenesis.

Journal

Microsc Res Tech 52:450-7 (2001)
DOI:10.1002/1097-0029(20010215)52:4<450::AID-JEMT1030>3.0.CO;2-O

Reference

PMID:16326109

Authors

Watson AJ.

Title

An overview of apoptosis and the prevention of colorectal cancer.

Journal

Crit Rev Oncol Hematol 57:107-21 (2006)
DOI:10.1016/j.critrevonc.2005.06.005

Reference

PMID:15479695

Authors

Watson AJ.

Title

Apoptosis and colorectal cancer.

Journal

Gut 53:1701-9 (2004)
DOI:10.1136/gut.2004.052704

Reference

PMID:11477132

Authors

Houlston RS.

Title

What we could do now: molecular pathology of colorectal cancer.

Journal

Mol Pathol 54:206-14 (2001)
DOI:10.1136/mp.54.4.206

Reference

PMID:19167459

Authors

Hector S, Prehn JH

Title

Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: a review.

Journal

Biochim Biophys Acta 1795:117-29 (2009)
DOI:10.1016/j.bbcan.2008.12.002

Reference

PMID:18568040

Authors

Karnoub AE, Weinberg RA

Title

Ras oncogenes: split personalities.

Journal

Nat Rev Mol Cell Biol 9:517-31 (2008)
DOI:10.1038/nrm2438

Reference

PMID:24213116

Authors

Wang D, Xia D, Dubois RN

Title

The Crosstalk of PTGS2 and EGF Signaling Pathways in Colorectal Cancer.

Journal

Cancers (Basel) 3:3894-908 (2011)
DOI:10.3390/cancers3043894

Reference

PMID:20554751

Authors

Dasari A, Messersmith WA

Title

New strategies in colorectal cancer: biomarkers of response to epidermal growth factor receptor monoclonal antibodies and potential therapeutic targets in phosphoinositide 3-kinase and mitogen-activated protein kinase pathways.

Journal

Clin Cancer Res 16:3811-8 (2010)
DOI:10.1158/1078-0432.CCR-09-2283

Reference

PMID:26149458

Authors

Hutchinson RA, Adams RA, McArt DG, Salto-Tellez M, Jasani B, Hamilton PW

Title

Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer.

Journal

J Transl Med 13:217 (2015)
DOI:10.1186/s12967-015-0531-z

Related
pathway

hsa04010