Colorectal cancer - Homo sapiens (human)

Curator(s): Joe Strothman

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).    
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Colorectal cancer - Homo sapiens (human) cluster_Membrane Membrane cluster_node44 !DNA cluster_node45 !2 cluster_node46 !in cell cluster_node47 Pro-apoptotic proteins cluster_node48 MSI path 1 cluster_node49 MSI path 2 cluster_node50 !5 node1 12 TGFB TGFB->node1 TGFB node2 TGFBR1 TGFBR2 TGFB->node2 node3 26 node4 9 Suppressed apoptosis node6 2 node8 K-Ras PI3K node8->PI3K Raf node8->Raf ral guanine nucleotide dissociation stimulator RALGDS node8->RALGDS node9 12 PI3K->node9 PI3K node11 PKB/Akt PI3K->node11 node10 17 node11->node10 PKB/Akt BCL2-associated agonist of cell death BAD node11->BAD +p caspase 9,apoptosis-related cysteine peptidase CASP9 node11->CASP9 +p node20 GSK-3B node11->node20 +p node12 4 Raf->node12 Raf MEK Raf->MEK +p node13 Rac/Rho RALGDS->node13 JNK node13->JNK node14 11 JNK->node14 JNK Survival JNK->Survival node15 2 MEK->node15 MEK ERK MEK->ERK +p node16 24 ERK->node16 ERK node35 c-Fos ERK->node35 +p node34 c-Jun ERK->node34 +p node37 c-Myc 2 ERK->node37 +p node17 2 node18 9 node19 5 node21 5 node23 5 node24 GSK-3B 2 node24->node23 GSK-3B 2 node26 Beta-catenin 2 node24->node26 +p Axin 2 node24->Axin 2 node25 5 node26->node25 Beta-catenin 2 APC 2 node26->APC 2 node28 TCF/LEF node26->node28 Axin 2->node26 node27 1 Survivin node29 Anti-apoptosis Survivin->node29 node30 5 node31 c-Myc node31->node30 c-Myc Proliferation 1 node31->Proliferation 1 node32 9 CyclinD1 CyclinD1->node32 CyclinD1 CyclinD1->Proliferation 1 node33 1 node36 5 node38 9 CyclinD1 2 CyclinD1 2->node38 CyclinD1 2 Proliferation 2 CyclinD1 2->Proliferation 2 Loss of growth inhibitory effects of TGFbeta node39 10 node40 16 node41 2 node42 21 Axin adenomatous polyposis coli APC Axin->APC BAD->Suppressed apoptosis BAD->node17 BAD BCL2-associated X protein BAX BAX->node40 BAX node43 Bcl-2 BAX->node43 Mitochondria BAX->Mitochondria node43->node42 Bcl-2 Cyt c node43->Cyt c Mitochondria->Cyt c Defective apoptosis Cyt c->node41 Cyt c node22 Beta-catenin node22->node21 Beta-catenin node22->APC node22->node28 node28->node27 TCF/LEF DNA 1 node28->DNA 1 caspase 3,apoptosis-related cysteine peptidase CASP3 CASP3->node3 CASP3 CASP3->Suppressed apoptosis deleted in colorectal carcinoma DCC CASP3->DCC node5 CASP9 APPL1 DCC->node5 CASP9->Suppressed apoptosis CASP9->node18 CASP9 node5->node4 CASP9~APPL1 node5->CASP3 DNA 1->Survivin DNA 1->node31 DNA 1->CyclinD1 DNA 2 DNA 2->CyclinD1 2 DNA 3 DNA 3->Loss of growth inhibitory effects of TGFbeta DNA 4 DNA 4->BAX transforming growth factor,beta receptor II (70/80kDa) TGFBR2 DNA 4->TGFBR2 hMSH3 DNA 4->hMSH3 TGFBR2->node2 hMSH6 hMSH3->hMSH6 DNA 5 Impaired G1 cycle arrest DNA 5->Impaired G1 cycle arrest Karyotypic instability DNA 5->Karyotypic instability Reduced apoptosis DNA 5->Reduced apoptosis DNA damage p53 DNA damage->p53 p53->node39 p53 p53->DNA 5 node35->DNA 2 node34->node33 c-Jun node34->DNA 2 node37->node36 c-Myc 2 node37->DNA 2 node20->node19 GSK-3B node20->Axin node20->node22 +p SMAD family member 4 SMAD4 node7 Smad2/3 SMAD4->node7 node7->node6 Smad2/3 node7->DNA 3 node2->node7 +p hMLH1 hMSH2 hMLH1->hMSH2 hMSH2->DNA 4 p53 signaling pathway print "