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Colorectal Cancer Metastasis Signaling

Colorectal cancer is one of the leading causes of cancer-related death. Several forms of genomic instability are common in colon cancer: microsatellite instability (MSI), chromosome instability (CIN) and chromosome translocations. The MSI and CIN mutations mainly alter the WNT, CdhE, prostaglandin, EGFR, TGF-βR and DCC signaling routes to facilitate colorectal carcinoma.Conceptually, a gatekeeper in neoplasia refers to a gene that controls the initiation of a neoplasm in a specific tissue. Mutation and subsequent inactivation of the APC tumor suppressor gene in colorectal neoplasia best exemplifies the gatekeeper model...

Colorectal Cancer Metastasis Signaling

Pathway Summary

Colorectal cancer is one of the leading causes of cancer-related death. Several forms of genomic instability are common in colon cancer: microsatellite instability (MSI), chromosome instability (CIN) and chromosome translocations. The MSI and CIN mutations mainly alter the WNT, CdhE, prostaglandin, EGFR, TGF-βR and DCC signaling routes to facilitate colorectal carcinoma.Conceptually, a gatekeeper in neoplasia refers to a gene that controls the initiation of a neoplasm in a specific tissue. Mutation and subsequent inactivation of the APC tumor suppressor gene in colorectal neoplasia best exemplifies the gatekeeper model. APC controls the WNT signaling pathway via regulation of Ctnn-β levels. In normal cells, WNT ligands signal via Fzd receptors and together with LRP5/6 co-receptors transduce signals through Dsh to inhibit GSK3β action. In the absence of WNT signaling, Ctnn-β is associated with a cytoplasmic complex containing GSK3β, AXIN and APC which leads to Ctnn-β degradation. However, in the presence of WNT signaling, Dsh enhances the phosphorylation of GSK3β thereby inhibiting GSK3β. This leads to accumulation of free and unphosphorylated Ctnn-β in the cytoplasm, which translocates to the nucleus and associates with TCF and LEF to promote cell survival and cell proliferation. CdhE also triggers Ctnn-β translocation to the nucleus. APC inactivation in tumors by MSI and CIN mutations leads to Ctnn-β stabilization, activation of the TCF/LEF transcription factor and subsequent up-regulation of c-Myc, Cyclin D1, COX2, Survivin, p53 and MMPs.PGE2 signals via PTGER2/4 and activates Ctnn-β/TCF-dependent transcription in colon cancer cells through the AC/cAMP/PKA pathway. In a parallel cascade, the free G-β and γ subunits activate PI3K and AKT leading to the phosphorylation of GSK3β and activation of Ctnn-β. Moreover, COX2-derived PGE2 also provides a growth advantage to colorectal carcinomas through transactivation of the EGF/EGFR signaling system. Binding of PGE2 to PTGER4 induces the phosphorylation of PTGER4 by GRKs. This phosphorylation attracts AR-β1 and its subsequent dephosphorylation, allowing its association with c-Src which then initiates the transactivation of EGFR and subsequent downstream signaling through AKT. The EGFR/SOS/GRB2, Ras, PI3K, Akt signaling cascades are involved in the migration and metastasis of colorectal carcinomas while activation of the EGFR/SOS/GRB2, Ras, BRaf, MEK, ERK signaling cascade is vital for PGE2-induced gene expression of Cyclin D1 and VEGF that play a critical role in colorectal carcinogenesis.Signaling by TGF-β is disrupted in various intestinal hyperproliferative states. The importance of SMAD4, a downstream regulator in the TGF-β signaling pathway in colorectal cancer is associated with late-stage or metastatic disease state. Inflammation-induced activation of TNF-α/TNF-αR and TLRs activates NF-κB, whereas IL-6/IL-6R and IFN-γ/IFN-γR activate STAT3 and STAT1, respectively. Aberrantly activated STAT3 and NF-κB signals participate in oncogenesis through up-regulation of genes such as BclXL, MCL1 and c-Myc, CcnD1/D2 to induce cell proliferation, and anti-apoptotic factors that lead to tumor progression.

Colorectal Cancer Metastasis Signaling Genes list

Explore Genes related to Colorectal Cancer Metastasis Signaling

Products related to Colorectal Cancer Metastasis Signaling

Explore products related to Colorectal Cancer Metastasis Signaling
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