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.