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Review
. 2011 Apr;50(4):264-79.
doi: 10.1002/mc.20665. Epub 2010 Jul 20.

Growth factor signaling pathways as _targets for prevention of epithelial carcinogenesis

Okkyung Rho  1 , Dae Joon Kim, Karou Kiguchi, John Digiovanni
Affiliations
Review

Growth factor signaling pathways as _targets for prevention of epithelial carcinogenesis

Okkyung Rho et al. Mol Carcinog. 2011 Apr.

Abstract

Growth factor receptor (GFR) signaling controls epithelial cell growth by responding to various endogenous or exogenous stimuli and subsequently activating downstream signaling pathways including Stat3, PI3K/Akt/mTOR, MAPK, and c-Src. Environmental chemical toxicants and UVB irradiation cause enhanced and prolonged activation of GFR signaling and downstream pathways that contributes to epithelial cancer development including skin cancer. Recent studies, especially those with tissue-specific transgenic mouse models, have demonstrated that GFRs and their downstream signaling pathways contribute to all three stages of epithelial carcinogenesis by regulating a wide variety of biological functions including proliferation, apoptosis, angiogenesis, cell adhesion, and migration. Inhibiting these signaling pathways early in the carcinogenic process results in reduced cell proliferation and survival, leading to decreased tumor formation. Collectively, these studies suggest that GFR signaling and subsequent downstream signaling pathways are potential _targets for the prevention of epithelial cancers including skin cancer.

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Figures

Figure 1
Figure 1
GFR signaling pathways in epithelial carcinogenesis. GFR signaling regulates multiple downstream signaling pathways. Several important pathways are shown in this Figure, including: Ras, Stat3, c-Src, and PI3K/Akt. These downstream pathways contribute to increase cell proliferation, survival, angiogenesis, adhesion and migration during epithelial carcinogenesis by regulating _target gene expression.
Figure 2
Figure 2
Role of Stat3 in epithelial carcinogenesis. Stat3 has an important role in all three stages of epithelial carcinogenesis induced by either chemical exposure or UVB irradiation. Stat3 regulates the expression of _target genes (e.g., c-Myc, cyclin D1, Bcl-xL, VEGF) that are involved in stem cell maintenance, proliferation, survival and EMT, respectively.
Figure 3
Figure 3
Akt signaling pathways contributing to epithelial tumor development. Activation of Akt can be initiated by the binding of growth factors to their receptors or by tumor promoters. Activated PI3K recruits Akt and PDK-1 to the cell membrane, and then Akt is phosphorylated by PDK1 at Thr308 site and mTORC2 at Ser473 site, respectively. Activated Akt mediates signaling pathways downstream to regulate diverse cellular processes. Activated Akt promotes cell proliferation by increased activity of cell cycle proteins, cell growth by enhanced protein synthesis through mTORC1 signaling, and cell survival by inhibiting apoptosis. Thus, elevated Akt activity contributes significantly to epithelial tumor promotion through multiple downstream signaling pathways.
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