Molecular mechanisms of mouse skin tumor promotion

Abstract

Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-a and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion.

Figure 1

Multistage mouse skin carcinogenesis model.

Figure 2

Growth factor signaling pathways important in tumor promotion. Epidermal growth factor (EGF) and other ligands of the EGF receptor (EGFR)/ErbB family of receptors, including transforming growth factor-α (TGFα), amphiregulin, heparin-binding EGF-like growth factor (HB-EGF) and betacellulin, activate signaling of both the Ras/Raf/mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Insulin-like growth factor-1 (IGF-1) signals through its receptor IGF1R, which phosphorylates insulin receptor substrate-1 (IRS1) and SH2-containing protein (Shc) as well as other substrates leading to the activation of both Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Members of the transforming growth factor-β (TGFβ) family (TGFβ1, TGFβ2 and TGFβ3) bind to TGFβ receptor type II (TβRII) causing the recruitment of the type I receptor (TβRI), which phosphorylates Smad2 and Smad3 allowing them to form a complex with Smad4 that then translocates to the nucleus to modulate gene expression.

Figure 3

Cytokine signaling pathways important in tumor promotion.

Figure 4

Cyclooxygenase-2 (COX-2) and prostaglandin E₂ (PGE₂) signaling in tumor promotion.