Signal transduction growth factors: the effective governance of transcription and cellular adhesion in cancer invasion

Abstract

Giulio Bizzozero classified the tissues concerning their capacity to self-renew during the adult life in labile, stable and permanent tissues. In 1940 Viktor Hamburger and Rita Levi Montalcini exposed the possibility to induce the growth of permanent cells thanks to a specific ligand Nerve Growth Factor (NGF). Stanley Cohen purified a protein the Epidermal Growth Factor (EGF), able to induce epidermis proliferation and to elicit precocious eye disclosure and teeth eruption, establishing the "inverse" relationships between the proliferation and differentiation. These two biological effects induced by EGF were according to EGFR signaling is involved in a large array of cellular functions such as proliferation, survival, adhesion, migration and differentiation. This review is focused on the key role of growth factors signaling and their downstream effectors in physiological and in pathological phenomena, the authors highlight the governance of Growth factors during the EMT in cancer invasion.

Keywords: EGFR TGFβ; KGF; cancer invasion; e-cadherin; phosphorylation.

Figure 1. Epithelial mesenchymal transition scheme

A. The broad spectrum of growth factors and related activating downstream effectors (EGF, TGF-α, WNT, Notch, Src, β-catenin, IGF-2 and FGF) involved in induction of EMT B. Epithelial cells promote the expression of mesenchymal markers by the production of growth factors cytokines.

Figure 2. Schematic representation of signal transduction pathways involved after EGFR activation

EGFR ligands binding leads to a receptor dimerization followed by Tyrosine Kinase (TK) autophosphorylation; this mechanism induces a down-stream precise signaling correlated to different biological effects.

Figure 3. EGFR activation, internalization, recycling and degradation

The down-stream signaling involve Ras/Raf/Mek/Erk; Jak/Stat and PI3K/Akt/mTOR pathways. These pathways activate the transcription of ZEB1/TCF8, Snail, ZEB2, Snail2, E12/E47, FOXC2 that are able to influence the cell fate. On the right side of the figure we show the internalization and endosomal sorting of EGFR.

Figure 4. Mechanism of action of TNF-α on fibroblast cells and keratinocytes cells

TNF-α stimulation induces an increase of KGF biosynthesis in fibroblast cells and FGFR2-III expression and the expression of KGFR on keratynocites cells. The interplay between KGF and KGFR on keratinocytes leads to an hyper-phosphorylation of pRb, inducing the release of transcriptionally active E2F1 allowing KGFR biosynthesis.

Figure 5. Physiological and pathological role of E-cadherin and N-cadherin genes

This figure shows the precise role of E-cadherin and N-cadherin in physiological and pathological biological effects such as embryogenesis, wound healing and carcinoma progression and metastasis.

Figure 6. Summary diagram of positive or negative feedback circuits that regulate key processes during EMT

The critical crosstalk between important oncogenic factors, and tumor suppressive proteins are represented by the involved pathways which consist of the activation of WNT by β-catenin, the involvement of PI3K and MAPK in response to EGF ligands and HGF, describes the expression of Jagged-1 (JAG1), induced by Notch ligand in the regulation of Snail/Slug and Twist at transcriptional, translational, and posttranslational levels. All these effectors converge on the shift of E-cadherin.