Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that induces growth arrest, tissue fibrosis, and epithelial-mesenchymal transition (EMT) through activation of Smad and non-Smad signaling pathways. EMT is the differentiation switch by which polarized epithelial cells differentiate into contractile and motile mesenchymal cells. Cell motility and invasive capacity are activated upon EMT. Multiple transcription factors, including deltaEF1/ZEB1, SIP1/ZEB2, and Snail/SNAI1, are induced by TGF-beta-Smad signaling and play critical roles in TGF-beta-induced EMT. In addition, both non-Smad signaling activated by TGF-beta and cross-talk with other signaling pathways play important roles in induction of EMT. Of these, Ras signaling synergizes with TGF-beta-Smad signaling, and plays an important role in the induction of EMT. TGF-beta inhibitors prevent invasion and metastasis of advanced cancer through multiple mechanisms, including inhibition of EMT. The discovery of molecules that inhibit TGF-beta-induced EMT but not TGF-beta-induced growth arrest may be an ideal strategy for treatment of invasion and metastasis of cancer.

Fig. 1

TGF-β transduces signaling through Smad and non-Smad signaling pathways. Smad pathway (right): TGF-β binds to TβRII and TβRI. TβRII phosphorylates TβRI, which activates Smad2 and Smad3. Activated Smad2/3 form complexes with Smad4, and translocate into the nucleus. The Smad complexes interact with various transcription factors and transcriptional co-activators, and regulate the transcription of target genes. Non-Smad pathways (left): TGF-β signals through multiple intra-cellular signaling cascades other than the Smad pathway. TGF-β receptors activate Erk, JNK, and p38 MAP kinases, PI3 kinase, and small GTPases such as Cdc42 and Rac. TGF-β receptors also bind Par6, induce TβRII kinase to phosphorylate Par6, and recruit Smurf1. Smurf1 then induces ubiquitylation and degradation of substrates such as RhoA.

Fig. 2

Processes of EMT and MET. During the process of EMT, epithelial cells expressing E-cadherin and claudin-1 differentiate into mesenchymal cells expressing N-cadherin, SMA, and FSP1. MET is the inverse process of EMT, in which mesenchymal cells differentiate into epithelial cells (Modified from R.A. Saito et al., Ref. 58).

Fig. 3

Transcriptional network for TGF-β-mediated induction of EMT. TGF-β induces the expression of several transcription factors involved in EMT, including the δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2) and the Snail family proteins (Snail and Slug). Left: TGF-β represses the expression of Id proteins and induces that of Ets1. Id proteins interact with and inhibit the transcriptional activity of E2A proteins. Ets1 acts in cooperative fashion with the E2A proteins released from Id proteins, and is involved in the up-regulation of δEF1 and SIP1. Right: TGF-β induces the expression of Snail in Smaddependent fashion. Ras signaling cooperates with TGF-β signaling in inducing Snail. In addition, HMGA2 is induced by TGF-β-Smad signaling, and induces the expression of Snail and Slug in certain types of cells.

Fig. 4

EMT and EndMT. During the process of EMT, epithelial cells forming an organized, tightly connected sheet trans-differentiate into disorganized, motile mesenchymal cells (upper panel; see also Fig. 2). During the process of EndMT, endothelial cells expressing VE-cadherin, PECAM-1, and claudin-5 differentiate into mesenchymal (or mural) cells expressing SMA and FSP1 (lower panel) (courtesy of Drs. Takuya Shirakihara and Hajime Mihira).