Clinical significance of epithelial-mesenchymal transition

Steinestel, Konrad; Eder, Stefan; Schrader, Andres Jan; Steinestel, Julie

doi:10.1186/2001-1326-3-17

Clinical and Translational Medicine

Table 2 Therapeutic approaches targeting EMT in benign and malignant processes

From: Clinical significance of epithelial-mesenchymal transition

Organ/entity	Target	Approach	Mechanism	Effect	Ref.
Liver (Hepatocytes)	STAT3	Sorafenib	Inhibition of STAT3 phosphorylation	TGF-β signaling ↓,	[134]
				Apoptosis ↓,
				Fibrosis ↓
Kidney (Tubular epithelium)	ALK3/6 receptors Smad5	Recombinant BMP-7	Antagonistic ALK receptor activation/Smad1 signaling	E-cadherin ↑	[111, [136]
Colorectal cancer	FGFR4	siRNA Knockdown	Reduction of Src and MEK1/2-ERK1/2 signaling	Tumor formation ↓,	[137]
		Targeting antibodies		Cell growth ↓
		PD173074, TKI-25		Angiogenesis ↓
Hepatocellular carcinoma	ILK	Kinase-inactivated ILK (S343A)	Reduction of Akt signaling	Sensitivity to anti-EGFR therapy ↑	[141]
Lung adenocarcinoma	HAT/HDAC	Sorafenib	HAT expression↑	Changes in histone acetylation and transcriptional repression of EMT-related genes	[138]
	HAT/HDAC	Sorafenib	HDAC expression↓, possibly via inhibition of Ras/Raf/MAPK and ErbB signaling		[138]
	Brachyury	Vaccination (Brachyury-specific T cells)	T-cell mediated cytotoxicity	Lysis of Brachyury-positive tumor cells	[3]
	Axl RTK	SGI-7079	Inhibition of Axl phosphorylation	Growth of mesenchymal NSCLC xenograft tumors ↓	[114]
Breast cancer	LYN kinase	Dasatinib	Inhibition of LYN kinase activity	Invasion ↓	[142]
	EMT master gene expression	Metformin	Transcriptional repression	Twist1 ↓, ZEB1 ↓,	[143]
				Slug ↓,
				TGF-β 1–3 ↓,
				MMP-3, MMP-9 ↓,
				E-cadherin ↑
Urothelial carcinoma in situ (UCIS)	Urokinase plasminogen activator (uPA) expression	Sorafenib	Inhibition of Ras/MAPK signaling	uPA ↓,	[23]
Urothelial carcinoma in situ (UCIS)	Urokinase plasminogen activator (uPA) expression	Sorafenib	Inhibition of Ras/MAPK signaling	E-cadherin ↑	[23]
Pancreatic cancer	Gli1, Ptch (Hedgehog target genes)	Cyclopamine, IPI-269609	Inhibition of Hedgehog signaling	Snail ↓,	[139, 140]
				E-cadherin ↑,
				Metastasis ↓
	EMT master gene expression	Resveratrol	Transcriptional repression	Slug ↓,	[144]
				Snail ↓,
				ZEB1↓,
				Migration/Invasion ↓
	Axl RTK	siRNA Knockdown	Inhibition of MAPK and PI3K/AKT kinase signaling	GTP-bound Rho/Rac↓,	[145]
				Slug ↓,
				Snail ↓,
				Twist ↓,
				MMP-9 ↓,
				Migration/Invasion ↓

STAT3, Signal transducer and activator of transcription 3; TGF-β, transforming growth factor β; ALK3, activin-like kinase 3; BMP-7, bone morphogenetic protein 7, FGFR4, fibroblast growth factor receptor 4; Src, sarcoma kinase; MEK, mitogen-associated protein kinase kinase; ERK, extracellular signal-related kinase; siRNA, small interfering RNA; ILK, integrin-linked kinase; AKT, protein kinase B; HAT, histone acetyltransferase; HDAC, histone deacetylase; EGFR, epidermal growth factor receptor; RTK, receptor tyrosine kinase; NSCLC, non-small cell lung cancer; LYN, Lck/Yes-related novel protein tyrosine kinase; MMP, matrix metalloproteinase; uPA, urokinase plasminogen activator; ZEB1, Zinc finger E-box-binding homeobox 1; PI3K, phosphatidylinositol-3-kinase.

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