The Role of TGF𝜷 Signaling in Squamous Cell Cancer: Lessons from Mouse Models

Table 1

Skin and oral carcinogenesis studies with mouse models of TGFβ1 signaling.

Signaling component	Mouse model	Study details	Phenotype	Reference
			TGF𝛽1 overexpression
	K6-TGFβ1*, K10-TGFβ1; DMBA/TPA	Constitutive and inducible suprabasal expression	Suppressed papilloma formation, increased malignant conversion and spindle cell carcinoma	Cui et al., 1996 [44]
TGF𝛽1 ligand	Loricrin-TGF𝛽1 gene switch; DMBA/TPA	Long-term expression in papillomas	Increased EMT, invasion, and metastasis	Weeks et al., 2001 [45]
	K5rTA x tetOTGF𝛽1; DMBA/TPA	Short-term expression in papillomas	Growth arrest, regression, and tumor inflammation	Mohammed et al., 2010 [46]
			TGFβ1 knockdown
	Tgfb1+/− versus Tgfb1+/+; DMBA/TPA	Germline Tgfb1 heterozygote	Reduced papillomas in TGFβ1+/−, increased malignant conversion	Pérez-Lorenzo et al., 2010 [47]
	Tgfb1−/−; v-𝑅𝑎𝑠^Ha xenotransplantation	Skin grafts of PMEK onto athymic mice	SCC with TGF𝛽1−/−, papilloma with TGFβ1+/− and +/+	Glick et al., 1994 [48]
TβRI	DMBA/TPA pharmacological inactivation	Topical SB431542 during TPA promotion	Reduced papilloma, increased conversion	Mordasky Markell et al., 2010 [49]
	DMBA/TPA pharmacological inactivation	Systemic LY2109761 during TPA promotion	Increased malignant phenotype of SCC	Connolly et al., 2011 [50]
	K14Cre^ER  x Tgfb1^fl/fl  DMBA	deletion of TβRI in oral mucosa	Accelerated HNSCC with AKT activation	Bian et al., 2009 [51]
	K14Cre^ER  x Tgfb1^fl/fl  x 𝑃𝑡𝑒𝑛^fl/fl	deletion of TβRI and PTEN in oral mucosa	Accelerated HNSCC	Bian et al., 2012 [52]
TβRII	Loricrin-ΔTgfbr2	Epidermal expression of dominant negative type II receptor	Reduced tumor latency, increased SCC	Go et al., 1999 [42]; Go et al., 2000 [43]
	K5Cre^Pr1  x Tgfbr2^fl/fl  DMBA or x K-Ras^12D	Oral mucosa deletion of TβRII	HNSCC only with DMBA or K-Ras	Lu et al., 2006 [53]
	K14-Cre x Tgfbr2^fl/fl	Epidermal deletion of TβRII	No skin tumors, spontaneous anogenital SCC	Guasch et al., 2007 [54]
	K14-Cre x Tgfbr2^fl/fl	v-Ras^Ha xenotransplantation	Aggressive SCC	Guasch et al., 2007 [54]
R-Smads	K5Cre^Pr1  x Smad2^fl/fl  DMBA/TPA	Basal/stem cell deletion of Smad2 in epidermis	Increased tumors accelerated; more aggressive SCC	Hoot et al., 2008 [38]; Hoot et al., 2010 [55]
	MMTV-Cre x Smad4^fl/fl	Epidermal deletion of Smad4	Hair follicle defects spontaneous SCC	Qiao et al., 2006 [56]
	K5Cre^Pr1 x Smad4^fl/fl	Deletion of Smad4 in oral mucosa	Spontaneous HNSCC w/genomic instability increased inflammation normal and tumor tissue	Bornstein et al., 2009 [35]
	Smad3−/−; DMBA/TPA	germline Smad3 null	Suppressed tumor formation, resistance to TPA	Li et al., 2004 [57]
	Smad3−/−; v-Ras^Ha	Primary mouse keratinocyte skin grafts	Progression to SCC	Vijaychandra et al., [58]
I-Smads	Smad7 + v-Ras^Ha; Smad6 + v-Ras^Ha	Primary mouse keratinocyte skin grafts	Smad7: rapid progression to SCC; Smad6: papilloma	Liu et al., 2003 [59]
TGFβ1/TβRII	TGFβ1 gene switch x ΔTgfbr2; DMBA/TPA	Inducible expression of TGFβ1 in papillomas with inhibition of TGF𝛽 receptor	Suppressed EMT in papillomas, increased metastasis	Han et al., 2005 [30]

∗Unless otherwise indicated TGFβ1 transgene used was TGFβ1^S223/S225 constitutively active mutant
fl/fl: floxed alleles.
Δ: truncation of cytoplasmic domain generating dominant negative receptor.
DMBA/TPA indicates 2-stage chemical carcinogenesis protocol.
Cre^ER: tamoxifen-inducible Cre recombinase.
Cre^Pr1: rU486 inducible Cre recombinase.