|
Signaling component | Mouse model | Study details | Phenotype | Reference |
|
| | | TGF1 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] |
TGF1 ligand | Loricrin-TGF1 gene switch DMBA/TPA | Long-term expression in papillomas | Increased EMT, invasion, and metastasis | Weeks et al., 2001 [45] |
| K5rTA x tetOTGF1 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-Ha xenotransplantation | Skin grafts of PMEK onto athymic mice | SCC with TGF1−/−, 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] |
| K14CreER x Tgfb1fl/fl DMBA | deletion of TβRI in oral mucosa | Accelerated HNSCC with AKT activation | Bian et al., 2009 [51] |
| x Tgfb1fl/fl x | deletion of TβRI and PTEN in oral mucosa | Accelerated HNSCC | Bian et al., 2012 [52] |
|
TβRII | Loricrin-Tgfbr2 | Epidermal expression of dominant negative type II receptor | Reduced tumor latency, increased SCC | Go et al., 1999 [42] Go et al., 2000 [43] |
| K5CrePr1 x Tgfbr2fl/fl DMBA or x K-Ras12D | Oral mucosa deletion of TβRII | HNSCC only with DMBA or K-Ras | Lu et al., 2006 [53] |
| K14-Cre x Tgfbr2fl/fl | Epidermal deletion of TβRII | No skin tumors, spontaneous anogenital SCC | Guasch et al., 2007 [54] |
| K14-Cre x Tgfbr2fl/fl | v-RasHa xenotransplantation | Aggressive SCC | Guasch et al., 2007 [54] |
|
R-Smads | K5CrePr1 x Smad2fl/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 Smad4fl/fl | Epidermal deletion of Smad4 | Hair follicle defects spontaneous SCC | Qiao et al., 2006 [56] |
| K5CrePr1 x Smad4fl/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-RasHa | Primary mouse keratinocyte skin grafts | Progression to SCC | Vijaychandra et al., [58] |
|
I-Smads | Smad7 + v-RasHa Smad6 + v-RasHa | Primary mouse keratinocyte skin grafts | Smad7: rapid progression to SCC Smad6: papilloma | Liu et al., 2003 [59] |
|
TGFβ1/TβRII | TGFβ1 gene switch x Tgfbr2 DMBA/TPA | Inducible expression of TGFβ1 in papillomas with inhibition of TGF receptor | Suppressed EMT in papillomas, increased metastasis | Han et al., 2005 [30] |
|