TGF
Nonmelanoma skin cancer including both basal cell carcinoma and squamous cell carcinoma is the most frequent cancer among Caucasian populations, with incidence rates matching all other cancers combined in these groups [
From its initial identification as a major negative regulatory pathway for epithelial cell proliferation, Transforming growth factor-beta (TGF
Schematic of TGF
There are a number of mechanisms for downregulating or inhibiting TGF
A number of immunohistochemical and mutational analysis studies have been done in human SCC to determine what changes in the TGF
Mice expressing a dominant negative
Skin and oral carcinogenesis studies with mouse models of TGF
Signaling component | Mouse model | Study details | Phenotype | Reference |
---|---|---|---|---|
TGF |
||||
K6-TGF |
Constitutive and inducible suprabasal expression | Suppressed papilloma formation, increased malignant conversion and spindle cell carcinoma | Cui et al., 1996 [ | |
TGF |
Loricrin-TGF |
Long-term expression in papillomas | Increased EMT, invasion, and metastasis | Weeks et al., 2001 [ |
K5rTA x tetOTGF |
Short-term expression in papillomas | Growth arrest, regression, and tumor inflammation | Mohammed et al., 2010 [ | |
TGF | ||||
|
Germline |
Reduced papillomas in TGF |
Pérez-Lorenzo et al., 2010 [ | |
|
Skin grafts of PMEK onto athymic mice | SCC with TGF |
Glick et al., 1994 [ | |
| ||||
T |
DMBA/TPA pharmacological inactivation | Topical SB431542 during TPA promotion | Reduced papilloma, increased conversion | Mordasky Markell et al., 2010 [ |
DMBA/TPA pharmacological inactivation | Systemic LY2109761 during TPA promotion | Increased malignant phenotype of SCC | Connolly et al., 2011 [ | |
K14CreER x |
deletion of T |
Accelerated HNSCC with AKT activation | Bian et al., 2009 [ | |
|
deletion of T |
Accelerated HNSCC | Bian et al., 2012 [ | |
| ||||
T |
Loricrin- |
Epidermal expression of dominant negative type II receptor | Reduced tumor latency, increased SCC | Go et al., 1999 [ |
K5CrePr1 x |
Oral mucosa deletion of T |
HNSCC only with DMBA or K-Ras | Lu et al., 2006 [ | |
K14-Cre x |
Epidermal deletion of T |
No skin tumors, spontaneous anogenital SCC | Guasch et al., 2007 [ | |
K14-Cre x |
v-RasHa xenotransplantation | Aggressive SCC | Guasch et al., 2007 [ | |
| ||||
R-Smads | K5CrePr1 x |
Basal/stem cell deletion of Smad2 in epidermis | Increased tumors accelerated |
Hoot et al., 2008 [ |
MMTV-Cre x |
Epidermal deletion of Smad4 | Hair follicle defects spontaneous SCC | Qiao et al., 2006 [ | |
K5CrePr1 x |
Deletion of Smad4 in oral mucosa | Spontaneous HNSCC w/genomic instability increased inflammation normal and tumor tissue | Bornstein et al., 2009 [ | |
Smad3−/− |
germline Smad3 null | Suppressed tumor formation, resistance to TPA | Li et al., 2004 [ | |
|
Primary mouse keratinocyte skin grafts | Progression to SCC | Vijaychandra et al., [ | |
| ||||
I-Smads | Smad7 + v-RasHa |
Primary mouse keratinocyte skin grafts | Smad7: rapid progression to SCC |
Liu et al., 2003 [ |
| ||||
TGF |
TGF |
Inducible expression of TGF |
Suppressed EMT in papillomas, increased metastasis | Han et al., 2005 [ |
fl/fl: floxed alleles.
DMBA/TPA indicates 2-stage chemical carcinogenesis protocol.
CreER: tamoxifen-inducible Cre recombinase.
CrePr1: rU486 inducible Cre recombinase.
Using a complimentary approach several groups have generated tissue-specific conditional knockouts of the type 2 and type 1 receptor. Deletion of
Similar observations were made using K14-CreER mice to drive an inducible conditional deletion of the
A number of small molecule inhibitors of T
In a 2-stage chemical carcinogenesis study,
In two chemical carcinogenesis studies using Smad3+/− and Smad3−/− mice, it was found that in contrast to Smad2 deletion, Smad3+/− mice developed fewer tumors compared to wild-type controls [
In two models of epidermal-specific Smad4 deletion, the mice exhibited progressive hair-loss due to defects in hair follicle cycling, and the majority developed spontaneous development of SCC within 1 year [
Transgenic mice in which Smad7 was targeted to the basal layer of the skin with a keratin 5 promoter exhibited hyperproliferation in the skin and other stratified epithelia, but these animals died within 10 days after birth [
Many different non-Smad-signaling pathways downstream of the TGF
Although there are three distinct TGF
Several transgenic mouse models overexpressing either active or latent TGF
In contrast to the suppressive effects of TGF
These proteins regulate interaction of TGF
Activation of latent TGF
The role of TGF
7,12-Dimethylbenz(a)anthracene
Epithelial-to-mesenchymal transition
Human head-&-neck squamous cell carcinoma
Immunohistochemistry
Squamous cell carcinoma
Type I TGF-
Type II TGF-
Murine transforming growth factor beta gene
Transforming growth factor-
12-tetradecanoyl-phorbol-13-acetate
Type I TGF-
Type II TGF-
The author acknowledges the exceptional work done by colleagues and apologizes for any omissions. Adam B. GLick is supported by Grants from the NIH, the National Psoriasis Foundation and the Elsa U. Pardee Foundation.