Table 1.
Mouse Models Mentioned in the Text for Studying the Roles of Transforming Growth Factor–β Signaling in Digestive Diseases and Cancers
| Gene (and function) | Mice model | Disease relevance | Model design | Model phenotype | Reference no. |
|---|---|---|---|---|---|
| TGFB1 (ligand) |
Tgfb1+/− TGFB1 heterozygosity (C57B1/6 NCr) |
Liver cancer | Disruption of TGFB1 exon 1 and intron 1 with neomycin-resistance cassette | By 6 mo, mice have increased susceptibility to chemically induced liver cancer. | 96 |
|
Tgfb1−/− Immunocompetent TGFB1 knockout (C3H/HeN × C57BL/6J) |
Inflammation, IBD | Disruption of TGFB1 exon 6 with neomycin-resistance cassette | By 3 wk, mice die from a wasting syndrome with multifocal, mixed inflammatory cell response and tissue necrosis. | 32 | |
|
TGF-βΔDC DC-specific TGFB1 knockout (C57BL6) |
Gastritis | Disruption of TGFB1 exon 6 with cCD11c-Cre driving DC-specific knockout | After 6 mo of Helicobacter felis infection, mice develop severe gastritis, with a trend toward increased metaplasia. | 17 | |
|
CD4-Cre/Tgfb1fl/fl T cell–specific TGFB1 knockout (C57BL/6) |
IBD | LoxP sites flanking TGFB1 exon 1 with CD4-Cre driving T cell–specific knockout | By 4–12 mo, mice developed inflammatory disorder and severe colitis. | 36 | |
|
Tgfb1−/−Rag2−/− Immunodeficient TGFB1 knockout (129S6 × CF-1) |
CRC | Disruption of TGFB1 exon 6 with neomycin-resistance cassette | By 5 mo, all mice develop severe hyperplasia and nonmetastatic carcinoma in the cecum and colon. | 59 | |
| PF4CreTgfb1f/f Platelet-specific TGFB1 knockout (C57BL/6) |
Liver fibrosis | LoxP sites flanking TGFB1 exon 6, with PF4-Cre driving deletion in platelets | Mice develop less liver fibrosis in response to chemically induced liver damage. | 83 | |
|
Alb/TGF-Β1 Liver-specific expression of TGF-β1 (C57BL/6 × CBA/J) |
Liver cancer | Porcine TGFB1 expressed from albumin promoter | By 16–18 mo, ~60% of mice spontaneously develop HCC | 101 | |
|
myc/TGF-Β1 Liver-specific expression of MYC and TGF-β1 (C57BL/6 × CBA/J) |
Liver cancer | MYC and porcine TGFB1 expressed from albumin promoter | By 13 mo, 100% of mice develop multifocal tumors in different lobes of the liver. | 101 | |
|
Alb-TGF-β1/ LFABP-cyclin D1 Liver-specific expression of TGF-β1 and multi-tissue expression of cyclin D1 (B6CBA × C57BL/6) |
Liver cancer | Porcine TGFB1 expressed from albumin promoter and CCND1 expressed from LFABP promoter | By 12 mo, 69% of mice develop liver cancer or high-grade tumors. | 102 | |
| TGFBRII (Type II receptor subunit for TGFβ1, TGF-β2, TGF-β3) |
Tgfbr2fspKO TGFBR2 knockout specifically in cells positive for S100A4 (DBA× Balb/c× C57BL/6) |
Pancreatitis, esophageal and gastric cancer | LoxP sites flanking TGFBR2 exon 2, with FSP1-Cre driving deletion in multiple cells of mesenchymal origin, including DCs and stromal fibroblasts | By 6 wk, mice spontaneously develop autoimmune pancreatitis. By 7 wk, all mice spontaneously develop invasive squamous cell carcinoma of the forestomach. | 16 |
| CRP/ΔkTβRII Liver-specific expression of dominant-negative TGFBR2 |
Liver cancer | Dominant-negative TGFBR2 with CRP promoter driving liver-specific expression | Mice exhibit increased susceptibility to chemically induced multifocal preneoplastic lesions and liver cancer. | 97 | |
| CD4-dnTGFβRII T cell–specific expression of dominant-negative TGFBR2 (C57BL/6 × 6XC3H) |
IBD, hepatitis | Dominant-negative TGFBR2 with CD4 promoter driving T cell–specific expression | By 4 mo, mice spontaneously develop IBD; mice have increased susceptibility to chemically induced liver disease. | 37 | |
| DC-Tgfbr2 KO DC-specific TGFBR2 knockout (B6.129S6) |
Hepatitis, pancreatitis, colitis, gastritis | Flox sites flanking TGFBR exon2 with CD11c-Cre driving DC-specific deletion | By 15 wk, mice die of autoimmune inflammation in multiple organs of digestive tract. | 38 | |
|
Apc1638N/wtTgfbr2IEKO Intestinal epithelial cell–specific TGFBR2 knockout with heterozygous APC mutation (C57BL/6JIco × C57BL6) |
CRC | LoxP sites flanking TGFBR2 exon 2, with Villin-Cre driving intestinal epithelial cell–specific deletion in the context of heterozygous APC loss of function | By 12 mo, all mice spontaneously develop intestinal adenocarcinoma that progresses to invasive disease. | 67 | |
|
ApcΔ716
Tgfbr2ΔIEC Intestinal epithelial cell–specific TGFBR2 knockout with APC mutation |
CRC | LoxP sites flanking TGFBR2 exon 2, with Villin-Cre driving intestinal epithelial cell–specific deletion in the context of APC mutation | By 15 wk, mice spontaneously develop intestinal adenocarcinomas with submucosal invasion in large polyps. | 68 | |
|
LAKTP Lgr5eGFPCreERT2/ApcLoxp/KrasLSL-G12D/Tgfbr2Loxp/Trp53Loxp Intestinal stem cell-specific knockout of APC, TGFBR2, TRP53 with KRAS activation (C57BL/6J) |
CRC | LoxP sites flanking regions of APC, TGFBR2, and TRP53 with inducible with Lgr5eGFP-creERT2 driving intestinal stem cell-specific deletion and expression of activating KRAS mutant | Mice exhibit increased susceptibility of chemically induced metastatic colon cancer. | 71 | |
|
Ptf1acre/+LSL-KrasG12D/+Tgfbr2flox/flox Pancreatic epithelial cell–specific TGFBR2 knockout with KRAS activation (C57BL/6×DBA/2×129/SvJae) |
Pancreatic cancer | LoxP sites flanking TGFBR2 exon 2, with Ptf1a-Cre driving pancreatic epithelial cell–specific deletion and expression of activating KRAS mutant | By 2 mo, mice die of PDAC. | 122 | |
| SMAD3 (R-SMAD activated by TGF-β1, TGF-β2, TGF-β3, Activin A, Activin B, Nodal, GDF1, GDF2, GDF8, GDF9, GDF11) | Smad3−/− SMAD3 knockout (C57BL/6 × 129/S) | Gastric cancer, CRC | Disruption of SMAD3 exon 2 with IRES-LacZ and neomycin cassette | By 10 mo, mice spontaneously develop invasive gastric cancer arising in the forestomach–stomach junction. By 4–6 mo, mice (30%) spontaneously develop large polyps and aggressive, metastatic colon cancer that depends on Helicobacter. | 60 |
|
Smad3ex8/ex8 SMAD3 knockout (C57BL/6 × Black Swiss) |
IBD | Targeted deletion of Smad3 exon 8 by homologous recombination, resulting in disruption of the interaction between SMAD3 and the TGFB receptor | More than 6 mo, nearly 77% of the mice spontaneously developed chronic inflammation in the intestines. | 31 | |
|
Smad3−/− + Helicobacter SMAD3 knockout infected with Helicobacter (129/J) |
CRC | Disruption of SMAD3 exon 2 with IRES-LacZ and neomycin cassette | Mice exhibit increased susceptibility to infection-induced colon cancer. | 60, 61 | |
| ApcMin/+Smad3−/−SMAD3 knockout with heterozygous APC mutation (129/Sv) | CRC | Disruption of SMAD3 exon 2 with neomycin cassette and mutation of APC | By 2 mo, mice spontaneously develop tumors in the distal colon, resembling human familial adenomatous polyposis. | 70 | |
| SMAD4 (c-SMAD) |
Smad4co/co; Lck-cre Smad4co/co; CD4-cre T cell–specific SMAD4 knockout (C57BL/6 × SvEv129 × FVB) |
Gastrointestinal epithelial cancer | LoxP sites flanking SMAD4 exon 8, with Lck-Cre or CD4-Cre driving T cell–specific deletion | Mice spontaneously develop inflammation and epithelial cancers throughout the GI tract. | 65 |
|
Smad4+/E6sad SMAD4 heterozygosity (129Ola × C57BL/6JIco) |
Intestinal cancer | Single nucleotide deletion of SMAD4 exon 6 | By 9–18 mo, mice spontaneously develop adenomas and mixed polyposis of the upper GI tract. | 69 | |
|
Apc+/1638N/Smad4+/E6sad Heterozygous loss of function of both SMAD4 and APC in cis or trans (129Ola × C57BL/6JIco) |
CRC | Single nucleotide deletion of SMAD4 exon 6, and disruption of APC exon 15 | Both trans and cis mice spontaneously develop tumors of the GI tract, desmoids, and epidermal tumors. Trans mice spontaneously develop high numbers of tumors. Cis mice spontaneously develop rapidly progressing disease, dying within 6 wk. |
69 | |
| SMAD7 (I-SMAD for SMAD2 and SMAD3) |
Smad7Tg T cell–specific expression of SMAD7 (C57BL/6) |
IBD | SMAD7 with CD2 promoter/enhancer driving T cell–specific expression | Mice exhibit more susceptibility to chemically induced colitis but fewer colitis-induced tumors. | 77 |
|
S7tg Hepatocyte-specific expression of SMAD7 (C57BL/6) |
Liver fibrosis | Flag-tagged SMAD7 with CRP promoter driving hepatocyte-specific expression | Mice exhibit decreased susceptibility to chemically induced liver damage and fibrosis. | 108 | |
|
Smad7 KO SMAD7 knockout (C57BL/6) |
Liver cancer | Disruption of SMAD7 exon 1 with PGKneobpA cassette | Mice exhibit increased susceptibility to chemically induced HCC. | 110 | |
| TTR-Cre-SMAD7 KO, Hepatocyte-specific SMAD7 knockout (C57BL/6) |
Liver cancer | LoxP sites flanking SMAD7 exon 1 with TTR-Cre driving hepatocyte-specific deletion | Mice exhibit increased susceptibility to chemically induced HCC. | 109 | |
|
SMAD7Tg Pancreas-specific expression of SMAD7 (DBA2) |
Pancreatic cancer | Myc-tagged SMAD7 with elastase I promoter driving pancreas-specific expression | By 6 mo, mice develop PanIN. | 126 | |
| SPTBN1 (Adaptor for activated SMAD2 and SMAD3) |
SMAD7Tg Pancreas-specific expression of SMAD7 (DBA2) Smad4+/− Sptbn1+/−Heterozygous loss of function of both SMAD4 and SPTBN1 (129SvEv × C57BL/6) |
Gastric cancer, liver cancer | Disruption of SPTBN1 exon 25 and SMAD4 exon 8 with neomycin cassette | All mice spontaneously develop gastric polyps with a subset progressing to cancer; a subset of mice develop colon cancer. | 62, 64 |
| Sptbn1+/−SPTBN1 heterozygosity (129SvEv/Black Swiss) | Liver steatosis, fibrosis, liver cancer | Disruption of SPTBN1 exon 25 with neomycin cassette | By 15 mo, 40% of mice spontaneously develop liver diseases and cancer. | 99 | |
|
Sptbn1+/−Iitih4−/− Heterozygous loss of SPTBN1 and knockout of ITIH4 |
Liver cancer | Disruption of SPTBN1 exon 25, and ITIH4 exons 2 and 3 with neomycin cassette | Mice exhibit increased susceptibility to liver cancer. | 100 |
c-SMAD, common SMAD; I-SMAD, inhibitory SMAD; R-SMAD, receptor-activated SMAD.