Table 1.
Overview of drugs used in in vitro/vivo studies targeting a signaling pathway in DTF.
| Drug | References | Setting | Effect |
|---|---|---|---|
| WNT/ß-CATENIN SIGNALING PATHWAY | |||
|
MMP inhibitor Ilomastat/Galardin (GM6001) |
(52) |
Apc+/Apc1638N mice Murine PCC from DTF and NF |
↓ DTF cell invasion and motility ↓ Tumor volume in mice |
| (53) | Human PCC from DTF and normal fascia | ↔Cell growth ↓ DTF cell invasion |
|
|
NSAID Sulindac/Indomethacin/DFU |
(56) | Human PCC from DTF and normal marginal tissues Apc+/Apc1638N-Cox2−/− and Apc+/Apc1638N -Cox2+/+ mice |
↓ DTF cell and NF proliferation ↔ Apoptosis in DTF cells and NF ↔ Tumor number in mice (sulindac) ↓ Tumor volume in mice (sulindac) |
|
NSAID Sulindac |
(57) | Human PCC from DTF, CRC | ↓ DTF cell growth ↔ Cell morphology |
|
NSAID Piroxicam (+DFMO) |
(58) |
Apc−/+p53+/−, Apc+/+p53+/−, Apc−/+p53+/+ mice |
↓ DTF tumor number |
|
Angiostatic factor Endostatin |
(59) | Human PCC from FAP-related DTF and CRC |
↑ Apoptosis (CRC cultures) ↑ Cell death (DTF cultures) |
|
Benzoxazocine Nefopam |
(60) | Human PCC from DTF and NF Apc1638N mice |
↓ Cell proliferation, modest change in apoptosis ↓ ß-catenin protein level ↓ tumor number and volume (mice) |
| HEDGEHOG SIGNALING PATHWAY | |||
|
Hedgehog inhibitor Triparanol |
(61) | Human PCC from DTF Apc+/1638N; Gli2+/− and Apc+/1638N; Gli2+/+ mice |
↓ Tumor volume (Apc+/1638N mice) ↓ Number of tumors (Apc+/1638N; Gli2+/−) ↓ Number of tumor cells, viability, proliferation rate (DTF cells) ↔ Apoptosis (DTF cells) |
| NOTCH SIGNALING PATHWAY | |||
|
γ-secretase inhibitor PF-03084014 |
(62) | Human PCC from DTF | ↓ Notch signaling (↓ NICD and Hes1 expression) ↑ Cell cycle arrest ↓ Cell growth, migration and invasion |
| JAK/STAT SIGNALING PATHWAY | |||
|
Cytokines Interferon-ß |
(63) | Human PCC from DTF and NF Apc/Apc1638N, Apc1638N; Ifnar1−/− and Apc/Apc1638N; Ifnar1+/+ |
↔ Apoptosis (human vs. murine DTF and NF) ↓ Cell proliferation (human/murine DTF and NF) |
| PI3K/AKT/mTOR SIGNALING PATHWAYS | |||
|
Tyrosine kinase inhibitor Sorafenib (±Everolimus) |
(64) | Human PCC from DTF | ↓ DTF cell proliferation and invasion (sorafenib) ↓ mTOR signaling [↓ phospho-S6K levels (everolimus)] |
| GROWTH REGULATORY SIGNALING PATHWAYS | |||
|
Cytokines TGF-ß1 |
(65) | Human PCC from DTF, fibroma, NF |
↔ Cell proliferation in DTF, fibroma and NF cell culture ↑ GAG accumulation in extra-cellular matrix ↑ Collagen synthesis |
| (66) | Human PCC from DTF and NF | ↑ Active unphosphorylated fraction of ß-catenin | |
|
Cytokines rhEGF/rhTGF-α |
(67) | Human PCC from DTF | Up- and down regulation of genes in response to stimulation with rhEGF/rhTGF-α |
|
Cytokines rhEGF/AG1478/SB431542 |
(68) | Human PCC from DTF | ↑ DTF cell motility (rhEGF) |
| ESTROGEN DRIVEN PATHWAY | |||
|
Anti-estrogen Tamoxifen/Toremifene |
(69) | Human PCC from DTF | ↓ Cell growth (tamoxifen ± estrogen) ↔ Cell growth (toremifene ± estrogen) |
|
Anti-estrogen Toremifene |
(70) | Human PCC from DTF, fibroma and NF | ↔ Cell proliferation (3H-tymidine incorporation) ↓ GAG (DTF, fibroma and NF cultures) ↓ Collagen production (3H-proline incorporation) ↓ TGF-ß1 levels in culture medium ↓ TGF-ß1 mRNA expression levels ↓ TGF-ß1 receptor affinity |
| (71) | Human PCC from DTF and NF | ↑Cell death (DTF and NF culture) ↓ Collagen production (3H-proline incorporation) ↓ Procollagen α1 mRNA expression (DTF culture) ↓ Type I and III collagen ↑ Collagenase activity ↔ MMP-1, ↑ MMP-2, ↓ TIMP-1 |
|
| (72) | Human PCC from DTF, Gardner-syndrome related fibroblast and NF |
↓ GAG synthesis and secretion ↓ Active TGF-ß1, ↔ total (active + latent) TGF-ß1 ↓ Number TGF-ß1 receptors (DTF cells) ↓ TNF-α production |
|
↓, decrease; ↑, increase; ↔, no effect; CRC, colorectal cancer; DFMO, Difluoromethylornithine; DFU, selective COX-2 blocker (5,5-dimethyl-3-(3-)4-(4-methylsulphonyl)phenyl-2(5H)-furon one); DTF, desmoid-type fibromatosis; FAP, familial adenomatous polyposis;, GAG, glycosaminoglycan; PCC, primary cell culture; NF, normal fibroblast; NSAID, non-steroidal anti-inflammatory drug.