Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-β, COX2 and sex steroid receptors

Abstract

Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and non-steroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor-β (TGFβ) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFβ superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFβ family signaling pathways, β-catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co-expression were explored via correlational statistical analyses. In addition to β-catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFβ signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor-β receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor-β was present in all cases studied. Transforming growth factor-β signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor-β and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

Figure 1

Representative hematoxylin and eosin (H&E) and immunohistochemical stains for β–catenin in desmoid‐type fibromatosis (Desmoid), reactive myofibroblasts in healing scar (Scar) and quiescent fibrous tissue (Fibrous tissue). Nuclear β–catenin is present in desmoid‐type fibromatosis, but not in healing scar or fibrous tissue (original magnification, ×100).

Figure 2

Representative immunohistochemical stains for transforming growth factor receptor–β type 1 (TGFR1), phosphorylated SMAD2/3 (p–SMAD2/3), COX2 and androgen receptor (AR) in desmoid‐type fibromatosis (Desmoid), reactive myofibroblasts in healing scar (Scar) and quiescent fibrous tissue (Fibrous tissue). TGFR1 and androgen receptor are detected in both desmoid‐type fibromatosis and scar, but not fibrous tissue. Phosphorylated SMAD2/3 and COX2 are present in desmoid tumor, but not in scar or fibrous tissue (original magnification, ×100).

Figure 3

Distribution of immunohistochemistry (IHC) intensity scores among desmoid‐type fibromatosis, healing scar tissue and quiescent fibrous tissue (results of Kruskal–Wallis tests are shown in parentheses; Dunn's post‐test comparisons: ***P < 0.001; **P = 0.001–0.01). p–SMAD1/5/8, phosphorylated‐SMAD1/5/8; p–SMAD2/3, phosphorylated‐SMAD2/3.