4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Fibromatosis--Aggressive

Desmoid tumors are benign but locally invasive myofibroblastic lesions that arise predominantly in the abdominal wall or shoulder and are prone to aggressive local recurrences. A perceived association between desmoid activity and the expression of growth factors during pregnancy or following trauma suggests a cause-and-effect relationship between growth factor stimulation and desmoid invasiveness. We used Boyden Chambers to quantify cell motility in order to determine the effect of growth factor stimulation on desmoid cell migration. Desmoid cell cultures were treated under serum-free conditions with epidermal growth factor (rhEGF) or transforming growth factor alpha (rhTGFalpha). Additional cell cultures were pretreated under serum-free conditions with the EGF receptor (EGFR) inhibitor AG1478, alone or in combination with the TGFbeta1 receptor inhibitor SB431542, and then stimulated with growth factor prior to being assayed for cell motility. The experiments demonstrated a direct dose-dependent relationship between rhEGF stimulation and desmoid motility. In contrast, rhTGFalpha was less effective at inducing cell migration. rhEGF-induced cell migration could be diminished, but not reduced to control levels, by inhibiting EGFR. When EGF and TGFbeta1 receptors were inhibited simultaneously, the level of rhEGF-induced cell migration was reduced significantly beyond the level of cell migration generated by inhibition of EGFR alone.

Topics: Benzamides; Cell Division; Cell Line, Tumor; Cell Movement; Culture Media, Serum-Free; Dioxoles; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Fibromatosis, Aggressive; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Integrin beta1; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Quinazolines; Receptors, Transforming Growth Factor beta; Recombinant Proteins; RNA, Messenger; RNA, Small Interfering; Soft Tissue Neoplasms; STAT3 Transcription Factor; Transforming Growth Factor alpha; Tyrphostins