transforming-growth-factor-alpha and Soft-Tissue-Neoplasms

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

The rare benign extra-abdominal desmoid tumor is characterized by aggressive invasion of normal tissue. Treatment is complicated by its recurrence, invasiveness, and persistence. The etiology is unknown and the pathophysiology is obscure. Because of exuberant fibroblastic proliferation with collagenous tissue being the primary tissue component, this desmoid tumor has been compared with keloids arising from excessive scar formation in healing wounds. Numerous cytokines are associated with signaling for growth and maintenance of mesenchymal cells. Altered expression of these proteins is associated with many pathologic conditions. It has been proposed that the enhanced expression of platelet-derived growth factor and its receptor characterize desmoid tumors. We tested the hypothesis that the exuberant fibrosis of desmoid tumors may have resulted from the initiation of the cascade of molecular events producing increased expression of cytokines. We used immunohistochemical analysis of cytokines in desmoid tumors compared with keloids and skin to localize the expression of cytokines. The results showed localized increased expression of the cytokines epidermal growth factor, transforming growth factor-beta, tumor necrosis factor-alpha, vascular endothelial growth factor, interleukin-1beta, and interleukin-6 in the endothelial cells of blood vessels in the tumors. Production of tumor necrosis factor-alpha and interleukin-1beta in tumor tissue was increased, but we did not find increased expression of platelet-derived growth factor. We concluded that the increased expression of cytokines associated with angiogenesis usually found in wound healing and invasive tumors may contribute to the pathophysiology of the desmoid tumor.

Topics: Adolescent; Adult; Aged; Endothelial Growth Factors; Epidermal Growth Factor; ErbB Receptors; Female; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Fibromatosis, Aggressive; Humans; Interleukin-1; Interleukin-6; Lymphokines; Male; Platelet-Derived Growth Factor; Receptors, Fibroblast Growth Factor; Receptors, Interleukin-6; Receptors, Platelet-Derived Growth Factor; Receptors, Vitronectin; Soft Tissue Neoplasms; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors