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In recent years, targeted therapies have become increasingly successful in the treatment of various cancers. These therapies, such as herceptin (a humanised anti-Her-2/neu antibody) to treat breast cancer and erlotinib (an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor) for lung cancer can bring survival benefit with minimal side effects to sensitive patients. New studies have found that targeted therapies designed for one cancer can sometimes be used to treat another. Currently EGFR targeted therapies are undergoing clinical trials for a few types of sarcomas including synovial sarcoma and neurofibrosarcoma. In this study, we aimed to investigate the potential application of EGFR targeted therapies in other types of sarcomas. We tested the EGFR expression and phosphorylation, as well as their association with tumor progression and/or metastasis in 8 types of soft tissue sarcomas. We also measured the regulative effects of EGF or gefitinib (an EGFR tyrosine kinase inhibitor) on EGFR-positive fibrosarcoma cell growth. Oligonucleotide microarray experiments of 19000 genes were performed on sarcoma cell lines with different metastatic potentials. A significantly higher mRNA level of EGF, EGFR, their downstream signalling factors, and target genes was found in metastatic and/or high grade sarcoma cell lines when compared with their low grade counterparts. The EGFR downstream signalling factors were part of the ras-MAPK, PI3K and PLCgamma pathways. The target genes were involved in cell cycle progression, angiogenesis, cancer spread and apoptosis. Clinical validation was carried out in 88 sarcoma cases including leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma (MFH), malignant peripheral nerve sheath tumors (MPNST), synovial sarcoma, angiosarcoma, epithelioid sarcoma and rhabdomyosarcoma by tissue array using wild-type or phosphorylated antibodies and immunohistochemistry. It revealed that EGFR and its signalling proteins (MAPK and Akt) were over-expressed and phosphorylated in a proportion of soft tissue sarcoma tissues. Fibrosarcoma cell line HT1080 was positive for EGFR expression when measured by flow cytometry with the non-EGFR expression cell line, SW620 as a negative control. The proliferation of HT1080 was enhanced by EGF treatment, but reduced by an EGFR inhibitor gefitinib. Our studies suggest that EGFR and its signalling system is an important pathway of sarcoma metastasis; activated EGFR, MAPK and Akt were expressed in various soft tissue sarcomas; and targeting EGFR therapies may have some potential in the treatment of these tumors.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]