Aberrant activation of signal transduction pathways regulating cell proliieration in human slid tumors. Molecular-pathological analysis and clinical application of molecular targeting therapy.

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During this term, analyses for aberration of oncogenes, such as EGFR (Epidermal growth factor receptor), HER-2 (human EGFR-2), c-myc and their signal pathways were performed in bone and soft tissue sarcomas (BSTS), gastric and lung carcinomas. We have clarified and reported the followings.1. In esophageal carcinomas, overexpression of EGFR was observed 50%, and amplification was in 14.2% (Int. J. Cancer, 2006). And also, in BSTS, EGFR overexpression was in 22.6%, and amplification was in 12.9%, but increase of EGFR gene, including that at low level, was noted up to 39% (Hum. Pathol, 2007). Thus, molecular targeting therapy against EGFR could be indicative for those malignancies2. Point mutation of EGFR was found in 29% of lung adenocarcinomas and, in those cases, Akt was specifically activated downstream of EGFR. In contrast, lung carcinoma with EGFR amplification, stat-3 was activated as a re sponsible effector molecule (Mod. Pathol. 2005). In BSTS, although point mutation was observed in 13%, Akt was not necessarily activated, unlike the cases in lung carcinomas (Hum. Pathol, 2007).3. Topoisomerase IIa gene was also amplified in 3% of gastric carcinomas, but they were always associated with HER-2 gene amplification (Hum. Pathol. 2006).4. c-myc was overexpressed in 16% and amplified in 3% of gastric carcinomas, and c-myc was co-amplified with EGFR or HER-2 in 5% of the cases (Mod. Pathol. 2007).5. Invasion-related protein, autocrine motility factor (AMF) was expressed in 72.5% of the BSTS, and in 67% of lung carcinomas. The tumor expressing high level of mRNA and secreting AMF at high amount were found to be the cases showing high metastatic probability. Furthermore, in osteosarcoma, high level of AMF expression correlated with high level of FDG-PET signals and was a marker of post-operative metastasis (Clin. Exp. Meta. 2007).