Molecular targets for signal transduction involved in the invasion and metastasis of malignant bone and soft tissue tumors.

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Distant metastasis is the most important factor to determine the prognosis of patients with malignant bone and soft tissue tumors. During the metastasis, tumor cells need to penetrate basement membrane twice; first intravasation at primary tumor, then extravasation at distant organs. Invasion of the basement membrane includes three steps, i.e., attachment to the membrane, destruction by catalytic enzymes, and movement of the cells into matrix of target organ. We have developed in vitro invasion assay and analyzed the molecular mechanisms of the tumor cell invasion and metastasis. We have reported that genes involved in the attachment, enzymatic degradation and motility are regulated simultaneously, and that the signaling pathway controlling the expression of these genes might be a good target for molecular based therapy of metastasis of malignant tumors. In the present study, our aim is to analyze the precise mechanisms of signal transduction pathway involved in the invasion and metast … More asis of tumor cells, and to develop the method for suppression of the invasive phenotypes of the tumor.Previously, we have found that reagents which elevate intraceflular cAMP concentration inhibited invasion and experimental metastasis of HT1080 human fibrosarcoma cells. We further analyzed this phenomenon and found that cAMP analogues could suppress the activation Rho, a small GTP-binding protein, via protein kinase A, and inhibit actin stress fiber formation leading to reduction of phosphorylation of the focal adhesion kinase (FAK). Among three steps of the tumor cell invasion, phosphorylated FAK plays important roles in the cell motility, however, FAK might not affect the attachment and enzymatic degradation of the basement membrane. We confirmed the significance of the FAK phosphorylation in clinical samples of malignant fibrous histiocytoma (MFH), the most common malignant soft tissue tumor. In the specimen of MFH, the levels of FAK phosphorylation were elevated in recurrent samples than in the primary samples, suggesting the association of phosphorylated FAK and tumor cell invasion and recurrence. We further investigated the VEGF signals in bone destruction and found that VEGF-Flt1- FAK pathway might play important roles in the bone destruction and metastasis of malignant tumor. Less