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

远处转移是决定恶性骨和软组织肿瘤患者预后的最重要因素。在转移过程中，肿瘤细胞需要两次穿透基底膜，首先是原发灶的渗入，然后是远处器官的渗出。基底膜的侵袭包括与基底膜的附着、催化酶的破坏和细胞向靶器官基质的移动三个步骤。我们建立了体外侵袭实验，分析了肿瘤细胞侵袭和转移的分子机制。我们已经报道，参与附着、酶降解和运动的基因同时受到调控，控制这些基因表达的信号通路可能成为恶性肿瘤转移的分子基础治疗的良好靶点。在本研究中，我们的目的是分析…侵袭和转移过程中信号转导途径的确切机制。更多的肿瘤细胞的ASIS，并开发抑制肿瘤侵袭表型的方法。此前，我们发现升高细胞内cAMP浓度的试剂可以抑制HT1080人纤维肉瘤细胞的侵袭和实验性转移。我们进一步分析了这一现象，发现cAMP类似物可以通过蛋白激酶A抑制小GTP结合蛋白Rho的激活，并抑制肌动蛋白应激纤维的形成，从而降低粘着斑激酶(FAK)的磷酸化。在肿瘤细胞侵袭的三个步骤中，磷酸化的FAK在细胞运动中起重要作用，而FAK可能不影响基底膜的附着和酶降解。我们证实了FAK磷酸化在恶性纤维组织细胞瘤(MFH)的临床标本中的意义，MFH是最常见的恶性软组织肿瘤。在MFH中，复发标本中FAK的磷酸化水平高于原发标本，提示FAK的磷酸化与肿瘤细胞的侵袭和复发有关。我们进一步研究了VEGF信号在骨破坏中的作用，发现VEGF-Flt1-FAK通路可能在恶性肿瘤的骨破坏和转移中起重要作用。较少

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