INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER

描述：（申请人的摘要）分子改变的研究， 导致前列腺癌进展是当今许多研究的主题。 调查事务所前列腺的异常迁移、增殖和存活 细胞有助于前列腺癌的进展;然而， 所涉及的需求和信号通路，知之甚少。 细胞和细胞外基质之间的粘附相互作用是由 整合素，粘附受体，触发细胞内信号级联 调节细胞运动、存活和增殖的事件。申请人已经 证明（α）v（β）3整合素在正常或 在良性前列腺上皮中表达，在前列腺癌中表达上调; 在原发性肿瘤以及转移性病变中发现表达。 （α）v（β）3表达赋予前列腺癌细胞迁移表型 在骨中发现的基质上，前列腺癌细胞优先 转移，并激活信号通路，有助于细胞 迁移研究（alpha）v（beta）3激活的下游通路 通过玻连蛋白或骨桥蛋白的参与，申请人将表征 PI 3-激酶和Src以及FAK/PI 3-激酶或FAK/Src联合在 调节LNCaP、PC 3和原发性前列腺癌细胞的迁移。的in 将评价（α）v（β）3在建立转移中的体内作用 在SCID小鼠和人骨/SCID小鼠模型中使用原位注射 系统（α）v（β）3激活AKT的结构要求， 还将研究前列腺癌细胞的迁移。AKT在以下方面的作用 支持原发性前列腺癌细胞迁移将使用 类似的方法。最后，（alpha）v（beta）3和FAK和PI的作用 3-激酶/AKT增加前列腺癌细胞存活和增殖 细胞将被研究。无论是增殖还是存活， 通过（α）v（β）3表达或参与增加， 下游通路将使用FAK和PI 3-激酶/AKT活性或 显性负变异最后，对前列腺进行免疫组化分析， 将对癌组织标本进行相关性分析，以确定（α）v（β）3 在转移部位表达凋亡和增殖标记物。作为 NCI前列腺癌审查小组审查了这一研究领域“关于 导致不受控制的生长和转移的分子、细胞事件”是 尚未得到探索，可能会在以下方面取得重要进展 前列腺癌的治疗

DESCRIPTION: (Applicant's Abstract) The study of the molecular alterations that contribute to prostate cancer progression is nowadays the subject of numerous investigations. Abnormal migration, proliferation and survival of prostate cells contribute to prostate cancer progress; however, the molecular requirements and the signaling pathways involved, are poorly understood. Adhesive interactions between cells and extracellular matrix are mediated by Integrins, adhesion receptors that trigger a cascade of intracellular signaling events regulating cell motility, survival and proliferation. The applicant has demonstrated that the (alpha)v(beta)3 integrin is undetectable in normal or benign prostatic epithelium and is upregulated in prostatic carcinoma; its expression is found in primary tumors as well as in metastatic lesions. (Alpha)v(beta)3 expression confers prostate cancer cells a migratory phenotype on substrates found in bone, where prostate cancer cells preferentially metastasize, and activates signaling pathways that contribute to cell migration. To investigate the downstream pathways activated by (alpha)v(beta)3 engagement by vitronectin or osteopontin, the applicant will characterize the role of PI 3-kinase and Src, and of FAK/PI 3-kinase or FAK/Src association in modulating migration of LNCaP, PC3 and primary prostate cancer cells. The in vivo role for (alpha)v(beta)3 in establishment of metastases will be evaluated using orthotopical injection in SCID mice and a human bone/scid mouse model system. (Alpha)v(beta)3 structural requirements for activation of AKT and migration of prostate cancer cells will also be studied. A role for AKT in supporting primary prostate cancer cell migration will be analyzed using a similar approach. Finally, the role of (alpha)v(beta)3 and FAK and PI 3-kinase/AKT in increasing cell survival and proliferation of prostate cancer cells will be investigated. Whether either proliferation or survival will be increased by either (alpha)v(beta)3 expression or engagement, activation of downstream pathways will be analyzed using FAK and PI 3-kinase/AKT active or dominant negative variants. Finally, immunohistochemical analysis of prostate cancer tissue specimens will be performed to correlate (alpha)v(beta)3 expression in metastatic sites with apoptosis and proliferation markers. As examined by the NCI Prostate Cancer Review group this area of research "on the molecular, cellular events that lead to uncontrolled growth and metastases" is under explored and is likely to provide important advances in the status of treatment of prostate cancer.