INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER

描述：(申请人摘要)对分子变化的研究 导致前列腺癌进展是当今许多人谈论的话题 调查。前列腺异常迁移、增殖和存活 细胞有助于前列腺癌的进展；然而，分子 对需求和所涉及的信号通路知之甚少。 细胞与细胞外基质之间的黏附相互作用是由 整合素，黏附受体，触发一系列细胞内信号转导 调节细胞运动、存活和增殖的事件。申请人有 证明(α)v(β)3整合素在正常或 良性前列腺上皮及其在前列腺癌中的上调；其 在原发灶和转移灶中均有表达。 (Alpha)v(Beta)3的表达使前列腺癌细胞具有迁移表型 在骨骼中发现的底物上，前列腺癌细胞优先 转移，并激活有助于细胞的信号通路 迁移。研究(α)v(β)3激活的下游通路 通过玻璃连结蛋白或骨桥蛋白的参与，申请者将描述 PI3-K和Src以及FAK/PI3-Kinase或FAK/Src联合作用 调节LNCaP、PC3和原代前列腺癌细胞的迁移。入内 将评估(α)v(β)3在建立转移瘤中的活体作用 SCID小鼠和人骨/SCID小鼠模型的原位注射 系统。(Alpha)v(Beta)3激活AKT的结构要求和 前列腺癌细胞的迁移也将被研究。AKT在以下方面的作用 支持原发前列腺癌细胞迁移的分析将使用 类似的方法。最后，(α)v(β)3与FAK和PI的作用 3-激酶/AKT促进前列腺癌细胞存活和增殖 将对细胞进行调查。无论是扩散还是生存 增加(α)v(β)3的表达或参与，激活 下游通路将使用FAK和PI 3-K/AKT活性或 显性负变异体。最后，前列腺的免疫组织化学分析。 癌症组织样本将被用来关联(α)v(β)3 在有细胞凋亡和增殖标记物的转移灶中表达。AS NCI前列腺癌审查小组审查了这一领域的研究 导致无法控制的生长和转移的分子、细胞事件“是 未得到充分探索，并有可能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.