Integrin regulation of prostate cancer progression

整合素对前列腺癌进展的调节

• 批准号: 7991928
• 负责人: Lucia R. Languino
• 金额: $ 20.75万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991928
• 关键词: Affect; Androgen Receptor; Apoptosis; Arts; Biological Markers; Bone remodeling; Bypass; Cancer Model; Cell Adhesion; Cell Cycle Checkpoint; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell surface; Complex; Developmental Therapeutics Program; Disease model; Dissection; Evaluation; Exhibits; Extracellular Matrix Proteins; Family; Fibronectin Receptors; Gene Silencing; Gene Targeting; Genetic Models; Gleason Grade for Prostate Cancer; Goals; Growth; Hereditary Disease; Histopathology; Human; Immunocompromised Host; In Vitro; Integrin Signaling Pathway; Integrins; Ionizing radiation; Lesion; Ligand Binding; Local Therapy; Lytic Metastatic Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Metastatic Prostate Cancer; Mitochondria; Modeling; Molecular; Molecular Genetics; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Physiological; Process; Promoter Regions; Property; Prostate; Prostate Adenocarcinoma; Prostatic; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Receptor Activation; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Transforming Growth Factors; Tumor Cell Invasion; Tumor Suppressor Proteins; Up-Regulation; Validation; Vitronectin; advanced disease; bone; cancer cell; efficacy testing; gene induction; human disease; in vivo; inhibitor/antagonist; irradiation; molecular imaging; neoplastic cell; new therapeutic target; novel; pre-clinical; preclinical study; research study; response; safety testing; survivin; therapeutic target; trafficking; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis

Integrins comprise a large family of cell surface receptors with critical roles in cell adhesion, and signal transduction. These properties are exploited in cancer, affecting the spectrum of growth, proliferation. Invasion and metastatic potential of human tumor cells. Because of these broad signaling functions, and easy accessibility at the cell surface, integrins are attractive therapeutic targets in cancer, but their molecular requirements in tumorigenesis are not completely understood. Recent studies have uncovered a novel pathway of integrin signaling critically exploited for prostate cancer progression. We found that integrin avp6 is prominently expressed in prostate cancer, but not in normal prostate, in vivo. In turn. avp6 orchestrates a broad signaling pathway in the prostatic epithelium, triggering androgen receptor (AR) activation, upregulating the expression of survivin, a master switch of cell proliferation and cell survival in cancer, and promoting osteolytic lesions in the bone microenvironment. This pathway results in increased tumor cell invasion, and enhanced metastatic dissemination, in vivo. Therefore, the hypothesis that avp6 orchestrates a novel signaling network of prostate cancer progression can be formulated, and will constitute the focus of the present application. In the first specific aim, experiments will be carried out to elucidate the mechanisfic requirements and functional implications of avp6 upregulafion of survivin in prostate cancer, with respect to transcriptional/post-transcriptlonal responses, modulation of mitochondrial apoptosis, and control of cell cycle checkpoints in response to ionizing irradiation. The second specific aim will investigate whether the signaling circuits mediated by avp6 and other integrins regulate an AR-Runx2 transcriptional complex in bone remodeling during metastatic prostate cancer growth. In the third specific aim, we will target the avp6 pathway with a novel function-blocking monoclonal antibody 6.SG9 in preclinical molecular and genetic models of localized and metastatic prostate cancer, in vivo. The overall application combines mechanistic evaluation of integrin-modulation of tumor progression with state-of the-art studies of developmental therapeutics in advanced prostate cancer. The results will open concrete opportunities for novel molecular molecular therapy of patients with advanced prostate cancer.

整合素包括在细胞粘附和信号转导中具有关键作用的细胞表面受体的大家族。 转导这些特性在癌症中被利用，影响生长、增殖的范围。 人肿瘤细胞的侵袭和转移潜能。由于这些广泛的信号功能， 整合素在细胞表面容易接近，是癌症中有吸引力的治疗靶点，但其分子生物学特性是， 在肿瘤发生中的需要还没有完全理解。最近的研究发现了一种新的 整合素信号传导途径对前列腺癌进展至关重要。我们发现整合素avp 6 在体内，在前列腺癌中显著表达，但在正常前列腺中不表达。依次avp 6编排a 前列腺上皮中广泛的信号传导途径，触发雄激素受体（AR）激活， - 上调存活素的表达，存活素是癌症中细胞增殖和细胞存活的主开关，和 促进骨微环境中的溶骨性损伤。这一途径导致肿瘤细胞 侵袭和增强的转移性播散。因此，假设avp 6 编排前列腺癌进展的一种新的信号传导网络， 构成本申请的焦点。在第一个具体目标中，将进行实验， 阐明了存活素avp 6上调的机制要求和功能意义， 前列腺癌，就转录/转录后克隆反应而言，线粒体 细胞凋亡和响应电离辐射的细胞周期检查点的控制。第二个具体目标 将研究avp 6和其他整合素介导的信号通路是否调节AR-Runx 2 在转移性前列腺癌生长过程中骨重建的转录复合物。在第三个具体 目的：我们将用一种新的功能阻断性单克隆抗体6.SG9靶向avp 6通路， 体内局部和转移性前列腺癌的分子和遗传模型。整体应用 将整合素调节肿瘤进展的机制评价与最新的 晚期前列腺癌的发展治疗。结果将为以下方面提供具体机会： 晚期前列腺癌患者的新型分子分子治疗。