Integrin regulation of prostate cancer progression

整合素对前列腺癌进展的调节

基本信息

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
项目类别：
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

项目摘要

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.

整合素包含一大类细胞表面受体，在细胞粘附和信号传导中发挥关键作用转导。这些特性在癌症中被利用，影响生长、增殖的范围。人类肿瘤细胞的侵袭和转移潜力。由于这些广泛的信号功能，并且整合素在细胞表面易于接近，是癌症中有吸引力的治疗靶点，但它们的分子肿瘤发生的要求尚未完全了解。最近的研究发现了一种新颖的整合素信号通路对前列腺癌的进展至关重要。我们发现整合素 avp6 体内在前列腺癌中显着表达，但在正常前列腺中不显着表达。反过来。 avp6 精心策划前列腺上皮中广泛的信号通路，触发雄激素受体（AR）激活，上调生存素的表达，这是癌症中细胞增殖和细胞存活的主开关，以及促进骨微环境中的溶骨性病变。该途径导致肿瘤细胞增加侵袭，并增强体内转移扩散。因此，假设 avp6 精心策划前列腺癌进展的新型信号网络，并将构成本申请的重点。在第一个具体目标中，将进行实验阐明avp6上调survivin的机制要求和功能意义前列腺癌，关于转录/转录后反应，线粒体的调节细胞凋亡以及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 avp6 和其他整合素介导的信号通路是否调节 AR-Runx2 转移性前列腺癌生长过程中骨重塑的转录复合物。在第三个具体目标是，我们将在临床前使用一种新型功能阻断单克隆抗体 6.SG9 来靶向 avp6 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估与最先进的研究相结合晚期前列腺癌的发育疗法。结果将为晚期前列腺癌患者的新型分子分子疗法。