Integrin alpha6beta4 Signaling in Prostate Carcinoma Growth and Invasion

前列腺癌生长和侵袭中的整合素 α6β4 信号传导

• 批准号: 7603051
• 负责人: FILIPPO G GIANCOTTI
• 金额: $ 39.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-14 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603051
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Androgens; Antibodies; Apoptosis; Biological Assay; Bone Marrow Transplantation; Carcinoma; Cell Line; Cell Proliferation; Cell Survival; Cells; Cytology; Cytoskeleton; ERBB2 gene; Extracellular Matrix; Family; Fibroblast Growth Factor 2; Goals; Growth; Human; Hypoxia; Impaired wound healing; Implant; In Vitro; Integrin alpha6beta4; Integrins; Invaded; Joints; Knockout Mice; Knowledge; LNCaP; Malignant Epithelial Cell; Malignant neoplasm of prostate; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutant Strains Mice; Neoplasm Metastasis; PTEN gene; Pathway interactions; Phenotype; Phosphorylation; Play; Primary Neoplasm; Proliferating; Prostate; Prostate carcinoma; Prostatic Neoplasms; Receptor Protein-Tyrosine Kinases; Recurrence; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Substrate Domain; Techniques; Testing; Tumor Cell Invasion; Viral Tumor Antigens; Wound Healing; Xenograft Model; angiogenesis; base; cancer cell; cohort; in vivo; knock-down; malignant phenotype; matrigel; meetings; migration; mouse model; mutant; neoplastic cell; probasin; receptor; reconstitution; research study; response; sialosyl-T antigen; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The alpha6beta4 integrin combines with RTKs, such as ErbB2 and Met, to promote cell survival, proliferation and migration. To examine the role of alpha6beta4 signaling in prostate cancer, we have generated mice carrying a targeted deletion of the beta4 signaling domain. These mice display defective wound healing and angiogenesis. Wild type and beta4 mutant mice have been intercrossed to TRAMP mice, which develop prostate cancer upon Probasin-mediated expression of the T Ag. Comparison of tumor onset and progression in the two cohorts of mice has revealed that beta4 signaling is necessary for efficient transition from high-grade PIN to invasive carcinoma. Our specific aims are: 1) To examine the mechanisms by which alpha6beta4 signaling promotes prostate cancer progression in vivo. Molecular and cellular techniques will be used to compare prostate tumor invasion and angiogenesis in TRAMP mice and PTEN-conditional null mice (PTENPC) mice carrying either wild type or mutant beta4. We will also evaluate the effect of androgen ablation in both models. 2) To examine the cellular mechanism by which beta4 signaling promotes prostate cancer progression. Prostate carcinoma cell lines will be isolated from TRAMP or PTENPC mice expressing wild type or mutant beta4. In vitro and in vivo assays will be used to compare their ability to proliferate, to resist apoptosis, to organize pseudoacini in Matrigel, and to migrate/invade. 3) To examine the molecular mechanism by which beta4 signaling promotes prostate cancer progression. Signaling methods will be used to compare the activation of various beta4 pathways in prostate cancer cells expressing wild type or mutant beta4. Reconstitution of beta4 knock-down cells with either wild type beta4 or various signaling-defective mutants will enable us to identify the major signaling pathways through which alpha6beta4 controls the malignant phenotype in prostate cancer. 4) To examine the validity of alpha6beta4 as a target for anti-tumor therapy. We will study the expression of alpha6beta4 during human prostate cancer progression and test the effect of beta4 signaling-inhibitory antibodies in xenograft models.

描述(申请人提供)：α6beta4整合素与RTK结合，如ErbB2和Met，促进细胞存活、增殖和迁移。为了研究Alpha6beta4信号在前列腺癌中的作用，我们产生了携带Beta4信号域的靶向缺失的小鼠。这些小鼠的伤口愈合和血管生成存在缺陷。野生型和Beta4突变型小鼠已经与TRAMP小鼠杂交，TRAMP小鼠通过前盆介导的T抗原表达而发展为前列腺癌。对两组小鼠肿瘤发生和发展的比较表明，Beta4信号对于从高级别PIN到浸润性癌的有效转变是必要的。我们的具体目标是：1)研究α6β4信号在体内促进前列腺癌进展的机制。分子和细胞技术将被用来比较携带野生型或突变型Beta4的TRAMP小鼠和PTEN条件缺失小鼠(PTENPC)的前列腺癌侵袭和血管生成。我们还将评估雄激素消融在两种模型中的效果。2)研究β4信号促进前列腺癌进展的细胞机制。将从表达野生型或突变型Beta4的TRAMP或PTENPC小鼠中分离出前列腺癌细胞株。体外和体内实验将用于比较它们的增殖能力、抗凋亡能力、在Matrigel中组织伪腺泡的能力以及迁移/侵袭的能力。3)探讨β4信号促进前列腺癌进展的分子机制。信号方法将被用来比较表达野生型或突变型Beta4的前列腺癌细胞中各种Beta4通路的激活情况。用野生型或各种信号缺陷突变体重组β4基因敲除细胞将使我们能够识别控制前列腺癌恶性表型的主要信号通路。4)验证α6β4作为抗肿瘤治疗靶点的有效性。我们将研究α6β4在人类前列腺癌进展过程中的表达，并测试β4信号抑制抗体在异种移植模型中的作用。