Integrin alpha6beta4 Signaling in Prostate Carcinoma Growth and Invasion

描述（由申请人提供）：α 6 β 4整联蛋白与RTK（如ErbB 2和Met）结合，以促进细胞存活、增殖和迁移。为了研究α 6 β 4信号传导在前列腺癌中的作用，我们产生了携带β 4信号传导结构域靶向缺失的小鼠。这些小鼠表现出缺陷的伤口愈合和血管生成。野生型和β 4突变小鼠与TRAMP小鼠杂交，TRAMP小鼠在TAg的Probasin介导的表达后发生前列腺癌。比较两组小鼠中的肿瘤发病和进展揭示了β 4信号传导对于从高级别PIN到浸润性癌的有效转变是必要的。我们的具体目标是：1）研究体内α 6 β 4信号促进前列腺癌进展的机制。将使用分子和细胞技术来比较TRAMP小鼠和携带野生型或突变型β 4的PTEN条件无效小鼠（PTENPC）中的前列腺肿瘤侵袭和血管生成。我们还将评估雄激素消融在两种模型中的作用。2)研究β 4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体β 4的TRAMP或PTENPC小鼠中分离前列腺癌细胞系。将使用体外和体内测定来比较它们增殖、抵抗细胞凋亡、在基质胶中组织假腺泡以及迁移/侵入的能力。3)研究β 4信号促进前列腺癌进展的分子机制。信号传导方法将用于比较表达野生型或突变型β 4的前列腺癌细胞中各种β 4途径的活化。用野生型β 4或各种信号缺陷突变体重建β 4敲低细胞将使我们能够鉴定α 6 β 4控制前列腺癌恶性表型的主要信号通路。4)检验α 6 β 4作为抗肿瘤治疗靶点的有效性。我们将研究人前列腺癌进展过程中α 6 β 4的表达，并测试β 4信号传导抑制抗体在异种移植模型中的作用。

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.