Integrin alpha6beta4 Signaling in Prostate Carcinoma Growth and Invasion

描述（申请人提供）：alpha6beta4整合素与rtk（如ErbB2和Met）结合，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，我们培养了携带靶向缺失beta4信号域的小鼠。这些小鼠表现出伤口愈合和血管生成缺陷。野生型和beta4突变型小鼠已与probasin介导的T Ag表达的TRAMP小鼠杂交，后者发展为前列腺癌。两组小鼠肿瘤发生和进展的比较表明，β 4信号对于从高级别PIN到侵袭性癌的有效转变是必要的。我们的具体目标是：1)研究α 6beta4信号通路在体内促进前列腺癌进展的机制。分子和细胞技术将用于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）的前列腺肿瘤侵袭和血管生成。我们还将评估两种模型中雄激素消融的效果。2)探讨β 4信号通路促进前列腺癌进展的细胞机制。从表达野生型或突变型beta4的TRAMP或PTENPC小鼠中分离前列腺癌细胞系。体外和体内实验将用于比较它们的增殖能力、抗凋亡能力、在基质中组织假腺泡病毒的能力以及迁移/侵袭能力。3)探讨β 4信号通路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beta4的前列腺癌细胞中各种beta4途径的激活。重组野生型beta4或各种信号缺陷突变体的beta4敲除细胞，将使我们能够确定alpha6beta4控制前列腺癌恶性表型的主要信号通路。4)检验alpha6beta4作为抗肿瘤治疗靶点的有效性。我们将研究alpha6beta4在人类前列腺癌进展过程中的表达，并在异种移植模型中检测beta4信号抑制抗体的作用。

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.