Pim 1 Protein Kinase in Regulating Stromal Cell Biology in Prostate Cancer

Pim 1 蛋白激酶调节前列腺癌基质细胞生物学

• 批准号: 8855025
• 负责人: Andrew S Kraft
• 金额: $ 19.96万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8855025
• 关键词: Angiogenic Factor; Animal Model; Biological Assay; Biology; CXCL12 gene; Cancer Etiology; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cellular biology; Cessation of life; Chemistry; Clinic; Collagen; Data; Dependency; Drops; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Extracellular Matrix; Extracellular Matrix Proteins; Feedback; Fibroblasts; Genetic; Genetic Recombination; Glycoproteins; Goals; Growth; Growth Factor; Human; Immunohistochemistry; Integration Host Factors; Integrins; Interleukin-6; Knock-out; Label; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Medical; Mesenchymal; Messenger RNA; Methods; Modality; Modeling; Mus; Myofibroblast; Neoplasm Metastasis; Normal Cell; PDGFRB gene; PIM1 gene; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Procedures; Production; Prostate; Prostatic Neoplasms; Protein Isoforms; Protein Kinase; Protein Secretion; Proteins; Regulation; Research Design; Research Personnel; Role; Serine; Signal Transduction; Signal Transduction Pathway; South Carolina; Stromal Cells; Stromal Neoplasm; Testing; Threonine; Tissue Microarray; Transforming Growth Factor beta; Tumor Cell Line; Universities; Work; angiogenesis; base; cancer therapy; cell motility; cell type; human migration; inhibitor/antagonist; men; migration; mortality; neoplastic cell; novel; novel therapeutic intervention; overexpression; periostin; phase I trial; prostate cancer cell; public health relevance; receptor; research study; small molecule; transdifferentiation; tumor; tumor growth; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) epithelial cells have a critically important interaction with the surrounding tumor stromal microenvironment, and this feedback relationship stimulates PCa progression and metastasis. PCa stroma is composed of activated myofibroblasts that produce growth, angiogenesis, migration factors, and extracellular matrix, all of which contribute to tumor invasiveness. Disrupting this mutual-dependency tumor stromal-epithelial interaction leads to marked inhibition of tumor growth and blocks metastasis. Investigators in the Kraft laboratory at the Medical University of South Carolina have discovered that the PIM1 serine-threonine protein, known to be elevated in prostate cancer, is significantly increased in human prostate stromal cells and plays an important role in controlling fiibroblast cell biology. Increasing the level of PIM1 kinase in a normal prostate fibroblast cell line leads t the transdifferentiation of these normal cells to activated myofibroblasts, followed by the increase in the PDGF receptor and secretion of multiple factors that play a critical role in stimulating tumor growth. Further, these PIM activated myofibroblasts are capable of markedly stimulating the growth and migration of human prostate epithelial cells. These exciting results lead to the unique hypothesis that activated PIM1 kinase plays an important role in transdifferentiation of prostate fibroblast cells potentially controlling prostate cancer growth an migration. This hypothesis suggests that small molecule PIM inhibitory compounds in phase I trials and available to the Kraft laboratory have the potential to interrupt this epithelial:stroma feedback relationship and block the growth of these tumors. The specific aims will evaluate this hypothesis by: 1) determining whether increases in PIM1 in freshly isolated cancer associated fibroblasts drive and section of growth and migration factors and whether this can be inhibited by drugs which block the PIM kinase; and 2) examining whether PIM1 overexpressing prostate myofibroblasts are capable of induced epithelial cell malignancy and tumor growth in animal models. The proposed study design will make use of a novel glycoprotein labelling procedure that employs "click" chemistry to measure the stromal secretome, and a subrenal capsular recombination assay in mice. These studies will employ novel small molecule PIM inhibitors developed by AstraZeneca and Genentech that are entering the clinic for cancer therapy. These studies will markedly increase the understanding of the role of PIM1 in prostate cancer fibroblast activity and develop the rationale for using PIM inhibitors as a potential method of interrupting stromal:epithelial interaction inhibiting prostate tumor growth.

 描述（由适用提供）：前列腺癌（PCA）上皮细胞与周围肿瘤基质微环境至关重要，这种反馈关系刺激了PCA的进展和转移。 PCA基质由激活的肌纤维细胞组成，这些成肌细胞产生生长，血管生成，迁移因子和细胞外基质，所有这些都会导致肿瘤的侵入性。破坏这种相互依赖性的肿瘤基质上皮相互作用会导致明显的抑制肿瘤生长并阻止转移。南卡罗来纳州医科大学的牛皮纸实验室的研究人员发现，在人类前列腺基质细胞中，已知在前列腺癌中升高的PIM1丝氨酸 - 苏氨酸蛋白显着增加，并且在控制纤维细胞生物学中起重要作用。在正常的前列腺成纤维细胞系中增加PIM1激酶的水平导致这些正常细胞的转分化导致激活的肌纤维细胞，然后PDGF受体的增加以及在刺激肿瘤生长中起关键作用的多种因素的分泌。此外，这些PIM激活的肌纤维细胞能够显着刺激人前列腺上皮细胞的生长和迁移。这些令人兴奋的结果导致了一个独特的假设，即激活的PIM1激酶在转差前列腺成纤维细胞中具有重要作用，从而控制了前列腺癌的生长A迁移。该假设表明，I期试验中的小分子PIM抑制性化合物，可用于牛皮纸实验室，有可能中断这种上皮：基质反馈关系并阻止这些肿瘤的生长。具体目的将通过以下方式评估这一假设：1）确定新鲜分离的癌症相关的成纤维细胞驱动和生长和迁移因子的PIM1是否增加，以及是否可以通过阻断PIM激酶的药物来抑制这一点； 2）检查PIM1过表达前列腺肌纤维细胞是否能够在动物模型中诱导上皮细胞恶性肿瘤和肿瘤生长。拟议的研究设计将利用一种新型的糖蛋白标记程序，该过程“单击”化学以测量基质分泌组，并在小鼠中进行下肾上腺囊膜重组测定法。这些研究将采用阿斯利康和Genentech开发的新型小分子PIM抑制剂，这些抑制剂正在进入癌症治疗诊所。这些研究将显着增加对PIM1在前列腺癌成纤维细胞活性中的作用的理解，并发展使用PIM抑制剂作为中断基质的潜在方法的理由：上皮相互作用抑制前列腺肿瘤的生长。