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Role of CCL25-CCR9 in Prostate Cancer

CCL25-CCR9 在前列腺癌中的作用

基本信息

批准号：
8414694
负责人：
Shailesh Singh
金额：
$ 35.38万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8414694
关键词：
Ablation Accounting Androgens Antibodies Apoptosis Binding Biological Bone Marrow CCL25 gene Cancer Patient Cell Survival Cells Cessation of life Clinic Clinical Data Development Disease Drug resistance Epithelial Epithelium GPR-9-6 receptor Growth Health Hormones Human Image Immunohistochemistry Immunoprecipitation In Vitro Injection of therapeutic agent Knock-out Knowledge Laboratories Lead Ligands Light Luciferases Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Molecular Molecular Profiling Molecular Target Monitor Mus Neoplasm Metastasis Organ Outcome PTK2 gene Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Play Population Prostate Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Publishing Refractory Regimen Resistance Role Sampling Series Serum Signal Transduction Signaling Molecule Small Interfering RNA Stromal Cells Testing Tissue Sample Toxic effect Treatment Efficacy base bone cancer cell cell motility chemokine chemokine receptor chemotherapy clinical efficacy deprivation design docetaxel expression vector hormone refractory prostate cancer improved in vitro Assay in vivo inhibitor/antagonist innovation migration neoplastic cell new therapeutic target novel overexpression paracrine prostate cancer cell response small hairpin RNA standard of care therapeutic target trafficking tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Despite recent additions in the clinical armamentarium of drugs for prostate cancer (PCa) therapy, hormone refractory metastatic disease accounts for an overwhelming majority (~90%) of PCa deaths with skeletal metastases, particularly in bones. Most currently-available chemotherapeutic regimens for PCa including docetaxel essentially target rapidly dividing cell populations non-selectively, thus presenting debilitating toxicities. Other major limitations are owing to the emergence of androgen-independence as well as lower proliferative capacity of the metastatic disease. Thus, identification of novel molecular targets that are selectively presented by the less-proliferative, androgen-independent metastatic prostate cancer cells might result in the near-complete elimination of this dreaded disease. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively over expressed in prostate cancers with negligible expression in normal prostate epithelia. Our recently published and preliminary data demonstrate that 1) CCR9 is highly expressed by PCa cells and mediates PCa cell migration, invasion and survival in vitro, 2) CCR9 is also highly expressed in clinical prostate cancer tissue samples, 3) CCL25, a natural ligand of CCR9, is expressed in a paracrine manner by PCa clinical sample and also elevated in PCa patient serum, 4) bone marrow stromal cells of tumor-bearing mice significantly produce CCL25, compared to non-tumor bearing ones, 5) inhibition of CCR9-CCL25 axis sensitizes cellular responses to chemotherapy in PCa cells. Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis plays a crucial role in prostate cancer metastasis and is a cancer-selective therapeutic target. Targeting this axis will enable development of new chemotherapeutic strategies as well as improving existing ones by sensitizing prostate cancer cells to currently available regimens. To validate our hypothesis, we propose to determine the role of CCR9-CCL25 axis in (i) inducing prostate cancer cell migration and invasion, (ii) prostate cancer cell survival and apoptosis, (iii) triggering prostate cancer growth and metastases iv) enhancing chemotherapeutic efficacy of clinical regimens. To accomplish our aims, we have generated CCR9 conditional knockout cells that will be used for in vitro assays to determine its role in PCa cell migration, invasion and survival, and determining its potential role in tumor growth, metastasis and therapeutic efficacy of docetaxel. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to evaluate the role of CCR9-CCL25 axis in promotion of metastases. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa and will go a long way to enhance our understanding of chemokines in mediating disease aggressiveness. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 axis for PCa.

描述（由申请人提供）：尽管最近在前列腺癌（PCa）治疗药物的临床装备中增加了一些药物，但激素难治性转移性疾病在伴有骨骼转移（尤其是骨骼转移）的 PCa 死亡中占绝大多数（约 90%）。目前大多数前列腺癌化疗方案（包括多西紫杉醇）本质上是非选择性地针对快速分裂的细胞群，因此呈现出使人衰弱的毒性。其他主要限制是由于雄激素非依赖性的出现以及转移性疾病的较低增殖能力。因此，鉴定由增殖较少的细胞选择性呈现的新分子靶标，不依赖雄激素的转移性前列腺癌细胞可能会导致这种可怕的疾病几乎完全消除。人们越来越认识到趋化因子-配体轴在肿瘤细胞运输和器官特异性转移的发展中发挥着至关重要的作用。我们的实验室首次证明 CC 趋化因子受体 9 (CCR9) 在前列腺癌中选择性过度表达，而在正常前列腺上皮细胞中表达可忽略不计。我们最近发表的初步数据表明：1) CCR9 在 PCa 细胞中高表达，并在体外介导 PCa 细胞迁移、侵袭和存活，2) CCR9 在临床前列腺癌组织样本中也高表达，3) CCL25 是 CCR9 的天然配体，在 PCa 临床样本中以旁分泌方式表达，并且在 PCa 患者血清中也升高，4) 骨髓与非荷瘤小鼠相比，荷瘤小鼠的基质细胞显着产生 CCL25，5) CCR9-CCL25 轴的抑制使 PCa 细胞对化疗的细胞反应敏感。基于这些令人鼓舞的数据，我们假设 CCR9-CCL25 轴在前列腺癌转移中发挥着至关重要的作用，并且是癌症选择性治疗靶点。针对该轴将能够开发新的化疗策略，并通过使前列腺癌细胞对当前可用的治疗方案敏感来改善现有的化疗策略。为了验证我们的假设，我们建议确定 CCR9-CCL25 轴在（i）诱导前列腺癌细胞迁移和侵袭，（ii）前列腺癌细胞存活和凋亡，（iii）触发前列腺癌生长和转移 iv）增强临床方案的化疗功效中的作用。为了实现我们的目标，我们生成了 CCR9 条件敲除细胞，将用于体外测定，以确定其在 PCa 细胞迁移、侵袭和存活中的作用，并确定其在肿瘤生长、转移和多西紫杉醇治疗效果中的潜在作用。此外，siRNA双链体或针对CCR9驱动信号分子的特异性药理学抑制剂将用于评估CCR9-CCL25轴在促进转移中的作用。我们乐观地认为，这些研究的成功完成将确定这种新发现的趋化因子在 PCa 中的作用，并将这对于增强我们对介导疾病侵袭性的趋化因子的理解大有帮助。此外，它将能够设计和开发针对 PCa CCR9-CCL25 轴的合理疗法。