Inflammatory Mediators of Prostate Cancer Metastasis and Responses to Curcumin

前列腺癌转移的炎症介质和姜黄素的反应

• 批准号: 8135289
• 负责人: MAGALY MARTINEZ-FERRER
• 金额: $ 9.51万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135289
• 关键词: Actins; Adenocarcinoma; Adjuvant Therapy; American; Biochemical; Biological; Biological Markers; Bone Marrow; CCL4 gene; CX3CL1 gene; Cancer Etiology; Cell Line; Cells; Cessation of life; Characteristics; Chemopreventive Agent; Clinical; Conditioned Culture Media; Curcumin; Development; Diagnosis; Epithelial Cells; Fetal Liver; Fibroblasts; Goals; Human; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-15; Knock-out; LNCaP; Malignant Neoplasms; Malignant neoplasm of prostate; Measurable; Metastatic Prostate Cancer; Modeling; Mus; Neoplasm Metastasis; Nested Case-Control Study; PC3 cell line; Pathologic; Patients; Population; Preventive; Prostate; Recombinant Chemokine; Recruitment Activity; Recurrence; Regulation; Role; Signal Transduction; Staging; Stromal Cells; Testing; Therapeutic Agents; Xenograft Model; Xenograft procedure; base; cancer cell; cancer recurrence; chemokine; disorder risk; feeding; high risk; in vivo; liver transplantation; men; receptor; response; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. Stratifying patients with high-risk of prostate cancer recurrence following primary therapy from those of low-risk disease at an early stage may support curative adjuvant-therapy for prostate cancers of metastatic potential. In a nested case control study, CX3CL1, IL-15, and CCL4 expression were independent predictors of recurrence status. This proposal tests the hypothesis that chemokine biomarkers that predict biochemical recurrence of prostate cancer regulate metastatic progression of the cancer and curcumin can inhibit metastasis of prostate cancer. In Aim 1, CX3CL1, CCL4 and IL-15 will be expressed in prostate cancer epithelial cell lines to determine whether cancer cells expressing recombinant chemokines CX3CL1 and IL-15 (biochemical recurrent-free patients) and CCL4 (biochemical recurrent patients) can differentially regulate metastasis of prostate cancer in vitro. Xenograft tumor models will test whether tumors expressing recombinant chemokines CX3CL1, IL-15 and CCL4 can differentially regulate metastasis of prostate cancer. Aim 2 will identify the role of inflammation on prostate cancer progression. Tgfbr2fspKO prostates that develop into adenocarcinoma will be grafted with stromal cells that express CX3CL1, CCL4 and IL-15. Bone marrow derived cells that are recruited to the prostate will be identified and quantified. Chimeric mice with bone marrow derived cells knocked out for the expression of the primary CX3CL1 receptor and CCL4 receptor will be developed. The goal will be to characterize the consequences of ablating the recruitment of specific populations of inflammatory cells to the prostate. In Aim 3, prostate cancer cell lines expressing CX3CL1, CCL4 and IL-15 will be treated with curcumin to determine whether curcumin can inhibit metastasis of prostate cancer in vitro through the regulation of CX3CL1, CCL4 and IL-15. Xenograft tumor models will test whether curcumin modulates tumor metastasis in vivo through the regulation of CX3CL1, CCL4 and IL-15. These results will provide biologic basis for the clinical use of the chemokine biomarkers and development of new therapies aimed to inhibit prostate cancer metastasis.

描述（由申请人提供）：前列腺癌是最常见的非皮肤癌症，是美国男性癌症死亡的第二大原因。将原发性前列腺癌复发高风险患者与早期低风险患者进行分层可能支持对具有转移潜力的前列腺癌进行治疗性辅助治疗。在一项嵌套病例对照研究中，CX3CL1、IL-15和CCL4表达是复发状态的独立预测因子。本研究验证了预测前列腺癌生化复发的趋化因子生物标志物调控癌症转移进展和姜黄素抑制前列腺癌转移的假设。在Aim 1中，我们将在前列腺癌上皮细胞系中表达CX3CL1、CCL4和IL-15，以确定表达重组趋化因子CX3CL1和IL-15（生化无复发患者）和CCL4（生化复发患者）的癌细胞是否能在体外差异调节前列腺癌转移。异种移植肿瘤模型将检测表达重组趋化因子CX3CL1、IL-15和CCL4的肿瘤是否能差异调节前列腺癌的转移。目的2将确定炎症在前列腺癌进展中的作用。发展为腺癌的Tgfbr2fspKO前列腺将移植表达CX3CL1、CCL4和IL-15的基质细胞。招募到前列腺的骨髓来源细胞将被识别和量化。嵌合小鼠将被开发，其骨髓来源的细胞被敲除以表达初级CX3CL1受体和CCL4受体。目标将是表征的后果消融募集的特定人群的炎症细胞的前列腺。在Aim 3中，我们将用姜黄素处理表达CX3CL1、CCL4和IL-15的前列腺癌细胞，以确定姜黄素是否可以通过调节CX3CL1、CCL4和IL-15在体外抑制前列腺癌的转移。异种移植肿瘤模型将检测姜黄素是否通过调节CX3CL1、CCL4和IL-15在体内调节肿瘤转移。这些结果将为趋化因子生物标志物的临床应用和开发抑制前列腺癌转移的新疗法提供生物学依据。