CD117 Signaling as a Mechanism of Prostate Cancer Metastasis

CD117 信号传导作为前列腺癌转移的机制

• 批准号: 8792201
• 负责人: Bethany Amber Kerr
• 金额: $ 9.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792201
• 关键词: Affect; Automobile Driving; Autopsy; Blood Circulation; Blood Platelets; Blood Vessels; Bone Marrow; Bone remodeling; Breast; C-KIT Gene; Cancer Patient; Cell Communication; Cell Proliferation; Cells; Cellular Structures; Clinical; Communication; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Drops; Future; Health; Homing; Human; Image; Implant; In Vitro; Indolent; Intervention; Knock-in Mouse; Knockout Mice; LNCaP; Label; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Metastatic to; Methods; Modeling; Mus; Neoplasm Metastasis; Nomograms; Osteogenesis; Outcome; Pain; Pathway interactions; Patients; Population; Preparation; Prevention; Primary Neoplasm; Prostate; Prostatectomy; Proteins; Proto-Oncogene Protein c-kit; Quality of life; Receptor Protein-Tyrosine Kinases; Research; Role; Severities; Signal Pathway; Signal Transduction; Site; Skeletal system; Sorting - Cell Movement; Source; Staining method; Stains; Stem Cell Factor; Stem cells; Survival Rate; Symptoms; Testing; Transgenic Mice; Tumor Markers; Tumor-Derived; Tumorigenicity; Unnecessary Surgery; angiogenesis; base; bone; cancer cell; cell growth; cell motility; improved; in vivo; inhibitor/antagonist; knock-down; migration; mortality; neoplastic cell; novel; patient population; prevent; progenitor; prostate cancer cell; research study; response; therapeutic development; therapeutic target; tomography; tool; tumor; tumor growth; tumor progression; tumorigenesis; two-photon

DESCRIPTION (provided by applicant): Current nomograms for diagnosing prostate cancer presence are unable to differentiate between indolent and aggressive disease resulting in a high number of unnecessary surgeries. The creation of improved diagnostic markers, such as circulating tumor progenitor cells, would improve patient treatment by identifying prostate cancer patients with aggressive disease who are more likely to progress to bone metastasis. Several markers of tumor progenitors, including CD117, have been identified based on their expression in primary tumors. Staining of CD117 and its ligand stem cell factor (SCF) are both upregulated with cancer severity, with the highest expression occurring in bone metastatic prostate cancer tumors. Preliminary experiments have shown that CD117 expression has also been found on circulating progenitor cells in prostate cancer patients and the levels of CD117+ cells in the circulation increased with cancer severity. The objective of this proposal is to determine how CD117 cells are mobilized into the circulation and contribute to prostate cancer metastasis. Using murine models, (1) the effects of C117 activation and downstream signaling on tumorigenicity and premetastatic niche formation will be examined and (2) the role of SCF expression originating from the microenvironment or the tumor itself on tumor growth, CD117+ cell mobilization and premetastatic niche formation. Experimental studies will utilize comparisons between CD117+ and negative prostate cancer cell populations tested in vivo and in vitro to measure changes in tumorigenicity, metastatic potential, and downstream signaling pathway activation. In addition, CD117+ cell localization and proliferation in vivo will be measured using two-photon imaging. Further, using transgenic mice with SCF labeled by GFP and cell-specific conditional knockout mice, the exact source of microenvironment-derived SCF and its effects on CD117+ and negative tumor cell tumorigenicity and mobilization will be measured. Correspondingly, alterations in tumor-derived SCF and their effects on CD117+ prostate cancer cell proliferation and metastatic potential will be examined. The long term objective of this proposal is to develop novel tools to differentiate patients likely to progress t metastasis and thus requiring aggressive treatment from those that would benefit from active surveillance. Understanding the mechanisms controlling metastatic initiation and premetastatic niche formation will lead to significant advances in the treatment and diagnosis of metastatic prostate cancer. More reliable identification of prostate cancer patients likely to progress to invasive or metastatic disease will result in earlier and more aggressive interventions in this patient population, while preventing excessive treatment of low grade cancer patients. Any findings and therapeutic developments discovered by the proposed research may extend to other tumor types with a tumor progenitor cell component (i.e. GIST, breast).

描述（由申请人提供）：目前用于诊断前列腺癌存在的列线图无法区分惰性和侵袭性疾病，导致大量不必要的手术。改进的诊断标志物，如循环肿瘤祖细胞的产生，将通过识别更有可能进展为骨转移的具有侵袭性疾病的前列腺癌患者来改善患者治疗。肿瘤祖细胞的几种标志物，包括CD117，已经基于它们在原发性肿瘤中的表达而被鉴定。CD117及其配体干细胞因子（SCF）的染色均随癌症严重程度而上调，在骨转移性前列腺癌肿瘤中表达最高。初步实验表明，在前列腺癌患者的循环祖细胞上也发现了CD 117表达，并且循环中CD 117+细胞的水平随着癌症的严重程度而增加。本提案的目的是确定CD117细胞如何被动员到循环中并促进前列腺癌转移。使用小鼠模型，（1）将检查C117活化和下游信号传导对致瘤性和转移前小生境形成的影响，以及（2）源自微环境或肿瘤本身的SCF表达对肿瘤生长、CD 117+细胞动员和转移前小生境形成的作用。实验研究将利用体内和体外检测的CD117+和阴性前列腺癌细胞群之间的比较，以测量致瘤性、转移潜力和下游信号传导通路激活的变化。此外，将使用双光子成像测量体内CD 117+细胞定位和增殖。此外，使用GFP标记SCF的转基因小鼠和细胞特异性条件性敲除小鼠，将测量微环境来源的SCF的确切来源及其对CD 117+和阴性肿瘤细胞致瘤性和动员的影响。相应地，将检查肿瘤源性SCF的改变及其对CD 117+前列腺癌细胞增殖和转移潜力的影响。该提案的长期目标是开发新的工具，以区分可能进展为转移并因此需要积极治疗的患者与那些将受益于积极监测的患者。了解控制转移启动和转移前生态位形成的机制将导致转移性前列腺癌的治疗和诊断取得重大进展。更可靠地识别可能进展为侵袭性或转移性疾病的前列腺癌患者将导致在该患者人群中更早和更积极的干预，同时防止对低级别癌症患者的过度治疗。拟议研究发现的任何发现和治疗进展都可能扩展到具有肿瘤祖细胞成分的其他肿瘤类型（即GIST，乳腺）。