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

基本信息

项目摘要

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疾病和侵袭性疾病,从而导致大量不必要的手术。改进的诊断标记物(例如循环肿瘤祖细胞)的创建将通过识别患有侵袭性疾病的前列腺癌患者(更有可能进展为骨转移)来改善患者的治疗。肿瘤祖细胞的几种标志物,包括 CD117,已经根据它们在原发性肿瘤中的表达被鉴定出来。 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,其中在骨转移性前列腺癌肿瘤中表达最高。初步实验表明,前列腺癌患者的循环祖细胞上也发现了CD117表达,并且循环中CD117+细胞的水平随着癌症严重程度的增加而增加。该提案的目的是确定 CD117 细胞如何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 激活和下游信号传导对致瘤性和转移前生态位形成的影响,以及 (2) 源自微环境或肿瘤本身的 SCF 表达对肿瘤生长、CD117+ 细胞动员和转移前生态位形成的作用。实验研究将利用体内和体外测试的 CD117+ 和阴性前列腺癌细胞群之间的比较来测量致瘤性、转移潜力和下游信号通路激活的变化。此外,将使用双光子成像测量 CD117+ 细胞体内定位和增殖。此外,使用带有 GFP 标记的 SCF 的转基因小鼠和细胞特异性条件敲除小鼠,将测量微环境衍生的 SCF 的确切来源及其对 CD117+ 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 的变化及其对 CD117+ 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来区分可能发生转移并因此需要积极治疗的患者和那些将从主动监测中受益的患者。了解控制转移起始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对该患者群体进行更早、更积极的干预,同时防止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(即胃肠道间质瘤、乳腺癌)。

项目成果

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Bethany Amber Kerr其他文献

Bethany Amber Kerr的其他文献

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{{ truncateString('Bethany Amber Kerr', 18)}}的其他基金

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:
    9197277
  • 财政年份:
    2015
  • 资助金额:
    $ 22.41万
  • 项目类别:
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:
    8634201
  • 财政年份:
    2014
  • 资助金额:
    $ 22.41万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 22.41万
  • 项目类别:
Molecular Mechanisms of Prostate Cancer Induced Bone Remodeling
前列腺癌诱导骨重塑的分子机制
  • 批准号:
    8403547
  • 财政年份:
    2013
  • 资助金额:
    $ 22.41万
  • 项目类别:
Molecular Mechanisms of Prostate Cancer Induced Bone Remodeling
前列腺癌诱导骨重塑的分子机制
  • 批准号:
    8001666
  • 财政年份:
    2011
  • 资助金额:
    $ 22.41万
  • 项目类别:
Molecular Mechanisms of Prostate Cancer Induced Bone Remodeling
前列腺癌诱导骨重塑的分子机制
  • 批准号:
    8201091
  • 财政年份:
    2011
  • 资助金额:
    $ 22.41万
  • 项目类别:

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