Imaging Hypoxia and Cancer Stem Cells

缺氧和癌症干细胞成像

• 批准号: 8475432
• 负责人: Zaver M. Bhujwalla
• 金额: $ 31.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475432
• 关键词: ABCB1 gene; ABCG2 gene; Apoptotic; Area; Blood Vessels; Blood flow; Breast Cancer Cell; CD44 gene; Cancer cell line; Cell Fraction; Cell Line; Cells; Characteristics; Choline; Choline Kinase; Data; Disease; Distant Metastasis; Environment; Estrogen Receptors; Etiology; Exclusion; Exhibits; Extracellular Matrix; Fluorescence; Fluorescence Microscopy; Freezing; Fresh Tissue; Genes; Gray unit of radiation dose; Health; Human; Hypoxia; Image; Intervention; Lead; Lymphatic vessel; MCF7 cell; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Metabolic; Metabolism; Modeling; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Permeability; Phenotype; Physiological; Population; Progesterone Receptors; Proteins; Protons; Quality of life; Radiation; Radiolabeled; Recurrence; Resistance; Response Elements; Rhodamine 123; Role; Site; Slice; Solid Neoplasm; Surface; Surrogate Markers; Testing; Therapeutic Effect; Tissues; Tumor-Derived; Vascularization; Xenograft Model; aldehyde dehydrogenase 1; aldehyde dehydrogenases; cancer cell; cancer stem cell; cancer therapy; extracellular; in vivo; insight; malignant breast neoplasm; molecular marker; mortality; novel; optical imaging; outcome forecast; overexpression; palliative; preclinical study; progesterone receptor negative; radiotracer; response; single photon emission computed tomography; stem; stem cell niche; therapy resistant; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Breast cancer continues to have a devastating effect in terms of mortality and quality of life, especially in the case of recurrent or metastatic disease. Local or regional recurrences and metastatic disease have unfavorable prognosis, and distant metastases are mostly treated with palliative rather than curative approaches. It is only too apparent that, although our current paradigms and treatments for cancer have resulted in substantial progress, the disease frequently evades control and cure. It is therefore imperative to search for new possibilities in the etiology, progression and treatment of cancer, and to understand causes for recurrence and metastasis. The discovery of subpopulations of breast cancer cells with stem-like characteristics is offering new paradigms for understanding and treating tumor recurrence and metastasis. The unique physiological and metabolic environments of solid tumors such as hypoxia, acidic extracellular pH, and altered choline metabolism can influence tumor progression, metastasis and response to therapy. Recent studies suggest that hypoxia provides a niche for stem cells to maintain their precursor status. Hypoxia is also a major cause of radiation and chemo-resistance. We intend to understand the role of hypoxia and choline metabolism in harboring or creating stem-like breast cancer cells. We will target hypoxia and choline metabolism and determine if these interventions reduce the stem-like cell burden in tumors, and reduce metastasis. The aims and hypotheses will be tested using invasive estrogen receptor/progesterone receptor (ER/PR) negative MDA-MB-231 human and noninvasive ER/PR positive MCF-7 human breast cancer cell lines stably expressing enhanced green or red fluorescence protein under control of a hypoxia response element (HRE). Co-registered maps of vascular volume, permeability, and total choline will be obtained with MR. Hypoxic regions will be identified by fluorescence microscopy. Stem-like cancer cells will be identified in vivo by SPECT imaging of CD44/CD24 expression and by immunostaining of fresh/frozen tissue slices. These studies will (i) provide insight into interactions between the tumor microenvironment and stem-like breast cancer cells, (ii) lead to image-guided strategies targeting specific microenvironmental or metabolic niches harboring stem-like breast cancer cells, and (iii) identify non-invasive clinically translatable imaging parameters to detect regions harboring stem-like breast cancer cells.

描述（由申请人提供）：乳腺癌在死亡率和生活质量方面继续具有破坏性影响，特别是在复发或转移性疾病的情况下。局部或区域复发和转移性疾病预后不良，远处转移大多采用姑息治疗而非根治性治疗。显而易见的是，尽管我们目前的癌症模式和治疗方法已经取得了实质性进展，但这种疾病往往无法控制和治愈。因此，迫切需要在癌症的病因、进展和治疗方面寻找新的可能性，并了解复发和转移的原因。具有干细胞样特征的乳腺癌细胞亚群的发现为理解和治疗肿瘤复发和转移提供了新的范例。实体瘤独特的生理和代谢环境，如缺氧、酸性细胞外pH和胆碱代谢改变，可影响肿瘤进展、转移和对治疗的反应。最近的研究表明，缺氧为干细胞提供了一个小生境，以维持其前体状态。缺氧也是辐射和化学抵抗的主要原因。我们打算了解缺氧和胆碱代谢在窝藏或创造干细胞样乳腺癌细胞中的作用。我们将针对缺氧和胆碱代谢，并确定这些干预措施是否减少肿瘤中的干细胞样细胞负荷，并减少转移。将使用在缺氧反应元件（HRE）控制下稳定表达增强的绿色或红色荧光蛋白的侵袭性雌激素受体/孕激素受体（ER/PR）阴性MDA-MB-231人和非侵袭性ER/PR阳性MCF-7人乳腺癌细胞系来测试目的和假设。将使用MR获得血管容积、渗透性和总胆碱的共配准图。将通过荧光显微镜识别低血糖区域。干细胞样癌细胞将通过CD 44/CD 24表达的SPECT成像和通过新鲜/冷冻组织切片的免疫染色在体内鉴定。这些研究将（i）提供对肿瘤微环境和干细胞样乳腺癌细胞之间相互作用的深入了解，（ii）导致针对特定微环境或代谢小生境的图像引导策略，这些微环境或代谢小生境包含干细胞样乳腺癌细胞，以及（iii）确定非侵入性临床可翻译的成像参数，以检测包含干细胞样乳腺癌细胞的区域。