Imaging Hypoxia and Cancer Stem 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产生破坏性影响，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，远处转移性疾病大多采用姑息治疗而非治愈方法。显而易见的是，尽管我们目前的癌症治疗模式和方法取得了重大进展，但这种疾病往往无法得到控制和治愈。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式。实体瘤独特的生理和代谢环境，如缺氧、酸性细胞外pH和改变的胆碱代谢可以影响肿瘤的进展、转移和对治疗的反应。最近的研究表明，缺氧为干细胞维持其前体状态提供了一个生态位。缺氧也是导致放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产生干细胞样乳腺癌细胞中的作用。我们将以缺氧和胆碱代谢为目标，确定这些干预措施是否能减少肿瘤中的干细胞负荷，并减少转移。研究的目的和假设将通过侵入性雌激素受体/孕激素受体（ER/PR）阴性的MDA-MB-231人乳腺癌细胞系和非侵入性ER/PR阳性的MCF-7人乳腺癌细胞系进行验证，这些细胞系在缺氧反应元件（HRE）的控制下稳定表达增强的绿色或红色荧光蛋白。mr将获得血管体积、通透性和总胆碱的共同登记图，缺氧区将通过荧光显微镜识别。干细胞样癌细胞将通过CD44/CD24表达的SPECT成像和新鲜/冷冻组织切片的免疫染色在体内鉴定。这些研究将(i)深入了解肿瘤微环境和干细胞样乳腺癌细胞之间的相互作用，（ii）导致针对特定微环境或代谢利基窝藏干细胞样乳腺癌细胞的图像引导策略，以及（iii）确定非侵入性临床可翻译的成像参数，以检测窝藏干细胞样乳腺癌细胞的区域。公共卫生相关性：乳腺癌中干细胞样癌细胞的发现为理解和治疗复发和转移提供了新的范例。无创成像在追踪这一亚群的动态方面尤其重要，特别是针对干细胞样癌细胞的治疗。我们的重点是了解缺氧、胆碱代谢和肿瘤微环境在产生或窝藏干样乳腺癌细胞中的作用，以及靶向缺氧和胆碱代谢对这一亚群的影响。这些研究将确定含有干细胞样乳腺癌细胞的肿瘤区域的非侵入性替代标记物，并创造针对这一致命亚群的新治疗方法。

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. PUBLIC HEALTH RELEVANCE: discovery of stem-like cancer cells in breast cancer is offering new paradigms for understanding and treating recurrence and metastasis. Noninvasive imaging is particularly important in tracking the dynamics of this subpopulation especially for therapies targeting stem-like cancer cells. Our focus is to understand the role of hypoxia, choline metabolism, and the tumor microenvironment in creating or harboring stem-like breast cancer cells, and the effect of targeting hypoxia and choline metabolism on this subpopulation. These studies will identify noninvasive surrogate markers for tumor regions containing stem-like breast cancer cells, and create novel treatments to target this lethal subpopulation.