Imaging Hypoxia and Cancer Stem Cells

描述(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疾病的情况下。局部或局部复发和转移性疾病预后不良，远处转移多采用姑息性治疗而非根治性治疗。非常明显的是，尽管我们目前的癌症治疗模式和治疗方法取得了实质性进展，但这种疾病经常逃脱控制和治愈。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。实体瘤独特的生理代谢环境，如低氧、酸性胞外pH、胆碱代谢改变等，都会影响肿瘤的进展、转移和治疗反应。最近的研究表明，低氧为干细胞提供了维持其前体状态的有利条件。低氧也是辐射和化疗耐药的主要原因。我们打算了解低氧和胆碱代谢在容纳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了肿瘤中干细胞的负担，并减少了转移。这些目标和假设将用侵袭性雌激素受体/孕激素受体(ER/PR)阴性的人和非侵袭性雌激素受体/孕激素受体(ER/PR)阳性的人乳腺癌细胞株MCF-7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。血管体积、通透性和总胆碱的共同配准图将与MR获得，缺氧区将通过荧光显微镜进行识别。干细胞样癌细胞将在体内通过CD44/CD24表达的SPECT成像和新鲜/冷冻组织切片的免疫染色来鉴定。这些研究将(I)深入了解肿瘤微环境与干细胞样乳腺癌细胞之间的相互作用，(Ii)导致针对含有干细胞样乳腺癌细胞的特定微环境或代谢环境的图像引导策略，以及(Iii)识别非侵入性临床可翻译成像参数，以检测含有干细胞样乳腺癌细胞的区域。公共卫生相关性：在乳腺癌中发现干细胞样癌细胞为理解和治疗复发和转移提供了新的范例。非侵入性成像在跟踪这一亚群的动态方面特别重要，特别是在针对干细胞样癌细胞的治疗中。我们的重点是了解低氧、胆碱代谢和肿瘤微环境在创造或窝藏干状乳腺癌细胞中的作用，以及靶向低氧和胆碱代谢对这一亚群的影响。这些研究将为含有干细胞样乳腺癌细胞的肿瘤区域识别非侵入性替代标记，并创造针对这一致命亚群的新疗法。

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.