Imaging Permissive Microenvironmental Niches for Cancer Stem Cells

描述(申请人提供)：虽然我们目前治疗乳腺癌和其他癌症的范例和治疗取得了实质性进展，但很明显，这种疾病经常逃脱控制和治愈。因此，我们必须继续在乳腺癌的病因、进展和治疗方面寻找新的可能性。干细胞样癌细胞的发现引起了巨大的兴奋，并为理解和治疗肿瘤的复发和转移提供了新的范式。实体瘤独特的生理环境以血流不畅、缺氧、高乳酸和低Phe为特征，影响肿瘤进展、远处转移和治疗反应等一系列特征。最近的研究表明，低氧为干细胞维持其前体状态提供了合适的环境。低氧也是辐射和化疗耐药的主要原因。我们在R21应用中的重点是使用分子和功能成像来了解缺氧以及生理和代谢特征在原发和转移部位产生或藏匿干细胞样癌细胞中的作用。这一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，该细胞系在缺氧反应元件(HRE)的控制下稳定表达增强型绿色荧光蛋白(EGFP)。磁共振成像将获得血管体积、通透性、质子代谢物和细胞外pH的共同配准地图。缺氧区将通过体内光学成像和荧光显微镜进行识别。通过对CD44/CD24表达的SPECT成像和新鲜/冷冻组织切片的免疫染色，将在体内鉴定干细胞样癌细胞。这些研究将深入了解肿瘤微环境和癌症干细胞之间的相互作用，并可能在未来导致针对特定的微环境利基含有癌症干细胞的成像引导策略。拟议的研究还将确定非侵入性的临床可翻译参数，以预测肿瘤中含有癌症干细胞的区域。与公共卫生相关：癌症干细胞在包括乳腺癌在内的几种肿瘤中的发现引起了极大的兴奋，并为理解和治疗乳腺癌的肿瘤复发和转移提供了新的范式。在这里，我们打算了解生理环境，如低氧和酸性细胞外pH，通常在肿瘤中发现的作用，在容纳癌症干细胞。低氧在癌症干细胞转移到远处的归巢信号中的作用也将被研究。这些研究将为癌症干细胞在复发和转移中的作用提供新的见解。

DESCRIPTION (provided by applicant): Although our current paradigms and treatments for breast and other cancers have resulted in substantial progress, it is apparent the disease frequently evades control and cure. It is therefore imperative that we continue to search for new possibilities in the etiology, progression and treatment of breast cancer. The discovery of stem-like cancer cells has generated tremendous excitement and is offering new paradigms for understanding and treating tumor recurrence and metastasis. The unique physiological environment of solid tumors is characterized by areas of poor flow, hypoxia, high lactate and low pHe that influence a wide-spectrum of characteristics including progression, distant metastasis and response to therapy. Recent studies suggest that hypoxia provides a suitable niche for stem cells to maintain their precursor status. Hypoxia is also a major cause of radiation and chemo-resistance. Our focus in this R21 application is to use molecular and functional imaging to understand the role of hypoxia and physiological and metabolic characteristics in creating or harboring stem-like cancer cells at primary and metastatic sites. The aim and hypothesis 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 fluorescent protein (EGFP) under control of a hypoxia response element (HRE). Co-registered maps of vascular volume, permeability, proton metabolites and extracellular pH will be obtained with MRI. Hypoxic regions will be identified by in vivo optical imaging and fluorescence microscopy. Stem-like cancer cells will be identified in vivo by SPECT imaging of CD44/CD24 expression and immunostaining of fresh/frozen tissue slices. These studies will provide insight into interactions between the tumor microenvironment and cancer stem cells, and may in the future lead to imaging-guided strategies targeting specific microenvironmental niches harboring cancer stem cells. The proposed studies will also identify non-invasive clinically translatable parameters to predict for cancer stem cell harboring regions in tumors. PUBLIC HEALTH RELEVANCE: The discovery of cancer stem cells in several tumors including the breast has generated tremendous excitement and is offering new paradigms for understanding and treating tumor recurrence and metastasis in breast cancer. Here we intend to understand the role of physiological environments such as hypoxia and acidic extracellular pH typically found in tumors in harboring cancer stem cells. The role of hypoxia in acting as a homing signal for cancer stem cells to metastasize to distant locations will also be investigated. These studies will provide new insights into the role of cancer stem cells in recurrence and metastasis.