Quantitative profiling of glycosaminoglycans from breast tumor tissue arrays

乳腺肿瘤组织阵列中糖胺聚糖的定量分析

• 批准号: 8889224
• 负责人: JOSEPH ZAIA
• 金额: $ 24.92万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889224
• 关键词: Address; Advanced Development; Age; American; Archives; Basic Cancer Research; Biological Markers; Biopsy; Biopsy Specimen; Breast Cancer Cell; Cancer Etiology; Cancer Prognosis; Cell Count; Cell surface; Cells; Chondroitin Sulfates; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Digestion; Enzymes; Extracellular Matrix; Funding; Glycosaminoglycans; Glycoside Hydrolases; Goals; Grant; Growth; Growth Factor; Health; Heparitin Sulfate; Heterogeneity; Human; Hyaluronan; In Situ; Knowledge; Lead; Malignant Neoplasms; Mammalian Cell; Mammary Gland Parenchyma; Mammary Neoplasms; Metastatic Carcinoma; Methods; Mission; Molecular; Molecular Structure; Nature; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Paraffin Embedding; Phase; Phenotype; Pilot Projects; Play; Polysaccharides; Process; Proteins; Proteoglycan; Relative (related person); Reproducibility; Research; Research Personnel; Role; Series; Signal Pathway; Slide; Specimen; Speed; Staging; Stimulus; Structure; Surface; Technology; Therapeutic; Tissue Microarray; Tissues; Tumor Tissue; Tumor stage; Woman; Work; analytical method; angiogenesis; anticancer research; base; cancer cell; cell growth; extracellular; improved; infiltrating duct carcinoma; liquid chromatography mass spectrometry; lymph nodes; malignant breast neoplasm; meetings; neoplastic cell; new technology; outcome forecast; programs; protein expression; receptor; technology development; therapeutic development; tumor; tumor progression

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer lethality, and the most common cancer among women; 12% of American women will be diagnosed with breast cancer. Unfortunately, breast cancer is notorious for its poor prognosis and lack of effective therapeutics due to its highly metastatic nature. Proteoglycans play a critical role in cell-cell, cell-matrix interaction and regulate important signaling pathways. Inded, proteoglycans and their extracellular processing enzymes are deregulated in human breast cancers relative to normal tissues. Despite this, there is a serious lack of information concerning the mechanisms whereby cancer cells become dysregulated through altering the structures of glycosaminoglycans (GAGs) on their surfaces and in extracellular matrices. While there is a wealth of archived breast tumor tissue microarrays (TMAs) available, no methods are available for determining GAG structures and abundances from these arrays. This application aims to develop new technology to catalyze progress in cancer research for better understanding of the changes to expression of GAGs that occur as a function of breast cancer grade and stage. The challenge of cancer heterogeneity is best addressed through the analysis of the minimum number of cells possible from graded and staged biopsy samples such as those available in breast tumor TMAs. We will develop new technology with the sensitivity and speed necessary for query of the molecular structures of GAGs expressed in these tissue arrays. The ability to analyze such arrays for GAG expression is beyond any technology available at present. This proposed technology development will give cancer researchers the means to determine the mechanisms whereby cancer cells alter the structures of cell surface and extracellular matrix GAGs in order to escape normal regulatory controls and progress towards metastasis. The goal of the requested R21 activity is to develop methods and demonstrate the feasibility of quantitative structural analysis of GAGs from breast tumor tissue arrays. This will be the basis of a subsequent request for phase II (R33) activity for advanced development of the technology. We will (1) develop technology with the speed and sensitivity required for analysis of GAGs from breast cancer tissue arrays; (2) conduct a set of pilot studies on GAG expression using graded human breast cancer tissue arrays. This activity will facilitate broader use of GAG glycomics in cancer research towards a better understanding of the remodeling of cancer cell surfaces and extracellular matrices necessary for dysregulated growth and metastasis. Such technology meets the mission of the NCI's goals of funding research with high potential for positive impact on understanding of GAG expression on cancer prognosis. The proposed glycomics technology development will meet the IMAT program's goal of supporting the development of transformative technologies for cancer research.

描述（由申请人提供）：乳腺癌是癌症致死性的第二主要原因，也是女性中最常见的癌症； 12％的美国女性将被诊断出患有乳腺癌。不幸的是，由于其高度转移性，乳腺癌因其预后不良和缺乏有效的治疗性而臭名昭著。蛋白聚糖在细胞 - 细胞，细胞 - 矩阵相互作用中起关键作用，并调节重要的信号通路。相对于正常组织，在人乳腺癌中，蛋白聚糖及其细胞外加工酶在人体乳腺癌中受到失调。尽管如此，仍然严重缺乏有关的信息 通过改变其表面和细胞外矩阵中糖胺聚糖（GAG）的结构，通过改变糖胺聚糖（GAGS）的结构而变得失调的机制。虽然可用的大量存档的乳腺肿瘤组织微阵列（TMA）可用，但没有可用于确定这些阵列中的堵塞结构和丰富的方法。该应用程序旨在开发新技术来催化癌症研究的进展，以更好地理解随着乳腺癌级和阶段的函数而发生的插科打s表达的变化。癌症异质性的挑战是通过分析分级和分期活检样本（例如乳腺肿瘤TMA中可用的细胞）的最小细胞数量来解决的。我们将以敏感性和速度来开发新技术，以查询这些组织阵列中表达的插科打s的分子结构所必需的速度。目前，分析此类阵列以插科打术的能力超出了任何可用的技术。这项提出的技术开发将使癌症研究人员确定癌细胞改变细胞表面和细胞外基质插科打结构的机制的手段，以避免正常的调节控制并朝着转移方向发展。请求的R21活性的目的是开发方法，并证明对乳腺肿瘤组织阵列中GAG的定量结构分析的可行性。这将是 随后要求II阶段（R33）活动的请求，以进行技术的高级开发。我们将（1）以分析乳腺癌组织阵列的插科打s所需的速度和灵敏度开发技术； （2）使用分级的人类乳腺癌组织阵列进行了一系列有关堵嘴表达的试验研究。这种活性将促进癌症研究中更广泛地使用gag甘油酸酯，以更好地理解癌细胞表面的重塑以及对于失调的生长和转移所必需的细胞外基质。这种技术符合NCI的资金研究目标的使命，其潜力很大，从而对了解癌症预后表达的表达有积极影响。拟议的甘体技术开发将满足IMAT计划的目标，即支持用于癌症研究的变革性技术的发展。