Breast microcalcifications and their role in breast cancer bone metastasis

乳腺微钙化及其在乳腺癌骨转移中的作用

• 批准号: 8551656
• 负责人: Claudia Fischbach
• 金额: $ 31.48万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551656
• 关键词: 3-Dimensional; Address; Adsorption; Animals; Biological Models; Bone neoplasms; Bone remodeling; Breast; Breast Cancer Cell; Breast Cancer Prognostic Factor; Breast Microcalcification; Cancer Biology; Cell Culture Techniques; Cells; Cessation of life; Chemicals; Clinical; Coupled; Cultured Cells; Cultured Tumor Cells; D Cells; Data; Development; Disease; Due Process; Endocrine; Endocytosis; Engineering; Fostering; Gene Expression; Growth; Homing; Hydroxyapatites; Implant; In Vitro; Injection of therapeutic agent; Integrins; Intervention; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Metastatic to; Minerals; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Osteolysis; Patients; Pharmaceutical Preparations; Phenotype; Process; Property; Proteins; Proteomics; Research; Research Personnel; Role; Science; Signal Transduction; Site; System; Techniques; Testing; Translations; Up-Regulation; Variant; Woman; base; bone; bone cell; cell behavior; clinically relevant; design; implantation; improved; in vivo; interdisciplinary approach; malignant breast neoplasm; mouse model; nanoparticle; neoplastic cell; novel; outcome forecast; overexpression analysis; prevent; public health relevance; response; tumor

DESCRIPTION (provided by applicant): Breast cancer frequently metastasizes to bone where it leads to osteolysis and poor clinical prognosis; however, the underlying roles of hydroxyapatite (HA) - a key component of breast microcalcifications (i.e., a negative prognostic factor for breast cancer) and the bone mineral matrix - remain unclear in this process, due in part to a lack of appropriate model systems. In the presence of a tumor, the physicochemical properties of HA (e.g., crystallinity, chemical composition, size, and aspect ratio) vary with disease state at both the primary (breast) and secondary (bone) sites. The overall hypothesis guiding the current investigator is: tumor-mediated changes to HA materials properties enhance breast cancer metastasis to bone by inducing a bone-metastatic phenotype at the primary site. These cells, in turn, promote premetastatic bone remodeling, which ultimately fosters bone colonization. We have previously developed mineral-containing 3-D tumor models, which permit testing of the importance of the physicochemical properties of HA in breast cancer spreading to bone. Using this system, coupled with advanced materials characterization techniques, we will test three subhypotheses: 1) HA in microcalcifications associated with more aggressive breast cancer is characterized by increased size and crystallinity and leads to the up-regulation of bone metastatic properties in breast cancer cells due in part to varied non-specific protein adsorption; 2) HA in the bones of tumor-bearing mice is characterized by decreased size and crystallinity even prior to metastatic colonization. These changes favor tumor cell seeding and growth, which are mediated by tumor-secreted endocrine signals that differentially regulate bone cell behavior; 3) Increased bone-metastatic potential of breast cancer cells due to interactions with HA enhances premetastatic bone remodeling, which, in turn, increases the osteotropism of breast cancer cells; pharmacological intervention with this process can decrease bone metastasis. There are three specific aims designed to test these hypotheses: In Aim 1, we will characterize HA materials properties in breast microcalcifications, and assess their impact on the bone-metastatic potential of tumor cells. In Aim 2, we will characterize HA materials properties in the bones of tumor-bearing animals pre- and post-colonization with breast cancer cells, and identify their role in secondary tumor formation. In Aim 3, we will assess the integrated effects of breast microcalcifications and premetastatic bone remodeling on breast cancer bone metastasis. The novel combination of cancer biology with engineering and materials science approaches will result in a highly reproducible and pathologically relevant culture platform that will allow us to deconvolute the complexity of bone metastasis and identify molecular targets for improved therapies. By elucidating the importance of materials-based mechanisms, the proposed research has the potential to challenge the currently accepted paradigm of bone metastasis as a disease that is solely mediated by cellular and molecular changes.

描述（由申请人提供）：乳腺癌经常向骨骼转移，导致骨溶解和临床预后不良；然而，羟基磷灰石（HA）的潜在作用 - 乳腺微钙化的关键组成部分（即，乳腺癌的负预后因素）和骨矿物质基质 - 在此过程中尚不清楚，部分原因是缺乏适当的模型系统。在存在肿瘤的情况下，HA（例如结晶度，化学成分，大小和纵横比）的物理化学特性在原发性（乳房）和次级（骨骼）部位都随疾病状态而变化。当前研究者的总体假设是：HA材料特性的肿瘤介导的变化通过在主要部位诱导骨骼 - 反移表型来增强乳腺癌转移对骨骼。这些细胞反过来促进了转移性骨重塑，最终促进了骨定殖。我们以前已经开发了含有矿物质的3-D肿瘤模型，该模型允许测试HA在扩散到骨骼的乳腺癌中HA物理化学特性的重要性。使用该系统，再加上先进的材料表征技术，我们将测试三个亚类型：1）与更具侵略性乳腺癌相关的微钙化中的HA的特征是大小和结晶度增加，并导致乳腺癌细胞中乳腺癌细胞中骨转移性的上调上调，这是由于多样化的非特异性蛋白质吸收; 2）含肿瘤小鼠的骨骼中的HA的特征是尺寸降低，甚至在转移性定植之前。这些变化有利于肿瘤细胞的播种和生长，这些变化是由差异调节骨细胞行为的肿瘤分泌的内分泌信号介导的。 3）由于与HA相互作用而引起的乳腺癌细胞的骨骼转移潜力增加，增强了转移性骨重塑，这反过来又增加了乳腺癌细胞的骨质性；该过程的药理干预可以减少骨转移。有三个特定的目的旨在检验这些假设：在AIM 1中，我们将表征HA材料在乳腺微钙化中的特性，并评估它们对肿瘤细胞骨骼转移潜力的影响。在AIM 2中，我们将表征乳腺癌细胞前后肿瘤动物骨骼骨骼中HA材料的特性，并确定其在继发性肿瘤形成中的作用。在AIM 3中，我们将评估乳腺微钙化和预内骨重塑对乳腺癌骨转移的综合作用。癌症生物学与工程和材料科学方法的新型组合将导致高度可再现和具有病理相关的培养平台，这将使我们能够解散骨转移的复杂性，并确定改善疗法的分子靶标。通过阐明基于材料机制的重要性，拟议的研究有可能挑战当前接受的骨转移范式作为一种仅由细胞和分子变化介导的疾病。