Breast microcalcifications and their role in breast cancer bone metastasis

描述(申请人提供)：乳腺癌经常转移到骨转移，导致骨溶解和不良的临床预后；然而，羟基磷灰石(HA)-乳腺微钙化的关键成分(即乳腺癌的负面预后因素)和骨矿物基质-在这一过程中的潜在作用仍不清楚，部分原因是缺乏适当的模型系统。在肿瘤存在的情况下，HA的物理化学性质(如结晶度、化学成分、大小和纵横比)在原发部位(乳房)和继发部位(骨)都会随着疾病状态的不同而变化。目前指导研究者的总体假设是：肿瘤介导的HA材料特性的变化通过诱导原发部位的骨转移表型来促进乳腺癌向骨的转移。这些细胞反过来促进转移前的骨重建，最终促进骨定植。我们以前已经开发了含有矿物质的三维肿瘤模型，它允许测试HA的物理化学性质在乳腺癌扩散到骨中的重要性。利用这个系统，结合先进的材料表征技术，我们将检验三个假设：1)与更具侵袭性的乳腺癌相关的微钙化中的HA的特征是尺寸和结晶度增加，并导致乳腺癌细胞骨转移特性的上调，部分原因是不同的非特异性蛋白质吸附； 2)荷瘤小鼠骨骼中的HA甚至在转移定植之前就表现为大小和结晶度降低。这些变化有利于肿瘤细胞的种植和生长，肿瘤分泌的内分泌信号调节骨细胞的行为；3)由于与HA的相互作用，增加了乳腺癌细胞的骨转移潜能，促进了转移前的骨重建，进而增加了乳腺癌细胞的趋骨性；通过这一过程的药物干预可以减少骨转移。有三个特定的目标来检验这些假设：在目标1中，我们将表征乳腺微钙化中HA材料的特性，并评估它们对肿瘤细胞骨转移潜能的影响。在目标2中，我们将表征乳腺癌细胞定植前后荷瘤动物骨骼中HA材料的特性，并确定它们在继发性肿瘤形成中的作用。在目标3中，我们将评估乳腺微钙化和转移前骨重建在乳腺癌骨转移中的综合作用。癌症生物学与工程和材料科学方法的新结合将产生一个高度可重复性和与病理相关的培养平台，使我们能够解开骨转移的复杂性，并为改进的治疗确定分子靶点。通过阐明基于材料的机制的重要性，拟议的研究有可能挑战目前公认的骨转移的范式，即骨转移是一种仅由细胞和分子变化介导的疾病。

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.