Tumor microenvironment, tissue liquidity, and cell interaction in prostate cancer

前列腺癌中的肿瘤微环境、组织流动性和细胞相互作用

• 批准号: 7935803
• 负责人: Ramsey A Foty
• 金额: $ 5.45万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935803
• 关键词: Adhesions; Adopted; Affinity; Behavior; Binding; Biochemical; Biological Assay; Biomechanics; Brain Neoplasms; Cancerous; Cell Adhesion Molecules; Cell Communication; Cell surface; Cell-Cell Adhesion; Cells; Cellular Structures; Complex; Cytoskeleton; Data; Databases; Development; Diagnosis; Disease; Embryonic Development; Environment; Epithelial; Equilibrium; Ethanol; Extracellular Matrix; Fibroblasts; Fibronectins; Grant; Health; Human; In Vitro; Invaded; Knowledge; Laboratories; Liquid substance; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Bone; Methods; Mixed Neoplasm; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; National Cancer Institute; Neoplasm Metastasis; Oils; Organ; Outcome; PC3 cell line; Patients; Phase; Phenotype; Play; Process; Property; Prostate; Prostatic Neoplasms; Quality of life; Relative (related person); Reporting; Research; Rheology; Role; Screening procedure; Sorting - Cell Movement; Source; Specific qualifier value; Stromal Cells; Stromal Neoplasm; Surface; System; Testing; Therapeutic Intervention; Tissues; Tumor Cell Invasion; Tumor Tissue; Water; advanced disease; base; bone; cancer cell; cell type; cohesion; driving force; fibrosarcoma; improved; in vivo; interfacial; lymphatic circulation; man; men; mortality; neoplastic cell; prevent; public health relevance; segregation; spatial relationship; tumor

DESCRIPTION (provided by applicant): The National Cancer Institute estimates that 232,000 new cases of prostate cancer will be diagnosed this year. Thirty thousand men will die of the disease and 15 billion dollars will be spent for screening, diagnosis, treatment, and research. Prostate cancer is lethal only when it spreads to other organs. Preventing the spread of prostate cancer would significantly reduce the morbidity and mortality associated with this disease. In order to disseminate to other organs, prostate cancer cells must acquire the ability to detach from the tumor and to attach to components of the tissue that surrounds them. Detachment from the main tumor and attachment to the surrounding tissue involves cell surface adhesion molecules that act to either hold tumor cells together or that facilitate interaction of cells with the extra-cellular matrix (ECM). A balance between these two opposing forces is required to maintain tumors in a non-invasive state. A switch in this balance away from cell-cell cohesion and towards cell-ECM adhesion would promote cancer cell invasion. Maintaining this balance of forces, or reversing it towards cell-cell adhesion could potentially be useful in maintaining tumor integrity and reducing invasive and metastatic potential of prostate cancer. The central theme of this grant is to better understand how these forces influence invasion and to determine whether it will be possible to genetically or pharmacologically alter them in favor of invasion suppression. Forces generated by cell-cell and cell-ECM adhesion, and the molecules which give rise to them, impart to tumors mechanical properties that can be accurately measured. We have previously shown that one such property, tumor cohesivity (TC), is not only strongly correlated with invasiveness of various cancers, but is also a fundamental driving force mediating interactions between tumor cells and the surrounding tissues into which they invade. We have developed methods to accurately measure TC and to discriminate between high and low affinity interactions between tumor and stromal cells. Tissue surface tensiometry (TST) exploits the liquid-like behavior of tumor tissue to measure a key regulator of invasion, namely, tumor cohesivity (TC). We discriminate between low and high affinity interactions using a model based on the observation that when mixed together, cells which do not recognize one another do not remain mixed, but rather, sort-out into two separate phases, whereas cells that have a high affinity for one another tend to remain intermixed. This behavior can be explained using the same physical principles underlying the mixing of liquids. Ethanol and water intermix because they have high affinity for one another, whereas oil and water separate because the affinity of water for itself or oil for itself is greater than that of oil for water. In liquids, affinity is a reflection of the balance between surface and interfacial tension. In cellular systems, these two parameters are a reflection of how strongly cells interact with their own kind, relative to how strongly they interact to other types of cells. This proposal has three objectives. First, we will determine whether TC measurements correlate with invasiveness. Second, we will explore how manipulating particular molecular components leads to associated alterations in TC and invasiveness. Third, we will investigate how TC regulates tumor-stromal interaction. Devising strategies aimed at altering tumor cohesion, maintaining or even restoring compartmentalization between tumor and stromal cells and reducing invasion, are critical to successful treatment of prostate cancer. This proposal aims to elucidate the role of cohesion, not only as a force holding tumor cells together, but also as a regulator of establishing specific spatial relationships between tumor and stromal cells. The information generated will establish a connection between tumor rheology and its molecular underpinnings. Successful completion of these aims will enhance our knowledge of how physical interactions between cancer cells and their surrounding tissue influence invasion. PUBLIC HEALTH RELEVANCE: Prostate cancer is rarely deadly unless it spreads. In man, prostate cancer most often spreads to bone. Bone metastasis can severely influence the quality of life of patients with advanced disease. Preventing spread of the disease can markedly improve outcome. In order to spread, cancer cells must detach from the tumor and must acquire the ability to interact with other cells in order to gain access to the general or lymphatic circulation. They do so as a consequence of complex changes in the expression and function of molecules that regulate forces that not only serve to hold tumor cells together but also allow tumor cells to interact with the environment into which they spread. These forces impart to tumors mechanical properties that can be measured and correlated with invasiveness. This proposal explores how these forces and the molecules giving rise to them contribute to invasiveness.

描述(由申请者提供)：国家癌症研究所估计今年将诊断出23.2万例前列腺癌新病例。3万人将死于这种疾病，150亿美元将用于筛查、诊断、治疗和研究。前列腺癌只有在扩散到其他器官时才是致命的。预防前列腺癌的扩散将大大降低与这种疾病相关的发病率和死亡率。为了扩散到其他器官，前列腺癌细胞必须获得从肿瘤中分离出来并附着在它们周围组织成分上的能力。与主要肿瘤的分离和与周围组织的附着涉及细胞表面的黏附分子，这些黏附分子要么将肿瘤细胞聚集在一起，要么促进细胞与细胞外基质(ECM)的相互作用。维持肿瘤处于非侵袭性状态需要这两种对立力量之间的平衡。这种平衡从细胞-细胞凝聚力转向细胞-细胞外基质粘附会促进癌细胞的侵袭。维持这种力量平衡，或逆转其向细胞-细胞黏附的方向，可能对维持肿瘤的完整性和降低前列腺癌的侵袭和转移潜力有潜在的帮助。这笔赠款的中心主题是更好地了解这些力量是如何影响入侵的，并确定是否有可能从遗传或药物上改变它们，以有利于入侵抑制。细胞-细胞和细胞-细胞外基质黏附产生的力，以及产生它们的分子，赋予肿瘤可以准确测量的机械特性。我们以前已经证明，肿瘤凝聚力(TC)不仅与各种癌症的侵袭性密切相关，而且也是调节肿瘤细胞与其侵袭的周围组织之间相互作用的基本驱动力。我们已经开发出准确测量TC的方法，并区分肿瘤和基质细胞之间的高亲和力和低亲和力相互作用。组织表面张力测量法(TST)利用肿瘤组织的类液体行为来测量肿瘤侵袭的关键调节因素，即肿瘤凝聚力(TC)。我们使用一个模型区分低亲和力和高亲和力的相互作用，该模型基于这样的观察：当混合在一起时，相互不识别的细胞不会保持混合，而是分成两个单独的阶段，而彼此具有高亲和力的细胞往往保持混合。这种行为可以用液体混合背后的相同物理原理来解释。乙醇和水混合是因为它们彼此有很高的亲和力，而油和水分离是因为水本身或油本身的亲和力大于油对水的亲和力。在液体中，亲和力反映了表面张力和界面张力之间的平衡。在细胞系统中，这两个参数反映了细胞与同类细胞相互作用的强弱，以及它们与其他类型细胞相互作用的强弱。这项提议有三个目标。首先，我们将确定TC测量是否与侵袭性相关。其次，我们将探索如何操纵特定的分子成分导致TC和侵袭性的相关变化。第三，我们将研究TC如何调节肿瘤-间质相互作用。制定旨在改变肿瘤凝聚力、维持甚至恢复肿瘤和间质细胞之间的区隔、减少侵袭的策略，对于前列腺癌的成功治疗至关重要。这一提议旨在阐明凝聚力的作用，它不仅是将肿瘤细胞聚集在一起的力量，也是在肿瘤和间质细胞之间建立特定空间关系的调节器。产生的信息将在肿瘤流变学及其分子基础之间建立联系。这些目标的成功实现将增强我们对癌细胞及其周围组织之间的物理相互作用如何影响侵袭的了解。与公共卫生相关：前列腺癌除非扩散，否则很少是致命的。在男性中，前列腺癌最常扩散到骨骼。骨转移严重影响晚期疾病患者的生活质量。预防疾病的传播可以显著改善预后。为了扩散，癌细胞必须从肿瘤中分离出来，并必须获得与其他细胞相互作用的能力，以便进入全身或淋巴循环。他们这样做是因为分子的表达和功能发生了复杂的变化，这些分子调节的力量不仅有助于将肿瘤细胞聚集在一起，而且还允许肿瘤细胞与它们扩散到的环境相互作用。这些力赋予肿瘤可以测量的机械特性，并与侵袭性相关。这项提议探索了这些力和产生它们的分子如何促成入侵。