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

描述（由申请人提供）：美国国家癌症研究所估计，今年将诊断出 232,000 例新的前列腺癌病例。 三万人将死于这种疾病，并且将花费 150 亿美元用于筛查、诊断、治疗和研究。 前列腺癌只有在扩散到其他器官时才致命。 预防前列腺癌的扩散将显着降低与该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分离并附着到周围组织成分的能力。 与主肿瘤的分离和与周围组织的附着涉及细胞表面粘附分子，这些分子的作用是将肿瘤细胞固定在一起或促进细胞与细胞外基质（ECM）的相互作用。 需要这两种相反力量之间的平衡来维持肿瘤处于非侵袭状态。 这种平衡从细胞-细胞内聚转向细胞-ECM 粘附将促进癌细胞侵袭。 维持这种力量平衡，或将其逆转为细胞间粘附，可能有助于维持肿瘤完整性并减少前列腺癌的侵袭和转移潜力。 这笔赠款的中心主题是更好地了解这些力量如何影响入侵，并确定是否有可能通过基因或药理学改变它们以有利于入侵抑制。 细胞与细胞和细胞与 ECM 粘附产生的力以及产生这些力的分子赋予肿瘤机械特性，可以精确测量。 我们之前已经证明，肿瘤粘附性（TC）这一特性不仅与各种癌症的侵袭性密切相关，而且还是介导肿瘤细胞与其所侵袭的周围组织之间相互作用的基本驱动力。 我们开发了准确测量 TC 并区分肿瘤和基质细胞之间高亲和力和低亲和力相互作用的方法。 组织表面张力测定法（TST）利用肿瘤组织的液体状行为来测量侵袭的关键调节因子，即肿瘤粘聚性（TC）。 我们使用一种模型来区分低亲和力和高亲和力相互作用，该模型基于以下观察：当混合在一起时，彼此不识别的细胞不会保持混合状态，而是分为两个单独的阶段，而彼此具有高亲和力的细胞往往保持混合状态。 这种行为可以使用液体混合的相同物理原理来解释。 乙醇和水混合，因为它们彼此之间具有高亲和力，而油和水分离，因为水对其自身或油对其自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其同类细胞相互作用的强度，相对于它们与其他类型细胞相互作用的强度。 该提案有三个目标。 首先，我们将确定 TC 测量值是否与侵袭性相关。 其次，我们将探讨如何操纵特定的分子成分导致 TC 和侵袭性的相关改变。 第三，我们将研究TC如何调节肿瘤-基质相互作用。 制定旨在改变肿瘤内聚力、维持甚至恢复肿瘤和基质细胞之间的区室化以及减少侵袭的策略，对于成功治疗前列腺癌至关重要。 该提案旨在阐明内聚力的作用，不仅作为将肿瘤细胞聚集在一起的力量，而且作为建立肿瘤和基质细胞之间特定空间关系的调节器。 生成的信息将在肿瘤流变学与其分子基础之间建立联系。 成功完成这些目标将增强我们对癌细胞与其周围组织之间的物理相互作用如何影响侵袭的了解。 公共卫生相关性：前列腺癌除非扩散，否则很少致命。 在人类中，前列腺癌最常扩散至骨骼。 骨转移会严重影响晚期疾病患者的生活质量。 防止疾病传播可以显着改善结果。 为了扩散，癌细胞必须与肿瘤分离，并且必须获得与其他细胞相互作用的能力，以便进入全身循环或淋巴循环。 它们这样做是分子表达和功能发生复杂变化的结果，这些分子调节力不仅可以将肿瘤细胞保持在一起，还可以使肿瘤细胞与其扩散的环境相互作用。 这些力赋予肿瘤机械特性，可以测量这些机械特性并将其与侵袭性相关联。 该提案探讨了这些力和产生它们的分子如何导致侵袭性。

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.