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会致命。预防前列腺癌的扩散将显著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脱离肿瘤并附着在周围组织上的能力。从主要肿瘤脱离并附着到周围组织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。这两种相反的力量之间的平衡是维持肿瘤处于非侵入状态所必需的。这种平衡从细胞-细胞内聚转向细胞- ecm粘附的转变将促进癌细胞的侵袭。维持这种力量的平衡，或将其逆转为细胞-细胞粘附，可能有助于维持肿瘤的完整性，减少前列腺癌的侵袭和转移潜力。这项资助的中心主题是更好地了解这些力量是如何影响入侵的，并确定是否有可能通过基因或药理学改变它们以抑制入侵。细胞-细胞和细胞- ecm粘附产生的力，以及产生这些力的分子，赋予肿瘤可以精确测量的机械特性。我们之前已经证明，肿瘤内聚性（TC）这一特性不仅与各种癌症的侵袭性密切相关，而且还是肿瘤细胞与其入侵的周围组织之间相互作用的基本驱动力。我们已经开发了精确测量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（TST）利用肿瘤组织的液体样行为来测量侵袭的关键调节因子，即肿瘤内聚性（TC）。我们使用基于观察的模型来区分低亲和性相互作用和高亲和性相互作用，当混合在一起时，不能识别彼此的细胞不会保持混合，而是分成两个独立的阶段，而彼此具有高亲和性的细胞往往保持混合。这种行为可以用与液体混合相同的物理原理来解释。乙醇和水混合是因为它们彼此有很高的亲和力，而油和水分开是因为水对自身或油对自身的亲和力大于油对水的亲和力。在液体中，亲合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。这项提议有三个目标。首先，我们将确定TC测量是否与侵入性相关。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、维持甚至恢复肿瘤与间质细胞之间的区隔化以及减少侵袭的策略，是成功治疗前列腺癌的关键。本研究旨在阐明内聚的作用，它不仅是一种将肿瘤细胞聚集在一起的力量，而且是肿瘤和基质细胞之间建立特定空间关系的调节剂。所产生的信息将建立肿瘤流变学及其分子基础之间的联系。这些目标的成功完成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认识。公共卫生相关性：除非前列腺癌扩散，否则很少致命。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。预防疾病传播可显著改善预后。为了扩散，癌细胞必须从肿瘤中分离出来，并且必须获得与其他细胞相互作用的能力，以便进入一般循环或淋巴循环。它们这样做是由于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的环境相互作用。这些力赋予肿瘤可测量的机械特性，并与侵袭性相关。这一提议探讨了这些力和产生这些力的分子是如何促进侵入性的。

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.