Biophysical roles of pre-metastatic niche evolution on transport of circulating tumor cells

转移性疾病对目前的治疗方法具有抵抗力，仍然是癌症相关死亡的主要原因。 探索促进循环肿瘤细胞(CTCs)在未来血管壁上滞留的最早事件 转移部位将暴露出理性预防的新靶点。除了生物因素，物理上的 CTCs的运输和与微环境的相互作用被认为是转移的关键决定因素 潜力。最近的研究表明，遥远的微环境已经准备好并准备好捕获四氯化碳，从而产生 转移前的利基位置，用于启动转移。我们的初步数据显示了时间和器官依赖性 原发性高血压小鼠肺、肝血管内血小板(PLT)积聚和活化增加 乳腺癌，在自发转移到这些器官之前。我们还发现血流速度是 在发生转移之前，肝脏毛细血管异质性减少，表明血流改变。 未来转移部位的血管动力学可能参与了肿瘤转移的启动过程。 虽然PLT对癌细胞的直接生物学效应是众所周知的，但PLT在肿瘤发生发展中的作用 转移前的生态位和这些PLT对CTCs生物物理转运机制的影响还没有 已经上报了。我们的目标是确定转移前细胞对CTC转运的生物物理调节。 由PLT使用正交异性小鼠肿瘤模型、新型微流体和多尺度/多物理启动的生态位 计算运输模型。我们的假设是：1)存在器官依赖和时间依赖 转移前生态位的发展/进化改变了CTC的流体动力学；2)只有转移前的 生态位足够发达，可以改变这些生物物理参数，促进船只上四氯化碳的滞留 3)抗PLT试剂对PLT功能的调节影响PLT在前壁的生物物理作用。 转移的生态位对CTC转运和转移的展望。多尺度/多物理传输 该方法将基于体内和体外的实验结果优化癌症转移的参数设置， 为了刻画CTCs与转移前生态位相互作用的生物物理转运机制。 这项研究的意义将为理解转移前生态位的作用建立一个科学框架 在物理肿瘤学中，PLT开创了合理预防转移的进化。我们的创新 建议阐明转移前生态位在CTCs运输中未知的生物物理作用，并使用 包含多尺度和多物理能力的计算性非物理传输模型。测试我们的 假设，我们提出以下特定目标(SA)：SA1：为了理解 血管作为转移前生态位发育/进化的函数。SA2：评估生物物理 转移前壁龛中积聚和激活的PLT对CTC在血管中转运的影响。SA3：TO 使用抗PLT试剂确定PLT功能的生物物理调节对CTCs转运的影响。

Metastatic disease is resistant to current therapies and remains the primary cause of cancer-related death. Exploring the earliest events that promote circulating tumor cells (CTCs) to arrest on vessel wall at future metastatic sites will expose new targets for rational prevention. In addition to biological factors, the physical transport of CTCs and interactions with the microenvironment are regarded as key determinants of the metastatic potential. Recent studies suggest that distant microenvironments are primed and ready to entrap CTCs, creating a pre-metastatic niche for initiating metastasis. Our preliminary data shows a time- and organ-dependent increase in platelet (PLT) accumulation and activation in vessels of both lung and liver in mice bearing primary breast cancer, prior to spontaneous metastasis to these organs. We also found blood flow velocity was heterogeneously reduced in capillaries of the liver before development of metastasis, indicating changes in flow dynamics in vessels of the future metastatic sites may be involved in the process of initiating metastasis. Whereas direct biological effects of PLT on cancer cells are well known, the roles of PLT in the development of the pre-metastatic niche and the effects of these PLTs on biophysical transport mechanisms of CTCs have not been reported. Our objective is to determine biophysical modulation of CTC transport by the pre-metastatic niche initiated by PLTs using orthotropic mouse tumor models, novel microfluidics, and multiscale/multi-physics computational transport models. Our hypotheses are: 1) there is an organ- and time-dependent development/evolution of the pre-metastatic niche alters hydrodynamics for CTCs; 2) only the pre-metastatic niche, which is sufficiently developed to alter these biophysical parameters, promotes arrest of CTCs on vessel walls; and 3) modulation of PLT functionality by anti-PLT reagents affects biophysical roles of PLTs in the pre- metastatic niche on CTC transport and the prospect of metastasis. The multiscale/multi-physics transport approach will optimize parameterization of cancer metastasis based on experimental results in vivo and in vitro, in order to characterize biophysical transport mechanisms of CTCs interacting with pre-metastatic niche. Significance of this study will establish a scientific framework for understanding roles of the pre-metastatic niche evolution initiated with PLTs in physical oncology for rational prevention of metastasis. Innovation of our proposal is to elucidate unknown biophysical roles of the pre-metastatic niche on CTCs transport and to employ computational oncophysical transport model incorporating multi-scale and multi-physics capabilities. To test our hypothesis, we propose the following Specific Aims (SA): SA1: To understand the flow fundamentals in vessels as a function of development/evolution of the pre-metastatic niche. SA2: To evaluate the biophysical effect of accumulated and activated PLTs in the pre-metastatic niche on CTC transport in vessels. SA3: To determine the effect of biophysical modulation of PLT functions on CTCs transport using anti-PLT reagents.