文章：

肿瘤学工程与物理科学：挑战与机遇

Engineering and physical sciences in oncology: challenges and opportunities

原文发布日期：2017-10-13

DOI: 10.1038/nrc.2017.83

类型: Review Article

开放获取: 否

要点：

1. Engineers and physical scientists have pioneered research into understanding cancer as more than simply malignant cells with genetic mutations and instead as aberrant organs composed of cancer cells and their surrounding stroma, referred to as the tumour microenvironment (TME). Many aspects of the microenvironment are abnormal, which fuels tumour progression and treatment resistance.
2. Recent work using advanced in vivo imaging, computational modelling and animal models has identified barriers in the TME that hinder therapy and promote tumour progression.
3. Under pathological conditions, remodelling of the extracellular matrix (ECM) leads to fibre alignment, bundling and stiffening, which in turn alters tumour and stromal cell–matrix mechanics and interactions to enhance pro-angiogenic secretion from a range of cells in the TME as well as the migration of cancer cells. This promotes the invasion of tumour cells from the primary site into the circulation and the recruitment of endothelial cells for vascularization of the tumour to initiate tumour growth, invasion into the surrounding stroma and, finally, metastasis.
4. Tumour cells with a larger glycocalyx than normal cells exhibit extended gaps between the membrane and ECM, clustering of integrins, the exclusion of glycopolymers from regions of integrin adhesion and membrane bending. Engineered glycoprotein mimetics have been used to study how the physical properties of the glycocalyx coating alter cellular signalling and promote tumour survival and metastasis.
5. Drug delivery scientists pioneered the development of engineering systems that deliver therapeutics in a safe, effective and targeted fashion. Recent advances have focused on new delivery systems for cancer immunotherapy and gene therapy, as well as implantable devices for developing personalized medicine regimens.
6. Engineers and physical scientists have advanced imaging in oncology through the development of macroscopic imaging techniques in clinical settings, in addition to intravital optical techniques used in research settings that are increasingly used to detect various biomarkers. Clinical imaging probes developed by engineers and material scientists, such as fluorescent proteins, nanomaterials and labelled small and large molecules, have complemented these modalities.
7. Advances in microfluidics and microfabrication have led to the development of tissue and organ models that can incorporate physiological fluid flow and real-time optical imaging to study tumour cell migration and mechanotransduction. Microfluidics are also used to create human 'organs-on-chip' models for high-throughput drug screening, as well as isolation of rare circulating tumour cells and exosomes from patient blood samples.

要点翻译：

1. 工程师和物理科学家开创性地将癌症研究推向新高度：不再仅将其视为携带基因突变的恶性细胞，而是由癌细胞及其周围基质组成的异常器官——即肿瘤微环境。该环境的诸多异常特征会加速肿瘤进展并诱发治疗抵抗。
2. 近期研究利用先进活体成像、计算模型及动物模型，揭示了肿瘤微环境中阻碍疗法并促进肿瘤进展的屏障机制。
3. 在病理条件下，细胞外基质重塑会导致纤维排列有序化、成束化及硬化，进而改变肿瘤与基质细胞的力学特性及相互作用，增强肿瘤微环境中多种细胞的促血管生成分泌功能，并加速癌细胞迁移。这一过程促使肿瘤细胞从原发部位侵入循环系统，同时招募内皮细胞完成肿瘤血管化，从而启动肿瘤生长、间质浸润及最终转移。
4. 与正常细胞相比，具有更厚糖萼的肿瘤细胞表现出膜与细胞外基质间隙增宽、整合素成簇分布、糖聚合物被排斥于整合素粘附区域之外以及细胞膜弯曲等特征。通过工程化糖蛋白模拟物，研究人员得以探究糖萼涂层的物理特性如何改变细胞信号传导并促进肿瘤存活与转移。
5. 药物递送科学家开创了以安全高效靶向方式递送疗法的工程系统。近期进展聚焦于癌症免疫治疗与基因治疗的新型递送系统，以及用于制定个性化医疗方案的植入式设备。
6. 工程师与物理科学家通过开发临床宏观成像技术及科研用活体光学技术，推动了肿瘤影像学发展，这些技术正日益广泛应用于多种生物标志物检测。由工程师与材料科学家研发的临床影像探针（如荧光蛋白、纳米材料及标记大小分子）进一步丰富了这些成像模式。
7. 微流控与微加工技术的进步催生了能模拟生理流体流动并实现实时光学成像的组织器官模型，用于研究肿瘤细胞迁移与力学信号转导。微流控技术还用于构建人体"芯片器官"模型，实现高通量药物筛选，并能从患者血液样本中分离稀有循环肿瘤细胞及外泌体。

英文摘要：

The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.

摘要翻译： 

工程学和物理学的原理已被应用于肿瘤学近50年。工程师和物理科学家在癌症生物学的各个方面都做出了贡献，从对肿瘤生长和进展的定量理解，到改进癌症检测与治疗。早期许多工作集中在药物分布、细胞周期动力学和肿瘤生长动力学的实验与计算建模上。在过去十年中，我们见证了工程学、物理学与肿瘤学交叉领域的指数级增长，这一增长受到材料科学、微加工、纳米医学、微流控、成像等领域进步的推动，并受到美国国立卫生研究院（NIH）新项目的催化，包括国家生物医学影像与生物工程研究所（NIBIB）、肿瘤物理科学项目，以及国家癌症研究所（NCI）纳米技术联盟。在此，我们回顾了工程与物理科学与肿瘤学交叉领域在四个重要方面取得的进展：肿瘤的物理微环境与药物递送的技术进步；细胞与分子成像；以及微流控与微加工技术。我们讨论了研究进展、机遇与挑战，以促进工程与物理科学与肿瘤学的融合，开发研究、检测和治疗癌症的新方法，并描述了这些新兴领域的未来前景。

原文链接：

Engineering and physical sciences in oncology: challenges and opportunities