Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nat Rev Cancer. 2024 Nov;24(11):768-791. doi: 10.1038/s41568-024-00745-z. Epub 2024 Oct 10.
Beyond their many well-established biological aberrations, solid tumours create an abnormal physical microenvironment that fuels cancer progression and confers treatment resistance. Mechanical forces impact tumours across a range of biological sizes and timescales, from rapid events at the molecular level involved in their sensing and transmission, to slower and larger-scale events, including clonal selection, epigenetic changes, cell invasion, metastasis and immune response. Owing to challenges with studying these dynamic stimuli in biological systems, the mechanistic understanding of the effects and pathways triggered by abnormally elevated mechanical forces remains elusive, despite clear correlations with cancer pathophysiology, aggressiveness and therapeutic resistance. In this Review, we examine the emerging and diverse roles of physical forces in solid tumours and provide a comprehensive framework for understanding solid stress mechanobiology. We first review the physiological importance of mechanical forces, especially compressive stresses, and discuss their defining characteristics, biological context and relative magnitudes. We then explain how abnormal compressive stresses emerge in tumours and describe the experimental challenges in investigating these mechanically induced processes. Finally, we discuss the clinical translation of mechanotherapeutics that alleviate solid stresses and their potential to synergize with chemotherapy, radiotherapy and immunotherapies.
除了它们许多已被充分证实的生物学异常之外，实体瘤还会产生异常的物理微环境，促进癌症进展并赋予治疗抵抗性。机械力在多种生物尺度和时间尺度上影响肿瘤，从涉及感知和传递的快速分子水平事件，到更缓慢和更大规模的事件，包括克隆选择、表观遗传改变、细胞浸润、转移和免疫反应。由于在生物系统中研究这些动态刺激存在挑战，尽管与癌症病理生理学、侵袭性和治疗抵抗性有明确的相关性，但异常升高的机械力所触发的作用和途径的机械机制理解仍然难以捉摸。在这篇综述中，我们研究了物理力在实体瘤中的新兴和多样化作用，并提供了一个全面的框架来理解固体压力的机械生物学。我们首先回顾了机械力（尤其是压缩应力）的生理重要性，并讨论了它们的定义特征、生物学背景和相对大小。然后，我们解释了异常压缩应力如何在肿瘤中出现，并描述了研究这些机械诱导过程的实验挑战。最后，我们讨论了缓解固体压力的机械治疗学的临床转化及其与化疗、放疗和免疫疗法协同的潜力。
