癌症中的压缩应力：特征及其对肿瘤进展和治疗的影响
Compressive stresses in cancer: characterization and implications for tumour progression and treatment
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影响因子:66.8
分区:医学1区 Top / 肿瘤学1区
发表日期:2024 Nov
作者:
Julia A Linke, Lance L Munn, Rakesh K Jain
DOI:
10.1038/s41568-024-00745-z
摘要
除了众所周知的生物异常之外，实体瘤还会形成异常的物理微环境，促进癌症进展并赋予抗治疗性。机械力影响肿瘤的不同生物尺寸和时间尺度，从分子水平的快速感知与传递事件，到较慢和更大尺度的事件，包括克隆选择、表观遗传变化、细胞侵袭、转移和免疫反应。由于在生物系统中研究这些动态刺激的挑战，关于异常增强机械力引发的效应和途径的机械机制理解仍然有限，尽管它们与癌症的病理生理、侵袭性及治疗抗性有明显相关性。在本综述中，我们探讨了物理力在实体瘤中的新兴多样化角色，提供了理解实体应力机械生物学的全面框架。首先回顾机械力的生理重要性，特别是压缩应力，讨论其定义特征、生物背景及相对大小。然后说明肿瘤中异常压缩应力的产生机制，并描述研究这些机械诱导过程的实验挑战。最后，讨论缓解实体应力的机械治疗方法的临床转化及其与化疗、放疗和免疫治疗的潜在协同作用。
Abstract
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.