基质硬度在肿瘤特征中的生物学意义

The biological implications of matrix stiffness in the hallmarks of cancer

肿瘤是全球第二大死亡因素,也是人类关注度最高的疾病之一。在恶性肿瘤的发生、发展过程中,肿瘤细胞通过获得遗传和表观遗传的变异进化出一系列特征,使它们能够生存并适应肿瘤微环境(TME)的应激相关条件。这些特征被认为是“肿瘤的标志”,包括持续的增殖信号、肿瘤转移、血管生成、代谢重编程、抵抗细胞死亡、促肿瘤炎症等。近年来,TME中的力学因素如基质硬度、流体剪切力、门静脉压力等的变化在肿瘤发生发展中的生物学作用越来越受到关注。其中,基质硬度也被称为细胞外基质(ECM)应力,是TME的一个关键物理因素。实体肿瘤中的基质硬度由于胶原蛋白的过度产生、病理性胶原交联和纤维排列而显著增加,而肿瘤细胞能够感知这种异常的ECM应力并通过其力学感受器将力学信号转化为生化信号,加剧疾病症状。然而,基质硬度与肿瘤发生及恶性转化的确切机制尚不完全明确。本文综述了ECM力学信号在调控肿瘤特征方面的研究进展,并讨论了靶向ECM硬度作为治疗肿瘤策略的可能性,为开发基于基质力学的临床肿瘤治疗提供新思路。

Tumor is the second leading cause of death worldwide and is one of the most concemed diseases in humanity.During the occurrence and progression of malignant tumors,tumor cells evolve a series of characteristics by the acquisition of genetic and epigenetie alterations that enable them to survive and adapt to stress-related conditions in the tumor microenvironment(TME).These properties,which are known hallmarks of cancer,include sustained proliferative signaling,tumor metastasis,angiogenesis,metabolic reprogramming,resistance to cell death,and promoting tumor inflammation.Recently,the biological implications of mechanical factors(matrix siffness,fluid shear stress,portal vein pressure,etc.)in TME have atracted increasing attention in tumorigenesis and development.Matrix siffness is a key physical factor of the tumor microenvironment,as known as extracellular matrix(ECM)sress.Studies have demonstrated that matrix sifnes in solid tumors increases signifcantly due to the collagen overproduction,pathological collagen crosslinking and fiber alignment;in tum,tumor cells sense this abnomal ECM stress and convert mechanical signals into biochemical signals through their mechanical receplors,and subsequently exacerbating cancer features.However,the exact mechanism of matrix siffness in tumorigenesis and malignant transformation is not fully understood.This review summarizes the study progress of ECM siffness in regulating tumor characteristics,and discusses the possibility of targeting ECM siffness as a tumor therapeutic strategy,which provides new ideas for the development of matrix mechanic-based clinical tumor therapy.