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The Matrix Environmental and Cell Mechanical Properties regulate Cell Migration and contribute to the Invasive Phenotype of Cancer Cells
Reports on Progress in Physics ( IF 18.1 ) Pub Date : 2019-05-21 , DOI: 10.1088/1361-6633/ab1628
Claudia Tanja Mierke

The minimal structural unit of a solid tumor is a single cell or a cellular compartment such as the nucleus. A closer look inside the cells reveals that there are functional compartments or even structural domains determining the overall properties of a cell such as the mechanical phenotype. The mechanical interaction of these living cells leads to the complex organization such as compartments, tissues and organs of organisms including mammals. In contrast to passive non-living materials, living cells actively respond to the mechanical perturbations occurring in their microenvironment during diseases such as fibrosis and cancer. The transformation of single cancer cells in highly aggressive and hence malignant cancer cells during malignant cancer progression encompasses the basement membrane crossing, the invasion of connective tissue, the stroma microenvironments and transbarrier migration, which all require the immediate interaction of the aggressive and invasive cancer cells with the surrounding extracellular matrix environment including normal embedded neighboring cells. All these steps of the metastatic pathway seem to involve mechanical interactions between cancer cells and their microenvironment. The pathology of cancer due to a broad heterogeneity of cancer types is still not fully understood. Hence it is necessary to reveal the signaling pathways such as mechanotransduction pathways that seem to be commonly involved in the development and establishment of the metastatic and mechanical phenotype in several carcinoma cells. We still do not know whether there exist distinct metastatic genes regulating the progression of tumors. These metastatic genes may then be activated either during the progression of cancer by themselves on their migration path or in earlier stages of oncogenesis through activated oncogenes or inactivated tumor suppressor genes, both of which promote the metastatic phenotype. In more detail, the adhesion of cancer cells to their surrounding stroma induces the generation of intracellular contraction forces that deform their microenvironments by alignment of fibers. The amplitude of these forces can adapt to the mechanical properties of the microenvironment. Moreover, the adhesion strength of cancer cells seems to determine whether a cancer cell is able to migrate through connective tissue or across barriers such as the basement membrane or endothelial cell linings of blood or lymph vessels in order to metastasize. In turn, exposure of adherent cancer cells to physical forces, such as shear flow in vessels or compression forces around tumors, reinforces cell adhesion, regulates cell contractility and restructures the ordering of the local stroma matrix that leads subsequently to secretion of crosslinking proteins or matrix degrading enzymes. Hence invasive cancer cells alter the mechanical properties of their microenvironment. From a mechanobiological point-of-view, the recognized physical signals are transduced into biochemical signaling events that guide cellular responses such as cancer progression after the malignant transition of cancer cells from an epithelial and non-motile phenotype to a mesenchymal and motile (invasive) phenotype providing cellular motility. This transition can also be described as the physical attempt to relate this cancer cell transitional behavior to a T1 phase transition such as the jamming to unjamming transition. During the invasion of cancer cells, cell adaptation occurs to mechanical alterations of the local stroma, such as enhanced stroma upon fibrosis, and therefore we need to uncover underlying mechano-coupling and mechano-regulating functional processes that reinforce the invasion of cancer cells. Moreover, these mechanisms may also be responsible for the awakening of dormant residual cancer cells within the microenvironment. Physicists were initially tempted to consider the steps of the cancer metastasis cascade as single events caused by a single mechanical alteration of the overall properties of the cancer cell. However, this general and simple view has been challenged by the finding that several mechanical properties of cancer cells and their microenvironment influence each other and continuously contribute to tumor growth and cancer progression. In addition, basement membrane crossing, cell invasion and transbarrier migration during cancer progression is explained in physical terms by applying physical principles on living cells regardless of their complexity and individual differences of cancer types. As a novel approach, the impact of the individual microenvironment surrounding cancer cells is also included. Moreover, new theories and models are still needed to understand why certain cancers are malignant and aggressive, while others stay still benign. However, due to the broad variety of cancer types, there may be various pathways solely suitable for specific cancer types and distinct steps in the process of cancer progression. In this review, physical concepts and hypotheses of cancer initiation and progression including cancer cell basement membrane crossing, invasion and transbarrier migration are presented and discussed from a biophysical point-of-view. In addition, the crosstalk between cancer cells and a chronically altered microenvironment, such as fibrosis, is discussed including the basic physical concepts of fibrosis and the cellular responses to mechanical stress caused by the mechanically altered microenvironment. Here, is highlighted how biophysical approaches, both experimentally and theoretically, have an impact on classical hallmarks of cancer and fibrosis and how they contribute to the understanding of the regulation of cancer and its progression by sensing and responding to the physical environmental properties through mechanotransduction processes. Finally, this review discusses various physical models of cell migration such as blebbing, nuclear piston, protrusive force and unjamming transition migration modes and how they contribute to cancer progression. Moreover, these cellular migration modes are influenced by microenvironmental perturbances such as fibrosis that can induce mechanical alterations in cancer cells, which in turn may impact the environment. Hence, the classical hallmarks of cancer need to be refined by including biomechanical properties of cells, cell clusters and tissues and their microenvironment to understand mechano-regulatory processes within cancer cells and the entire organism.

中文翻译:

基质环境和细胞机械特性调节细胞迁移并促成癌细胞的侵袭性表型

实体瘤的最小结构单位是单个细胞或细胞区室,例如细胞核。仔细观察细胞内部会发现有功能区室甚至结构域决定了细胞的整体特性,例如机械表型。这些活细胞的机械相互作用导致复杂的组织,例如包括哺乳动物在内的生物体的隔室、组织和器官。与被动的非生命材料相反,活细胞对纤维化和癌症等疾病期间发生在其微环境中的机械扰动做出积极反应。在恶性癌症进展过程中,单个癌细胞在高度侵袭性的恶性癌细胞中的转化包括基底膜穿越、结缔组织的侵袭、基质微环境和跨屏障迁移,所有这些都需要侵袭性和侵袭性癌细胞与周围细胞外基质环境(包括正常嵌入的相邻细胞)的直接相互作用。转移途径的所有这些步骤似乎都涉及癌细胞与其微环境之间的机械相互作用。由于癌症类型的广泛异质性,癌症的病理学仍未完全了解。因此,有必要揭示信号通路,例如机械转导通路,这些通路似乎通常参与几种癌细胞中转移和机械表​​型的发展和建立。我们仍然不知道是否存在调节肿瘤进展的不同转移基因。然后,这些转移性基因可能会在癌症进展过程中通过它们自身的迁移路径被激活,或者在肿瘤发生的早期阶段通过激活的致癌基因或失活的肿瘤抑制基因被激活,这两种基因都会促进转移表型。更详细地说,癌细胞与其周围基质的粘附诱导了细胞内收缩力的产生,通过排列纤维使它们的微环境变形。这些力的幅度可以适应微环境的机械特性。此外,癌细胞的粘附强度似乎决定了癌细胞是否能够迁移通过结缔组织或跨越屏障,例如基底膜或血管或淋巴管的内皮细胞衬里以进行转移。反过来,粘附的癌细胞暴露于物理力,例如血管中的剪切流或肿瘤周围的压力,增强细胞粘附,调节细胞收缩性并重组局部基质基质的顺序,随后导致交联蛋白或基质降解酶的分泌。因此,侵袭性癌细胞会改变其微环境的机械特性。从机械生物学的角度来看,识别的物理信号被转导为生化信号事件,在癌细胞从上皮和非运动表型恶性转变为间充质和运动(侵袭性)后,指导细胞反应,例如癌症进展提供细胞运动性的表型。这种转变也可以描述为将这种癌细胞转变行为与 T1 相变(例如干扰到解除干扰的转变)联系起来的物理尝试。在癌细胞侵袭过程中,局部基质的机械改变发生细胞适应,例如纤维化后基质增强,因此我们需要揭示潜在的机械耦合和机械调节功能过程,这些过程会加强癌细胞的侵袭。此外,这些机制也可能是微环境中休眠残留癌细胞苏醒的原因。物理学家最初倾向于将癌症转移级联的步骤视为由癌细胞整体特性的单一机械改变引起的单一事件。然而,这一普遍而简单的观点受到以下发现的挑战:癌细胞的几种机械特性及其微环境相互影响并持续促进肿瘤生长和癌症进展。此外,通过将物理原理应用于活细胞,无论其复杂性和癌症类型的个体差异如何,在癌症进展过程中的基底膜穿越、细胞侵袭和跨屏障迁移都得到了物理解释。作为一种新方法,还包括癌细胞周围个体微环境的影响。此外,仍然需要新的理论和模型来理解为什么某些癌症是恶性和侵袭性的,而其他癌症仍然是良性的。然而,由于癌症种类繁多,可能存在多种仅适用于特定癌症类型和癌症进展过程中不同步骤的途径。在这篇综述中,从生物物理学的角度提出和讨论了癌症发生和进展的物理概念和假设,包括癌细胞基底膜穿越、侵袭和跨屏障迁移。此外,还讨论了癌细胞与慢性改变的微环境(如纤维化)之间的串扰,包括纤维化的基本物理概念和细胞对机械改变的微环境引起的机械应力的反应。在这里,强调了生物物理方法如何在实验和理论上,对癌症和纤维化的经典标志产生影响,以及它们如何通过机械转导过程感知和响应物理环境特性,从而有助于理解癌症的调节及其进展。最后,这篇综述讨论了细胞迁移的各种物理模型,例如起泡、核活塞、突出力和畅通无阻的过渡迁移模式,以及它们如何促进癌症进展。此外,这些细胞迁移模式受微环境干扰的影响,如纤维化,可诱导癌细胞发生机械改变,进而可能影响环境。因此,需要通过包括细胞的生物力学特性来完善癌症的经典标志,
更新日期:2019-05-21
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