The matrix environmental and cell mechanical properties regulate cell migration and contribute to the invasive phenotype of cancer cells.

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.