Mechanics, malignancy, and metastasis: the force journey of a tumor cell

Abstract

A cell undergoes many genetic and epigenetic changes as it transitions to malignancy. Malignant transformation is also accompanied by a progressive loss of tissue homeostasis and perturbations in tissue architecture that ultimately culminates in tumor cell invasion into the parenchyma and metastasis to distant organ sites. Increasingly, cancer biologists have begun to recognize that a critical component of this transformation journey involves marked alterations in the mechanical phenotype of the cell and its surrounding microenvironment. These mechanical differences include modifications in cell and tissue structure, adaptive force-induced changes in the environment, altered processing of micromechanical cues encoded in the extracellular matrix (ECM), and cell-directed remodeling of the extracellular stroma. Here, we review critical steps in this "force journey," including mechanical contributions to tissue dysplasia, invasion of the ECM, and metastasis. We discuss the biophysical basis of this force journey and present recent advances in the measurement of cellular mechanical properties in vitro and in vivo. We end by describing examples of molecular mechanisms through which tumor cells sense, process and respond to mechanical forces in their environment. While our understanding of the mechanical components of tumor growth, survival and motility remains in its infancy, considerable work has already yielded valuable insight into the molecular basis of force-dependent tumor pathophysiology, which offers new directions in cancer chemotherapeutics.

Fig. 1

The force journey of a tumor cell. Starting from their participation in normal tissue homeostasis and continuing through all stages of tissue dysplasia, tumor cell invasion, and metasasis, tumor cells both absorb and exert mechanical force. This interplay establishes a dynamic, mechanical reciprocity between tumor cells and their environment (represented schematically as arrows). a Even in normal tissues, such as the epithelium depicted here, cells experience mechanical force from their neighbors and the extracellular matrix, which are often channeled through specific receptor-ligand interactions to trigger signaling events. Cells may also be subject to nonspecific forces applied to the whole tissue, such as interstitial pressure and shear flow. b As a tumor cell detaches from the primary tumor mass and invades the surrounding parenchyma, it continues to exchange mechanical force with its environment, including tractional forces associated with locomotion and protrusive forces of the leading edge of the cell. In some cases, protrusive structures are also used to spatially focus secretion of matrix metalloproteases, e.g., invadopodia. c If a tumor cell escapes its primary tissue and reaches the vasculature, it must withstand shear forces associated with blood flow. Shear has been demonstrated to activate gene programs associated with cytoskeletal remodeling and altered cell-cell adhesion. d In order for a tumor cell to escape the vasculature and metastasize to a distal tissue, it must undergo diapedesis through the endothelial wall, which introduces additional mechanical interactions between the tumor cell and endothelial cells and precedes a transition from cell-cell adhesion to cell-ECM adhesion

Fig. 2

Effect of extracellular matrix stiffness on mammary epithelial morphogenesis. Phase and immunofluorescence images of mammary epithelial cells (MECs) cultured on ECM substrates of Young’s moduli of 150 Pa (left column), 1050 Pa (middle column) and >5000 Pa (right column). Cells cultured on substrates with elasticities of 150 Pa, which is similar to the elasticity of normal mammary tissue, form patent acinar structures with clearly defined cell-cell junctions and integrin distributons. A modest increase in ECM elasticity to 1050 Pa leads to loss of luminal patency, disruption of cell-cell contacts, and altered acinar morphology. For ECM elasticities greater than 5000 Pa, acinar organization, cell-cell junctions, and cellular ECM deposition are all completely disrupted. Figure reproduced with permission from [149]

Fig. 3

Methods for characterizing the mechanical phenotype. (a–c) Atomic force microscopy (AFM). AFM may be used to obtain topographic images of living cells by scanning a nanoscale probe mounted on a force-sensitive cantilever. This may be accomplished by maintaining the probe in a constant contact or b oscillatory contact with the cell and using the deflections of the cantilever to reconstruct an image. c AFM may also be used to obtain mechanical properties of living cells by indenting the surface of the cell with the probe and recording the resistive force of the cell during indentation. (d–e) Subcellular laser ablation (SLA). In SLA, sub-micron structures inside living cells are irradiated with a high-intensity and tightly-focused laser, resulting in nonlinear absorption and optical breakdown. SLA has been used to d sever and e puncture actomyosin stress fiber bundles in endothelial cells, and the response of these structures (e.g., the retraction of the severed ends) have been used to measure stress fiber mechanical properties and contribution to cell shape. (a)–(c) reproduced from [71] with permission from Blackwell; (d) and (e) reproduced from [80] with permission from Biophysical Society