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.

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Fibroblasts are capable of 'sensing' physical changes in their local ECM environment and in turn converting this physical stimulation into chemical signals, thereby leading to selective changes in gene expression that foster neoplastic progression, invasion, and metastasis [45,46]. While there are few cancer-related studies that directly connect mechano-sensing by fibroblasts with pro-inflammatory signalling, several studies performed in other fields have reported that activation of fibroblasts by biomechanical forces induces pro-inflammatory signalling: For example, periodontal fibroblasts respond to compression forces by increased TNF-α production at the compression site, resulting in the activation of CD4 + T cells and facilitating bone resorption [47].…”

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

“…FAs play important roles in many cellular behaviors, including proliferation, differentiation, and locomotion, and pathological processes like tumorigenesis and wound healing (1)(2)(3)(4). For this reason, intense efforts have been devoted to understanding how key signaling molecules and ECM characteristics influence the formation and growth of FAs.…”

An investigation of the influence of extracellular matrix anisotropy and cell–matrix interactions on tissue architecture

“…The normal development, growth and regeneration of biological tissues all require the coordination of cell behaviours such as proliferation, differentiation and migration, dysregulation of these processes being associated with disease states e.g. Ingber (2008); Jaalouk and Lammerding (2009); Kumar and Weaver (2009) ;Soto and Sonnenschein (2004). In the late 19 th century, embryologists often focused on the role of mechanics in developmental events (see e.g.…”

“…The importance of cell-ECM interactions in tissue development has received particular attention in the context of the mammary gland (both normal development and tumourigenesis) (Kumar and Weaver, 2009;Martins-Green and Bissell, 1995;Ronnov-Jessen and Bissell, 2008;Weigelt and Bissell, 2008), vasculogenesis and angiogenesis (Kirkpatrick et al, 2007;Korff and Augustin, 1999;Manoussaki et al, 1996). For the mammary gland, it has been observed that normal and malignant breast cells are morphologically indistinguishable when grown as monolayers in vitro, but when cultured in a three-dimensional, laminin-rich ECM, normal cells stop proliferating and form polarised acinar (spherical) structures, whilst cancer cells continue to proliferate and form disorganised, tumour-like structures (Petersen et al, 1992;Weigelt and Bissell, 2008).…”