Physical traits of cancer

Abstract

The role of the physical microenvironment in tumor development, progression, metastasis, and treatment is gaining appreciation. The emerging multidisciplinary field of the physical sciences of cancer is now embraced by engineers, physicists, cell biologists, developmental biologists, tumor biologists, and oncologists attempting to understand how physical parameters and processes affect cancer progression and treatment. Discoveries in this field are starting to be translated into new therapeutic strategies for cancer. In this Review, we propose four physical traits of tumors that contribute to tumor progression and treatment resistance: (i) elevated solid stresses (compression and tension), (ii) elevated interstitial fluid pressure, (iii) altered material properties (for example, increased tissue stiffness, which historically has been used to detect cancer by palpation), and (iv) altered physical microarchitecture. After defining these physical traits, we discuss their causes, consequences, and how they complement the biological hallmarks of cancer.

Fig. 1.. Physical traits of cancer.

On the basis of the advancements of the past few decades, we suggest that the physical traits of cancer can be categorized into four major groups: (i) elevated solid stress, (ii) elevated interstitial pressure, (iii) increased stiffness, and (iv) altered architecture and geometry. Solid stresses and fluid pressure are the mechanical stresses (force per unit area) contained in, and transmitted by, solid and fluid phases of the tumor, respectively. Solid stresses and fluid pressure are reported in pascals or millimeters of mercury (1 mmHg ≅ 133.3 Pa). Stiffness (elasticity) is defined as the resistance of a material to deformation in response to an applied force, and elastic modulus is reported in pascals. Viscoelasticity defines the resistance of the material to deformation in response to a force applied at a given rate. Most soft tissues, including tumors, exhibit higher resistance to force (e.g., higher stiffness) when the force is applied at high rates. Solid stress, the latent or stored stress in a tissue, should not be confused with elasticity (stiffness) or viscoelasticity (time-dependent stiffness), which define how much or how fast, respectively, a tissue will deform if a force is applied. A tissue can be stiff (rigid) or soft (compliant), and, independently, it can be under compressive and/or tensile solid stresses (4) or, like most normal tissues, it can be unstressed. The proposed physical traits characterize most cancers, and their distinct origins and consequences make them indispensable to a comprehensive picture of cancer.

Fig. 2.. Origins of the physical traits of cancer.

Physical interactions of cancer cells with stroma give rise to physical traits of tumors through distinct and interconnected mechanisms. Leaky and compressed blood vessels and nonfunctional lymphatics lead to increased interstitial fluid pressure within the tumor and interstitial fluid flow in the tumor margin. Cellular proliferation, matrix deposition, cell contraction, and abnormal growth patterns lead to compressive and tensile solid stresses. Matrix deposition and cross-linking cause increased stiffness in tumors. Cell contraction, matrix deposition, and cross-linking also alter the architecture of the tissue. The physical traits also interact with each other; solid stresses compress blood and lymphatic vessels and contribute to increased fluid pressure in tumors. Tensile solid stresses result in stretched and aligned matrix, and through strain-stiffening, solid stresses also increase tumor stiffness. Fluid flow activates fibroblasts, which then contribute to increased solid stresses and stiffness values and alter ECM architecture.

Fig. 3.. Pathways associated with the physical traits of cancer.

Physical traits of cancer activate a large cascade of mechanoresponsive pathways in cancer cells and stromal cells, including endothelial, epithelial, mesenchymal, and immune cells. Pathways such as integrin and YAP/TAZ are responsive to all four physical traits, whereas many other pathways appear to be more specific.