The physics of cancer: the role of physical interactions and mechanical forces in metastasis

Abstract

Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies.

Figure 1. The metastatic process

In this complex process, cells detach from a primary, vascularized tumour, penetrate the surrounding tissue, enter nearby blood vessels (intravasation) and circulate in the vascular system. Some of these cells eventually adhere to blood vessel walls and are able to extravasate and migrate into the local tissue, where they can form a secondary tumour.

Figure 2. The physics of invasion and intravasation

The epithelial-to-mesenchymal transition (EMT) is associated with a loss of adhesion through downregulation of E-cadherin (E-cad) and a change in morphology. Invasion by tumour cells of the surrounding tissue and subsequent motion is dictated by the physicochemical properties of the extracellular matrix (ECM). By squeezing between blood vessel endothelial cells, tumour cells can enter the vascular system. All of these steps involve physicochemical processes, such as adhesion and deformation, that are dependent on the local environment. LOX, lysyl oxidase; MMPs, matrix metalloproteinases; N-cad, N-cadherin.

Figure 3. Arrest of circulating tumour cells

Tumour cells with a diameter (d_cell) less than the diameter of the blood vessel wall (d_vessel) will follow a trajectory that is determined by the local flow pattern and by collisions with host cells and blood vessel walls. Collisions with a blood vessel wall may lead to arrest. Tumour cells with diameter greater than the diameter of a blood vessel will be arrested owing to mechanical trapping (physical occlusion).

Figure 4. Capture and arrest of circulating tumour cells

a | A collision between a cell and a vessel wall may lead to transient and/or persistent (firm) adhesion as a result of ligand-receptor interactions. Transient adhesion is characterized by weaker bonds involving ligands such as CD44, carcinoembryonic antigen (CEA) or podocalyxin (PODXL) binding with selectin receptors. Persistent adhesion either follows transient binding or is initiated at very low shear stress and involves interactions between integrins and their receptors, such as intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1). For consistency we designate the adhesion molecules on the surface of endothelial cells as receptors and the interacting molecules on the circulating tumour cells as ligands. We note that in the literature, integrins participating in receptor-ligand pairs are usually identified as receptors. b | The association of tumour cells with platelets may enhance arrest through platelet-mediated capture, a process analogous to nucleation and growth. The growth process is achieved by a platelet-bridging mechanism, whereby platelets adherent to an endothelium-bound carcinoma cell serve as a ‘nucleus’ to capture free-flowing cells that subsequently attach to the blood vessel wall downstream or next to the already adherent cell. This nucleation mechanism, which is primarily dependent on P-selectin, results in the formation of growing clusters of adherent cells.