Role of the endothelium during tumor cell metastasis: is the endothelium a barrier or a promoter for cell invasion and metastasis?

Abstract

The malignancy of cancer disease depends on the ability of the primary tumor to metastasize to distant organs. The process of the metastasis formation has largely been analyzed, but still main pathways regarding the extravasation step at the end of the metastasis formation process are controversially discussed. An agreement has been reached about the importance of the endothelium to promote metastasis formation either by enhancing the growth of the primary tumor or by homing (targeting) the tumor cells to blood or lymph vessels. The mechanical properties of the invading tumor cells become the focus of several studies, but the endothelial cell mechanical properties are still elusive. This paper describes the different roles of the endothelium in the process of metastasis formation and focuses on a novel role of the endothelium in promoting tumor cell invasion. It discusses how novel biophysical tools and in vivo animal models help to determine the role of the endothelium in the process of tumor cell invasion. Evidence is provided that cell mechanical properties, for example, contractile force generation of tumor cells, are involved in the process of tumor cell invasion.

Figure 1

Metastasis formation involves several steps. Two possible ways of metastasis formation: (a) first, single tumor cells disseminate form the primary tumor and invade the extracellular matrix, intravasate into blood or lymph vessels, and get transported and adhere to the endothelium. Secondly, (a) invasive tumor cells grow in vessels and do not transmigrate or (b) invasive tumor cells transmigrate through the endothelium, invade and from a secondary tumor in the targeted tissue.

Figure 2

Prerequisites for tumor cell migration on a 2D substrate and tumor cell invasion in a 3D extracellular matrix. (a) Scanning electron microscopic image of an MDA-MB-231 breast carcinoma cell on a planar glass and (b) transmission electron microscopic image of an MDA-MB-231 cell invaded in 3D collagen gel matrix. (a) For proper 2D motility, a cell needs to adhere/deadhere fast, remodel its cytoskeleton fast, and possess a high CSK-fluidity. (d) For proper 3D motility, a cell needs, in addition to the 2D motility properties, to generate high contractile forces, and the cells needs to overcome the viscous drag of the surrounding extracellular matrix to move forward.

Figure 3

Three currently discussed strategies for tumor cell transmigration through an endothelial cell monolayer. (a) The tumor cell transmigrates through the cytoplasm of the cell body. (b) The tumor cell induced apoptosis in the adjacent endothelial cell and migrated through the hole in the endothelial cell layer. (c) The tumor cell transmigrates through the endothelial cell-cell contacts without permanent destroying the endothelial cell monolayer.

Figure 4

Interactions between tumor and endothelial cells during tumor cell adhesion and transmigration.

Figure 5

Prerequisites for tumor cell transendothelial migration. Single tumor cells adhere to the endothelium via cell adhesion receptors like integrins, muccins, or immunoglobulins and their counter-receptors on endothelial cells. Many other factors like enzymes, cytokines/chemokines influence these interaction as well as biomechanical properties of both cells (CSK-dynamics, CSK-fluidity, cell stiffness, and contractile force generation).

Figure 6

New role of the endothelium in the process of tumor cell invasion. (a) A human endothelial cell monolayer (e.g., HUVEC) cultured on top of a collagen fiber network-induced tumor cell invasion of cocultured human tumor cell lines. (b) The endothelium decreased the invasion of several invasive tumor cell lines (barrier for cell invasion), did not alter the invasion of tumor cells, or even enhanced tumor cell invasion into a collagen gel fiber matrix (enhancer for cell invasion).