The functional role of integrins during intra- and extravasation within the metastatic cascade

Abstract

Formation of distant metastases is by far the most common cause of cancer-related deaths. The process of metastasis formation is complex, and within this complex process the formation of migratory cells, the so called epithelial mesenchymal transition (EMT), which enables cancer cells to break loose from the primary tumor mass and to enter the bloodstream, is of particular importance. To break loose from the primary cancer, cancer cells have to down-regulate the cell-to-cell adhesion molecuIes (CAMs) which keep them attached to neighboring cancer cells. In contrast to this downregulation of CAMS in the primary tumor, cancer cells up-regulate other types of CAMs, that enable them to attach to the endothelium in the organ of the future metastasis. During EMT, the expression of cell-to-cell and cell-to-matrix adhesion molecules and their down- and upregulation is therefore critical for metastasis formation. Tumor cells mimic leukocytes to enable transmigration of the endothelial barrier at the metastatic site. The attachment of leukocytes/cancer cells to the endothelium are mediated by several CAMs different from those at the site of the primary tumor. These CAMs and their ligands are organized in a sequential row, the leukocyte adhesion cascade. In this adhesion process, integrins and their ligands are centrally involved in the molecular interactions governing the transmigration. This review discusses the integrin expression patterns found on primary tumor cells and studies whether their expression correlates with tumor progression, metastatic capacity and prognosis. Simultaneously, further possible, but so far unclearly characterized, alternative adhesion molecules and/or ligands, will be considered and emerging therapeutic possibilities reviewed.

Keywords: Cancer; Epithelial mesenchymal transition; Extravasation; Integrin; Integrin inhibitor; Integrin ligands; Leukocyte adhesion cascade; Metastasis; Prognosis; Selectin.

Fig. 1

The extravasation of tumor cells. To achieve improved clarity the figure is limited to the major adhesion molecules and their interactions. Tumor adhesion molecules are shown in brown, endothelial ligands are shown in green

Fig. 2

Rolling of tumor cells. Representation of tumor cell rolling mediated by the interaction with selectin adhesion molecules. (*) Example of a possible interaction between tumor cell and the endothelium using an intermediate to link both interaction partners, forming a bridge [6, 156]

Fig. 3

Representation of an αI-domain-containing integrin heterodimer and the distribution of its domains. All integrins contain a ßI domain in the ß subunit, whilst nine out of the 18 integrin α chains contain an αI-domain of around 200 amino acids, inserted between blades two and three of the ß-propeller [35, 157]. The α subunit is formed by a calf-2 (C2), calf-1 (C1) and a thigh domain supporting the seven-bladed ß-propeller [31]. The αI-domain is coordinated by a Mg²⁺ ion in the metal-ion-dependent adhesion site (MIDAS) and represents the ligand-binding site. The ß subunit contains a MIDAS and ADMIDAS site mediating conformational changes resulting in an active form of the integrin. The ß subunit contains a ßI-domain, a hybrid domain (H), a plexin-semaphorin-integrin (PSI), four cysteine-rich epidermal growth factor repeats (E1–4) and a ß-tail/transmembrane (ß-T) domain [35]. As bi-directional signaling receptors, integrins convey inside-out and outside-in signaling [31]

Fig. 4

Leukocyte lineage integrins. All of the leukocyte integrins [29] bind to LDV motifs. Subunits containing an αI-domain are marked in red

Fig. 5

Tumor cell adhesion molecules. Representation of cell adhesion mediated by integrins and other cell adhesion molecules binding to their corresponding endothelial ligands. Depiction of the specific integrins that are found overexpressed on tumor cells allowing extravasation and formation of distant metastases