Extracellular matrix determinants and the regulation of cancer cell invasion stratagems

Abstract

During development, wound repair and disease-related processes, such as cancer, normal, or neoplastic cell types traffic through the extracellular matrix (ECM), the complex composite of collagens, elastin, glycoproteins, proteoglycans, and glycosaminoglycans that dictate tissue architecture. Current evidence suggests that tissue-invasive processes may proceed by protease-dependent or protease-independent strategies whose selection is not only governed by the characteristics of the motile cell population, but also by the structural properties of the intervening ECM. Herein, we review the mechanisms by which ECM dimensionality, elasticity, crosslinking, and pore size impact patterns of cell invasion. This summary should prove useful when designing new experimental approaches for interrogating invasion programs as well as identifying potential cellular targets for next-generation therapeutics.

Keywords: Extracellular matrix (ECM); MT1-MMP; invasion.

Fig. 1

Collagen-invasive and degradative activities of cancer cells versus leukocytes. Light micrographs of cross-sections of type I collagen gels (2.2 mg/mL) traversed by HT-1080 or human PMNs prepared as described (Sabeh et al., 2009) for 3 d or 1 d, respectively. Collagen-invasive cells are H&E stained and marked with black arrows. Double-headed arrow marks the boundaries of the underlying collagen gel. Black bar = 100 μm. Laser confocal micrographs of HT-1080 cells cultured atop 3D gels of rhodamine-labeled type I collagen for 3 d demonstrate that invasion is associated with the formation of well-demarcated tunnels (white arrows; white bar = 50 μm). On the other hand, PMNs stimulated with zymosan-activated plasma (Huber and Weiss, 1989) invade rhodamine-labeled collagen gels without perturbing matrix architecture (far right-hand panel). Invasion and collagen-degradative activities of HT-1080, PMNs, T cells, and monocytes were quantified in the absence or presence of BB-2516 (1.5 μM) as described previously (bar graphs, bottom panel) (Sabeh et al., 2004). PMN invasion was also assessed in the presence of the protease inhibitor cocktail prepared as described (Wolf et al., 2003). Results are expressed as mean ± SEM (n = 4). Images and data are reproduced from the original work (Sabeh et al., 2009).