Follow the Leader

Abstract

The epithelial-mesenchymal transition allows cancer cells to remodel the extracellular matrix and invade tissues. However, invasive squamous cell carcinoma (SCC) cells do not lose their epithelial markers, which led Gaggioli et al . to investigate how these cells invaded tissues. The authors devised a three-dimensional culture system consisting of a matrix block, containing mainly collagen and laminin, placed in culture medium with its upper surface exposed. SCC cells placed on this surface did not invade the matrix when cultured alone but did so when cultured with fibroblasts from tumors, as determined by immunohistochemical staining. Invasion by SCC cells was blocked when a thin sheet of matrix was placed between the fibroblasts and the SCC cells. Differential fluorescent labeling of SCC cells and fibroblasts showed that a chain of invading SCC cells in the matrix was always preceded by a fibroblast. Electron and reflectance microscopy revealed that "tracks" in the matrix generated by fibroblasts contained deposits of fibronectin and evidence of matrix remodeling. Inhibitor studies showed that, whereas the invasion of the matrix by fibroblasts was dependent on the activities of matrix metalloproteinases, matrix remodeling was dependent on the small guanosine triphosphatase (GTPase) Rho and Rho-associated kinase (ROCK). Antibodies against the α3 and α5 integrins also inhibited matrix remodeling by fibroblasts. Inhibiting Rho or ROCK activity in SCC cells had no effect on their ability to follow fibroblasts; however, inhibition of the GTPase Cdc42 prevented invasion. Immunohistochemical analysis of sections from head and neck SCCs showed invading groups of SCC cells in close association with fibroblasts and fibronectin deposits. In commentary, Radisky discusses how the invasion process revealed in this study can help us in our understanding of metastasis. C. Gaggioli, S. Hooper, C. Hidalgo-Carcedo, R. Grosse, J. F. Marshall, K. Harrington, E. Sahai, Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9 , 1392-1400 (2007). [PubMed] D. C. Radisky, Leading the charge. Nat. Cell Biol . 9 , 1341-1342 (2007). [PubMed]