Cell force-mediated collagen remodeling in cancer metastasis

Metastasis, the development of additional tumor(s) in organs other than the primary tumor, is the leading cause of death from cancer. In general, the metastatic cascade associated with solid tumors is summarized in stages including focal invasion where cells invade through the stroma, the process of intravasation where cells enter into the vasculature (or may enter the lymphatic system), survival in circulation, and extravasation where cells exit the vasculature and move into a host site where they form another tumor (Gupta and Massague 2006; Sahai 2007). While our understanding of each of these processes is incomplete, it is clear that the early switch from noninvasive cell behavior toward an invasive cell phenotype that ultimately results in cell invasion through the stroma is a critical step in the metastasis cascade. In this context, the features of the cellular microenvironment and the features of the tumor stroma in general play a dominant role in dictating the fate of a genetically aberrant cancerous cell. Not every genetically abnormal cell throughout the tumor behaves the same, largely due to heterogeneities that exist throughout solid tumors. Where one cell may invade throughout the stroma and successfully negotiate the stages of metastasis to develop a new tumor, another tumor cell may never proliferate robustly, become robustly invasive, or leave the tumor. This is due in large part to spatial and temporal variations in the microenvironment surrounding these cells. The tumor microenvironment contains a wide range of cells including fibroblasts, immune cells, and the tumor supporting vasculature as well as a robust extracellular matrix (ECM), most notably collagen, which are associated with a robust fibroinflammatory response, or desmoplasia, found in many solid tumors. The spatial distribution of these elements is not random or uniform throughout the tumor, while the dynamic interactions among these components coordinate to promote tumor progression (Folkman 1971; Mintz and Illmensee 1975; Teicher et al. 1990; Elenbaas et al. 2001; Shekhar et al. 2003; Pollard 2004; Condeelis et al. 2005; Orimo et al. 2005; Condeelis and Pollard 2006; Gaggioli et al. 2007; Sahai 2007; Calvo et al. 2013). Here, in this chapter, the focus will be primarily directed toward the discussion of work that elucidates the physical processes associated with focal invasion at the single cell level in 3D microenvironments and the importance of cell contractile forces that reorganize the stromal ECM in the tumor microenvironment to provide mechanical and spatial cues to help facilitate cancer cell invasion.