Compressive stress enhances coordinated migration of mammary carcinoma cells

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student submitted PDF version of thesis.Includes bibliographical references.Cancer research has traditionally focused on genetic and biochemical changes during tumor progression. Uncontrolled cell proliferation of a solid tumor in a confined space not only creates well-studied oxidative stress (hypoxia), but also generates growth-induced mechanical stress (compression). However, the importance of such compressive stress in tumor biology has been largely ignored. Our lab has previously shown that compressive stress influences tumor spheroid growth and stimulates production of extracellular matrix molecules. Others have also demonstrated the importance of matrix rigidity in tumor development and enhanced tumor cell adhesion by hydrostatic pressure. Yet whether growth-induced compressive stress can enhance caner cell migration and invasion remains unclear. The focus of this thesis is to evaluate the effect of anisotropic compressive stress on cancer cell motility. To mimic growth-induced compressive stress experienced by cancer cells in vivo, we developed an in vitro compression device for compressing a monolayer of cancer cells with precisely-defined normal forces. Here we show, for the first time, that externally-applied compressive stress resulted in faster migration of some mammary carcinoma cell lines. Independent of multi-cellular micro-organization, compression induced migration of mammary carcinoma cells in a coordinated sheet, initiated by "leader cells" -- single cells at the leading edge of the sheet, extending long filopodia.(cont.) Accompanied by redistribution of fibronectin deposition, compression enhanced cell-matrix adhesion and stabilized cell distension, thereby promoting coordinated cell migration. Using a stochastic model to simulate 2-D collective cell migration, cell distension and uniform cell migration were found to be crucial factors for effective collective migration. Our finding on compression-induced coordinated migration of mammary carcinoma cells has significant implications for in vivo situations where epithelial cancer cells form a "coordinated" invading mass guided by "leader" cells. Our work suggests that compressive stress generated by proliferating cancer cells can distort their shape, enhance cell-substrate adhesion and stimulate formation of leader cells responsible for collective cell migration. This discovery could open the door to characterization of novel pathways driven by mechanical-stress and improved strategies for cancer treatment.by Janet M. Tse.Sc.D