Adipose-Derived Progenitor Cell Alterations To The Tumor Microenvironment Promote Tumorigenesis
Rather than simply focusing on the malignant cancer cells, the role of the tumor microenvironment as a whole is increasingly being studied. As this amalgamation of malignantly transformed cells, host tissue cells, growth factors, cytokines, and extracellular matrix (ECM) proteins forms the tumor, the interactions between these heterotypic components contribute to tumorigenesis. As the origin of the various components of what has not been fully elucidated, the work presented here focuses on a likely contributor - the breast tumor stroma. A cell type of interest in the tumor stroma is the myofibroblast, which is largely responsible for the excessive ECM accumulated within tumors. Adipose-derived stem/progenitor cells (ASCs) are adult mesenchymal stem cells present within adipose tissue, a main component of the mammary tissue surrounding breast tumors, which are utilized for regenerative tissueengineering approaches. These multipotent cells have been shown to play a critical role in wound healing, which has similarities to the stromal reaction seen in tumors and therefore may contribute to the tumor stroma by undergoing myofibroblastic differentiation. Within the tumor microenvironment chemical cues in the form of secreted molecules from tumor cells as well as altered ECM composition and stiffness are mechanisms through which ASC function may be altered. Here the ability of ASCs to be altered by tumor conditioned media (TCM) as well as enhanced stiffness has been studied. The results indicate that ASCs cultured in TCM take on an altered tumorassociated (TA) phenotype which entails increased proliferation and pro-angiogenic potential as well as the ability to alter the tumor ECM composition, by differentiating into myofibroblasts. Through a positive feedback loop system, the increased ECM stiffness of tumors also signals ASCs to proliferate and become more pro-angiogenic. These resultant changes within the TA-ASC ECM propagate protumorigenic signals. In essence, ASCs receiving tumor-derived chemical and mechanical cues alter the tumor stroma to produce the malignant microenvironment. With this knowledge, the regenerative potential of ASCs should be mindfully harnessed to ensure that their pro-tumorigenic capacities do not induce undesirable effects.
stiffness; myofibroblast; breast cancer
Stokol, Tracy; Bonassar, Lawrence
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis