Adipose Tissue And Its Role In Modulating The Mammary Tumor Microenvironment

Targeting cancer cells has been the primary focus of most cancer therapies, and only recently has the interaction of cancer cells with host stroma been recognized as a driving force for cancer evolution. In the presence of tumor-derived physicochemical cues, the host stroma fails to fulfill its primary role - the maintenance of tissue or organ homeostasis - and in fact aids in shaping a pro-tumorigenic microenvironment, ultimately promoting tumor progression. This interaction of cancer cells with the host stroma often complicates conventional cancer therapy and ultimately leads to unfavorable outcomes. The mammary stroma is largely composed of adipose tissue, and upon the onset of mammary tumors, the residing stromal vascular cells and adipocytes possibly partake in extracellular matrix (ECM) remodeling and blood vessel recruitment. Both tumor-associated ECM remodeling and neovascularization are typically mediated by myofibroblasts, which are known to be recruited or differentiated from other stromal cells. However, whether tumor-derived biochemical and mechanical cues can induce the conversion of adipose-derived stem cells (ASCs) or adipocytes into myofibroblastic cells is yet unknown. Furthermore, obesity has been highlighted as a risk factor for breast cancer possibly due to its role in modulating the mammary microenvironment. Nevertheless, whether obesity influences the phenotype of host cells in the mammary stroma in a manner similar to tumors, thereby advancing tumorigenesis, has yet to be determined. The goal of this dissertation is to find answers to these aforementioned unanswered questions by leveraging in vivo and in vitro engineering techniques. The results presented here demonstrate that implanted or host ASCs and adipocytes indeed possess pro-tumorigenic potential to stimulate breast tumor malignancy in part due to their ability to convert into myofibroblastic lineages upon tumor or obesity-associated microenvironmental cues. The findings of this work emphasize the importance of contextual cues and their roles in inducing the participation of the host stroma in regulating mammary tumor progression. Finally, the conclusions of this work potentially provide new insight for the development of therapeutic approaches for cancer and tissue regeneration