Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Drs Ann F Chambers

2nd Supervisor

Ian C MacDonald

Joint Supervisor

Abstract

Tumor and metastasis formation are not cell autonomous phenomena, but rather an evolution of disease within and responding to the host environment. Metastatic spread from a primary tumor occurs as a result of a complex interplay between tumor cells and the host, wherein tumor cells must escape the primary tumor, enter the host vasculature, travel to and arrest in a distant tissue and survive and grow in that new organ. It is known that cells that progress through these stages must both escape and exploit host systems, yet the mechanisms used are not fully understood. Therefore, the goal of this work was to investigate the interactions between tumor cells and the host and to determine the role that host systems play in supporting tumor development and progression. Specifically, the interaction between hemostatic factors and metastatic cells was evaluated, and the effect of a primary tumor in influencing this interaction was investigated using a murine melanoma cell line. It was determined that tumor cells are capable of exploiting host hemostatic factors to increase lung metastasis, and stabilization of this interaction increased metastasis. Intriguingly, a depletion of circulating platelets was observed in animals bearing primary tumors, which had a significant impact on hemostasis and ultimately the fate of introduced metastatic cells. This led to reduced interaction between tumor cells and host hemostatic factors and decreased metastasis. To determine if this effect of a primary tumor was unique to melanoma, a human breast carcinoma cell line was also used. In agreement with murine melanoma data, it was found that the presence of a breast primary tumor also reduced the development of lung metastases. The ability of metastatic cells to exploit host hemostatic factors and the identification of global modulation of this interaction by a primary tumor indicates that the interaction between primary tumor, host, and distant metastatic cells is complex and multi-faceted. Full understanding of the interplay between a primary tumor, the host and metastases will be essential to the development of strategies to inhibit metastatic progression, either before or after the surgical resection of the primary tumor.