Date of Award

Spring 2023

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

E. Angela Murphy

Abstract

Cancer remains a leading cause of death worldwide. More specifically, breast cancer (BrCa) and colorectal cancer (CRC) continue to be the most diagnosed cancers and leading causes of cancer-related death worldwide. Given that surgery followed by adjuvant chemotherapy is only effective in 20% of CRC patients, and that there are no preventive agents for BrCa metastasis for hormone receptor negative patients, more effective agents and strategies are needed in both the prevention and treatment of these cancers. As one of the most abundant immune cells in the tumor microenvironment, macrophages help regulate primary tumor growth, angiogenesis, and metastasis in many cancers. Targeting tumor-associated macrophages has shown promise pre-clinically but has not been exploited as a target in BrCa metastasis prevention or in CRC treatment in clinic. This led us to explore the potential for targeting macrophages in treatment strategies to combat these cancers. Surgery alongside toxic chemotherapies is a commonly used strategy to treat BrCa; however, it is becoming more evident that tumor resection surgery and the subsequent wound healing response may promote distant tumor cell growth to result in accelerated metastasis. We reveal that surgical wounding, at a distant site and without tumor resection, results in accelerated primary tumor growth and enhanced tumor metastasis in a TNBC murine model. Our results add to the very limited experimental research linking surgical wounding to acceleration of local and distant tumor outgrowth and suggest a role for pro-tumor macrophages in this response. Moreover, we demonstrate that natural compound emodin is beneficial in preventing surgery induced BrCa tumor growth and metastasis when given perioperatively through its suppressive effects on macrophages and inflammation. Additionally, we evaluated the therapeutic potential of panaxynol in murine CRC. We demonstrate that panaxynol mitigates CRC development and associated clinical symptoms through improving the colonic environment and suppressing macrophages. Taken together, we demonstrate that macrophage and associated inflammatory responses play a role in the acceleration of surgical wounding induced BrCa metastasis, and that natural compounds emodin and panaxynol represent promising agents to prevent surgical induced BrCa metastasis and CRC progression through their ability to modulate the inflammatory environment and suppress macrophages.

Available for download on Thursday, May 15, 2025

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