Graduation Date

Summer 8-9-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Rakesh K. Singh

Abstract

Cancer-related fatalities rank as the second leading cause of death in all ages and both genders in the United States. Moreover, breast cancer-related mortality rank as the second leading cause of death in females in the United States in 2019. The main concerns regarding breast cancer management include chemotherapy resistance and metastasis. Thus, the advanced understanding of cancer progression is required to develop improved therapeutic methods for breast cancer patients.

Recent studies demonstrate that neutrophils, as the most abundant leukocytes, play an essential role in breast progression. However, the mechanisms regarding neutrophils recruitment to the tumor sites, and the precise role of neutrophils in the tumor microenvironment, together with the specific mechanisms of neutrophil stimulated cancer progression remains unclear.

Therefore, this dissertation mainly investigated the role of IL17-CXCR2 axis, which positively promotes the recruitment of tumor-associated neutrophils to the tumor sites, and how tumor-associated neutrophils facilitated cancer progression. Our results indicated that there were higher levels of CXCR2, CXCR2 ligands, and IL17R present on the resistant and metastatic tumors. In addition, resistant tumors recruited higher levels of neutrophils and Th17 cells. Moreover, our experimental results revealed that IL17 facilitated cancer cell proliferation and secretion of CXCR2 ligands, which resulted in increased neutrophil chemotaxis; additionally, the neutrophil chemotaxis was dependent on CXCR2 signaling. We also observed that the neutrophils facilitated cancer progression through multiple mechanisms, including upregulation of IL1b and CCLs, and the formation of neutrophil extracellular traps (NETs). When cultured in chemotherapy-resistant tumor cells’ supernatant, the neutrophils especially possessed elongated survival time and secretion of MMP2 and MMP9.

Moreover, our studies indicated the differences between the chemotherapy-resistant tumor microenvironment and the non-resistant tumor microenvironment, which indicates why patients with established chemo-resistance result in lower survival rates. Our experimental results showed the therapeutic biomarkers for these patients and facilitated the improved clinical benefits for cancer patients in the future. In addition, our studies demonstrated that neutrophils could be considered as therapeutic targets and biomarkers for breast cancer patients, shedding light on an improved therapeutic strategy for breast cancer treatment.

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