Author

Evan Martin

Date of Award

2018

Degree Type

Dissertation

Degree Name

Masters of Science in Chemistry

Department

Chemistry

First Advisor

Berdis, Anthony

Subject Headings

Biochemistry, Chemistry

Abstract

Colorectal cancer is a disease characterized by abnormal, invasive cell growth beginning in the colon or rectum. The third most common type of cancer worldwide, approximately one million new cases of the disease are diagnosed across the globe annually, resulting in an estimated 700,000+ deaths. One major risk factor associated with development of colorectal cancer is the presence of chronic inflammation in the large intestine, also known as colitis. Inflammation is a complex immune response against harmful stimuli, characterized by symptoms including heat, redness, swelling and pain. One important molecular mediator of this process is interleukin 17 (IL-17), a pro-inflammatory cytokine. While acute inflammation is a useful defensive response against invading pathogens, the presence of chronic inflammation is associated with an increased risk of tumorigenesis. Colorectal cancer is frequently observed to metastasize from the colon to the liver, the body’s largest storage site of copper, after which it becomes significantly more difficult to treat effectively. Copper is a trace nutrient required by all living systems, due to its ability to participate in one-electron exchange reactions, a vital mechanism of ubiquitous biological processes. STEAP4, a cell membrane protein, is a copper reductase. In this thesis, data are presented that show that colon cancer cells in which STEAP4 is overexpressed take up more copper from their environment than colon cancer cells in which STEAP4 is expressed normally. Additional data show that IL-17 stimulation, previously linked to colorectal cancer progression, increases copper uptake by colon cancer cells. A mouse model experiment also shows that induction of colitis mobilizes copper from the liver into systemic circulation. Further, it is shown that overexpression of STEAP4 enhances activation of IL-17-mediated growth pathways that have previously been shown to drive cancer progression. Finally, it is shown that colitis-associated colorectal cancer mice treated with a copper chelator may develop fewer tumor nodules that untreated mice. Taken together, these data suggest that IL-17 signaling drives tumor progression through a STEAP4-dependent mechanism of copper uptake. It is further suggested that lowering body copper levels through chelation therapy could be an effective method of stopping colorectal cancer progression.

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