Copper is an essential trace element required to produce energy in the body and allows humans to live in our atmosphere. But research has found that increased accumulation of copper is associated with worse outcomes for patients with the most common type of kidney cancer called clear cell renal cell carcinoma (ccRCC).

In adults, ccRCC makes up about 80% of all renal cell carcinoma cases. The disease is =is more common in adults than children. *

Today, the main treatment methods for ccRCC focuses on drug-targeted therapy and immunotherapy. And while there are many treatment options to treat ccRCC, they all have limitations, including drug resistance and long-term adverse events. Hence,  it is crucial to identify more effective therapeutic targets. [1]

Copper
Copper, a trace element in the human body, has been strongly associated with various signaling pathways and tumor-related biological behavior. [2] Excess of copper can lead to a type of programmed cell death, known as cuproptosis, which may have an impact on cancer development, including clear cell renal cell carcinoma (ccRCC). [3][4]

To better understand the how copper contributes to the advancements and recurrence of ccRCC, the University of Cincinnati Cancer Center’s Maria Czyzyk-Krzeska, MD, PhD, has been awarded a five-year, $2.8 million grant from the National Institutes of Health (NIH) to investigate the role of copper, tobacco smoking and ccRCC.

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Maria Czyzyk-Krzeska, MD, Ph.D. Cancer Biology.  Photo courtesy: © 2024 University of Cincinnati.

Study background
Tobacco smoking is a risk factor for ccRCC. Analyzing patient samples from the University of Cincinnati, the Cincinnati VA Medical Center and the National Cancer Institute’s Urology Oncology branch, Czyzyk-Krzeska and her team of collaborators discovered that tumors from patients who were smokers had significantly higher levels of copper compared to nonsmokers.

This observation was confirmed in follow-up studies in which data from several separate groups of patients also showed increased copper accumulation in more advanced tumors and tumors that came back following surgical removal.

“That indicated to us that copper has a potential driving effect in tumor progression of clear cell renal cell carcinoma,” noted Czyzyk-Krzeska, a University of Cincinnati Cancer Center researcher and professor in the Department of Cancer Biology in UC’s College of Medicine.

Identifying mechanisms
Czyzyk-Krzeska said the first aim of the study will seek to identify the mechanisms that allow ccRCC cells to take up more copper. The research team will also learn more about copper’s metabolic effects on the tumor cells, specifically the role it plays in the metabolism of mitochondria, the parts of the cell responsible for producing energy.

The third aim of the study will test whether any of the copper-specific features of the tumor cells have vulnerabilities that can open up new treatments for ccRCC.

“There are essentially two or three major lines of treatment for kidney cancer, but ultimately there’s always a group of tumors that are not responsive or recur” said Czyzyk-Krzeska.

“We hope what we find is going to provide opportunities for new treatments,” she added.

Biomarker
The data from the study may also shed light on the potential of copper as a biomarker for ccRCC, Czyzyk-Krzeska said.

“Because these levels of copper are higher in certain tumors, we think that copper could be used as a biomarker for evaluation of prognosis and potentially also for predicting which treatment could be appropriate for this specific group of tumors,” she said. “We think that this data will be important for personalized medicine in the treatment of ccRCC.”

Czyzyk-Krzeska said the ongoing research is a multidisciplinary effort between cancer biologists in her department including Tom Cunningham, David Plas and Krushna Patra; UC bioinformatics expert Jarek Meller; and former UC faculty member and analytical chemist Julio Landero, now at Icahn School of Medicine at Mount Sinai New York. The team also collaborates with urologic oncologists, urologists and pathologists at UC.
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Note: * Renal cell carcinoma makes up 2-6% of childhood and young adult kidney cancer cases.

Reference
[1] Qi X, Wang J, Che X, Li Q, Li X, Wang Q, Wu G. The potential value of cuprotosis (copper-induced cell death) in the therapy of clear cell renal cell carcinoma. Am J Cancer Res. 2022 Aug 15;12(8):3947-3966. PMID: 36119838; PMCID: PMC9442008.
[2] Festa RA, Thiele DJ. Copper: an essential metal in biology. Curr Biol. 2011 Nov 8;21(21):R877-83. doi: 10.1016/j.cub.2011.09.040. PMID: 22075424; PMCID: PMC3718004.
[3] Xie M, Cheng B, Yu S, He Y, Cao Y, Zhou T, Han K, Dai R, Wang R. Cuproptosis-Related MiR-21-5p/FDX1 Axis in Clear Cell Renal Cell Carcinoma and Its Potential Impact on Tumor Microenvironment. Cells. 2022 Dec 31;12(1):173. doi: 10.3390/cells12010173. PMID: 36611966; PMCID: PMC9818076.
[4] Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, Dou QP, Franz KJ, Gohil VM, Gupta S, Kaler SG, Lutsenko S, Mittal V, Petris MJ, Polishchuk R, Ralle M, Schilsky ML, Tonks NK, Vahdat LT, Van Aelst L, Xi D, Yuan P, Brady DC, Chang CJ. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer. 2022 Feb;22(2):102-113. doi: 10.1038/s41568-021-00417-2. Epub 2021 Nov 11. PMID: 34764459; PMCID: PMC8810673.

Featured image Ore containing copper, cobalt and nickel at the Andover mine in Western Australia. Photo courtesy: Paul-Alain Hunt on Unsplash. Used with permission.

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