Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer

Our plain-English summary of Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer, by S. Akatsuka, Y. Yamashita, H. Ohara, et al (PloS One, 2012).

The study

• Authors: S. Akatsuka, Y. Yamashita, H. Ohara, Y.T. Liu, M. Izumiya, K. Abe, M. Ochiai, L. Jiang, H. Nagai, Y. Okazaki, H. Murakami, Y. Sekido, E. Arai, Y. Kanai, O. Hino, T. Takahashi, H. Nakagama, S. Toyokuni
• Journal: PloS One
• Published: 2012;7(8):e43403
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

In plain English

This was an animal experiment. Male rats, a cross of the Fischer 344 and Brown-Norway strains, were given repeated injections into the abdominal cavity of ferric nitrilotriacetate (Fe-NTA). Fe-NTA is an iron compound that drives a chemical reaction called the Fenton reaction and causes kidney cancer (renal cell carcinoma) in rodents. The study did not test asbestos. The authors scanned the DNA of 15 rat kidney cancer samples, 13 tumors and 2 cell lines, for lost or extra copies of genetic material. They found widespread losses, especially on chromosomes 3, 5, 6, 8, 9, 14, 15, 17 and 20. Complete loss was most often seen at the Cdkn2a/2b genes. A region containing the Met gene was amplified in 11 of 15 samples. Every sample had either Met amplification or a Cdkn2a/2b deletion, and in some samples that deletion was a loss of only one copy. Higher Met gene expression went with larger tumors. Compared with five types of human cancer, the rat patterns most resembled human kidney cancer, followed by human malignant mesothelioma (mesothelioma cell line data). The authors concluded this suggests oxidative stress is a major factor in human cancer.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (rat carcinogenesis model) with genome-wide copy-number analysis (array-based comparative genomic hybridization) and comparison with published human cancer data
• Who was studied: 15 Fe-NTA-induced rat renal cell carcinoma DNA samples (13 primary tumors and 2 cell lines) from male F1 hybrid Fischer 344 by Brown-Norway rats, Japan. These were compared with human array data for pancreatic ductal adenocarcinoma, T-cell acute lymphoblastic leukemia, glioblastoma, a mesothelioma cell line data set and renal cell carcinoma.
• Exposure: Repeated intraperitoneal administration of ferric nitrilotriacetate (Fe-NTA), an iron chelate that catalyzes the Fenton reaction. This article does not give doses; it refers to previously published methods. No asbestos exposure was studied.
• Main results:
  • In the 15 rat RCC samples, the main feature was loss of wide chromosomal regions, especially chromosomes 3, 5, 6, 8, 9, 14, 15, 17 and 20
  • Homozygous (complete) deletions were most frequent at the Cdkn2a/2b locus on chromosome 5
  • The most commonly amplified section of chromosome 4 was amplified in 11/15 samples and contained only the Met gene
  • Met mRNA expression was more than 5-fold higher in 6 of the 9 tumors with Met amplification
  • Every carcinoma examined, including the two cell lines, had either Met amplification or a Cdkn2a/2b deletion. Some samples had only a hemizygous (one-copy) deletion at Cdkn2a.
  • Examples of samples with a hemizygous deletion at the Cdkn2a locus were FB32-4 and FB28-7
  • Met expression was proportionally associated with tumor size, and large tumors formed a distinct cluster in whole-genome pattern clustering
  • Among five human cancer types compared, the rat RCC copy-number patterns were most similar to human RCC, followed by human malignant mesothelioma
• The authors' conclusion: The authors concluded that repeated Fenton reactions in wild-type rats induced cancer with genomic alterations similar to those in human cancers. They wrote that this suggests oxidative stress is involved as a major factor in human carcinogenesis.
• Limitations the authors state:
  • The authors note that whole exome or genome sequencing may reveal point mutations and chromosomal translocations not examined here
  • The authors say the high p16/p19 expression in some tumors requires further clarification with epigenetic analysis

Topics

Medical terms in this study, explained in our Lexicon: Fenton Reaction, Carcinogenesis, Tubule, Carcinoma, Oxidative Stress, CDKN2A, Malignant Mesothelioma.

Related studies

• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats — Y. Okazaki, S.H. Chew, et al. (2020)
• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats — Y. Okazaki, N. Misawa, et al. (2020)
• Integrated high-resolution array CGH and SKY analysis of homozygous deletions and other genomic alterations present in malignant mesothelioma cell lines — G. Klorin, E. Rozenblum, et al. (2013)

Browse more research in PloS One, or return to medical research.