Tumor-localized catalases can fail to alter tumor growth and transcriptional profiles in subcutaneous syngeneic mouse tumor models
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Published version
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Author(s)
Sheen, Allison
Agarwal, Yash
Cheah, Keith M
Cowles, Sarah C
Stinson, Jordan A
Palmeri, Joseph R
Sikes, Hadley D
Wittrup, K Dane
Date Issued
August 2023
Journal
Redox Biology
Publisher
Elsevier BV
Citation
Sheen, Allison, Agarwal, Yash, Cheah, Keith M, Cowles, Sarah C, Stinson, Jordan A et al. 2023. "Tumor-localized catalases can fail to alter tumor growth and transcriptional profiles in subcutaneous syngeneic mouse tumor models." Redox Biology, 64.
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Final published version
Abstract
Catalase is an antioxidant enzyme that catalyzes the rapid conversion of hydrogen peroxide to water and oxygen. Use of catalase as a cancer therapeutic has been proposed to reduce oxidative stress and hypoxia in the tumor microenvironment, both activities which are hypothesized to reduce tumor growth. Furthermore, exposing murine tumors to exogenous catalase was previously reported to have therapeutic benefit. We studied the therapeutic effect of tumor-localized catalases with the aim to further elucidate the mechanism of action. To do this, we engineered two approaches to maximize intratumoral catalase exposure: 1) an injected extracellular catalase with enhanced tumor retention, and 2) tumor cell lines that over-express intracellular catalase. Both approaches were characterized for functionality and tested for therapeutic efficacy and mechanism in 4T1 and CT26 murine syngeneic tumor models. The injected catalase was confirmed to have enzyme activity >30,000 U/mg and was retained at the injection site for more than one week in vivo. The engineered cell lines exhibited increased catalase activity and antioxidant capacity, with catalase over-expression that was maintained for at least one week after gene expression was induced in vivo. We did not observe a significant difference in tumor growth or survival between catalase-treated and untreated mice when either approach was used. Finally, bulk RNA sequencing of tumors was performed, comparing the gene expression of catalase-treated and untreated tumors. Gene expression analysis revealed very few differentially expressed genes as a result of exposure to catalase and notably, we did not observe changes consistent with an altered state of hypoxia or oxidative stress. In conclusion, we observe that sustained intratumoral catalase neither has therapeutic benefit nor triggers significant differential expression of genes associated with the anticipated therapeutic mechanism in the subcutaneous syngeneic tumor models used. Given the lack of effect observed, we propose that further development of catalase as a cancer therapeutic should take these findings into consideration.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1016/j.redox.2023.102766
