Abstract
Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer considerable translational applicability, as a permanent regression process may be therapeutically replicated on patients. For this, we developed a systems biological formulation of the regression process with experimental verification and identified the relevant candidate biomolecules for therapeutic utility. We devised a cellular kinetics-based quantitative model of tumor extinction in terms of the temporal behavior of three main tumor-lysis entities: DNA blockade factor, cytotoxic T-lymphocyte and interleukin-2. As a case study, we analyzed the time-wise biopsy and microarrays of spontaneously regressing melanoma and fibrosarcoma tumors in mammalian/human hosts. We analyzed the differentially expressed genes (DEGs), signaling pathways, and bioinformatics framework of regression. Additionally, prospective biomolecules that could cause complete tumor regression were investigated. The tumor regression process follows a first-order cellular dynamics with a small negative bias, as verified by experimental fibrosarcoma regression; the bias is necessary to eliminate the residual tumor. We identified 176 upregulated and 116 downregulated DEGs, and enrichment analysis showed that the most significant were downregulated cell-division genes: TOP2A–KIF20A–KIF23–CDK1–CCNB1. Moreover, Topoisomerase-IIA inhibition might actuate spontaneous regression, with collateral confirmation provided from survival and genomic analysis of melanoma patients. Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically.
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All the data are included in this manuscript. For further clarifications, please communicate with the corresponding author PKR at Dept. of Life Sciences, Shiv Nadar University, Dadri 201314, India.
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Acknowledgements
Bindu Kumari is thankful for the student opportunity furnished by Indian Institute of Technology – Banaras Hindu University, Varanasi. Deep appreciation is acknowledged for the support extended by the iHub NTIHAC Foundation, sponsored by Department of Science & Technology, Ministry of Science & Technology, Govt. of India.
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BK: conceptualisation, methodology, validation, formal analysis, writing–original draft, writing—review and editing. CS, RL, PP, AB: methodology, formal analysis, validation. PKR: conceptualisation, methodology, validation, formal analysis, writing—original draft, writing—review and editing.
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Kumari, B., Sakode, C., Lakshminarayanan, R. et al. A mechanistic analysis of spontaneous cancer remission phenomenon: identification of genomic basis and effector biomolecules for therapeutic applicability. 3 Biotech 13, 113 (2023). https://doi.org/10.1007/s13205-023-03515-0
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DOI: https://doi.org/10.1007/s13205-023-03515-0