Kumari Bindu, Sakode Chandrashekhar, Lakshminarayanan Raghavendran, Purohit Pratik, Bhattacharjee Anindita, Roy Prasun K
School of Bio-Medical Engineering, Indian Institute of Technology (B.H.U.), Varanasi, 221005 India.
Department of Applied Sciences, Indian Institute of Information Technology, Nagpur, 44005 India.
3 Biotech. 2023 Apr;13(4):113. doi: 10.1007/s13205-023-03515-0. Epub 2023 Mar 6.
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.
The online version contains supplementary material available at 10.1007/s13205-023-03515-0.
基于充分记录的研究，许多肿瘤在未经治疗的情况下会间歇性地永久消退。了解宿主组织引发的致病因素将具有相当大的转化应用价值，因为永久消退过程可能在患者身上通过治疗得以复制。为此，我们开发了一种具有实验验证的消退过程的系统生物学公式，并确定了具有治疗效用的相关候选生物分子。我们根据三种主要肿瘤溶解实体（DNA阻断因子、细胞毒性T淋巴细胞和白细胞介素-2）的时间行为，设计了一种基于细胞动力学的肿瘤消退定量模型。作为案例研究，我们分析了哺乳动物/人类宿主中自发消退的黑色素瘤和纤维肉瘤肿瘤的时间序列活检和微阵列。我们分析了差异表达基因（DEGs）、信号通路和消退的生物信息学框架。此外，还研究了可能导致肿瘤完全消退的潜在生物分子。如实验性纤维肉瘤消退所验证的，肿瘤消退过程遵循具有小负偏差的一阶细胞动力学；这种偏差对于消除残留肿瘤是必要的。我们确定了176个上调和116个下调的DEGs，富集分析表明最显著的是下调的细胞分裂基因：TOP2A-KIF20A-KIF23-CDK1-CCNB1。此外，拓扑异构酶-IIA抑制可能引发自发消退，黑色素瘤患者的生存和基因组分析提供了旁证。候选分子如右丙亚胺/米托蒽醌，与白细胞介素-2和抗肿瘤淋巴细胞一起，可能潜在地复制黑色素瘤的永久肿瘤消退过程。总之，间歇性永久肿瘤消退是恶性进展的独特生物逆转过程，对信号通路的理解以及候选生物分子可能在临床上合理地通过治疗复制肿瘤的消退过程。
在线版本包含可在10.1007/s13205-023-03515-0获取的补充材料。
