School of Biomedical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, India.
Department of Applied Sciences, Indian Institute of Information Technology, Nagpur 44005, India.
Math Biosci Eng. 2023 Mar 21;20(5):9572-9606. doi: 10.3934/mbe.2023420.
Complete spontaneous tumor regression (without treatment) is well documented to occur in animals and humans as epidemiological analysis show, whereby the malignancy is permanently eliminated. We have developed a novel computational systems biology model for this unique phenomenon to furnish insight into the possibility of therapeutically replicating such regression processes on tumors clinically, without toxic side effects. We have formulated oncological informatics approach using cell-kinetics coupled differential equations while protecting normal tissue. We investigated three main tumor-lysis components: (ⅰ) DNA blockade factors, (ⅱ) Interleukin-2 (IL-2), and (ⅲ) Cytotoxic T-cells (CD8 T). We studied the temporal variations of these factors, utilizing preclinical experimental investigations on malignant tumors, using mammalian melanoma microarray and histiocytoma immunochemical assessment. We found that permanent tumor regression can occur by: 1) Negative-Bias shift in population trajectory of tumor cells, eradicating them under first-order asymptotic kinetics, and 2) Temporal alteration in the three antitumor components (DNA replication-blockade, Antitumor T-lymphocyte, IL-2), which are respectively characterized by the following patterns: (a) Unimodal Inverted-U function, (b) Bimodal M-function, (c) Stationary-step function. These provide a time-wise orchestrated tri-phasic cytotoxic profile. We have also elucidated gene-expression levels corresponding to the above three components: (ⅰ) DNA-damage G2/M checkpoint regulation [genes: ], (ⅱ) Chemokine signaling: IL-2/15 [genes: ], (ⅲ) T-lymphocyte signaling (genes: ). All three components quantitatively followed the same activation profiles predicted by our computational model (Smirnov-Kolmogorov statistical test satisfied, = 5%). We have shown that the genes are signatures of Negative-bias dynamics, enabling eradication of the residual tumor. Using the negative-biasing principle, we have furnished the dose-time profile of equivalent therapeutic agents (DNA-alkylator, IL-2, T-cell input) so that melanoma tumor may therapeutically undergo permanent extinction by replicating the spontaneous tumor regression dynamics.
完全自发的肿瘤消退（未经治疗）在动物和人类中都有很好的记录，流行病学分析表明，恶性肿瘤已被永久消除。我们为这种独特的现象开发了一种新的计算系统生物学模型，以深入了解在临床上复制这种肿瘤消退过程的可能性，而不会产生有毒的副作用。我们使用细胞动力学耦合微分方程制定了肿瘤信息学方法，同时保护正常组织。我们研究了三种主要的肿瘤溶解成分：（i）DNA 阻断因子，（ii）白细胞介素 2（IL-2），和（iii）细胞毒性 T 细胞（CD8 T）。我们利用哺乳动物黑色素瘤微阵列和组织细胞瘤免疫化学评估，对恶性肿瘤进行了临床前实验研究，研究了这些因素的时间变化。我们发现，永久性肿瘤消退可能是通过以下两种方式发生的：1）肿瘤细胞群体轨迹的负偏差，在一阶渐近动力学下消除它们；2）三种抗肿瘤成分（DNA 复制阻断、抗肿瘤 T 淋巴细胞、IL-2）的时间变化，它们分别具有以下模式：（a）单峰倒 U 函数，（b）双峰 M 函数，（c）静止步函数。这些提供了一个时间协调的三阶段细胞毒性谱。我们还阐明了与上述三个成分相对应的基因表达水平：（i）DNA 损伤 G2/M 检查点调节[基因：]，（ii）趋化因子信号：IL-2/15[基因：]，（iii）T 淋巴细胞信号（基因：）。所有三个成分都按照我们的计算模型预测的相同激活模式定量变化（Smirnov-Kolmogorov 统计检验满足，=5%）。我们表明，基因是负偏差动力学的特征，使残余肿瘤得以消除。我们利用负偏置原理，提供了等效治疗剂（DNA 烷化剂、IL-2、T 细胞输入）的剂量-时间曲线，使黑色素瘤肿瘤能够通过复制自发肿瘤消退动力学而进行永久消退。
