Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
Sci Rep. 2020 Feb 20;10(1):3025. doi: 10.1038/s41598-020-59658-0.
The search for efficient chemotherapy drugs and other anti-cancer treatments would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. Because in vivo experimental methods are unable to isolate or control individual factors of the TME and in vitro models often do not include all the contributing factors, some questions are best addressed with systems biology mathematical models. In this work, we present a new fully-coupled, agent-based, multi-scale mathematical model of tumor growth, angiogenesis and metabolism that includes important aspects of the TME spanning subcellular-, cellular- and tissue-level scales. The mathematical model is computationally implemented for a three-dimensional TME, and a double hybrid continuous-discrete (DHCD) method is applied to solve the governing equations. The model recapitulates the distinct morphological and metabolic stages of a solid tumor, starting with an avascular tumor and progressing through angiogenesis and vascularized tumor growth. To examine the robustness of the model, we simulated normal and abnormal blood conditions, including hyperglycemia/hypoglycemia, hyperoxemia/hypoxemia, and hypercarbia/hypocarbia - conditions common in cancer patients. The results demonstrate that tumor progression is accelerated by hyperoxemia, hyperglycemia and hypercarbia but inhibited by hypoxemia and hypoglycemia; hypocarbia had no appreciable effect. Because of the importance of interstitial fluid flow in tumor physiology, we also examined the effects of hypo- or hypertension, and the impact of decreased hydraulic conductivity common in desmoplastic tumors. The simulations show that chemotherapy-increased blood pressure, or reduction of interstitial hydraulic conductivity increase tumor growth rate and contribute to tumor malignancy.
寻找高效的化疗药物和其他抗癌疗法将受益于对肿瘤微环境（TME）及其在肿瘤进展中的作用的更深入了解。由于体内实验方法无法分离或控制 TME 的单个因素，体外模型通常也不包括所有促成因素，因此一些问题最好通过系统生物学数学模型来解决。在这项工作中，我们提出了一个新的完全耦合的基于代理的多尺度肿瘤生长、血管生成和代谢数学模型，该模型涵盖了 TME 的重要方面，跨越了亚细胞、细胞和组织尺度。该数学模型在三维 TME 中进行了计算实现，并应用了双杂交连续离散（DHCD）方法来求解控制方程。该模型再现了实体瘤的独特形态和代谢阶段，从无血管肿瘤开始，然后发展为血管生成和血管化肿瘤生长。为了检验模型的稳健性，我们模拟了正常和异常的血液条件，包括高血糖/低血糖、高氧血症/低氧血症和高碳酸血症/低碳酸血症——这些都是癌症患者常见的情况。结果表明，高氧血症、高血糖和高碳酸血症会加速肿瘤进展，但低氧血症和低血糖会抑制肿瘤进展；低碳酸血症没有明显影响。由于间质液流在肿瘤生理学中的重要性，我们还研究了低血压或高血压的影响，以及在纤维瘤肿瘤中常见的间质水力传导率降低的影响。模拟结果表明，化疗引起的血压升高或间质水力传导率降低会增加肿瘤生长速度并导致肿瘤恶性程度增加。
