Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
Cancer Res Commun. 2023 Aug 7;3(8):1473-1485. doi: 10.1158/2767-9764.CRC-23-0097. eCollection 2023 Aug.
Over 10% of men will be diagnosed with prostate cancer during their lifetime. Arising from luminal cells of the prostatic acinus, prostate cancer is influenced by multiple cells in its microenvironment. To expand our knowledge and explore means to prevent and treat the disease, it is important to understand what drives the onset and early stages of prostate cancer. In this study, we developed an agent-based model of a prostatic acinus including its microenvironment, to allow for studying of prostate cancer development. The model was based on prior reports and in-house data of tumor cells cocultured with cancer-associated fibroblasts (CAF) and protumor and/or antitumor macrophages. Growth patterns depicted by the model were pathologically validated on hematoxylin and eosin slide images of human prostate cancer specimens. We identified that stochasticity of interactions between macrophages and tumor cells at early stages strongly affect tumor development. In addition, we discovered that more systematic deviations in tumor development result from a combinatorial effect of the probability of acquiring mutations and the tumor-promoting abilities of CAFs and macrophages. modeled tumors were then compared with 494 patients with cancer with matching characteristics, showing strong association between predicted tumor load and patients' clinical outcome. Our findings suggest that the likelihood of tumor formation depends on a combination of stochastic events and systematic characteristics. While stochasticity cannot be controlled, information on systematic effects may aid the development of prevention strategies tailored to the molecular characteristics of an individual patient.
We developed a computational model to study which factors of the tumor microenvironment drive prostate cancer development, with potential to aid the development of new prevention strategies.
一生中超过 10%的男性将被诊断患有前列腺癌。前列腺癌起源于前列腺腺泡的腔细胞，受其微环境中的多种细胞影响。为了扩展我们的知识并探索预防和治疗这种疾病的方法，了解是什么驱动了前列腺癌的发生和早期阶段非常重要。在这项研究中，我们开发了一个包括其微环境在内的前列腺腺泡的基于代理的模型，以允许研究前列腺癌的发展。该模型基于肿瘤细胞与癌相关成纤维细胞（CAF）以及促肿瘤和/或抗肿瘤巨噬细胞共培养的先前报告和内部数据。模型描绘的生长模式通过人类前列腺癌标本的苏木精和伊红幻灯片图像进行了病理学验证。我们发现，巨噬细胞和肿瘤细胞之间在早期的相互作用的随机性强烈影响肿瘤的发展。此外，我们发现，肿瘤发展的更系统偏差源自获得突变的概率和 CAF 和巨噬细胞的肿瘤促进能力的组合效应。然后将模型肿瘤与 494 名具有匹配特征的癌症患者进行比较，结果显示预测的肿瘤负荷与患者的临床结果之间存在很强的关联。我们的研究结果表明，肿瘤形成的可能性取决于随机事件和系统特征的组合。虽然随机性无法控制，但有关系统效应的信息可能有助于制定针对个体患者分子特征的预防策略。
我们开发了一种计算模型来研究肿瘤微环境中的哪些因素驱动前列腺癌的发展，这可能有助于开发新的预防策略。
