The response of tumors to anti-cancer therapies is defined not only by cell-intrinsic therapy sensitivities but also by local interactions with the tumor microenvironment. Fibroblasts that make tumor stroma have been shown to produce paracrine factors that can strongly reduce the sensitivity of tumor cells to many types of targeted therapies. Moreover, a high stroma/tumor ratio is generally associated with poor survival and reduced therapy responses. However, in contrast to advanced knowledge of the molecular mechanisms responsible for stroma-mediated resistance, its effect on the ability of tumors to escape therapeutic eradication remains poorly understood. To a large extent, this gap of knowledge reflects the challenge of accounting for the spatial aspects of microenvironmental resistance, especially over longer time frames. To address this problem, we integrated spatial inferences of proliferation-death dynamics from an experimental animal model of targeted therapy responses with spatial mathematical modeling. With this approach, we dissected the impact of tumor/stroma distribution, magnitude and distance of stromal effects. While all of the tested parameters affected the ability of tumor cells to resist elimination, spatial patterns of stroma distribution within tumor tissue had a particularly strong impact.
肿瘤对抗癌疗法的反应不仅取决于细胞内在的治疗敏感性，还取决于其与肿瘤微环境的局部相互作用。研究表明，构成肿瘤基质的成纤维细胞能够分泌旁分泌因子，显著降低肿瘤细胞对多种靶向治疗的敏感性。此外，较高的基质/肿瘤比例通常与患者生存率降低及治疗反应减弱相关。然而，尽管对基质介导耐药性的分子机制已有深入认识，但其对肿瘤逃避治疗根除能力的影响仍知之甚少。这种认知差距在很大程度上反映了考虑微环境耐药性空间特性（尤其是在较长时间范围内）所面临的挑战。为解决这一问题，我们将靶向治疗反应的实验动物模型中增殖-死亡动力学的空间推断与空间数学模型相结合。通过这种方法，我们解析了肿瘤/基质分布、基质效应强度及作用距离的影响。虽然所有测试参数均影响肿瘤细胞抵抗清除的能力，但肿瘤组织内基质分布的空间模式具有特别显著的影响。
肿瘤(癌症)患者之家