Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Int J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):866-75. doi: 10.1016/j.ijrobp.2014.12.004.
To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model.
The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non-small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated.
Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations.
The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from stereotactic ablative radiation therapy. The DLQ model also predicted the remarkable GBM radioresistance, a result that is highly consistent with clinical observations. The radioresistance putatively stemmed from accelerated DCC regrowth that rapidly restored compartmental equilibrium between CSCs and DCCs.
通过建立一个简单的癌症干细胞（CSC）相互作用模型进行初步探索，以确定肿瘤内在异质性和 CSC 与分化癌细胞（DCC）之间的动态平衡是否可以通过双室线性二次（DLQ）模型更好地解释放射治疗的反应。
使用 DLQ 模型对已发表的集落形成生存数据进行稳健最小二乘拟合，确定包括胶质母细胞瘤（GBM）、非小细胞肺癌、黑色素瘤、骨肉瘤和前列腺、宫颈和乳腺癌在内的癌细胞系中 CSC 和 DCC 的放射敏感性参数。将拟合性能与单室 LQ（SLQ）和通用生存曲线模型进行比较。然后，将拟合结果用于描述 2 至 14.3Gy 分段治疗中 DCC 和 CSC 动力学的常微分方程。计算达到肿瘤控制所需的总剂量和实现最小正常生物等效剂量的分数大小。
除了 SLQ 中α/β值为 0.16 的黑色素瘤外，DLQ 观察到更小的细胞存活拟合误差。常微分方程模拟表明，与 SLQ 相比，DLQ 模型下，4 种细胞系采用亚分割方法达到相同的肿瘤控制时，正常组织的生物等效剂量更低，除了黑色素瘤之外，所有细胞都更倾向于 2Gy/次的分割。DLQ 模型表明 CSCs 的放射抗性大于 SLQ，但亚分割克服了放射抗性，而 GBM 细胞对所有分割都反应不佳。
在放射治疗反应中 CSCs 和 DCC 之间明显不同的放射敏感性和动力学特性，可能是解释肿瘤对亚分割和立体定向消融放射治疗的不同反应以及在某些情况下获得更好结果的一个可能原因。DLQ 模型还预测了 GBM 令人瞩目的放射抗性，这一结果与临床观察高度一致。这种抗性可能源于 DCC 的快速恢复，从而迅速恢复 CSCs 和 DCC 之间的隔室平衡。
