PDF(Pubmed)
Abstract：
BACKGROUND: Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME.
METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T.
RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α.
CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T.
RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α.
CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
摘要：
背景：过度的周细胞覆盖促进肿瘤生长，而下调可能会解决这一困境。由于血管周细胞在肿瘤微环境（TME）中的双刃剑作用，伊马替尼不加选择地降低周细胞覆盖率会导致不良的治疗结局.这里,我们优化了在高周细胞覆盖状态的结直肠癌（CRC）模型中使用伊马替尼，并揭示了9.4T时多参数磁共振成像（mpMRI）在监测与治疗相关的周细胞覆盖率和TME变化中的价值。
方法：通过组织学血管表征和mpMRI评估CRC异种移植模型。周细胞覆盖率最高的小鼠用伊马替尼或盐水治疗；然后，血管特征，对肿瘤细胞凋亡和HIF-1α水平进行组织学分析，通过qPCR评估Bcl-2/bax通路表达的改变。通过动态对比增强（DCE）监测伊马替尼的效果-，扩散加权成像（DWI）-和酰胺质子转移化学交换饱和转移（APTCEST）-MRI在9.4T。
结果：DCE参数提供了与肿瘤血管特征良好的组织学匹配。在高周细胞覆盖率状态下，伊马替尼表现出显著的肿瘤生长抑制，坏死增加和周细胞覆盖率下调，这些变化伴随着血管渗透性的增加，微血管密度（MVD）降低，肿瘤细胞凋亡增加，凋亡相关Bcl-2/bax通路基因表达改变。战略上,4天伊马替尼有效降低周细胞覆盖率和HIF-1α水平，连续治疗导致周细胞覆盖率下降不明显，HIF-1α水平再次升高。相关性分析证实了使用mpMRI参数监测伊马替尼治疗的可行性，DCE衍生的Ve和Ktrans与周细胞覆盖率最相关，Ve与血管渗透性，AUC与微血管密度（MVD），DWI衍生的ADC与肿瘤凋亡，和APTCEST衍生的MTRasym在1µT与HIF-1α。
结论：这些结果提供了优化的伊马替尼方案，以在高周细胞覆盖率CRC模型中降低周细胞覆盖率和HIF-1α水平，并提供了一种超高场多参数MRI方法，用于监测周细胞覆盖率和TME对治疗的动力学反应。
方法：通过组织学血管表征和mpMRI评估CRC异种移植模型。周细胞覆盖率最高的小鼠用伊马替尼或盐水治疗；然后，血管特征，对肿瘤细胞凋亡和HIF-1α水平进行组织学分析，通过qPCR评估Bcl-2/bax通路表达的改变。通过动态对比增强（DCE）监测伊马替尼的效果-，扩散加权成像（DWI）-和酰胺质子转移化学交换饱和转移（APTCEST）-MRI在9.4T。
结果：DCE参数提供了与肿瘤血管特征良好的组织学匹配。在高周细胞覆盖率状态下，伊马替尼表现出显著的肿瘤生长抑制，坏死增加和周细胞覆盖率下调，这些变化伴随着血管渗透性的增加，微血管密度（MVD）降低，肿瘤细胞凋亡增加，凋亡相关Bcl-2/bax通路基因表达改变。战略上,4天伊马替尼有效降低周细胞覆盖率和HIF-1α水平，连续治疗导致周细胞覆盖率下降不明显，HIF-1α水平再次升高。相关性分析证实了使用mpMRI参数监测伊马替尼治疗的可行性，DCE衍生的Ve和Ktrans与周细胞覆盖率最相关，Ve与血管渗透性，AUC与微血管密度（MVD），DWI衍生的ADC与肿瘤凋亡，和APTCEST衍生的MTRasym在1µT与HIF-1α。
结论：这些结果提供了优化的伊马替尼方案，以在高周细胞覆盖率CRC模型中降低周细胞覆盖率和HIF-1α水平，并提供了一种超高场多参数MRI方法，用于监测周细胞覆盖率和TME对治疗的动力学反应。
