低剂量~(125)I内照射A549肺癌的有关分子生物学及~(99)Tc~m-AnnexinV与MR-DWI影像学研究
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摘要
目的
观察低剂量~(125)I持续内照射对A549肺癌细胞裸鼠肿瘤的抑瘤作用、可能的机制及其肿瘤分子生物学特性与辐射敏感性相关调节因子表达的影响，并探索用放射性核素~(99)Tc~m-AnnexinV细胞凋亡显像联合磁共振弥散加权成像（MR-DWI）观察~(125)I内照射辐射致肺癌A549细胞凋亡的可行性。
方法
制作A549肺癌细胞BALB/c-nu裸鼠肿瘤模型共36只，用随机数字表法随机分为A、B和C三组，每组裸鼠12只，A组进行常规剂量~(125)I放射性粒子（25.5~27.8MBq/粒，平均26.9MBq/粒）瘤体内植入治疗，B组植入极低剂量（4.4~6.3MBq/粒，平均5.1MBq/粒）~(125)I放射性粒子，C组植入无放射性的“冷粒子”作为对照，每只裸鼠每瘤体植入粒子1粒。治疗前、治疗后14d进行~(99)Tc~m-AnnexinV显像和MR-DWI成像，分析各组治疗前、治疗后~(99)Tc~m-AnnexinV显像和MR-DWI成像特征变化，观察~(125)I粒子对A549细胞裸鼠肿瘤的制瘤效果；HE病理切片分析、免疫组化（S-P法）检测A549细胞裸鼠肿瘤细胞核因子κB（NF-κB）、乏氧诱导因子1α（HIF-1α）、细胞凋亡相关蛋白（survivin、caspase-3）、细胞周期调节蛋白（cyclinD1、p27）和热休克蛋白90（HSP90）等的表达，分析~(125)I持续内照射对上述各分子病理指标表达的影响及其各指标之间的相关关系。
结果
1抑瘤效果：~(125)I放射性粒子瘤体内植入对A549肺癌细胞裸鼠肿瘤产生抑瘤作用，常规剂量~(125)I放射性粒子植入治疗14d的肿瘤体积抑制率为51.2%，极低剂量~(125)I放射性粒子植入治疗的肿瘤体积抑制率为20.9%，“冷粒子”治疗无抑瘤效果。
2HE染色病理观察：A组见~(125)I粒子周边部肿瘤细胞损伤严重，呈红染的弥漫性坏死，损伤程度由粒子周边部向外逐渐减弱；B组~(125)I粒子内照射所致坏死程度和范围不如A组；C组见“冷粒子”周围肿瘤细胞轮廓清晰，生长良好，肿瘤细胞核大、深染，部分裸鼠可见肿瘤组织直接浸润到周围肌肉组织中；无论A组还是B组肿瘤瘤体内血管周围的肿瘤细胞生长良好。
3免疫组化（S-P法）检测：~(125)I粒子治疗后各组A549肺癌细胞NF-κB、HIF-1α、survivin、caspase-3、cyclinD1、p27和HSP90的表达不尽相同，其中HIF-1α和HSP90的表达，A组与B组比较差异显著（P<0.05），survivin、caspase-3和p27的表达，A组与对C组比较差异显著（P <0.05），cyclinD、 p27和HSP90的表达，B组与C组比较差异显著（P<0.05）。各指标之间，部分呈一定程度的正相关（r=0.322~0.591，P <0.05）或负相关（r=-0.339~-0.503，P <0.05）。TUNEL细胞凋亡检测显示A组细胞凋亡指数（AI）显著大于B组和C组（分别为0.39±0.20、0.26±0.15和0.17±0.11，P=0.015）。
4~(99)Tc~m-Annexin V细胞凋亡显像：A组治疗后A549肺癌裸鼠肿瘤~(99)Tc~m-Annexin V细胞凋亡显像阳性率58.3%（7/12）明显高于治疗前8.1%（1/12）（P<0.05），B、C两组治疗前、后无显著性差异（P>0.05）；治疗前A、B和C各组~(99)Tc~m-Annexin V摄取比值（RI）差异无显著性（分别为1.30±0.39，1.72±0.71和1.39±0.42，P>0.05），A组治疗14d后的RI（3.03±1.69）比治疗前显著增高（t=3.346，P=0.007）。
5MR-DWI成像：治疗前A、B和C组MR-DWI成像表观扩散系数（ADC）分别为（1.35±0.38）×10~(-3)mm~2/s，（1.24±0.28）×10~(-3)mm~2/s和（1.51±0.46）×10~(-3)mm~2/s，各组间无显著性差异（P>0.05）。A组~(125)I粒子治疗后ADC为（2.50±1.08）×10~(-3)mm~2/s，大于治疗前（P <0.05），B组和C组治疗前、后ADC无显著变化（P>0.05）。RI与ADC低度正相关（r=0.310，P <0.05）。治疗后RI与AI中度正相关（r=0.566，P <0.05），ADC与AI和RI低度正相关（r分别为0.311和0.329，P <0.05）。
结论
1常规治疗剂量~(125)I放射性粒子（25.5~27.8MBq/粒，平均26.9MBq/粒）对A549肺癌细胞裸鼠肿瘤有明显的抑瘤作用，治疗后14d的肿瘤体积抑制率达51.2%，~(125)I内照射抑瘤作用的机制之一可能是细胞凋亡诱导。
2~(99)Tc~m-Annexin V细胞凋亡显像和MR-DWI成像可有效观察~(125)I内照射电离辐射致A549肺癌细胞凋亡。
3不同辐射剂量~(125)I内照射对多个与A549肺癌细胞裸鼠肿瘤分子生物学特性和辐射敏感性密切相关的细胞调节因子（NF-κB、HIF-1α、survivin、caspase-3、cyclinD1、p27和HSP90）表达的影响不尽相同。
Objective:
To investigate the tumor inhibitory effect, possible mechanism and the influence ofregulatory proteins' expression related to molecular biological characteristics andradiosensitivity of continuous low-dose~(125)I irradiation seeds interstitial brachytherapy onimplanted A549lung adenocarcinoma cells in nude mice, and explore the feasibility ofnoninvasive way detecting apoptosis induced by~(125)I ionization radiation using~(99)Tc~m-AnnexinV combined with diffusion weighted magnetic resonance imaging(MR-DWI).
Methods:
36BALB/c-nu nude mice bearing A549cells were randomly stratified into three groups:group A, B and C(control group). One conventional dose~(125)I seed with the apparent activityof (25.5~27.8, mean26.9)MBq was implanted into each tumor in group A，extremelylow-dose~(125)I seed with the apparent activity was (4.4~6.3, mean5.1)MBq was implantedinto group B, while the control group received "cold seeds" treatment. After treatment,the volume of the tumors was measured every two days. Both~(99)Tc~m-Annexin V imaging andMR-DWI were performed before and after14days of the brachytherapy, then all mice weresacrificed for pathological examination, routine pathological slides of tumor tissue wereobserved under light microscope to evaluate the range of tumor tissues damaged induced by~(125)I seeds, the weight of tumors was measured, tumor control rate was calculated, apoptosiswas detected in tumor tissue by TUNEL immunofluorescence, the expression of molecularbiomarkers such as NF-κB, HIF-1α, survivin, caspase-3, cyclinD1, p27and HSP90was alsoassayed by immunohistochemical(S-P)determination.
Results:
1The inhibition rate of tumor volume were51.2%and20.9%in group A and group B,respectively, not any inhibitory effect could be found in group C which handled with "coldseeds".
2Pathological examination showed diffuse necrosis dramatically presented aroundingactive~(125)I seeds both in groups A and B, but damage induced by~(125)I ionization radiation wasmore serious in groups A than groups B with a much larger area of necrosis, no pathologicalchanges but slight fibroplasia were observed at the periphery of dummy seeds("cold seeds"),more over, A549lung cell could be seen infiltrating into the nearing muscle tissue directly.Tumor cells which arounding blood vessels avoided from~(125)I ionization radiation both in the A group and group B.
3The results of immunohistochemistry showed, the expression rate of NF-κB, HIF-1α,survivin, caspase-3, cyclinD1, p27and HSP90in A549lung cells were not the same amongthe three groups after treatment.The expression of HIF-1α and HSP90in group A weredifferent from that of group A(P<0.05), the expression of survivin, caspase-3and p27weresignificantly different (P<0.05) between group A and group C, the expression of cyclinD,p27and HSP90were also significantly different(P<0.05)between group B and group C.Positive or nagtive correlation to some degree among these molecular biomarkers were found,cell apoptosis index(AI)detected by TUNEL in group A was significantly higher than that ingroup B and group C (0.39±0.20,0.26±0.15and0.17±0.11repectively, P<0.05).
4Positive rate of~(99)Tc~m-Annexin V imaging after14days of~(125)I brachytherapy was58.3%(7/12), which was significantly higher than that of before brachytherapy [8.3%(1/12), P<0.05)]. The uptake ratio of~(99)Tc~m-Annexin V(RI)before the treatment in groupsA, B and C was1.30±0.39,1.72±0.71and1.39±0.42, respectively(P>0.05). However, RIafter14days' treatment(3.03±1.69)was increased significantly compared with that of thebefore brachytherapy in groups A(t=3.346, P=0.007).
5Apparent diffusion coefficient(ADC) value of the tumor in groups A, B and C was(1.35±0.38)×10~(-3)mm~2/s,(1.24±0.28)×10~(-3)mm~2/s and(1.51±0.46)×10~(-3)mm~2/s respectivelybefore the treatment, no significant difference were found among them(P>0.05), ADC ingroup A after the brachytherapy was (2.50±1.08)×10~(-3)mm~2/s, which significantlyincreased compared with that of before the treatment(t=3.924, P=0.007). In all, the value ofADC was correlated with RI(r=0.310, P<0.05). Positive relationship between RI and AI afterthe brachytherapy was found(r=0.566, P<0.05), and ADC was positively correlated with RIand AI in some degree(r=0.311and0.329, repectively, P<0.05).
Conclusion:
1The interstitial brachytherapy with~(125)I seeds of the dosage was25.5~27.8MBq in eachseed could significantly inhibit the growth of A549solid tumor in mice, with the inhibitionrate of tumor volume was51.2%after14days' treatment, one of the mechanisms of~(125)Iinterstitial brachytherapy may be the apoptosis induced by~(125)I ionization radiation.
2~(99)Tc~m-Annexin V imaging combined with magnetic resonance diffusion weightedimaging (MR-DWI)could effectively evaluating the apoptosis of lung adenocarcinoma cellsinduced by~(125)I interstitial brachytherapy in a noninvasive way, hence,~(99)Tc~m-Annexin V combined with MR-DWI is conductive to determining the early efficacy of25I seedsbrachytherapy.
3Some key molecular proteins such as NF-κ B, HIF-1α, survivin, caspase-3, cyclinD1,p27and HSP90which playing an important role in tumor molecular biological behavior andthe radiosensitivity were expressed diversely under the low dose of~(125)I irradiation on A549lung cancer.
观察低剂量~(125)I持续内照射对A549肺癌细胞裸鼠肿瘤的抑瘤作用、可能的机制及其肿瘤分子生物学特性与辐射敏感性相关调节因子表达的影响，并探索用放射性核素~(99)Tc~m-AnnexinV细胞凋亡显像联合磁共振弥散加权成像（MR-DWI）观察~(125)I内照射辐射致肺癌A549细胞凋亡的可行性。
方法
制作A549肺癌细胞BALB/c-nu裸鼠肿瘤模型共36只，用随机数字表法随机分为A、B和C三组，每组裸鼠12只，A组进行常规剂量~(125)I放射性粒子（25.5~27.8MBq/粒，平均26.9MBq/粒）瘤体内植入治疗，B组植入极低剂量（4.4~6.3MBq/粒，平均5.1MBq/粒）~(125)I放射性粒子，C组植入无放射性的“冷粒子”作为对照，每只裸鼠每瘤体植入粒子1粒。治疗前、治疗后14d进行~(99)Tc~m-AnnexinV显像和MR-DWI成像，分析各组治疗前、治疗后~(99)Tc~m-AnnexinV显像和MR-DWI成像特征变化，观察~(125)I粒子对A549细胞裸鼠肿瘤的制瘤效果；HE病理切片分析、免疫组化（S-P法）检测A549细胞裸鼠肿瘤细胞核因子κB（NF-κB）、乏氧诱导因子1α（HIF-1α）、细胞凋亡相关蛋白（survivin、caspase-3）、细胞周期调节蛋白（cyclinD1、p27）和热休克蛋白90（HSP90）等的表达，分析~(125)I持续内照射对上述各分子病理指标表达的影响及其各指标之间的相关关系。
结果
1抑瘤效果：~(125)I放射性粒子瘤体内植入对A549肺癌细胞裸鼠肿瘤产生抑瘤作用，常规剂量~(125)I放射性粒子植入治疗14d的肿瘤体积抑制率为51.2%，极低剂量~(125)I放射性粒子植入治疗的肿瘤体积抑制率为20.9%，“冷粒子”治疗无抑瘤效果。
2HE染色病理观察：A组见~(125)I粒子周边部肿瘤细胞损伤严重，呈红染的弥漫性坏死，损伤程度由粒子周边部向外逐渐减弱；B组~(125)I粒子内照射所致坏死程度和范围不如A组；C组见“冷粒子”周围肿瘤细胞轮廓清晰，生长良好，肿瘤细胞核大、深染，部分裸鼠可见肿瘤组织直接浸润到周围肌肉组织中；无论A组还是B组肿瘤瘤体内血管周围的肿瘤细胞生长良好。
3免疫组化（S-P法）检测：~(125)I粒子治疗后各组A549肺癌细胞NF-κB、HIF-1α、survivin、caspase-3、cyclinD1、p27和HSP90的表达不尽相同，其中HIF-1α和HSP90的表达，A组与B组比较差异显著（P<0.05），survivin、caspase-3和p27的表达，A组与对C组比较差异显著（P <0.05），cyclinD、 p27和HSP90的表达，B组与C组比较差异显著（P<0.05）。各指标之间，部分呈一定程度的正相关（r=0.322~0.591，P <0.05）或负相关（r=-0.339~-0.503，P <0.05）。TUNEL细胞凋亡检测显示A组细胞凋亡指数（AI）显著大于B组和C组（分别为0.39±0.20、0.26±0.15和0.17±0.11，P=0.015）。
4~(99)Tc~m-Annexin V细胞凋亡显像：A组治疗后A549肺癌裸鼠肿瘤~(99)Tc~m-Annexin V细胞凋亡显像阳性率58.3%（7/12）明显高于治疗前8.1%（1/12）（P<0.05），B、C两组治疗前、后无显著性差异（P>0.05）；治疗前A、B和C各组~(99)Tc~m-Annexin V摄取比值（RI）差异无显著性（分别为1.30±0.39，1.72±0.71和1.39±0.42，P>0.05），A组治疗14d后的RI（3.03±1.69）比治疗前显著增高（t=3.346，P=0.007）。
5MR-DWI成像：治疗前A、B和C组MR-DWI成像表观扩散系数（ADC）分别为（1.35±0.38）×10~(-3)mm~2/s，（1.24±0.28）×10~(-3)mm~2/s和（1.51±0.46）×10~(-3)mm~2/s，各组间无显著性差异（P>0.05）。A组~(125)I粒子治疗后ADC为（2.50±1.08）×10~(-3)mm~2/s，大于治疗前（P <0.05），B组和C组治疗前、后ADC无显著变化（P>0.05）。RI与ADC低度正相关（r=0.310，P <0.05）。治疗后RI与AI中度正相关（r=0.566，P <0.05），ADC与AI和RI低度正相关（r分别为0.311和0.329，P <0.05）。
结论
1常规治疗剂量~(125)I放射性粒子（25.5~27.8MBq/粒，平均26.9MBq/粒）对A549肺癌细胞裸鼠肿瘤有明显的抑瘤作用，治疗后14d的肿瘤体积抑制率达51.2%，~(125)I内照射抑瘤作用的机制之一可能是细胞凋亡诱导。
2~(99)Tc~m-Annexin V细胞凋亡显像和MR-DWI成像可有效观察~(125)I内照射电离辐射致A549肺癌细胞凋亡。
3不同辐射剂量~(125)I内照射对多个与A549肺癌细胞裸鼠肿瘤分子生物学特性和辐射敏感性密切相关的细胞调节因子（NF-κB、HIF-1α、survivin、caspase-3、cyclinD1、p27和HSP90）表达的影响不尽相同。
Objective:
To investigate the tumor inhibitory effect, possible mechanism and the influence ofregulatory proteins' expression related to molecular biological characteristics andradiosensitivity of continuous low-dose~(125)I irradiation seeds interstitial brachytherapy onimplanted A549lung adenocarcinoma cells in nude mice, and explore the feasibility ofnoninvasive way detecting apoptosis induced by~(125)I ionization radiation using~(99)Tc~m-AnnexinV combined with diffusion weighted magnetic resonance imaging(MR-DWI).
Methods:
36BALB/c-nu nude mice bearing A549cells were randomly stratified into three groups:group A, B and C(control group). One conventional dose~(125)I seed with the apparent activityof (25.5~27.8, mean26.9)MBq was implanted into each tumor in group A，extremelylow-dose~(125)I seed with the apparent activity was (4.4~6.3, mean5.1)MBq was implantedinto group B, while the control group received "cold seeds" treatment. After treatment,the volume of the tumors was measured every two days. Both~(99)Tc~m-Annexin V imaging andMR-DWI were performed before and after14days of the brachytherapy, then all mice weresacrificed for pathological examination, routine pathological slides of tumor tissue wereobserved under light microscope to evaluate the range of tumor tissues damaged induced by~(125)I seeds, the weight of tumors was measured, tumor control rate was calculated, apoptosiswas detected in tumor tissue by TUNEL immunofluorescence, the expression of molecularbiomarkers such as NF-κB, HIF-1α, survivin, caspase-3, cyclinD1, p27and HSP90was alsoassayed by immunohistochemical(S-P)determination.
Results:
1The inhibition rate of tumor volume were51.2%and20.9%in group A and group B,respectively, not any inhibitory effect could be found in group C which handled with "coldseeds".
2Pathological examination showed diffuse necrosis dramatically presented aroundingactive~(125)I seeds both in groups A and B, but damage induced by~(125)I ionization radiation wasmore serious in groups A than groups B with a much larger area of necrosis, no pathologicalchanges but slight fibroplasia were observed at the periphery of dummy seeds("cold seeds"),more over, A549lung cell could be seen infiltrating into the nearing muscle tissue directly.Tumor cells which arounding blood vessels avoided from~(125)I ionization radiation both in the A group and group B.
3The results of immunohistochemistry showed, the expression rate of NF-κB, HIF-1α,survivin, caspase-3, cyclinD1, p27and HSP90in A549lung cells were not the same amongthe three groups after treatment.The expression of HIF-1α and HSP90in group A weredifferent from that of group A(P<0.05), the expression of survivin, caspase-3and p27weresignificantly different (P<0.05) between group A and group C, the expression of cyclinD,p27and HSP90were also significantly different(P<0.05)between group B and group C.Positive or nagtive correlation to some degree among these molecular biomarkers were found,cell apoptosis index(AI)detected by TUNEL in group A was significantly higher than that ingroup B and group C (0.39±0.20,0.26±0.15and0.17±0.11repectively, P<0.05).
4Positive rate of~(99)Tc~m-Annexin V imaging after14days of~(125)I brachytherapy was58.3%(7/12), which was significantly higher than that of before brachytherapy [8.3%(1/12), P<0.05)]. The uptake ratio of~(99)Tc~m-Annexin V(RI)before the treatment in groupsA, B and C was1.30±0.39,1.72±0.71and1.39±0.42, respectively(P>0.05). However, RIafter14days' treatment(3.03±1.69)was increased significantly compared with that of thebefore brachytherapy in groups A(t=3.346, P=0.007).
5Apparent diffusion coefficient(ADC) value of the tumor in groups A, B and C was(1.35±0.38)×10~(-3)mm~2/s,(1.24±0.28)×10~(-3)mm~2/s and(1.51±0.46)×10~(-3)mm~2/s respectivelybefore the treatment, no significant difference were found among them(P>0.05), ADC ingroup A after the brachytherapy was (2.50±1.08)×10~(-3)mm~2/s, which significantlyincreased compared with that of before the treatment(t=3.924, P=0.007). In all, the value ofADC was correlated with RI(r=0.310, P<0.05). Positive relationship between RI and AI afterthe brachytherapy was found(r=0.566, P<0.05), and ADC was positively correlated with RIand AI in some degree(r=0.311and0.329, repectively, P<0.05).
Conclusion:
1The interstitial brachytherapy with~(125)I seeds of the dosage was25.5~27.8MBq in eachseed could significantly inhibit the growth of A549solid tumor in mice, with the inhibitionrate of tumor volume was51.2%after14days' treatment, one of the mechanisms of~(125)Iinterstitial brachytherapy may be the apoptosis induced by~(125)I ionization radiation.
2~(99)Tc~m-Annexin V imaging combined with magnetic resonance diffusion weightedimaging (MR-DWI)could effectively evaluating the apoptosis of lung adenocarcinoma cellsinduced by~(125)I interstitial brachytherapy in a noninvasive way, hence,~(99)Tc~m-Annexin V combined with MR-DWI is conductive to determining the early efficacy of25I seedsbrachytherapy.
3Some key molecular proteins such as NF-κ B, HIF-1α, survivin, caspase-3, cyclinD1,p27and HSP90which playing an important role in tumor molecular biological behavior andthe radiosensitivity were expressed diversely under the low dose of~(125)I irradiation on A549lung cancer.
引文
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