Targeted imaging of breast tumor progression and therapeutic response in a human uMUC-1 expressing transgenic mouse model
Targeted imaging of breast tumor progression and therapeutic response in a human uMUC-1 expressing transgenic mouse model
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DOI：
10.1002/ijc.27872
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发表时间：
2013-04-15
影响因子：
6.4
通讯作者：
Medarova, Zdravka
中科院分区：
文献类型：
--
作者：
Ghosh, Subrata K.;Uchida, Masashi;Medarova, Zdravka
在分子水平上监测乳腺癌的发生和进展的能力将为早期诊断和治疗提供有效的工具。在本研究中，我们重点关注低糖基化MUC-1肿瘤抗原（uMUC-1），它与乳腺癌从癌前病变到晚期恶性肿瘤的肿瘤进展直接相关，并已被确定为局部复发和肿瘤的独立预测因素化疗反应。我们研究了在肿瘤发展和治疗干预过程中uMUC-1表达的变化是否可以使用分子成像方法进行非侵入性监测，该方法使用可通过磁共振和荧光光学成像检测的uMUC-1特异性造影剂（MN-EPPT）。这是在表达人uMUC-1肿瘤抗原的小鼠（MMT小鼠）中进行的，并以分期方式发展自发性乳腺癌。注射MN-EPPT后，在癌前病变和癌症之间，乳腺脂肪垫的平均T2弛豫时间显著减少。此外，与非荷瘤小鼠相比，这些小鼠在癌前状态下的T2弛豫时间已经改变。这表明靶向uMUC-1可用于检测乳腺脂肪垫中的癌前转化。我们还探测了在用阿霉素（Dox）治疗期间用MN-EPPT的uMUC-1表达的变化。我们观察到，通过用Dox处理，肿瘤Δ T2显著降低，表明MN-EPPT的累积较低。免疫印迹证实，这与Dox处理的肿瘤中MUC-1表达水平较低相关。我们的研究为监测肿瘤进展和治疗反应提供了一种非常灵敏的分子成像方法。
The ability to monitor breast cancer initiation and progression on the molecular level would provide an effective tool for early diagnosis and therapy. In the present study, we focused on the underglycosylated MUC-1 tumor antigen (uMUC-1), which is directly linked to tumor progression from pre-malignancy to advanced malignancy in breast cancer and has been identified as the independent predictor of local recurrence and tumor response to chemotherapy. We investigated whether changes in uMUC-1 expression during tumor development and therapeutic intervention could be monitored non-invasively using molecular imaging approach with the uMUC-1-specific contrast agent (MN-EPPT) detectable by magnetic resonance and fluorescence optical imaging. This was done in mice that express human uMUC-1 tumor antigen (MMT mice) and develop spontaneous mammary carcinoma in a stage-wise fashion. After the injection of MN-EPPT there was a significant reduction in average T2 relaxation times of the mammary fat pad between pre-malignancy and cancer. In addition, T2 relaxation times were already altered at pre-malignant state in these mice compared to non-tumor bearing mice. This indicated that targeting uMUC-1 could be useful for detecting pre-malignant transformation in the mammary fat pad. We also probed changes in uMUC-1 expression with MN-EPPT during therapy with doxorubicin (Dox). We observed that tumor delta-T2s were significantly reduced by treatment with Dox indicating lower accumulation of MN-EPPT. This correlated with a lower level of MUC-1 expression in the Dox-treated tumors, as confirmed by immunoblotting. Our study could provide a very sensitive molecular imaging approach for monitoring tumor progression and therapeutic response.