同种移植小鼠乳腺癌超声造影增强模式与缺氧诱导因子1α的相关性

Correlation of Contrast-enhanced Ultrasound with Expression of Hypoxia Inducible Factor-1α in Transplanted Mice Mammary Cancer

目的探讨乳腺癌超声造影（CEUS）增强模式与缺氧诱导因子1α（HIF-1α）表达及微血管密度（MVD）的关系。方法在22只小鼠体内建立同种移植性乳腺癌,于接种后第4、6、7、8、9、10、11天随机抓取3~4只小鼠进行常规超声及CEUS检查,检查结束后处死小鼠并使用免疫组织化学方法检测肿瘤标本中HIF-1α表达及MVD,分析CEUS增强模式与HIF-1α表达及MVD的关系。结果 22只小鼠乳腺癌中瘤体〈0.05 cm3组5例,CEUS表现为Ⅰ型增强模式,周边环状增强,内部无增强4例,Ⅱ型增强模式,周边环状增强并向病灶内呈点线状穿入1例;0.05~0.75 cm3组9例,多表现为Ⅲ型增强模式,病灶弥漫性增强,均匀/不均匀5例;〉0.75 cm3组8例,多表现为Ⅳ型增强模式,周边环状增强,内部结节状增强7例。3组瘤体在CEUS增强模式上差异有统计学意义（P〈0.01）,Ⅰ~Ⅳ型CEUS增强模式与肿瘤大小相关（r=0.841,P〈0.05）。小鼠乳腺癌中HIF-1α表达与增强模式（Ⅰ~Ⅳ型）呈负相关（r=-0.596,P=0.003）,与肿瘤大小无相关性（P〉0.05）。Ⅰ~Ⅳ型CEUS增强模式间MVD均值差异无统计学意义,MVD与肿瘤大小无相关性（P〉0.05）。结论 CEUS可动态评估同种移植性小鼠乳腺癌的血管生成,肿瘤增强模式与肿瘤HIF-1α的表达水平相关。

Objective To investigate the correlation of contrast-enhanced pattern with expression ofhypoxia inducible factor-1α（ HIF-1α） and microvessel density（ MVD） in mice breast cancer. Methods A total of 22 mice were implanted with breast cancer cells（ Ca761） subcutanously in the thigh. The tumors were examined with conventional ultrasound and contrast-enhanced ultrasound（ CEUS） on days 4,6,7,8,9,10,and11 after implantation and then sacrificed. Three or four mice were included each time. Expressions of HIF-1αand MVD in cancer tissues were detected immunohistochemically. Correlation of contrast-enhanced patterns with expression of HIF-1α and MVD in breast cancer was analyzed. Results Mice were divided into 3 groups according to the tumor volume： group 1（ volume 0. 05 cm3,n = 5）,group 2（ volume 0. 05-0. 75 cm3,n = 9）,and group 3（ volume 0. 75 cm3,n = 8）. The CEUS pattern was different in different groups： four mice in group 1 presented as type Ⅰ（ peripheral ring enhancement with no enhancement within the tumor） and 1 case presented as type Ⅱ（ peripheral ring enhancement with deep penetration）. Most mice in group 2 presented as type Ⅲ（ homogeneous or heterogeneous enhancement in the whole tumor,n = 5）. In group 3,most mice presented as type Ⅳ（ peripheral ring enhancement with focal nodular enhancement within the tumor,n = 7）. Contrast-enhanced pattern was significantly different in different volume groups（ P〈0. 01）. Enhanced pattern（ type Ⅰ-Ⅳ） was closely correlated with tumor volume（ r = 0. 841,P〈0. 05）. The expression of HIF-1α was negatively correlated with enhanced patterns（ type Ⅰ-Ⅳ）（ r =- 0. 596,P = 0. 003）,but not with tumor volume（ P〈0. 05）. There was no significant difference in MVD values between different enhanced patterns（ typeⅠ-Ⅳ）,and there was no correlation between the MVD and tumor volumes（ P〉0. 05）. Conclusion CEUS can be used as a noninvasive tool to monitor tumor angiogenesis in tumor and the enhanced patterns may reflect the expression of HIF-1α inside the tumor.