欢迎来到《四川大学学报(医学版)》 2025年4月6日 星期日

电针围刺诱导小鼠乳腺癌微血管正常化的初步研究

常馨, 卢涛, 黄金昶

常馨, 卢涛, 黄金昶. 电针围刺诱导小鼠乳腺癌微血管正常化的初步研究[J]. 四川大学学报(医学版), 2023, 54(5): 972-977. DOI: 10.12182/20230960401
引用本文: 常馨, 卢涛, 黄金昶. 电针围刺诱导小鼠乳腺癌微血管正常化的初步研究[J]. 四川大学学报(医学版), 2023, 54(5): 972-977. DOI: 10.12182/20230960401
CHANG Xin, LU Tao, HUANG Jinchang. Preliminary Study on Microvasculature Normalization Induced by Peritumoral Electroacupuncture in Mice With Breast Cancer Xenografts[J]. Journal of Sichuan University (Medical Sciences), 2023, 54(5): 972-977. DOI: 10.12182/20230960401
Citation: CHANG Xin, LU Tao, HUANG Jinchang. Preliminary Study on Microvasculature Normalization Induced by Peritumoral Electroacupuncture in Mice With Breast Cancer Xenografts[J]. Journal of Sichuan University (Medical Sciences), 2023, 54(5): 972-977. DOI: 10.12182/20230960401

电针围刺诱导小鼠乳腺癌微血管正常化的初步研究

基金项目: 国家自然科学基金面上项目(No. 82074545)资助
详细信息
    通讯作者:

    黄金昶: E-mail:zryhhuang@163.com

Preliminary Study on Microvasculature Normalization Induced by Peritumoral Electroacupuncture in Mice With Breast Cancer Xenografts

More Information
  • 摘要:
      目的  本研究旨在探讨电针围刺诱导小鼠乳腺癌微血管正常化的作用。
      方法  用6~8周龄雌性BALB/c小鼠构建4T1乳腺癌皮下移植瘤模型,并随机分为荷瘤组(tumor-bearing group, TG)、电针围刺组(electroacupuncture tumor-bearing group, EATG)、贝伐单抗组(bevacizumab tumor-bearing group, BTG),每组18只。TG组不予干预,EATG组电针围刺30 min,BTG组腹腔注射10 mg/kg贝伐单抗。在干预前和干预后第3、5天利用免疫荧光检测肿瘤组织CD31、α-肌动蛋白(alpha smooth muscle actin, α-SMA)、缺氧诱导因子1α(hypoxia-inducible factor 1-alpha, HIF-1α)表达情况;干预后第3天用苏木精-伊红(HE)染色、扫描电镜观察肿瘤微血管形态。
      结果  干预前各组肿瘤组织CD31、α-SMA、HIF-1α表达均无明显差异(P>0.05)。干预后第3天,EATG组、BTG组肿瘤组织CD31、HIF-1α表达水平均明显降低(P<0.01),α-SMA表达水平均明显增加(P<0.01)。干预后第5天,EATG组、BTG组肿瘤组织CD31、 HIF-1α表达水平仍低于TG组(P<0.01),α-SMA表达水平高于TG组(P<0.05)。干预后第3天,HE染色各组肿瘤组织均可见微血管;扫描电镜观察显示,TG组肿瘤微血管管壁粗糙、有缺损、管腔出现明显畸形,而EATG组、BTG组肿瘤微血管管壁完整性较好,管腔未出现明显畸形。
      结论  电针围刺可能通过降低微血管密度,提高新生血管的周细胞覆盖,诱导小鼠乳腺癌微血管正常化,从而改善肿瘤乏氧微环境。

     

    Abstract:
      Objective  To observe the effect of peritumoral electroacupuncture on the induction of vascular normalization in a mouse breast cancer model.
      Methods  A subcutaneous graft model of breast cancer was established with 4T1 breast cancer cell line in female BALB/c mice aged 6-8 weeks. The mice were randomly assigned to three groups, a tumor-bearing group (TG), peritumoral electroacupuncture tumor-bearing group (EATG), and bevacizumab tumor-bearing group (BTG), with 18 mice in each group. The TG mice did not receive any intervention, the EATG mice received peritumoral electroacupuncture for 30 minutes, and the BTG mice were intraperitoneally injected with bevacizumab at 10mg/kg. Immunofluorescence was performed to assess the expression of CD31/alpha smooth muscle actin (α-SMA) and hypoxia-inducible factor 1-alpha (HIF-1α) in the tumor tissue at various points of time, including before intervention and 3 days and 5 days after intervention. Then, 3 days after intervention, observation of morphological changes of the microvessels in the tumor tissue was performed through Hematoxylin and Eosin (HE) staining and scanning electron microscope.
      Results  There was no significant difference in the expression of CD31, α-SMA, and HIF-1α in the tumor tissues of all groups before experimental intervention (P>0.05). On day 3 of the experimental interventions, the CD31 and HIF-1α expression levels in the tumor tissues of the EATG and BTG mice were significantly reduced (P<0.01), while α-SMA expression levels were significantly increased (P<0.01) in both groups. On day 5 of the experimental interventions, the CD31 and HIF-1α expression levels in the tumor tissues of the EATG and BTG mice were still significantly lower than those in the TG mice (P<0.01), while the α-SMA expression level was significantly higher than that in the TG group (P<0.05). On day 3 of the experimental interventions, H&E staining showed visible microvessels in the tumor tissues of all 3 groups. In addition, scanning electron microscopic observation showed that the tumor microvessel walls of the TG mice were rough and defective, and that obvious deformities appeared in the lumen. In contrast, the walls of the microvessels of the EATG and BTG mice were generally intact and there was no obvious deformities in the lumen.
      Conclusion  Peritumoral electroacupuncture may induce microvasculature normalization by decreasing microvascular density and increasing pericyte coverage of the neovasculature, thereby improving hypoxic microenvironment of breast cancer in mice.

     

  • 乳腺癌是女性最常见的恶性肿瘤[1],早期预后较好,中晚期乳腺癌治疗仍面临严峻挑战[2]。不同病理类型的乳腺癌预后不同,其中雌激素受体、孕激素受体以及表皮生长因子受体2表达较低或不表达的三阴性乳腺癌侵袭性强、异质性高,其临床预后较差,缺乏特异性治疗手段[2]。围刺属于中医传统外治疗法,是以病变部位为中心,沿病变边缘包围性针刺,具有疏通气血之效。前期研究发现,围刺可抑制肿瘤生长,其与化疗药物联合可增强抗肿瘤效应[3-6]。此外,围刺可显著提高小鼠乳腺癌肿瘤部位紫杉醇药物浓度,围刺及其与化疗药物的协同抗肿瘤作用与肿瘤微血管正常化密切相关[7]。肿瘤微血管正常化是指通过促进肿瘤异常血管的结构与功能向正常血管转化,以增强血管运输能力、改善肿瘤组织灌注、纠正酸性乏氧微环境,促使药物更高效地输送至肿瘤细胞,从而提高抗肿瘤疗效。本研究拟通过构建4T1小鼠乳腺癌皮下移植瘤模型,观察电针围刺诱导肿瘤微血管正常化的作用。

    来源于BALB/c小鼠的4T1乳腺癌细胞株(中国医学科学院肿瘤医院肿瘤研究所细胞库)。6~8周龄SPF级雌性Balb/c小鼠54只,体质量16~18 g(动物合格证号:SCXK2016-0006),饲养于北京中医药大学和平街校区动物室SPF级实验室。本研究过程严格遵守北京中医药大学医学与实验动物伦理委员要求(伦理编号:BUCM-4-2021060701-2085)。

    贝伐珠单抗注射液(上海罗氏制药有限公司,中国),CD31、α-肌动蛋白(alpha smooth muscle actin, α-SMA)、缺氧诱导因子1α(hypoxia-inducible factor 1-alpha, HIF-1α)抗体(Abcam,美国),RPMI-1640培养基、胎牛血清、胰蛋白酶(Thermo,美国),扫描电子显微镜(无锡创辉测量技术有限公司,中国),一次性无菌针灸针(0.18 mm×15 mm)、SDZ-V系列电子低频针疗仪(华佗牌,中国),组织脱水机、组织包埋机、切片机(樱花株式会社,日本),CO2培养箱(Thermo,美国),生物数字显微镜(Leica,德国)。

    小鼠4T1乳腺癌细胞株用含10%胎牛血清、1%青霉素-链霉素培养于37 ℃、体积分数为5%CO2的培养箱。取对数生长期4T1细胞,于小鼠左侧大腿外侧皮下接种肿瘤细胞悬液0.1 mL(约1×106个细胞),构建BALB/c小鼠乳腺癌皮下移植瘤模型[8]。判断小鼠移植瘤模型成功的标准:H&E病理证实组织为乳腺癌,且肿瘤体积大小约200 mm3[9]

    以小鼠肿瘤体积为协变量,将造模成功的乳腺癌模型小鼠随机分为荷瘤组(tumor-bearing group, TG)、电针围刺组(electroacupuncture tumor-bearing group, EATG)和贝伐单抗组(bevacizumab tumor-bearing group, BTG),每组18只。TG组不进行干预;BTG组腹腔注射10 mg/kg贝伐单抗[10],作为阳性对照组;EATG组进行围刺治疗:小鼠经2%戊巴比妥钠(3 mL/kg)腹腔注射麻醉后,采用一次性无菌针灸针在距瘤体边界约5 mm瘤周与体表呈60°角度向瘤根方向进针,深度约5 mm;采用低频针疗仪以疏密波交替刺激30 min(疏波频率3~4 Hz,串长5 s;密波频率15~20 Hz,串长10 s),刺激强度以动物未出现明显肢体颤抖为宜[7]。分别在干预前(D0)、干预后第3天(D3)、干预后第5天(D5)各组取6只小鼠,用2%戊巴比妥钠(3 mL/kg)腹腔注射麻醉后处死,完整剥离肿瘤组织,将肿瘤组织分别固定于10%甲醛溶液和2.5%戊二醛溶液,用于组织病理学检测和扫描电镜检测。

    肿瘤组织经石蜡包埋后制备5~10 μm石蜡切片,依次用二甲苯脱蜡,梯度乙醇脱水后,柠檬酸缓冲液修复抗原,3%过氧化氢室温30 min阻断内源性过氧化物酶的活性,3%山羊血清封闭抗原,加入CD31/α-SMA、HIF-1α抗体(1∶1000)4 ℃孵育过夜。加入荧光二抗,室温避光孵育1 h,PBS洗3次,DAPI溶液室温避光孵育10 min,PBS洗3次,甘油封片,荧光显微镜下任意选取3个视野采集图像。采用Image J软件对荧光强度进行定量分析。

    用2.5%戊二醛溶液充分固定肿瘤组织,梯度酒精脱水后真空干燥,IB-3型真空离子镀膜仪中喷金镀膜,放入扫描电子显微镜载物台上,加速电压15 kV,低真空(40 Pa)模式下观察并采集图像。

    实验数据采用SAS 9.3软件进行统计分析,计量资料表达以$ \bar x \pm s $表示。多组独立计量资料,若满足正态分布并符合方差齐性标准,则执行单因素方差分析,若不能同时满足正态分布相符和方差齐性,则执行Welch检验。P<0.05为差异有统计学意义。

    细胞接种7 d后可在皮下触及小米粒大小的肿瘤,瘤体逐渐增大,质硬。HE染色证实其为增殖异常活跃的乳腺癌细胞。所有小鼠皮下移植瘤生长情况基本一致,第14~16天肿瘤体积约200 mm3,造模成功率100%。

    实验期间所有小鼠均无明显异常。干预后第 3 天(D3)、第 5 天(D5)肿瘤体积均较实验干预前增加( P<0.05),第 5 天(D5)肿瘤体积均较第 3 天(D3)增加( P<0.05),相同时间点组间肿瘤体积无明显差异(P>0.05)(表1)。

    表  1  不同时间点小鼠肿瘤生长情况(n=6)
    Table  1.  Comparison of the tumor volume at different time points (n=6)
    TimeTumor volume/mm3
    TGBTGEATG
    D0376.89±53.42376.82±56.66387.28±63.43
    D3428.42±41.78#437.80±30.17#423.10±31.43#
    D5527.50±76.22*538.20±53.22*539.76±78.38*
     TG: tumor-bearing group; BTG: bevacizumab tumor-bearing group; EATG: electroacupuncture tumor-bearing group. # P<0.05, vs. D0 in the same group; * P<0.05, vs. D3 in the same group.
    下载: 导出CSV 
    | 显示表格

    CD31、α-SMA分别为血管内皮细胞、周细胞标记物。由图1可见,干预前(D0)各组CD31、α-SMA表达水平无明显差异(P>0.05)。干预后第3天(D3),EATG组与BTG组CD31表达水平均显著降低(P<0.01),α-SMA表达水平明显增加(P<0.01)。干预后第5天(D5),EATG组与BTG组CD31表达水平仍低于TG组(P<0.01),α-SMA表达水平仍高于TG组(P<0.05)。EATG组CD31表达水平在D5较D3有所增加,但差异不显著(P>0.05),EATG组α-SMA表达水平在D5、D3均无明显差异。干预后第3(D3)、5天(D5)EATG组与BTG组α-SMA、CD31表达水平均无明显差异(P>0.05)。

    图  1  围刺对肿瘤组织CD31、α-SMA表达的影响。×200
    Figure  1.  Effect of peritumoral electroacupuncture on the expression of CD31 and α-SMA in the tumor tissue. ×200
    The red fluorescence represents positive expression of CD31, the green fluorescence represents positive expression of α-SMA, and the blue fluorescence represents the nucleus. * P<0.05, ** P<0.01, vs. TG. Image J software was used for semi-quantitative analysis.

    HIF-1α为缺氧诱导因子,可反映肿瘤组织乏氧情况。由图2可见,干预前(D0),各组HIF-1α表达水平无明显差异(P>0.05);干预后第3天(D3),第5天(D5)EATG组、BTG组HIF-1α表达水平低于TG组(P<0.01),EATG组与BTG组HIF-1α表达水平无明显差异(P>0.05);干预后第5天(D5),EATG组与BTG组HIF-1α表达水平较第3天(D3)有所增加,但差异不显著(P>0.05)。

    图  2  围刺对肿瘤组织HIF-1α表达的影响。×200
    Figure  2.  Effect of peritumoral electroacupuncture on the expression of HIF-1α in the tumor tissue. ×200
    The red fluorescence represents positive expression of HIF-1α and the blue fluorescence represents the nucleus. ** P<0.01, vs. TG.

    结合免疫荧光结果,我们进一步观察了干预后第3天肿瘤微血管的形态结构。HE染色显示各组肿瘤组织均可见微血管(图3)。采用扫描电镜观察肿瘤微血管形态发现,TG组新生血管管壁粗糙、有缺损、完整性差、管腔明显畸形,而EATG组和BTG组血管管壁完整性较好,管腔未出现明显变形(图4)。结果提示,围刺干预在一定程度上可改善肿瘤微血管形态和结构,使其形态结构趋于正常化。

    图  3  HE染色观察肿瘤血管。×400
    Figure  3.  Observation of tumor vessels by HE staining. ×400
    图  4  扫描电镜观察肿瘤微血管
    Figure  4.  Observation of microvessels in the tumor tissue by scanning electron microscope
    Magnification rates from left to right are ×1000, ×2000, and ×5000, with the arrows indicating the vascular wall.

    血管正常化是促进肿瘤异常的血管向正常的血管转化的过程,其成为近年来肿瘤领域的研究热点[11-12]。相对于正常血管,肿瘤血管曲折迂回、基底膜松散、周细胞覆盖减少、血流灌注不足,并处于乏氧环境中。通过诱导肿瘤异常血管结构趋向正常化,以增加基底膜完整性、提高周细胞的覆盖水平、纠正失衡的微环境,以及改善血液循环水平,为药物进入肿瘤组织提供支持,从而可提高抗肿瘤效果[13]。围刺是指围病灶或围穴而刺的方法[14],通常以施术部位为中心,进行多针单层或多层环状包围性针刺。针对肿瘤的围刺法可疏通经络,调节肿瘤局部经脉、络脉、浮络与皮部之间的联系[15],其作用类似局部活血化瘀。研究表明,部分活血中药或中药有效成分可诱导肿瘤血管正常化,如当归可减少瘤内微血管密度,降低血管通透性,诱导肿瘤血管正常化[16];丹参酮ⅡA促进血管周细胞生成,显著提高微血管壁完整性,抑制肿瘤新生血管,诱导血管正常化[17]。前期研究证实,围刺可增加肿瘤局部紫杉醇药物浓度,从而提高化疗药物抗肿瘤的效果[7],但并不清楚围刺提高化疗药物效果是否与围刺诱导血管正常化有关。因此,本研究以4T1乳腺癌皮下移植瘤小鼠模型为研究对象,采用围刺治疗方式,探讨围刺诱导肿瘤微血管正常化的作用。

    CD31为血小板-内皮细胞黏附分子,多表达于血管内皮细胞、血小板、白细胞,与血管形成密切相关,是内皮细胞常见标记物[18]。在乳腺癌组织中CD31显著上调,且CD31的高表达与肿瘤直径和TNM分期密切相关[19]。周细胞与内皮细胞构成血管壁,对血管具有稳定和支撑作用[20]。α-SMA表达于周细胞,但不表达于内皮细胞,可用α-SMA标记周细胞[21]。通过双荧光标记CD31/α-SMA观察微血管结构,评价肿瘤微血管密度和周细胞覆盖率[22-23]。本研究发现,电针围刺或小剂量贝伐单抗治疗后第3、5天肿瘤组织CD31的表达水平均明显下降,α-SMA表达水平显著增加,表明电针围刺和贝伐单抗均能降低微血管密度,促进周细胞的募集和覆盖,且该治疗作用具有一定的持续性效应,为课题组后期临床针药结合研究提供研究基础。

    血管的结构异常引起血流紊乱、灌注不足,导致氧气无法正常供应,肿瘤局部微环境处于乏氧状态。HIF-1α是HIF-1的活性亚基,可反映肿瘤组织乏氧情况。在三阴性乳腺癌中,HIF-1α在癌组织的阳性率较癌旁组织显著增加,且与血管密度显著相关[24-25]。本研究发现,电针围刺、贝伐单抗治疗后第3、5天HIF-1α表达水平明显下降,表明电针围刺和贝伐单抗均可改善肿瘤乏氧状态。

    血管功能的正常化依赖于血管结构的正常化。本研究进一步采用HE染色和扫描电镜观察肿瘤组织的微血管结构,发现电针围刺和贝伐单抗均可促进肿瘤微血管形成较完整的管壁,减少管腔畸形,从形态学上进一步验证电针围刺具有诱导肿瘤微血管正常化的作用。但本研究中电针围刺或小剂量贝伐单抗均未见明显抑瘤效应,这可能与电针围刺、贝伐单抗治疗频次少有关(仅治疗1次)。

    以上研究表明电针围刺可通过降低微血管密度、促进周细胞覆盖以诱导肿瘤血管结构的正常化,并改善肿瘤组织乏氧状态,这将为后期探索电针围刺诱导血管正常化机制及其与化疗药物协同抗肿瘤研究提供重要依据。

    *    *    *

    作者贡献申明 常馨负责论文调查研究和初稿写作,卢涛负责论文提供资源和监督指导,黄金昶负责论文构思和审读与编辑写作。所有作者已经同意将文章提交给本刊,且对将要发表的版本进行最终定稿,并同意对工作的所有方面负责。

    利益冲突 所有作者均声明不存在利益冲突

  • 图  1   围刺对肿瘤组织CD31、α-SMA表达的影响。×200

    Figure  1.   Effect of peritumoral electroacupuncture on the expression of CD31 and α-SMA in the tumor tissue. ×200

    The red fluorescence represents positive expression of CD31, the green fluorescence represents positive expression of α-SMA, and the blue fluorescence represents the nucleus. * P<0.05, ** P<0.01, vs. TG. Image J software was used for semi-quantitative analysis.

    图  2   围刺对肿瘤组织HIF-1α表达的影响。×200

    Figure  2.   Effect of peritumoral electroacupuncture on the expression of HIF-1α in the tumor tissue. ×200

    The red fluorescence represents positive expression of HIF-1α and the blue fluorescence represents the nucleus. ** P<0.01, vs. TG.

    图  3   HE染色观察肿瘤血管。×400

    Figure  3.   Observation of tumor vessels by HE staining. ×400

    图  4   扫描电镜观察肿瘤微血管

    Figure  4.   Observation of microvessels in the tumor tissue by scanning electron microscope

    Magnification rates from left to right are ×1000, ×2000, and ×5000, with the arrows indicating the vascular wall.

    表  1   不同时间点小鼠肿瘤生长情况(n=6)

    Table  1   Comparison of the tumor volume at different time points (n=6)

    TimeTumor volume/mm3
    TGBTGEATG
    D0376.89±53.42376.82±56.66387.28±63.43
    D3428.42±41.78#437.80±30.17#423.10±31.43#
    D5527.50±76.22*538.20±53.22*539.76±78.38*
     TG: tumor-bearing group; BTG: bevacizumab tumor-bearing group; EATG: electroacupuncture tumor-bearing group. # P<0.05, vs. D0 in the same group; * P<0.05, vs. D3 in the same group.
    下载: 导出CSV
  • [1]

    SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin,2021,71(3): 209–249. DOI: 10.3322/caac.21660

    [2]

    BIANCHINI G, De ANGELIS C, LICATA L, et al. Treatment landscape of triple-negative breast cancer-expanded options, evolving needs. Nat Rev Clin Oncol,2022,19(2): 91–113. DOI: 10.1038/s41571-021-00565-2

    [3]

    TIAN Y, JIANG X, ZHAO W, et al. Acupuncture enhances anticancer effects of cyclophosphamide on 4T1 tumors via suppression of angiogenesis in BALB/c mice. J Tradition Chinese Med Sci ,2017,4: 216–221. DOI: 10.1016/j.jtcms.2017.05.002

    [4] 李洪峥, 姜欣, 刘苗苗, 等. 瘤周围刺对4T1小鼠乳腺癌移植瘤作用研究. 陕西中医,2018,39(6): 683–686. DOI: 10.3969/j.issn.1000-7369.2018.06.001
    [5]

    JIANG X, TIAN Y, XU L, et al. Inhibition of triple-negative breast cancer tumor growth by electroacupuncture with encircled needling and its mechanisms in a mice xenograft model. Int J Med Sci,2019,16(12): 1642–1651. DOI: 10.7150/ijms.38521

    [6]

    TIAN Y, QIU X, QI X, et al. Electroacupuncture promotes apoptosis and inhibits axonogenesis by activating p75 neurotrophin receptor for triple-negative breast xenograft in mice. J Chem Neuroanat,2022,124: 102133. DOI: 10.1016/j.jchemneu.2022.102133

    [7]

    YANG M, WAN Y, JIANG X, et al. Electro-acupuncture promotes accumulation of paclitaxel by altering tumor microvasculature and microenvironment in breast cancer of mice. Front Oncol,2019,9: 576. DOI: 10.3389/fonc.2019.00576.

    [8]

    MOLLARD S, MOUSSEAU Y, BAAJ Y, et al. How can grafted breast cancer models be optimized? Cancer Biol Ther,2011,12(10): 855–864. DOI: 10.4161/cbt.12.10.18139

    [9]

    HOLLIS C P, WEISS H L, LEGGAS M, et al. Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the effect and image-guided drug delivery. J Control Release,2013,172(1): 12–21. DOI: 10.1016/j.jconrel.2013.06.039

    [10]

    MOLLARD S, CICCOLINI J, IMBS D C, et al. Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis. Oncotarget,2017,8(14): 23087–23098. DOI: 10.18632/oncotarget.15484

    [11]

    YI M, JIAO D, QIN S, et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer,2019,18(1): 60. DOI: 10.1186/s12943-019-0974-6

    [12]

    LUO X, ZOU W, WEI Z, et al. Inducing vascular normalization: a promising strategy for immunotherapy. Int Immunopharmacol,2022,112: 109167. DOI: 10.1016/j.intimp.2022.109167

    [13]

    WEBB T. Vascular normalization: study examines how antiangiogenesis therapies work. J Natl Cancer Inst,2005,97(5): 336–337. DOI: 10.1093/jnci/97.5.336

    [14] 张笑菲. 围刺法及其临床应用规律探讨. 河南中医,2004,24(7): 61–62. DOI: 10.3969/j.issn.1003-5028.2004.07.045
    [15] 奚胜艳, 高学敏, 张建军, 等. 从中医络病与病络理论认识肿瘤血管生成. 北京中医药大学学报,2008,31(12): 804–807. DOI: 10.3321/j.issn:1006-2157.2008.12.003
    [16] 杜钢军, 时小燕. 治疗癌症的新途径: 靶向肿瘤微环境. 国际药学研究杂志,2011,38(5): 336–340. DOI: 10.13220/j.cnki.jipr.2011.05.007
    [17]

    WANG W Q, LIU L, SUN H C, et al. Tanshinone ⅡA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization. J Hematol Oncol,2012,5: 69. DOI: 10.1186/1756-8722-5-69.PMID:23137165

    [18]

    CRISTINA C, PEREZ-MILLAN M I, LUQUE G, et al. VEGF and CD31 association in pituitary adenomas. Endocr Pathol,2010,21(3): 154–160. DOI: 10.1007/s12022-010-9119-6

    [19] 张文进, 李云涛, 陈鑫, 等. CD31标记的微血管密度在乳腺浸润性导管癌中的表达及其临床意义. 中华乳腺病杂志(电子版),2014,8(1): 22–25. DOI: 10.3877/cma.j.issn.1674-0807.2014.01.005.
    [20]

    KESKIN D, KIM J, COOKE V G, et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep,2015,10(7): 1066–1081. DOI: 10.1016/j.celrep.2015.01.035

    [21] 王医术, 李玉林, 王心蕊, 等. 采用双重免疫组织化学及免疫电镜方法可将α-平滑肌肌动蛋白定位于乳腺癌间质新生血管周细胞. 中国实验诊断学,2002(4): 203–205. DOI: 10.3969/j.issn.1007-4287.2002.04.001
    [22]

    M N, Y A, C G R, et al. Ultrastructure of the capillary pericytes and the expression of smooth muscle alpha-actin and desmin in the snake infrared sensory organs. Anat Rec,2000,260(3): 299–307. DOI: 10.1002/1097-0185(20001101)260:3<299::AID-AR67>3.0.CO;2-V

    [23] 王医术, 李玉林, 王心蕊, 等. 用α-SMA结合部位标记新生血管周细胞. 吉林大学学报(医学版),2003(5): 594–595. DOI: 10.13481/j.1671-587x.2003.05.027
    [24] 葛忠耀, 田寅, 王博, 等. SIRT6和HIF-1α在三阴性乳腺癌中的表达及临床价值. 医学信息,2019,32(5): 95–97. DOI: 10.3969/j.issn.1006-1959.2019.05.028
    [25] 郝朗松, 王耕, 钱昆, 等. 乳腺癌组织中缺氧诱导因子-1α的表达及其与肿瘤细胞增殖、血管形成的关系. 四川大学学报(医学版),2007,38(1): 60–63. DOI: CNKI:SUN:HXYK.0.2007-01-014
  • 期刊类型引用(1)

    1. 梁泓冰,宁宁,赵思奇,李远飞,武玥琪,宋清伟,杨洁,高雪,张莫云,张丽娜. 基于DCE-MRI的3D-MIP重建及多参数评估BI-RADS 4类乳腺肿瘤. 磁共振成像. 2024(05): 94-101 . 百度学术

    其他类型引用(0)

cc

开放获取 本文遵循知识共享署名—非商业性使用4.0国际许可协议(CC BY-NC 4.0),允许第三方对本刊发表的论文自由共享(即在任何媒介以任何形式复制、发行原文)、演绎(即修改、转换或以原文为基础进行创作),必须给出适当的署名,提供指向本文许可协议的链接,同时标明是否对原文作了修改;不得将本文用于商业目的。CC BY-NC 4.0许可协议详情请访问 https://creativecommons.org/licenses/by-nc/4.0

图(4)  /  表(1)
计量
  • 文章访问数:  338
  • HTML全文浏览量:  128
  • PDF下载量:  22
  • 被引次数: 1
出版历程
  • 收稿日期:  2023-05-08
  • 修回日期:  2023-09-04
  • 网络出版日期:  2023-10-12
  • 发布日期:  2023-10-12

目录

/

返回文章
返回