Van den Eynden G G, Van der Auwera I, Van Laere S J, Colpaert C G, Turley H, Harris A L, van Dam P, Dirix L Y, Vermeulen P B, Van Marck E A
Translational Cancer Research Group, Lab Pathology, University of Antwerp/University Hospital Antwerp, Wilrijk, Antwerp, Belgium.
Br J Cancer. 2005 Nov 14;93(10):1128-36. doi: 10.1038/sj.bjc.6602828.
Hypoxia and angiogenesis are important factors in breast cancer progression. Little is known of hypoxia and angiogenesis in lymph node metastases of breast cancer. The aim of this study was to quantify hypoxia, by hypoxia-induced marker expression levels, and angiogenesis, by endothelial cell proliferation, comparing primary breast tumours and axillary lymph node metastases. Tissue sections of the primary tumour and a lymph node metastasis of 60 patients with breast cancer were immunohistochemically stained for the hypoxia-markers carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1alpha (Hif-1alpha) and DEC-1 and for CD34/Ki-67. Endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. On haematoxylin-eosin stain, the growth pattern and the presence of a fibrotic focus were assessed. Hypoxia-marker expression, ECP% and TCP% in primary tumours and in lymph node metastases were correlated to each other and to clinico-pathological variables. Median ECP% and TCP% in primary tumours and lymph node metastases were comparable (primary tumours: ECP%=4.02, TCP%=19.54; lymph node metastases: ECP%=5.47, TCP%=21.26). ECP% correlated with TCP% (primary tumours: r=0.63, P<0.001; lymph node metastases: r=0.76, P<0.001). CA9 and Hif-1alpha expression were correlated (primary tumours P=0.005; lymph node metastases P<0.001). In primary tumours, CA9 and Hif-1alpha expression were correlated with DEC-1 expression (P=0.05), presence of a fibrotic focus (P<0.007) and mixed/expansive growth pattern (P<0.001). Primary tumours and lymph node metastases with CA9 or Hif-1alpha expression had a higher ECP% and TCP% (P<0.003); in primary tumours, mixed/expansive growth pattern and fibrotic focus were characterised by higher ECP% (P=0.03). Furthermore, between primary tumours and lymph node metastases a correlation was found for ECP%, TCP%, CA9 and Hif-1alpha expression (ECP% r=0.51, P<0.001; TCP r=0.77, P<0.001; CA9 and Hif-1alpha P<0.001). Our data demonstrate that the growth of breast cancer lymph node metastases is angiogenesis dependent and that angiogenesis and hypoxia in the primary tumour predict angiogenesis and hypoxia in the lymph node metastases. Together with previous findings in breast cancer liver metastases, which grow in 96% of cases angiogenesis independently, these data suggest that both the intrinsic growth characteristics and angiogenic potential of breast cancer cells and the site-specific tumour microenvironment determine angiogenesis and hypoxia in breast cancer.
缺氧和血管生成是乳腺癌进展中的重要因素。目前对乳腺癌淋巴结转移中的缺氧和血管生成了解甚少。本研究旨在通过缺氧诱导标志物表达水平来量化缺氧情况，并通过内皮细胞增殖来量化血管生成情况，比较原发性乳腺肿瘤和腋窝淋巴结转移灶。对60例乳腺癌患者的原发性肿瘤和淋巴结转移灶的组织切片进行免疫组织化学染色，检测缺氧标志物碳酸酐酶9（CA9）、缺氧诱导因子-1α（Hif-1α）和DEC-1以及CD34/Ki-67。评估内皮细胞增殖分数（ECP%）和肿瘤细胞增殖分数（TCP%）。在苏木精-伊红染色切片上，评估生长模式和纤维化灶的存在情况。原发性肿瘤和淋巴结转移灶中的缺氧标志物表达、ECP%和TCP%相互之间以及与临床病理变量进行相关性分析。原发性肿瘤和淋巴结转移灶中的ECP%和TCP%中位数具有可比性（原发性肿瘤：ECP% = 4.02，TCP% = 19.54；淋巴结转移灶：ECP% = 5.47，TCP% = 21.26）。ECP%与TCP%相关（原发性肿瘤：r = 0.63，P < 0.001；淋巴结转移灶：r = 0.76，P < 0.001）。CA9和Hif-1α表达相关（原发性肿瘤P = 0.005；淋巴结转移灶P < 0.001）。在原发性肿瘤中，CA9和Hif-1α表达与DEC-1表达相关（P = 0.05）、纤维化灶的存在相关（P < 0.007）以及混合/膨胀性生长模式相关（P < 0.001）。有CA9或Hif-1α表达的原发性肿瘤和淋巴结转移灶具有更高的ECP%和TCP%（P < 0.003）；在原发性肿瘤中，混合/膨胀性生长模式和纤维化灶的特征是ECP%更高（P = 0.03）。此外，在原发性肿瘤和淋巴结转移灶之间发现ECP%、TCP%、CA9和Hif-1α表达存在相关性（ECP% r = 0.51，P < 0.001；TCP r = 0.77，P < 0.001；CA9和Hif-1α P < 0.001）。我们的数据表明，乳腺癌淋巴结转移灶的生长依赖于血管生成，并且原发性肿瘤中的血管生成和缺氧情况可预测淋巴结转移灶中的血管生成和缺氧情况。结合先前关于乳腺癌肝转移的研究结果，其中96%的病例生长独立于血管生成，这些数据表明乳腺癌细胞的内在生长特性和血管生成潜能以及特定部位的肿瘤微环境共同决定了乳腺癌中的血管生成和缺氧情况。
Zotero 插件
