Valtola R, Salven P, Heikkilä P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, Alitalo K
Molecular/Cancer Biology Laboratory, Department of Pathology, Haartman Institute, University of Helsinki, Finland.
Am J Pathol. 1999 May;154(5):1381-90. doi: 10.1016/S0002-9440(10)65392-8.
Recently, monoclonal antibodies against the human vascular endothelial growth factor receptor VEGFR-3 were shown to provide a specific antigenic marker for lymphatic endothelium in various normal tissues. In this study we have investigated the expression of VEGFR-3 and its ligand VEGF-C in normal breast tissue and in breast tumors by immunohistochemistry. VEGFR-3 was weakly expressed in capillaries of normal breast tissue and in fibroadenomas. In intraductal breast carcinomas, VEGFR-3 was prominent in the "necklace" vessels adjacent to the basal lamina of the tumor-filled ducts. VEGF receptor 1 and 2 as well as blood vessel endothelial and basal lamina markers were colocalized with VEGFR-3 in many of these vessels. Antibodies against smooth muscle alpha-actin gave a weak staining of the necklace vessels, suggesting that they were incompletely covered by pericytes/smooth muscle cells. A highly elevated number of VEGFR-3 positive vessels was found in invasive breast cancer in comparison with histologically normal breast tissue (P < 0.0001, the Mann-Whitney test). VEGF-C was located in the cytoplasm of intraductal and invasive cancer cells. The results demonstrate that the expression of VEGFR-3 becomes up-regulated in the endothelium of angiogenic blood vessels in breast cancer. The results also suggest that VEGF-C secreted by the intraductal carcinoma cells acts predominantly as an angiogenic growth factor for blood vessels, although this paracrine signaling network between the cancer cells and the endothelium may also be involved in modifying the permeabilities of both blood and lymphatic vessels and metastasis formation.
最近，针对人类血管内皮生长因子受体VEGFR - 3的单克隆抗体被证明可为多种正常组织中的淋巴管内皮提供一种特异性抗原标记物。在本研究中，我们通过免疫组织化学方法研究了VEGFR - 3及其配体VEGF - C在正常乳腺组织和乳腺肿瘤中的表达情况。VEGFR - 3在正常乳腺组织的毛细血管和纤维腺瘤中表达较弱。在导管内乳腺癌中，VEGFR - 3在与充满肿瘤的导管基底膜相邻的“项链样”血管中显著表达。VEGF受体1和2以及血管内皮和基底膜标记物在许多这些血管中与VEGFR - 3共定位。抗平滑肌α - 肌动蛋白抗体对项链样血管染色较弱，表明它们未被周细胞/平滑肌细胞完全覆盖。与组织学正常的乳腺组织相比，浸润性乳腺癌中VEGFR - 3阳性血管数量显著增加（P < 0.0001，曼 - 惠特尼检验）。VEGF - C位于导管内和浸润性癌细胞的细胞质中。结果表明，VEGFR - 3的表达在乳腺癌血管生成的内皮细胞中上调。结果还表明，导管内癌细胞分泌的VEGF - C主要作为血管的血管生成生长因子，尽管癌细胞与内皮细胞之间的这种旁分泌信号网络也可能参与改变血管和淋巴管的通透性以及转移的形成。
