Sheski F D, Natarajan V, Pottratz S T
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
J Lab Clin Med. 1999 Mar;133(3):265-73. doi: 10.1016/s0022-2143(99)90083-5.
Tumor cell attachment to endothelial cells (ECs) is an important step in the metastasis of small cell lung carcinoma (SCLC). Tumor necrosis factor-alpha (TNF-alpha) stimulation of ECs increases the attachment of some malignant cell types to ECs by affecting the expression of cell adhesion molecules (CAMs). Similarly, the inhibition of EC protein kinase C (PKC) and tyrosine kinase (TK) pathways modulates TNF-alpha-mediated effects on CAM expression. We hypothesized that TNF-alpha would increase SCLC attachment to ECs by affecting CAM expression through activation of PKC and TK pathways. To test this hypothesis, human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-alpha (0 to 500 U/mL) for variable time periods (1 to 24 hours), and the attachment of H82 cells (an SCLC cell line) to the HUVECs was quantified. TNF-alpha stimulation of the HUVECs increased H82 attachment from 28.1% +/- 1.6% to 48.8% +/- 1.7% (P < .05). Preincubation of HUVECs with the PKC inhibitors bis-indolylmaleimide (BIN) or calphostin C or the TK inhibitors genistein or herbimycin A (HMA) blocked the TNF-alpha-induced increase in H82 cell attachment. The addition of antibodies to vitronectin (Vn) or beta1-integrin to TNF-alpha-activated HUVECs before the addition of the H82 cells also significantly decreased H82 attachment, whereas the addition of antibodies to E-selectin, P-selectin, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), neural cell adhesion molecule (NCAM), sialyl-Lewis(x), fibronectin (Fn), alpha(v)-integrin, alpha3-integrin, alpha4-integrin, or alpha5-integrin had no effect on SCLC attachment. In summary, the TNF-alpha-mediated increase in SCLC attachment to ECs appears to be mediated by the activation of EC PKC and TK pathways as well as through effects on the function or expression of EC Vn and beta1 integrin.
肿瘤细胞与内皮细胞（ECs）的黏附是小细胞肺癌（SCLC）转移过程中的重要一步。肿瘤坏死因子-α（TNF-α）刺激内皮细胞可通过影响细胞黏附分子（CAMs）的表达，增加某些恶性细胞类型与内皮细胞的黏附。同样，抑制内皮细胞蛋白激酶C（PKC）和酪氨酸激酶（TK）途径可调节TNF-α对CAM表达的影响。我们推测，TNF-α会通过激活PKC和TK途径影响CAM表达，从而增加SCLC与内皮细胞的黏附。为验证这一假设，用TNF-α（0至500 U/mL）刺激人脐静脉内皮细胞（HUVECs）不同时间段（1至24小时），并对H82细胞（一种SCLC细胞系）与HUVECs的黏附进行定量分析。TNF-α刺激HUVECs后，H82细胞的黏附率从28.1%±1.6%增至48.8%±1.7%（P<0.05）。用PKC抑制剂双吲哚马来酰亚胺（BIN）或钙磷蛋白C，或TK抑制剂染料木黄酮或赫曲霉素A（HMA）预孵育HUVECs，可阻断TNF-α诱导的H82细胞黏附增加。在加入H82细胞之前，向TNF-α激活的HUVECs中添加玻连蛋白（Vn）或β1整合素抗体，也可显著降低H82细胞的黏附，而添加E选择素、P选择素、血管细胞黏附分子（VCAM）、细胞间黏附分子（ICAM）、神经细胞黏附分子（NCAM）、唾液酸化路易斯寡糖（sialyl-Lewis(x)）、纤连蛋白（Fn）、α(v)整合素、α3整合素、α4整合素或α5整合素抗体对SCLC细胞黏附无影响。总之，TNF-α介导的SCLC与内皮细胞黏附增加似乎是通过激活内皮细胞PKC和TK途径以及影响内皮细胞Vn和β1整合素的功能或表达来实现的。
