Garofalo A, Chirivi R G, Foglieni C, Pigott R, Mortarini R, Martin-Padura I, Anichini A, Gearing A J, Sanchez-Madrid F, Dejana E
Laboratory of Cancer Metastasis Treatment, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Cancer Res. 1995 Jan 15;55(2):414-9.
We have previously reported that treatment with interleukin 1 (IL-1) induced the augmentation of lung tumor colonies by a human melanoma in nude mice. Here we have investigated the involvement of the alpha 4 beta 1 integrin, the very late antigen 4 (VLA-4) in this augmentation. A375M melanoma cells expressed high levels of VLA-4 and preferentially adhered to a surface coated with vascular cell adhesion molecule 1 (VCAM-1), the ligand for VLA-4 on activated endothelial cells. This adhesion was inhibited by treating tumor cells with saturating concentrations of mAb to VLA-4. The production of lung colonies was significantly enhanced in nude mice given an injection of IL-1 before A375M melanoma cells. Immunoperoxidase staining showed that VCAM-1 could be expressed on lung vascular endothelium of mice in response to IL-1. Pretreatment of melanoma cells with a mAb to VLA-4 completely abrogated the IL-1-induced augmentation of lung colonies. Using two metastatic melanoma clones (clones 2/4 and 2/60) that expressed different levels of VLA-4, we found that only VLA-4-bearing cells adhered to a VCAM-1-coated surface and formed enhanced numbers of lung colonies in IL-1-treated nude mice. This augmentation was inhibited by pretreating the tumor cells with anti-VLA-4 mAb. These results demonstrate, in vivo, the functional involvement of VLA-4 on melanoma cells in IL-1-mediated lung colony augmentation, most probably involving the interaction of tumor cells with VCAM-1 on activated endothelial cells.
我们之前报道过，用白细胞介素1（IL-1）治疗可诱导人黑色素瘤在裸鼠体内增加肺肿瘤集落。在此，我们研究了α4β1整合素，即极迟抗原4（VLA-4）在这种增加过程中的作用。A375M黑色素瘤细胞表达高水平的VLA-4，并优先黏附于包被有血管细胞黏附分子1（VCAM-1）的表面，VCAM-1是活化内皮细胞上VLA-4的配体。用饱和浓度的抗VLA-4单克隆抗体处理肿瘤细胞可抑制这种黏附。在接种A375M黑色素瘤细胞前注射IL-1的裸鼠中，肺集落的产生显著增强。免疫过氧化物酶染色显示，VCAM-1可在小鼠肺血管内皮细胞上因IL-1而表达。用抗VLA-4单克隆抗体预处理黑色素瘤细胞可完全消除IL-1诱导的肺集落增加。使用两个表达不同水平VLA-4的转移性黑色素瘤克隆（克隆2/4和克隆2/60），我们发现只有携带VLA-4的细胞黏附于包被有VCAM-1的表面，并在经IL-1处理的裸鼠中形成更多的肺集落。这种增加可通过用抗VLA-4单克隆抗体预处理肿瘤细胞来抑制。这些结果在体内证明了VLA-4在黑色素瘤细胞上在IL-1介导的肺集落增加中的功能作用，很可能涉及肿瘤细胞与活化内皮细胞上的VCAM-1的相互作用。
