Intracellular distribution of TM4SF1 and internalization of TM4SF1-antibody complex in vascular endothelial cells.
Intracellular distribution of TM4SF1 and internalization of TM4SF1-antibody complex in vascular endothelial cells.
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DOI：
10.1016/j.bbrc.2015.07.142
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发表时间：
2015-09-25
影响因子：
3.1
通讯作者：
Jaminet SC
中科院分区：
文献类型：
--
作者：
Sciuto TE;Merley A;Lin CI;Richardson D;Liu Y;Li D;Dvorak AM;Dvorak HF;Jaminet SC
Transmembrane-4 L-six family member-1（TM 4SF 1）是一种小的质膜相关糖蛋白，其在肿瘤细胞、培养的内皮细胞的质膜上以及在体内在肿瘤相关内皮上高度且选择性地表达。免疫荧光显微镜也表明TM 4SF 1在细胞质中，暂时，在细胞核内。与单克隆抗体8 G4，和免疫纳米金透射电子显微镜提供的更精细的分辨率，我们现在证明TM 4SF 1在未涂层的细胞质囊泡，核孔和核质。由于其在肿瘤细胞和肿瘤相关内皮上的突出表面位置，TM 4SF 1具有使用抗体药物缀合物（ADC）方法作为双重治疗靶点的潜力。为了使ADC成功，与细胞表面抗原反应的抗体必须被内化以将相关毒素递送至细胞内靶标。我们现在报告说，8 G4是有效地采取了培养的内皮细胞由未涂层囊泡在动力蛋白依赖，网格蛋白独立的方式。然后，它被运输沿着微管通过细胞质，并通过核孔进入细胞核。这些发现验证了TM 4SF 1作为具有抗体结合毒素的癌症治疗的有吸引力的候选物，所述抗体结合毒素具有与肿瘤细胞或肿瘤相关血管内皮中的细胞质或核靶点反应的能力。
Transmembrane-4 L-six family member-1 (TM4SF1) is a small plasma membrane-associated glycoprotein that is highly and selectively expressed on the plasma membranes of tumor cells, cultured endothelial cells, and, in vivo, on tumor-associated endothelium. Immunofluorescence microscopy also demonstrated TM4SF1 in cytoplasm and, tentatively, within nuclei. With monoclonal antibody 8G4, and the finer resolution afforded by immuno-nanogold transmission electron microscopy, we now demonstrate TM4SF1 in uncoated cytoplasmic vesicles, nuclear pores and nucleoplasm. Because of its prominent surface location on tumor cells and tumor-associated endothelium, TM4SF1 has potential as a dual therapeutic target using an antibody drug conjugate (ADC) approach. For ADC to be successful, antibodies reacting with cell surface antigens must be internalized for delivery of associated toxins to intracellular targets. We now report that 8G4 is efficiently taken up into cultured endothelial cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner. It is then transported along microtubules through the cytoplasm and passes through nuclear pores into the nucleus. These findings validate TM4SF1 as an attractive candidate for cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium.