Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate.
Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate.
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DOI：
10.18632/oncotarget.15340
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发表时间：
2017-04-11
期刊：
影响因子：
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通讯作者：
Lovat LB
中科院分区：
文献类型：
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作者：
Adil Butt M;Pye H;Haidry RJ;Oukrif D;Khan SU;Puccio I;Gandy M;Reinert HW;Bloom E;Rashid M;Yahioglu G;Deonarain MP;Hamoudi R;Rodriguez-Justo M;Novelli MR;Lovat LB
粘蛋白糖蛋白1（MUC1）是上皮细胞上的糖基化跨膜蛋白。我们研究MUC1作为Barrett上皮（BE）和食管腺癌（EA）的治疗靶点，并提供基于光的MUC1靶向治疗的概念证明。与鳞状上皮相比，BE和EA分别在21%和30%的显著富集途径中存在MUC1。MUC1基因表达在BE（p=<0.001）和EA（p=0.03）中分别高出x2.3和x2.2。MUC1免疫组化表达增加进展到EA和肿瘤浸润。基于HuHMFG1的光敏抗体药物缀合物（ADC）显示出细胞内化、MUC1选择性和光依赖性细胞毒性（p=0.0006）以及优于单独光敏剂的上级毒性（p=0.0022）。基因集富集分析（GSEA）评估BE和EA发展过程中的途径，并定量MUC1基因表达。免疫组化和流式细胞术评价了不同病理级别食管细胞中的抗MUC1抗体HuHMFG1。共聚焦显微镜检查了HuHMFG1内化，并产生HuHMFG1 ADC以递送MUC1靶向的光毒性有效载荷。MUC1是一个很有前途的EA靶点。用光敏ADC靶向MUC1的分子和光基靶向在体外是有效的，并且在开发后可以通过内窥镜治疗局部肿瘤。
Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett’s epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1. MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022). Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload. MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically.