GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer.
GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer.
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DOI：
10.18632/oncotarget.2455
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Waldman SA
中科院分区：
文献类型：
--
作者：
Marszalowicz GP;Snook AE;Magee MS;Merlino D;Berman-Booty LD;Waldman SA
靶向癌症治疗的出现受到缺乏决定因素的限制，这些决定因素是肿瘤特异性的并且通常与疾病相关，并且具有有效部署细胞毒性有效载荷的细胞动力学。鸟苷酸环化酶C（GUCY2C）可能是理想的靶向，因为它通常只在绝缘的屏障隔室，包括肠和脑中表达，但过表达的全身转移性结直肠肿瘤。在这里，我们揭示了GUCY2C在肠和结直肠癌细胞中从细胞表面迅速内化到溶酶体。内吞作用不依赖于配体结合和受体活化，并且由网格蛋白介导。该机制表明了免疫毒素的设计，其包含通过可还原的二硫键与蓖麻毒蛋白A链缀合的GUCY2C定向的单克隆抗体，其在溶酶体中被活化为有效的细胞毒素。事实上，这种免疫毒素以溶酶体和网格蛋白依赖的方式特异性杀死表达GUCY2C的结直肠癌细胞。此外，这种免疫毒素在具有结直肠癌转移的小鼠中减少了>80%（p<0.001）的肺肿瘤，并提高了25%（p<0.001）的存活率。此外，在正常组织中没有毒性的组织学证据的情况下实现了治疗功效。这些观察结果支持GUCY2C靶向免疫毒素作为起源于胃肠道（包括结直肠、胃、食管和胰腺）的转移性肿瘤的新型治疗剂。
The emergence of targeted cancer therapy has been limited by the paucity of determinants which are tumor-specific and generally associated with disease, and have cell dynamics which effectively deploy cytotoxic payloads. Guanylyl cyclase C (GUCY2C) may be ideal for targeting because it is normally expressed only in insulated barrier compartments, including intestine and brain, but over-expressed by systemic metastatic colorectal tumors. Here, we reveal that GUCY2C rapidly internalizes from the cell surface to lysosomes in intestinal and colorectal cancer cells. Endocytosis is independent of ligand binding and receptor activation, and is mediated by clathrin. This mechanism suggests a design for immunotoxins comprising a GUCY2C-directed monoclonal antibody conjugated through a reducible disulfide linkage to ricin A chain, which is activated to a potent cytotoxin in lysosomes. Indeed, this immunotoxin specifically killed GUCY2C-expressing colorectal cancer cells in a lysosomal- and clathrin-dependent fashion. Moreover, this immunotoxin reduced pulmonary tumors >80% (p<0.001), and improved survival 25% (p<0.001), in mice with established colorectal cancer metastases. Further, therapeutic efficacy was achieved without histologic evidence of toxicity in normal tissues. These observations support GUCY2C-targeted immunotoxins as novel therapeutics for metastatic tumors originating in the GI tract, including colorectum, stomach, esophagus, and pancreas.
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影响因子：
4.5
作者：
Hodson, CA;Ambrogi, IG;Milgram, SL
通讯作者：
Milgram, SL
DOI：
10.1073/pnas.93.25.14827
发表时间：
1996-12-10
影响因子：
11.1
作者：
Carrithers, SL;Barber, MT;Waldman, SA
通讯作者：
Waldman, SA
DOI：
10.1073/pnas.1218138109
发表时间：
2012-12-18
影响因子：
11.1
作者：
Mazor, Ronit;Vassall, Aaron N.;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
120.1
作者：
Nelson, Aaron L.;Dhimolea, Eugen;Reichert, Janice M.
通讯作者：
Reichert, Janice M.
影响因子：
45.3
作者：
Burris, Howard A., III;Rugo, Hope S.;O'Shaughnessy, Joyce A.
通讯作者：
O'Shaughnessy, Joyce A.