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首页> 美国卫生研究院文献>PLoS Clinical Trials >Efficient Targeting of Head and Neck Squamous Cell Carcinoma by Systemic Administration of a Dual uPA and MMP-Activated Engineered Anthrax Toxin
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Efficient Targeting of Head and Neck Squamous Cell Carcinoma by Systemic Administration of a Dual uPA and MMP-Activated Engineered Anthrax Toxin

机译：通过系统管理双uPA和MMP激活的工程炭疽毒素的系统管理的头颈部鳞状细胞癌的有效靶向。

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.
机译：头颈部鳞状细胞癌（HNSCC）是全球第六大最常见的癌症。尽管在阐明该病的病因方面已经取得了相当大的进展，但诊断为HNSCC的个体的预后仍然很差，从而强调了开发其他治疗方式的必要性。 HNSCC的特征是上调多种蛋白水解酶，包括尿激酶纤溶酶原激活剂（uPA）和各种基质金属蛋白酶（MMP），这些蛋白可能由肿瘤细胞，肿瘤支持基质细胞或由两者表达。在这里，我们探索了相互补充的炭疽毒素的用途，该炭疽毒素需要细胞表面uPA和MMP的结合活性才能引起细胞中毒，并特别靶向ERK / MAPK途径治疗HNSCC。我们发现，这种毒素通过诱导凋亡和坏死性肿瘤细胞死亡，并损害肿瘤细胞的增殖和血管生成，对多种异种移植的人HNSCC细胞系显示出强大的系统性抗肿瘤活性。有趣的是，人HNSCC细胞系离体培养时对互补毒素不敏感，这表明该毒素靶向肿瘤支持基质细胞腔室或ERK / MAPK信号传导的肿瘤细胞需求在体内和体外均不同。这种相互补充的毒素作为抗HNSCC剂值得进一步研究。

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