Targeting of interleukin-13 receptor α2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of TGF-β and PTEN signaling.
Targeting of interleukin-13 receptor α2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of TGF-β and PTEN signaling.
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DOI：
10.1186/1479-5876-11-45
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发表时间：
2013-02-19
影响因子：
7.4
通讯作者：
Kulkarni AB
中科院分区：
文献类型：
--
作者：
Hall B;Nakashima H;Sun ZJ;Sato Y;Bian Y;Husain SR;Puri RK;Kulkarni AB
全球第六大癌症是头颈癌，其通常发生在口腔粘膜的鳞状上皮内。人类头颈部鳞状细胞癌（HNSCC）是一种难以治疗的肿瘤，五年生存率只有50%。对于HNSCC，需要沿着新的治疗方法以及在体内快速筛选抗癌剂的手段，例如小鼠模型。为了开发新的癌症动物模型以测试用于人HNSCC的新型治疗剂的安全性和功效，在基因工程小鼠模型的头颈上皮中诱导类似于人HNSCC临床病例的肿瘤。该小鼠模型通过条件性删除口腔上皮中的两种肿瘤抑制因子转化生长因子-β受体1（TGFβRI）和磷酸酶和张力蛋白同源物（PTEN）而产生。我们发现这些Tgfbr 1/Pten双条件性敲除（2cKO）小鼠的肿瘤过度表达IL-13 R α2，IL-13的高亲和力受体可作为肿瘤抗原发挥作用。为了证明针对IL-13 R α2表达的靶向治疗在该自发性肿瘤模型中具有任何抗肿瘤疗效的概念验证，这些小鼠全身接受IL-13-PE（一种由IL-13与假单胞菌外毒素A融合组成的重组免疫毒素）治疗。与未处理的对照小鼠相比，用IL-13-PE处理的Tgfbr 1/Pten 2cKO小鼠显示出显著增加的存活率。未治疗的小鼠表现出体重减轻，特别是舌肿瘤的快速发作，但治疗的小鼠在IL-13-PE治疗时体重增加，并且没有表现出由于免疫毒素引起的毒性的临床体征。与对照组相比，IL-13-PE处理组肿瘤中IL-13 R α2的表达显著降低，IL-13-PE处理组小鼠脾脏中髓源性抑制细胞（MDSC）的数量也显著减少。我们的研究表明，人HNSCC的Tgfbr 1/Pten 2cKO小鼠模型是用于评估新的癌症治疗剂的抗肿瘤活性的有用模型，并且IL-13-PE具有治疗人头颈癌的治疗潜力。
The sixth leading class of cancer worldwide is head and neck cancer, which typically arise within the squamous epithelium of the oral mucosa. Human head and neck squamous cell carcinoma (HNSCC) is known to be difficult to treat and has only a 50% five-year survival rate. With HNSCC, novel therapeutics are needed along with a means of rapidly screening anti-cancer agents in vivo, such as mouse models. In order to develop new animal models of cancer to test safety and efficacy of novel therapeutic agents for human HNSCC, tumors resembling clinical cases of human HNSCC were induced in the head and neck epithelium of a genetically engineered mouse model. This mouse model was generated by conditional deletion of two tumor suppressors, Transforming Growth Factor-β Receptor 1 (TGFβRI) and Phosphatase and Tensin homolog (PTEN), in the oral epithelium. We discovered that the tumors derived from these Tgfbr1/Pten double conditional knockout (2cKO) mice over-expressed IL-13Rα2, a high affinity receptor for IL-13 that can function as a tumor antigen. To demonstrate a proof-of-concept that targeted therapy against IL-13Rα2 expression would have any antitumor efficacy in this spontaneous tumor model, these mice were treated systemically with IL-13-PE, a recombinant immunotoxin consisting of IL-13 fused to the Pseudomonas exotoxin A. Tgfbr1/Pten 2cKO mice when treated with IL-13-PE displayed significantly increased survival when compared to the untreated control mice. The untreated mice exhibited weight loss, particularly with the rapid onset of tongue tumors, but the treated mice gained weight while on IL-13-PE therapy and showed no clinical signs of toxicity due to the immunotoxin. Expression of IL-13Rα2 in tumors was significantly decreased with IL-13-PE treatment as compared to the controls and the number of myeloid-derived suppressor cells (MDSC) was also significantly reduced in the spleens of the IL-13-PE treated mice. Our study demonstrates that the Tgfbr1/Pten 2cKO mouse model of human HNSCC is a useful model for assessing antitumor activity of new cancer therapeutic agents, and that IL-13-PE has therapeutic potential to treat human head and neck cancer.
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影响因子：
5.1
作者：
Kawakami, K;Kawakami, M;Puri, RK
通讯作者：
Puri, RK
影响因子：
5.7
作者：
Debinski, W;Gibo, DM
通讯作者：
Gibo, DM
影响因子：
6.4
作者：
Fujisawa, Toshio;Nakashima, Hideyuki;Puri, Raj K.
通讯作者：
Puri, Raj K.
影响因子：
7.4
作者：
Nakashima H;Fujisawa T;Husain SR;Puri RK
通讯作者：
Puri RK
影响因子：
11.2
作者：
Fujisawa, Toshio;Joshi, Bharat;Puri, Raj K.
通讯作者：
Puri, Raj K.