Sato-Dahlman Mizuho, Miura Yoshiaki, Huang Jing Li, Hajeri Praveensingh, Jacobsen Kari, Davydova Julia, Yamamoto Masato
Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
Oncotarget. 2017 Jun 2;8(44):76044-76056. doi: 10.18632/oncotarget.18340. eCollection 2017 Sep 29.
Oncolytic Adenoviruses (OAds) are one of the most promising anti-cancer agents that can induce cancer specific cell death. Recently, we generated infectivity-selective OAd, and the resultant OAd tumor-specific binding shows strong efficacy and mitigates toxicity. In this study, we applied this strategy based on adenovirus library screening system for generation of CD133-targeted OAd, and examined their oncolytic activity against colorectal cancer (CRC) and . CD133 (Prominin-1) is an important cell surface marker of cancer stem (like) cells (CSCs) in various cancers, including CRC. Elimination of CSCs has a high likelihood to improve CRC treatment because CSCs population in the tumor contributes to recurrence, metastases, chemotherapy resistance, and poor survival. The OAd with CD133-targeting motif (AdML-TYML) selectively infected CD133 cultured cells and lysed them efficiently. Treatment with AdML-TYML prior to tumor inoculation inhibited the establishment of tumor of CD133 CRC cell lines in nude mice. AdML-TYML also showed strong antitumor effect after intratumoral injections in already established CD133 CRC subcutaneous xenografts. Our results indicate that CD133-targeted OAd selectively infected CD133 CRC, and exhibited anti-tumorigenicity and therapeutic effect in established tumors. This novel infectivity selective virus could be a potent tool for the prevention of metastases and relapses in CRC.
溶瘤腺病毒（OAds）是最有前景的抗癌药物之一，能够诱导癌症特异性细胞死亡。最近，我们构建了感染性选择性OAd，其肿瘤特异性结合表现出强大的疗效并减轻了毒性。在本研究中，我们应用基于腺病毒文库筛选系统的策略来生成靶向CD133的OAd，并检测它们对结直肠癌（CRC）的溶瘤活性。CD133（Prominin-1）是包括CRC在内的多种癌症中癌干细胞样细胞（CSCs）的重要细胞表面标志物。消除CSCs很有可能改善CRC治疗，因为肿瘤中的CSCs群体与复发、转移、化疗耐药性及生存率低有关。带有CD133靶向基序的OAd（AdML-TYML）选择性感染CD133培养细胞并有效裂解它们。在肿瘤接种前用AdML-TYML处理可抑制裸鼠中CD133 CRC细胞系肿瘤的形成。在已建立的CD133 CRC皮下异种移植瘤中进行瘤内注射后，AdML-TYML也显示出强大的抗肿瘤作用。我们的结果表明，靶向CD133的OAd选择性感染CD133 CRC，并在已形成的肿瘤中表现出抗肿瘤发生性和治疗效果。这种新型感染性选择性病毒可能是预防CRC转移和复发的有力工具。
