Abstract
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) in vitro and in vivo. 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.
Highlights
Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer death in the US [1]
In order to isolate the CD133targeting Oncolytic Adenovirus (OAd), high-throughput screening of the Ad library was performed with target-overexpressing cells based on selective binding and replication (Figure 1A). 293 cells overexpressing CD133 (293-CD133) were infected with the Ad library, and the viral DNA was extracted from crude viral lysate in each round
We focused on CD133 as a target molecule of colorectal cancer stem (like) cells (CSCs)
Summary
Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer death in the US [1]. In CRC, CSCs have been isolated from a number of tumor types, including brain [5], breast [6], ovarian [7], head and neck [8], pancreas [9] and liver [10]. In this sense, elimination of CSCs has a high potential to improve CRC treatment, and development of therapeutics targeting CSC makes a good clinical sense in a variety of cancers
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