Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, and Mackay Memorial Hospital, Taipei, Taiwan.
Cancer Gene Ther. 2013 May;20(5):308-16. doi: 10.1038/cgt.2013.22. Epub 2013 Apr 26.
The safety of oncolytic viruses, such as conditionally replicative adenoviruses (CRAds), has been validated in clinical trials for cancer therapy. Their antitumor efficacy is limited by the presence of preexisting neutralizing antibodies (NAbs). Mesenchymal stem cells (MSCs) are attractive as a cellular vehicle to carry antitumor agents, not only because they are easily obtained and expanded to great numbers in vitro, but also because of their ability to migrate and engraft to tumors. MSCs expanded under hypoxic conditions decrease in replicative senescence and increase in proliferation capacity and differentiation potentials. However it remains to be clarified whether these hypoxic MSCs also are good carriers for the delivery of CRAds to tumor cells in the presence of NAbs. This study firstly demonstrated hypoxic MSCs with an increased ability to migrate toward tumors through the upregulation of chemokine receptors, such as CXCR4 and CX3CR1. It is then demonstrated that hypoxic MSCs has the capacity to carry CRAds, without inducing apoptosis, for up to one week. Using an in vitro coculture with human colon cancer cells and with intraperitoneally (i.p.) and subcutaneously (s.c.) developed human colon cancer xenografts, it is demonstrated that hypoxic MSCs are able to protect CRAds from attack by NAbs, thereby successfully delivering them to the target tumor cells. These results show that hypoxic MSCs can serve as cell carriers for CRAds and may help to develop new strategies against cancer.
溶瘤病毒（如条件复制腺病毒 [CRAds]）的安全性已在癌症治疗的临床试验中得到验证。其抗肿瘤疗效受到预先存在的中和抗体（NAb）的限制。间充质干细胞（MSCs）作为携带抗肿瘤药物的细胞载体具有吸引力，不仅因为它们易于获得并且可以在体外大量扩增，还因为它们具有迁移和植入肿瘤的能力。在低氧条件下扩增的 MSCs 减少复制衰老，增加增殖能力和分化潜能。然而，仍然需要澄清这些低氧 MSC 对于在存在 NAb 的情况下向肿瘤细胞递呈 CRAd 是否也是良好的载体。本研究首先证明了低氧 MSC 通过上调趋化因子受体（如 CXCR4 和 CX3CR1）而增加向肿瘤迁移的能力。然后证明低氧 MSC 具有携带 CRAd 的能力，而不会诱导凋亡，长达一周。通过与人结肠癌细胞的体外共培养以及腹腔内（i.p.）和皮下（s.c.）发展的人结肠癌细胞异种移植，证明低氧 MSC 能够保护 CRAd 免受 NAb 的攻击，从而成功地将其递送至靶肿瘤细胞。这些结果表明低氧 MSC 可以作为 CRAd 的细胞载体，并可能有助于开发针对癌症的新策略。
