| Of various current antitumor treatments, immunogene therapy is one of the most promising approaches, where interleukin (IL)-12 belongs to one of an ideal gene candidate. As a heterodimeric cytokine, IL-12 consists of p35 and p40 subunits and mainly produced by activated antigen-presenting cells including macrophages, dendritic cells, and B cells. It acts as a growth factor for activated T cells and plays a pivotal role in cellular immunoregulatory responses against tumor such as the abduction of Th1 -mediated CD4+ cells differentiation, stimulation of interferon-r production, activation of natural killer cells (NK) and induction of effective antiangiogenesis. The cytokine has shown its antitumor efficiency in some different animal models loaded with tumors as well as in clinical trials. Although direct administration of IL-12 protein, cDNA expressing IL-12 can affect tumor progression and metastasis, its antineoplastic activities could be generally obtained only at high dose range which usually was accompanied with serious adverse effects or even toxic death. Therefore, it is difficult for IL-12 to be directly applied tooncological clinic, and procedures allowing production of the cytokine within or locally around the tumor sites to activate the immunological reaction against the tumors may lead to tumor regression without accompanying obvious toxicities.Recent advances in studying Mesenchymal stem cells (MSCs) have shown that this cell population exhibits some properties that suggest the feasibility of their use as a cellular vehicle. First, grafted MSCs could evade the attacks from immune system because they own the cell surface phenotype mirroring a poorer immunogenicity recognized by T-cells. Secondly, MSCs also have the unusual tropism towards matrix components and could target the pathologic organs including tumor stroma, which could make them ideal vehicles used to express therapeutic reagents such as cytokines gradually on targeted tumor sites, and meanwhile, escape being destroyed owing to entering circulation system and being accompanied by adverse effects due to interfering spontaneously with other systems and thereby improve their pharmacokinetics wonderfully. Thirdly, they are easily isolated, cultivated and expanded to large numbers in vitro without changing their phenotype, multilineage potential and average telomere length. Fourthly, the MSCs could be transduced with efficient and long-term expression in vivo. Given these intrinsic properties of MSCs satisfying some of the criteria for the ideal cell vector, this cell population can be considered as an attractive candidate for a cellular vehicle. In this study, we applied MSCs transduced by adenovirus encoding IL-12 (AdIL-12-MSC) to three tumor models to investigate the antitumor efficacy. It have been demonstrated that, for two therapeutic antitumor models and one protective antitumorigenesis model, MSC-AdIL-12 had induced powerfulimpacts on tumor formation and progress. For the survival model, the survival rates of MSC-AdIL-12 treated group were prolonged conspicuously in comparison with other regimens. Especially for the early therapeutic cohort, 3 out of 12 animals treated with AdIL-12-MSC survived the tumor cells challenge for more than six months, and they could even stand against re-challenge of double doses of parent tumor cells at a distant site, whereas all seven age-matched animals serving as control and receiving normal dose of tumor cells shown 100% carcinogenesis within one week. For the metastatic model, the metastasis rates of the group treated with AdIL-12-MSC, including lung, liver, spleen, bone marrow and distant lymph nodes, were obviously lower than other groups without obvious adverse effects, toxicities or immunologic rejection. Control groups demonstrated a prolific intra- and/or peritumoral LYVE-1+ lymphangiogenesis, an important initial step to increase the risk for metastasis both in animal models and in human tumors. In contrast to control groups, AdIL-12-MSC group unveiled a decreased dynamic in Lymphatic vessels density (LVD). In addition, the specific and long-term expression of AdIL-12-MSC in local tumor sites was identified by in situ fluorescence observation of cryosections from fresh tumor tissues. Lots of CD4+, CD8+ lymphocytes infiltrated into tumor foci as well as angiogenesis and lymphangiogenesis was apparently inhibited in tumors treated with AdIL-12-MSC. Especially for prophylactic model against oncogenesis, none of preventive group with AdIL-12-MSC developed tumors, whereas the control groups were validated 100% of tumorigenesis.In conclusion, as a novel approach, MSC loaded with AdIL-12 has revealed anticipative antitumor as well as antitumorigenic effects ordepriving hibernating tumor cells from revival and recurrence, without evident aside effects, toxicities or graft rejection, and genetically modified MSCs can display ideal candidates for future gene vehicles used to express therapeutic reagents such as cytokines gradually on targeted tumor sites and thus showed a promising potential for future antitumor gene therapy.
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