Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs

Abstract

Mesenchymal stem cells (MSCs) were adenovirally engineered to secrete interleukin-12 (AdIL-12-MSCs) and evaluated for their anticarcinogenesis efficacy against three kinds of unestablished tumor models including B16 melanoma, LLC Lewis lung cancer and HCC hepatoma. Injection of AdIL-12-MSCs into protected mice before tumor inoculation prevented all of 12 mice in B16 preventive groups, 10 out of 12 in LLC lung cancer model and 11 out of 12 mice in HCC hepatoma model from developing tumors, whereas the control groups pre-receiving PBS were validated for 100% carcinogenesis; the tumor formation rates in free-AdIL-12 and vacant MSC groups were unveiled between approximately 83 and 100% even with plentiful angiogenesis and newborn lymphatic vessels, as well as distant metastases. As a novel approach, AdIL-12-MSC has revealed expected preventive effects on carcinogenesis (P<0.01) with low-toxic, broad-spectrum and long-range superiorities. In conclusion, our data indicate that AdIL-12-MSC possess the potential for tropism to preclinical tumor lesions and deprives surviving or hibernating tumor cells, which have escaped from conventional treatments, of revival and recurrence.

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

“…Therapeutic proteins which raised great interest because of the possibility to be managed by MSCs are interferon (IFN ) [31,32] and (IFN ) [23,[31][32][33][34], interleukin (IL) 12 [35], cytokine IL2 [36] and chemokine CX3CL1 (fractalkine) [37]. There are a number of studies of effects of IFN and IFN incorporated into systems delivered by MSCs over tumor growth showing the inhibitory effect of IFN and its usefulness as adjuvant therapy for the elimination of micrometastasis in risk patients [38], while anticancer effect of IFN is determined as apoptosis-stimulation effect [39,40] and only toxicity observed after its systemic administration limits its clinical applications [41].…”

“…IL-12 (a heterodimeric glycoprotein) [35,42,43] or IL-2 [36,44] secreted by MSCs initiates an immunoreaction and stimulates infiltration of inflammatory cells at the tumor site, which is a way to avoid systemic toxicity at the same time [45]. There is a study performed by Chen et al in 2006, where genetically modified MSCs for secretion of IL-12 of mouse origin were evaluated according to their anti-cancer potential in three types of tumor models in experimental animals [35].…”

“…There is a study performed by Chen et al in 2006, where genetically modified MSCs for secretion of IL-12 of mouse origin were evaluated according to their anti-cancer potential in three types of tumor models in experimental animals [35]. In a similar study, Stagg et al [44] showed that in the case of melanoma cancer model investigated, when MSCs producing IL-2 are mixed with B16 cells, delayed tumor growth is achieved in 90 % of examined cases.…”

Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma

“…Therefore in this study, IL-2 gene modification of MSCs conferred additional therapeutic benefits. Chen et al 25 transduced MSCs with an adenovirus engineered to secrete IL-12. Human MSCs, engineered to express interferon-b, have been used for targeted delivery of interferon-b, a potent antiproliferative and proapoptotic agent, in both metastatic 26 and gliomas 10 models.…”

Les cellules souches mésenchymateuses

“…En se fondant sur cette observation, nous avons construit un modèle expérimental dans lequel des CSM expriment un inhibiteur de l'angiogenèse (le fragment amino- terminal antagoniste de l'urokinase-type plasminogen [uPA]), ce qui a eu pour effet d'inhiber la croissance de métastases osseuses de cellules de cancer de prostate [26]. Les CSM ont également été utilisées pour apporter au site de la tumeur des molécules stimulant la réponse immunitaire telles que l'interleukine-12 (IL-12) [27] ou l'interféron gamma (IFN-) [28]. Enfin, les CSM ont aussi été utilisées comme vecteurs de virus oncolytiques au site tumoral, une stratégie particulièrement efficace dans le cas du cancer de l'ovaire [29] (voir aussi [33])…”