Role of Mesenchymal Stem Cells in Delivering Newcastle Disease Virus to Non-Small Cell Lung Cancer

Background and Aim: Lung cancer represents one of the majorchallenges in oncology. About 85% of lung cancers are non-small celllung carcinoma (NSCLC). Despite progress in chemo-radiotherapy andtargeted therapy, its survival rate is still low. Hence, using oncolyticviruses such as Newcastle disease virus (NDV) can be effective. NDVsignificantly cause tumor regression in intratumoral injection but theabsence of an effective delivery system and immune clearance systemcause non-significant in the systemic injection. Mesenchymal stem cells(MSC) have a tropism to the tumor and they can be used as a carrier ofNDV.Methods: MSCs were isolated from bone marrow and adipose tissue. Theevaluation of a characteristic of MSCs by biomarkers (CD90, CD73, andCD105) was performed using flow cytometry. B1, V4 and La-Sota strainsof NDV were propagated in MDBK cell line and allantoic cavity of 7- to9- day-old embryonated chicken eggs, purified using ultracentrifugationand titrated using HA assay. Infection of MSCs with a different strainof NDV evaluated using flow cytometry by staining with anti-virusconjugated antibodies. The effect of infected MSC with the best strain ofNDV on A549 cells (NSCLC cell line) was evaluated using the XTT assay.This evaluation was performed with co-culture and using the supernatantmedium of infected MSC with appropriate controls including MSC alone,NDV alone at different concentrations and PBS.Results: MSCs were isolated and confirmed by biomarkers. The titerof B1, V4 and La-Sota strains of NDV, propagating in MDBK cell line,were 1 HU, 8 HU, and 4 HU respectively. The titer of them reachedto at least 36 HU after propagation in embryonated chicken egg and65536 HU after purification. The different strains of NDV could infectMSCs and the best stain was V4 with 1000HU/mL. The evaluation ofthe effects of NDV alone, MSC alone and infected MSC with NDV onA549 cells demonstrate that NDV induced a dose-dependent cell deathin A549 cells and MSCs are more resistant to NDV than A549 cells. Ingroups existing MSCs, A549 cells highly proliferate and formed multilayercolonies. Nonetheless, the proliferation in infected MSC with NDVgroup was less than MSC group.Conclusion: The proliferation of A549 cells was increased in co-culturedMSCs and using the supernatant medium of MSCs, probably due tothe release of various growth stimulants. However, it was less in NDVinfectedMSCs which may due to the effects of NDV releasing frominfected MSCs. The results showed that MSCs can be employed to deliverNDV to NSCLC cell line. Considering the limitation of chemotherapyand radiation therapy of NSCLC, treatment with MSC-mediated targeted oncolytic NDV may provide a novel effective therapeutic approach forthe treatment of advanced NSCLC.

کلیدواژه ها:

Mesenchymal stem cells ، Newcastle disease virus ، non-small cell lung cancer