title: Genetically modified murine adipose-derived mesenchymal stem cells producing interleukin-2 favor B16F10 melanoma cell proliferation.
abstract: Adipose-derived mesenchymal stem cells (ADSCs) are attractive tools for cancer gene therapy due to their intrinsic tropism to the tumor environment. Interleukin-2 (IL2) is recognized as a key regulatory molecule, which enhances the activity and growth of the immune effector cell function. High-Dose IL2 Therapy is an option for treatment of malignant melanoma but has frequent, often serious and sometimes life-threatening side effects. Here we investigated the effect of genetically modified ADSCs (GM-ADSCs) expressing IL2 in immunocompetent mouse models of subcutaneous and lung metastatic melanoma. Prior to in vivo studies, we demonstrated that IL2 produced by GM-ADSCs may act as a growth factor for melanoma cells due to the increased viability and reduced apoptosis of melanoma cells after in vitro treatment. Subcutaneous co-injection of IL2-expressing ADSCs with melanoma cells significantly enhanced the melanoma tumor growth. Furthermore, histological analysis of subcutaneous tumors for IL2 and Melan-A (a melanocytic differentiation marker) confirmed that most of cells in melanoma/IL2-ADSC co-injected tumors are melanoma cells, not IL2-ADSCs. In pulmonary metastases model, melanoma cells were injected intravenously and 10 days later mice were treated by systematical injection of GM-ADSCs. Intravenously injected IL2-ADSCs engrafted into melanoma lung tumors but were unable to reduce melanoma lung metastases. Besides, administered IL2-ADSCs significantly reduced systemic CD4+ cells and did not impact the total survival of lung metastases melanoma bearing mice. In conclusion, this study showed that IL2-producing ADSCs can favor B16F10 melanoma cell proliferation. Therefore, therapies utilizing IL2 have to be taken into careful consideration.
authors.affiliation: Physiology Research Center, Isfahan University of Medical Sciences , Isfahan , Iran .
authors.forename: Vahid
authors.initials: V
authors.lastname: Bahrambeigi
authors.forename: Nafiseh
authors.initials: N
authors.lastname: Ahmadi
authors.forename: Rasoul
authors.initials: R
authors.lastname: Salehi
authors.forename: Shaghayegh Haghjooy
authors.initials: SH
authors.lastname: Javanmard
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D059016:Tumor Microenvironment
chemical_list: D007376:Interleukin-2
keywords: Adipose-derived mesenchymal stem cell (ADSC); T regulatory (Treg) cell; interleukin-2 (IL2); melanoma B16F10