title: Pigment epithelial-derived factor and melanoma differentiation associated gene-7 cytokine gene therapies delivered by adipose-derived stromal/mesenchymal stem cells are effective in reducing prostate cancer cell growth.
abstract: Adipose-derived stromal/mesenchymal stem cells (ASC) have gained interest as promising tools for delivering cancer therapy. Adipose tissue can be obtained readily in amounts sufficient for ASC isolation, which can be expanded rapidly, allowing its use at low passage numbers, and can be transduced by viral and nonviral means. Our goal was to examine the potential of ASC to deliver cytokine gene therapies melanoma differentiation associated gene-7 (MDA-7) or pigment epithelial-derived factor (PEDF) to cancer cells. These novel cytokines are a potent proapoptotic and an antiangiogenesis mediator, respectively, with potential as antitumor agents. Expression of cytokine therapies did not adversely affect ASC biology, and these cells were still able to differentiate and retain normal viability. The ASC cytokine therapies were efficient in reducing tumor cell growth in coculture and also in suppressing in vitro angiogenesis phenotypes. We also observed that ASC retained their innate ability to migrate toward tumor cells in coculture, and this ability could be blocked by inhibition of CXCR4 signaling. The ASC were found to be nontumorigenic in vitro using a soft agar assay, as well as in vivo, utilizing 2 prostate cancer xenograft models. The ASC-MDA7 only reduced tumor growth in the TRAMP-C2-Ras (TC2Ras) prostate cancer model. The ASC-PEDF, however, reduced growth in both the TC2Ras and the PC3 highly aggressive prostate cancer models, and it was able to completely prevent prostate tumor establishment in vivo. In conclusion, ASC expressing PEDF and MDA7 could effectively reduce prostate tumor growth in vivo, suggesting ASC-cytokine therapies might have translational applications, especially the PEDF modality.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Zolochevska
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gimble
authors.forename: Marxa L
authors.initials: ML
authors.lastname: Figueiredo
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D001943:Breast Neoplasms; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015843:Serpins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D000099174:Pigment Epithelium-Derived Factor; D000099180:Interleukin-24
chemical_list: D054377:Chemokine CXCL12; D005136:Eye Proteins; D007378:Interleukins; D009414:Nerve Growth Factors; D019718:Receptors, CXCR4; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; D000099180:Interleukin-24; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human