A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs.
The poor prognosis for patients with advanced malignancy relates partly to the inability to reverse cancer metastasis. In this study we have investigated an integrated immunotherapy method against pre-established metastases in three kinds of advanced cancer models including B16 melanoma, 4T1 breast tumor, and Hca hepatoma. The progression of metastases into multistep lymph nodes (LN) and internal organs was, markedly impeded in the midway stage and reversed in the ultimate stage following a 20-day course of intravenous immunotherapy [with interleukin-12 (IL-12) gene-engineered mesenchymal stem cells (MSCs), administered once every 5 days P < 0.05)]; the therapy was without systemic toxic effects. As the control, obvious systemic toxicity was observed in the free AdIL-12 group, yet metastasis was partly delayed only in the midway stage but not in the ultimate stage. Enzyme-linked immunosorbent assay (ELISA) showed that the intratumoral expression levels of IL-12 were enhanced by cytokine-engineered MSCs to be tenfold greater than that of free AdIL-12 groups in the ultimate stage; conversely, free AdIL-12 groups showed elevated serum, but not intratumoral levels of IL-12, during the midway stage. Furthermore, histomorphometric analysis revealed a reductive tendency toward reversion of tumor-associated lymphatic sprouts and an increased tumor apoptosis index in engineered MSC groups (P < 0.05). These data indicate the potential of cytokine-engineered MSCs to be considered as an integrated therapeutic weapon for targeting advanced malignancies.
Chen
Xiancheng
X
Department of Gynecology and Obstetrics, West China Medical School, Second West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Lin
Xiaojuan
X
Zhao
Jianlei
J
Shi
Wei
W
Zhang
Heng
H
Wang
Yongsheng
Y
Kan
Bing
B
Du
Licheng
L
Wang
Baiding
B
Wei
Yuquan
Y
Liu
Yi
Y
Zhao
Xia
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008198:Lymph Nodes / Q000473:pathology; D042601:Lymphatic Vessels / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
D042643:Vascular Endothelial Growth Factor D; D018664:Interleukin-12