title: Mesenchymal Stem Cells Engineered to Secrete Pigment Epithelium-Derived Factor Inhibit Tumor Metastasis and the Formation of Malignant Ascites in a Murine Colorectal Peritoneal Carcinomatosis Model.
abstract: The therapeutic effects of conventional treatments for advanced colorectal cancer with colorectal peritoneal carcinomatosis (CRPC) and malignant ascites are not very encouraging. Vascular endothelial growth factor-A/vascular permeability factors (VEGF-A/VPF) play key roles in the formation of malignant ascites. In previous work, we demonstrated that pigment epithelium-derived factor (PEDF) antagonized VEGF-A and could repress tumor growth and suppress metastasis in several cancer types. Thus, PEDF may be a therapeutic candidate for treating malignant ascites. Mesenchymal stem cells (MSCs) are promising tools for delivering therapeutic agents in cancer treatment. In the study, MSCs derived from bone marrow were efficiently engineered to secrete human PEDF by adenoviral transduction. Then, intraperitoneal Ad-PEDF-transduced MSCs were analyzed with respect to CRPC and malignant ascites in a CT26 CRPC model. MSCs engineered to secrete PEDF through adenoviral transduction significantly inhibited tumor metastasis and malignant ascites formation in CT26 CRPC mice. Antitumor mechanisms of MSCs-PEDF (MSCs transduced with Ad-PEDF: MOI 500) were associated with inhibiting tumor angiogenesis, inducing apoptosis, and restoring the VEGF-A/sFLT-1 ratio in ascites. Moreover, MSC-mediated Ad-PEDF delivery reduced production of adenovirus-neutralizing antibodies, prolonged PEDF expression, and induced MSCs-PEDF migration toward tumor cells. As a conclusion, MSCs engineered to secrete PEDF by adenoviral transduction may be a therapeutic approach for suppressing tumor metastasis and inhibiting malignant ascites production in CRPC.
authors.affiliation: 1 Tumor Biotherapy Center/Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Gansu Province, Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, People's Republic of China .
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.affiliation: 2 Division of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, People's Republic of China .
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 3 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital of Sichuan University, Chengdu, People's Republic of China .
authors.forename: Liuliu
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 3 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital of Sichuan University, Chengdu, People's Republic of China .
authors.forename: Dan
authors.initials: D
authors.lastname: Yue
authors.affiliation: 3 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital of Sichuan University, Chengdu, People's Republic of China .
authors.forename: Jinhu
authors.initials: J
authors.lastname: Ma
authors.affiliation: 4 Oncology Medicine Department, Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, People's Republic of China .
authors.forename: Da
authors.initials: D
authors.lastname: Zhao
authors.affiliation: 4 Oncology Medicine Department, Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, People's Republic of China .
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hou
authors.affiliation: 5 School of Medicine/Collaborative Innovation Center for Biotherapy, Nankai University , Tianjin, People's Republic of China .
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: 3 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital of Sichuan University, Chengdu, People's Republic of China .
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D017209:Apoptosis; D001201:Ascites / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary*; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor