Pigment epithelium-derived factor gene therapy inhibits human pancreatic cancer in mice.
OBJECTIVE
Pigment epithelium-derived factor (PEDF), which has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, is also expressed in the pancreas. Previously, we have screened the expression of PEDF by immunohistochemical analysis and showed that low expression of PEDF is associated with increased risk of hepatic metastasis and short survival. The purpose of this study was to investigate whether PEDF gene is a potent tumor suppressor and a potential candidate for cancer gene therapy.


METHODS
We investigated both in vitro and in vivo growth characteristics of human pancreatic adenocarcinoma cell lines that were stably transfected to overexpress human PEDF and therapeutic effects of lentivirus-based vectors expressing PEDF on tumor growth in murine s.c. tumor model.


RESULTS
We discovered that cells secreted PEDF protein in the media and this exhibited strong inhibitory effects on proliferation and migration of human umbilical vein endothelial cells. The size of PEDF-overexpressing pancreatic adenocarcinoma tumors was significantly smaller than that of control tumors in s.c. tumor models. Moreover, the growth of PEDF-overexpressing pancreatic adenocarcinoma cells was significantly suppressed in comparison with control cells in peritoneal metastasis models. In gene transfer models, intratumoral injection of a lentivirus vector encoding PEDF (LV-PEDF) caused significant inhibition of tumor growth. The antitumor effect observed after treatment with LV-PEDF was associated with decreased microvessel density in tumors.


CONCLUSIONS
Our data suggest that PEDF may exert a biological effect on tumor angiogenesis and PEDF gene therapy may provide a new approach for treatment of pancreatic adenocarcinoma.
Hase
Ryunosuke
R
Department of Surgical Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan. ryu-hase@med.hokudai.ac.jp
Miyamoto
Masaki
M
Uehara
Hirofumi
H
Kadoya
Masatoshi
M
Ebihara
Yuma
Y
Murakami
Yoshihiro
Y
Takahashi
Ryo
R
Mega
Seiji
S
Li
Li
L
Shichinohe
Toshiaki
T
Kawarada
Yo
Y
Kondo
Satoshi
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000556:secondary / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D005136:Eye Proteins / Q000097:blood / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy*; D009414:Nerve Growth Factors / Q000097:blood / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000517:prevention & control / Q000556:secondary; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015843:Serpins / Q000097:blood / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor