Selective killing of hypoxia-inducible factor-1-active cells improves survival in a mouse model of invasive and metastatic pancreatic cancer.
OBJECTIVE
Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested.


METHODS
We orthotopically transplanted pancreatic cancer cells stably transfected with a HIF-1-dependent luciferase reporter gene and monitored HIF-1 activity in vivo in control and POP33-treated mice. POP33 is a novel prodrug, which has potential to increase caspase-3 activity and induce apoptosis in HIF-1-active/hypoxic cells.


RESULTS
In vivo optical imaging showed that HIF-1 activity proceeded along with local invasion, the peritoneal dissemination, and the liver metastasis. HIF-1-active hypoxic cells were selectively eradicated by POP33. Moreover, selective killing of HIF-1-active hypoxic cells significantly suppressed malignant progression, resulting in a significant improvement in survival rate.


CONCLUSIONS
These results show that HIF-1-active cells constitute a large proportion of invading and metastatic cells and suggest that eradication of these cells may improve the outcome in advanced pancreatic cancer, a condition for which no effective therapy currently exists.
Kizaka-Kondoh
Shinae
S
Innovative Techno-Hub for Integrated Medical Bio-Imaging and Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan. skondoh@kuhp.kyoto-u.ac.jp
Itasaka
Satoshi
S
Zeng
Lihua
L
Tanaka
Shotaro
S
Zhao
Tao
T
Takahashi
Yumi
Y
Shibuya
Keiko
K
Hirota
Kiichi
K
Semenza
Gregg L
GL
Hiraoka
Masahiro
M
D034841:Abdominal Cavity / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D016019:Survival Analysis; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D051793:Hypoxia-Inducible Factor 1; D011993:Recombinant Fusion Proteins; C498363:TOP3 fusion protein; D049452:Green Fluorescent Proteins; D008156:Luciferases; D053148:Caspase 3; D010100:Oxygen