TY - JOUR
T1 - Selective killing of hypoxia-inducible factor-1-active cells improves survival in a mouse model of invasive and metastatic pancreatic cancer
AU - Kizaka-Kondoh, Shinae
AU - Itasaka, Satoshi
AU - Zeng, Lihua
AU - Tanaka, Shotaro
AU - Zhao, Tao
AU - Takahashi, Yumi
AU - Shibuya, Keiko
AU - Hirota, Kiichi
AU - Semenza, Gregg L.
AU - Hiraoka, Masahiro
PY - 2009/5/15
Y1 - 2009/5/15
N2 - Purpose: 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. Experimental Design: 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.
AB - Purpose: 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. Experimental Design: 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.
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U2 - 10.1158/1078-0432.CCR-08-2267
DO - 10.1158/1078-0432.CCR-08-2267
M3 - Article
C2 - 19417024
AN - SCOPUS:66149164442
SN - 1078-0432
VL - 15
SP - 3433
EP - 3441
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -