Selective Killing of Hypoxia-Inducible Factor-1–Active Cells Improves Survival in a Mouse Model of Invasive and Metastatic Pancreatic Cancer

• Published in: Clinical cancer research 2009-05, Vol.15 (10), p.3433-3441
• Main Authors: KIZAKA-KONDOH, Shinae, ITASAKA, Satoshi, LIHUA ZENG, TANAKA, Shotaro, TAO ZHAO, TAKAHASHI, Yumi, SHIBUYA, Keiko, HIROTA, Kiichi, SEMENZA, Gregg L, HIRAOKA, Masahiro
• Format: Article
• Language: English
• Subjects: Abdominal Cavity - pathology; Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; Caspase 3 - metabolism; Cell Line, Tumor; Disease Progression; Gastroenterology. Liver. Pancreas. Abdomen; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HIF-1; Humans; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Luciferases - genetics; Luciferases - metabolism; Luminescent Measurements - methods; Male; Medical sciences; metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Neoplasm Invasiveness; Oxygen - metabolism; pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Peritoneum - drug effects; Peritoneum - metabolism; Peritoneum - pathology; Pharmacology. Drug treatments; protein transduction domain; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - pharmacology; Survival Analysis; Transfection; tumor hypoxia; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2267

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.