Imaging and Targeting of Hypoxic Tumor Cells by Use of HIF-1

Abstract

Tumor hypoxia is a potential therapeutic problem because it is closely associated with resistance to anti-cancer therapies and with the phenomenon of malignant progression. Therefore, although hypoxic tumor cells account for a very limited area in a solid tumor, conquering tumor hypoxia is crucial for treatment of malignant tumors. To image hypoxic tumor cells in vivo, we isolated a transfectant clone HeLa/5HRE-Luc, whose luciferase activity under hypoxic conditions was more than 100-fold of the one under aerobic conditions, and monitored the luciferase activity in HeLa/5HRE-luc xenografts with an in vivo real-time imaging system. To target tumor hypoxia, we recently constructed a fusion protein POP33, which is composed of the protein transduction domain (PTD), a part of HIF-1 α ODD and the dormant form of caspase-3, procaspase-3. PTD fusion proteins are previously demonstrated to be delivered to every cell in the whole body. POP33 did not affect well-oxygenized cells but efficiently increased caspase-3 activity and induced cell death to hypoxic cells in vitro. To investigate if POP33 can target hypoxic tumor cells in vivo, we monitored the luciferase activity in orthotopically transplanted human pancreatic cancer cells during POP33 treatment. The metastasis of the pancreatic cancer was significantly suppressed and their lucif erase activity was reduced during the sequential administration of POP33. These data demonstrate that POP33 specifically targets tumor hypoxia and provide direct evidence that hypoxic tumor cells play a crucial role in t metastasis of pancreatic cancers.