Importance of hypoxic regions as cancer stem cell niche; in vivo analyses using a novel mouse model

2015 Fiscal Year Final Research Report

• Project/Area Number: 26670555
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Kyoto University
• Principal Investigator: Hiraoka Masahiro 京都大学, 医学(系)研究科(研究院), 教授 (70173218)
• Co-Investigator(Kenkyū-buntansha): HARADA Hiroshi 京都大学, 白眉センター, 特定准教授 (80362531)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: がん / 放射線治療 / がん幹細胞 / 低酸素 / HIF-1

Outline of Final Research Achievements

Accumulating evidence has suggested that cancer cells acquire radioresistance in hypoxic regions of solid tumors with the help of a transcription factor, HIF-1. However, there is no direct evidence for the involvement of HIF-1-active cancer cells in tumor recurrence after radiotherapy so far. Here, we established a novel system to specifically eliminate HIF-1-active hypoxic cells from a tumor xenograft by combining a HIF-1-dependent promoter (5HRE) with a diphtheria toxin receptor (DTR) and establishing breast cancer cell line, EMT6, with the plasmid (EMT6/5HRE-DTR), and approached the problem. Immunohistochemical analyses demonstrated that, when xenografted into immunodeficient nude mice, the EMT6/5HRE-DTR stable transfectant exhibited TUNEL-positive nuclei after DT treatment in HIF-1-active hypoxic regions. Growth delay assay demonstrated a possibility that the tumor recurrence after radiotherapy is influenced by the elimination of HIF-1-active hypoxic cells from tumor xenografts.

Free Research Field

放射線腫瘍生物学