Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance

Zoltán Wiener; Jenny Högström; Ville Hyvönen; Arja M Band; Pauliina Kallio; Tanja Holopainen; Olli Dufva; Caj Haglund; Olli Kruuna; Guillermo Oliver; Yinon Ben-Neriah; Kari Alitalo

doi:10.1016/j.celrep.2014.08.034

Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance

Cell Rep. 2014 Sep 25;8(6):1943-1956. doi: 10.1016/j.celrep.2014.08.034. Epub 2014 Sep 18.

Authors

Affiliations

¹ Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
² Department of Surgery, Helsinki University Central Hospital, 00029 Helsinki, Finland.
³ Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁴ Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
⁵ Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, 00014 Helsinki, Finland. Electronic address: kari.alitalo@helsinki.fi.

PMID: 25242330
DOI: 10.1016/j.celrep.2014.08.034

Abstract

Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of these cells. We show here that a subpopulation of Prox1-transcription-factor-expressing cells have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth via induction of annexin A1 and reduction of the actin-binding protein filamin A, which has been implicated as a prognostic marker in CRC. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Annexin A1 / antagonists & inhibitors
Annexin A1 / genetics
Annexin A1 / metabolism
Autophagy
Cell Culture Techniques
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Filamins / antagonists & inhibitors
Filamins / genetics
Filamins / metabolism
Homeodomain Proteins / antagonists & inhibitors
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Ischemia / pathology
Ischemia / prevention & control
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Receptors, G-Protein-Coupled / metabolism
Transplantation, Heterologous
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Up-Regulation

Substances

Annexin A1
Filamins
Homeodomain Proteins
Lgr5 protein, mouse
RNA, Small Interfering
Receptors, G-Protein-Coupled
Tumor Suppressor Proteins
prospero-related homeobox 1 protein

Associated data

GEO/GSE47568