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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1943-1956
Number of pages14
JournalCell Reports
Volume8
Issue number6
DOIs
StatePublished - 25 Sep 2014

Bibliographical note

Funding Information:
We thank Dr. Leif Andersson for the consultations on histopathology, Dr. Taija Mäkinen for the Prox1-Cre ER mice, Dr. Darren Tyson for the ANXA1-modulating constructs, Dr. David Calderwood for the FLNA antibody, Dr. Meenhard Herlyn (Wistar Institute) for the SW1222 cell line, Dr. Tatiana Petrova for discussions of PROX1 functions in CRC, Dr. Pekka Katajisto, Dr. Tuomas Tammela, and Dr. Timo Otonkoski for comments on the manuscript, and Lari Pyöriä, Kirsi Lintula, Katja Salo, Laura Raitanen, and Tapio Tainola for their help with the experiments. The Biomedicum Imaging Unit is acknowledged for microscopy services. This work was funded by the Sigrid Juselius Foundation, the Finnish Cancer Organizations, and the Academy of Finland (262976). Z.W. was supported by the Sigrid Juselius Foundation and by the Marie-Curie Intra-European Fellowship (PIEF-GA-2009-236695).

Publisher Copyright:
© 2014 The Authors.

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