title: Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance.
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.
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Wiener
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Högström
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Hyvönen
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Arja M
authors.initials: AM
authors.lastname: Band
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Kallio
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00014 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Dufva
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, 00029 Helsinki, Finland.
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, 00029 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kruuna
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver
authors.affiliation: Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.affiliation: 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.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D064448:Filamins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D017305:Annexin A1; D064448:Filamins; D018398:Homeodomain Proteins; C493597:Lgr5 protein, mouse; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein