Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD...

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Bibliographic Details
Published in:Cell stem cell 2007-10, Vol.1 (4), p.389-402
Main Authors: Todaro, Matilde, Alea, Mileidys Perez, Di Stefano, Anna B, Cammareri, Patrizia, Vermeulen, Louis, Iovino, Flora, Tripodo, Claudio, Russo, Antonio, Gulotta, Gaspare, Medema, Jan Paul, Stassi, Giorgio
Format: Article
Language:English
Subjects:
AC133 Antigen
Aged
Animals
Antigens, CD - metabolism
Antineoplastic Agents - pharmacology
Cell Death - drug effects
Cell Line, Tumor
Colonic Neoplasms - pathology
Female
Fluorouracil - pharmacology
Glycoproteins - metabolism
Humans
Interleukin-4 - biosynthesis
Male
Mice
Mice, Nude
Middle Aged
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Neutralization Tests
Organoplatinum Compounds - pharmacology
Peptides - metabolism
Receptors, Interleukin-4 - metabolism
Spheroids, Cellular - drug effects
Spheroids, Cellular - metabolism
Spheroids, Cellular - pathology
Xenograft Model Antitumor Assays
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Summary:A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133(+) cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133(+) cells. Further analysis revealed that the CD133(+) cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Ralpha antagonist or anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133(+) cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2007.08.001