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 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.
Todaro
Matilde
M
Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, 90127 Palermo, Italy.
Alea
Mileidys Perez
MP
Di Stefano
Anna B
AB
Cammareri
Patrizia
P
Vermeulen
Louis
L
Iovino
Flora
F
Tripodo
Claudio
C
Russo
Antonio
A
Gulotta
Gaspare
G
Medema
Jan Paul
JP
Stassi
Giorgio
G
D000071916:AC133 Antigen; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D009500:Neutralization Tests; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010455:Peptides / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D009944:Organoplatinum Compounds; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019948:Receptors, Interleukin-4; D000077150:Oxaliplatin; D015847:Interleukin-4; D005472:Fluorouracil