Epithelial vanin-1 controls inflammation-driven carcinogenesis in the colitis-associated colon cancer model.
BACKGROUND
Vanin-1 is an epithelial pantetheinase that provides cysteamine to tissue and regulates response to stress. Vanin-1 is expressed by enterocytes, and its absence limits intestinal epithelial cell production of proinflammatory signals. A link between chronic active inflammation and cancer is illustrated in patients with ulcerative colitis, who have an augmented risk of developing colorectal cancer. Indeed, sustained inflammation provides advantageous growth conditions to tumors. We examined whether epithelial cells affect tumorigenesis through vanin-1-dependent modulation of colonic inflammation.


METHODS
To vanin-1(-/-) mice, we applied the colitis-associated cancer (CAC) protocol, which combines injection of azoxymethane (AOM) with repeated administrations of dextran sodium sulfate (DSS). We numbered tumors and quantified macrophage infiltration and molecular markers of cell death and proliferation. We also tested DSS-induced colitis. We scored survival, tissue damages, proinflammatory cytokine production, and tissue regeneration. Finally, we explored activation pathways by biochemical analysis on purified colonic epithelial cells (CECs) and in situ immunofluorescence.


RESULTS
Vanin-1(-/-) mice displayed a drastically reduced incidence of colorectal cancer in the CAC protocol and manifested mild clinical signs of DSS-induced colitis. The early impact of vanin-1 deficiency on tumor induction was directly correlated to the amount of inflammation and subsequent epithelial proliferation rather than cell death rate; all this was linked to the modulation of NF-kappaB pathway activation in CECs.


CONCLUSIONS
These results emphasize the importance of the intestinal epithelium in the control of mucosal inflammation acting as a cofactor in carcinogenesis. This might lead to novel anti-inflammatory strategies useful in cancer therapy.
Pouyet
Laurent
L
Aix Marseille Université, Faculté des Sciences de Luminy, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
Roisin-Bouffay
Céline
C
Clément
Aurélie
A
Millet
Virginie
V
Garcia
Stéphane
S
Chasson
Lionel
L
Issaly
Nathalie
N
Rostan
Agathe
A
Hofman
Paul
P
Naquet
Philippe
P
Galland
Franck
F
D000581:Amidohydrolases; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D058851:GPI-Linked Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D016264:Dextran Sulfate; D000581:Amidohydrolases; C022314:pantetheinase; D001397:Azoxymethane