RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis.
Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the molecular mechanisms linking inflammation and cancer are not well defined. We earlier showed that carboxylated N-glycans expressed on receptor for advanced glycation end products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor kappa B (NF-kappaB). Because NF-kappaB signaling plays a critical role in the molecular pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans, RAGE and its ligands might promote CAC. Carboxylated glycans are expressed on a subpopulation of RAGE on colon cancer cells and mediate S100A8/A9 binding to RAGE. Colon tumor cells express binding sites for S100A8/A9 and binding leads to activation of NF-kappaB and tumor cell proliferation. Binding, downstream signaling and tumor cell proliferation are blocked by mAbGB3.1, an anti-carboxylate glycan antibody, and by anti-RAGE. In human colon tumor tissues and in a mouse model of CAC, we found that myeloid progenitors expressing S100A8 and S100A9 infiltrate regions of dysplasia and adenoma. mAbGB3.1 administration markedly reduces chronic inflammation and tumorigenesis in the mouse model of CAC and RAGE-deficient mice are resistant to the onset of CAC. These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor-stromal interactions, leading to inflammation-associated colon carcinogenesis.
Turovskaya
Olga
O
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
Foell
Dirk
D
Sinha
Pratima
P
Vogl
Thomas
T
Newlin
Robbin
R
Nayak
Jonamani
J
Nguyen
Mien
M
Olsson
Anna
A
Nawroth
Peter P
PP
Bierhaus
Angelika
A
Varki
Nissi
N
Kronenberg
Mitchell
M
Freeze
Hudson H
HH
Srikrishna
Geetha
G
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D040501:Calgranulin A / Q000032:analysis / Q000502:physiology*; D040502:Calgranulin B / Q000032:analysis / Q000502:physiology*; D049109:Cell Proliferation; D003092:Colitis / Q000150:complications*; D015179:Colorectal Neoplasms / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D022423:Myeloid Cells / Q000737:chemistry / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011134:Polysaccharides / Q000032:analysis / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000502:physiology*
D039481:CD11b Antigen; D040501:Calgranulin A; D040502:Calgranulin B; C509295:ITGAM protein, human; D016328:NF-kappa B; D011134:Polysaccharides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic