Deficiency of GMDS leads to escape from NK cell-mediated tumor surveillance through modulation of TRAIL signaling.
OBJECTIVE
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes apoptosis in cancer cells, but not normal cells, and is critically involved in tumor rejection through natural killer (NK) cell-mediated immune surveillance. Oligosaccharides are involved in various aspects in carcinogenesis, and fucosylation is one of the most important oligosaccharide modifications in cancer. Here, we report for the first time mutations of the GDP-mannose-4,6-dehydratase (GMDS) gene, which plays a pivotal role in fucosylation, in human colon cancer. The mutations resulted in resistance to TRAIL-induced apoptosis followed by escape from immune surveillance.


METHODS
The mock and GMDS-rescued HCT116 cells were investigated in terms of NK cell-mediated tumor surveillance by TRAIL signaling both in vitro and in vivo. The mutational analysis for GMDS was performed with kinds of cancer cell lines and tissues.


RESULTS
The mutation found here led to a virtually complete deficiency of cellular fucosylation, and transfection of the wild-type GMDS into HCT116 cells restored the cellular fucosylation. When mock and GMDS-rescued cells were transplanted into athymic mice, tumor growth and metastasis of the GMDS-rescued cells were dramatically suppressed through NK cell-mediated tumor surveillance. Furthermore, the GMDS-rescued cells showed high susceptibility to TRAIL-induced apoptosis, and anti-TRAIL blocking antibody suppressed the accelerated direct cell lysis of the GMDS-rescued cells by splenocytes. Similar mutations of the GMDS were found in certain human cancer tissues and other cell lines.


CONCLUSIONS
This pathway by GMDS mutation could be a novel type of cancer progression through cellular fucosylation and NK cell-mediated tumor surveillance.
Moriwaki
Kenta
K
Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
Noda
Katsuhisa
K
Furukawa
Yoichi
Y
Ohshima
Kenji
K
Uchiyama
Airi
A
Nakagawa
Tsutomu
T
Taniguchi
Naoyuki
N
Daigo
Yataro
Y
Nakamura
Yusuke
Y
Hayashi
Norio
N
Miyoshi
Eiji
E
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000556:secondary; D005260:Female; D005643:Fucose / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D006836:Hydro-Lyases / Q000172:deficiency* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D019139:Tumor Escape
D012333:RNA, Messenger; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D005643:Fucose; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase