The DOI matches its Crossref record; 45 of the 46 references it cites were found in a registry or an index.
NKG2D Ligand Expression in Human Colorectal Cancer Reveals Associations with Prognosis and Evidence for Immunoediting
Open accessAbstract
Purpose: NKG2D (natural killer group 2, member D) binds to cellular ligands of the MIC and ULBP/RAET family. These ligands have restricted expression in normal tissue, but are frequently expressed on primary tumors. The role of NKG2D ligands is thought to be important in carcinogenesis but its prognostic effect has not been investigated in such a large cohort. Experimental Design: In our study, 462 primary colorectal tumors were screened for the expression of all MIC/ULBP/RAET proteins and NK cell infiltration. Tumor microarray technology was used for the purpose of this investigation. Results: NKG2D ligands were expressed by the majority of colorectal tumors; however, the level of expression varied considerably. High expression of MIC (68 versus 56 months) or RAET1G (74 versus 62 months) showed improved patient survival. Tumors expressing high levels of MIC and RAET1G showed improved survival of 77 months over tumors that expressed high levels of one ligand or low levels of both. High-level expression of all ligands was frequent in tumor-node-metastasis stage I tumors, but became progressively less frequent in stages II, III, and IV tumors. Expression of MIC was correlated with NK cellular infiltration. Conclusion: The observations presented are consistent with an immunoediting mechanism that selects tumor cells that have lost or reduced their expression of NKG2D ligands. The combination of MIC and tumor-node-metastasis stage was found to be the strongest predictor of survival, splitting patients into eight groups and suggesting prognostic value in clinical assessment. Of particular interest were stage I patients with low expression of MIC who had a similar survival to stage III patients, and may be candidates for adjuvant therapy. (Clin Cancer Res 2009;15(22):69937002)
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“These findings may be one explanation for why expression of NKG2D ligands in some cancers is insufficient to trigger NKG2D-dependent elimination of tumors (Jinushi et al., 2003; Guerra et al., 2008; McGilvray et al., 2009; Hilpert et al., 2012).”
From p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells (2013) · cites this paper as McGilvray et al., 2009
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Tissue microarrays for high-throughput molecular profiling of tumor specimens
Kononen, J., Bubendorf, L., Kallionimeni, A., Barlund, M. T., Schraml, P., Leighton, S. B., Torhorst, J. K. H., Mihatsch, M. J., Sauter, G., & Kallionimeni, O.-P. (1998) · Nature Medicine · doi:10.1038/nm0798-844 · Cited by 4,101 · cited 1×
“Tissue microarray technology allows simultaneous immunohistochemical analysis of hundreds of tumor specimens for target protein expression (30).”
BackgroundActivation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J., Lanier, L., & Spies, T. (1999) · Science · doi:10.1126/science.285.5428.727 · Cited by 3,272
The Three Es of Cancer Immunoediting
Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104803 · Cited by 3,235 · cited 3×
“Cancer cells that survive must adapt to avoid the immune system, a process variously described as immunoediting, immune sculpting, or cancer immune evasion (21).”
BackgroundInfluentialReporting Recommendations for Tumor Marker Prognostic Studies (REMARK)
McShane, L. M., Altman, D. G., Sauerbrei, W., Taube, S. E., Gion, M., & Clark, G. M. (2005) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/dji237 · Cited by 2,162
Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation
Groh, V., Wu, J. D., Yee, C., & Spies, T. (2002) · Nature · doi:10.1038/nature01112 · Cited by 1,674
Cosman, D., Müllberg, J., Sutherland, C. L., Chin, W. A., Armitage, R., Fanslow, W., Kubin, M., & Chalupny, N. (2001) · Immunity · doi:10.1016/s1074-7613(01)00095-4 · Cited by 1,394 · cited 1×
“It is known that NKG2D ligands can be expressed independently of each other in human cell lines and primary tumors (4, 12, 28).”
BackgroundRoles of the NKG2D immunoreceptor and its ligands
Raulet, D. H. (2003) · Nature reviews. Immunology · doi:10.1038/nri1199 · Cited by 1,351 · cited 1×
“NKG2D (natural killer group 2, member D) is a stimulatory receptor expressed on the surface of NK cells and subsets of T cells (1).”
BackgroundThe DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
Gasser, S., Orsulic, S., Brown, E. J., & Raulet, D. H. (2005) · Nature · doi:10.1038/nature03884 · Cited by 1,308 · cited 1×
“Some stimuli have been reported to result in the expression of all NKG2D ligands tested, such as DNA damage responses in mice (15).”
BackgroundRae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity
Diefenbach, A., Jensen, E. R., Jamieson, A. M., & Raulet, D. H. (2001) · Nature · doi:10.1038/35093109 · Cited by 1,083 · cited 1×
“In mouse models, it has been shown that tumor cell lines transfected with Rae1 are rejected in vivo via NKG2D-mediated immunity (18, 19).”
BackgroundGroh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M. D., & Spies, T. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.22.12445 · Cited by 1,018 · cited 1×
“In humans, both primary tumors and tumor-derived cell lines frequently express NKG2D ligands (11, 12, 14).”
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Research works printed but not linked: 1
- NICE, 2004, Improving outcomes in colorectal cancers: manual update
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Mamessier, É., Sylvain, A., Thibult, M., Houvenaeghel, G. F., Jacquemier, J. D., Castellano, R., Gonçalvès, A., André, P., Romagné, F., Thibault, G., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45816 · Cited by 722
Regulation of immune cell function and differentiation by the NKG2D receptor
Zafirova, B., Wensveen, F. M., Gulin, M., & Polić, B. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0797-0 · Cited by 562
“Also, expression of NKG2D ligands, both the soluble and the membrane-bound form, has been shown to be a reliable marker for disease progression in a variety of malignancies [85, 94, 110], illustrating its value as a clinical marker.”
Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130783 · Cited by 414
“…by activation of p53/p21 and p16/Rb tumor sup pressor pathways, which promote senescence by transactivating genes that arrest cell cycle progression and promote the senescent state (Serrano et al., 1997; Narita et al., 2003; Braig et al., 2005; Michaloglou et al., 2005; Ventura et al., 2007).”
Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities
Hu, W., Wang, G., Huang, D., Sui, M., & Xu, Y. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01205 · Cited by 406
“For example, high levels of NKG2D (Natural-killer Group 2, Member D) ligands are detected in the early stages of colorectal cancer, but their expression decreases as the disease progresses (8).”
BackgroundCourau, T., Bonnereau, J., Vivier-Chicoteau, J., Bottois, H., Remark, R., Miranda, L. A., Toubert, A., Bléry, M., Aparicio, T., Allez, M., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0553-9 · Cited by 278
Metadata
- Authors
- McGilvray, R. W., Eagle, R. A., Watson, N. F. S., Al-Attar, A., Ball, G., Jafferji, I., Trowsdale, J., & Durrant, L. G.
- Affiliations
- University of Nottingham (GB)
- Authors' Affiliations: 1Academic Division of Clinical Oncology, University of Nottingham, City Hospital Campus, 2Section of Gastrointestinal Surgery, Queen's Medical Centre, 3John Van Geest Research Centre, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom, and 4Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrookes Hospital, Cambridge, United Kingdom
- Venue
- Clinical Cancer Research
- Published
- 2009-11-11
- Volume
- 15
- Issue
- 22
- Pages
- 6993-7002
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2778653
- OpenAlex
- W2101699880
- Cited by
- 196
- References
- 46
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 8 · 2023: 13 · 2022: 18 · 2021: 13 · 2020: 13 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 6 · 2015: 17 · 2014: 18 · 2013: 14 · 2012: 10
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Nottingham Trent University's Institutional Repository (Nottingham Trent Repository) (submittedVersion)
- Funders
- Cancer Research UK (A7607)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- NKG2D ligands, colorectal cancer, NK cell infiltration, immunoediting, prognostic factors, patient survival, tumor stage, adjuvant therapy
- MeSH terms
- Aged, Female, Humans, Immunohistochemistry, Ligands, Male, Middle Aged, Models, Theoretical, Neoplasm Metastasis, Prognosis, Time Factors, Colorectal Neoplasms, Cohort Studies, Proportional Hazards Models, Treatment Outcome, Disease-Free Survival, Oligonucleotide Array Sequence Analysis, NK Cell Lectin-Like Receptor Subfamily K
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