title: Effects on tumor development and metastatic dissemination by the NKG2D lymphocyte receptor expressed on cancer cells.
abstract: The stimulatory NKG2D lymphocyte receptor together with its tumor-associated ligands enable the immune system to recognize and destroy cancer cells. However, with dynamic changes unfolding, cancers exploit NKG2D and its ligands for immune evasion and suppression. Recent findings have added yet another functional dimension, wherein cancer cells themselves co-opt NKG2D for their own benefit to complement the presence of its ligands for self-stimulation of parameters of tumorigenesis. Those findings are here extended to in vivo tumorigenicity testing by employing orthotopic xenotransplant breast cancer models in mice. Using human cancer lines with ectopic NKG2D expression and RNA interference (RNAi)-mediated protein depletion among other controls, we show that NKG2D self-stimulation has tumor-promoting capacity. NKG2D signals had no notable effects on cancer cell proliferation and survival but acted at the level of angiogenesis, thus promoting tumor growth, tumor cell intravasation and dissemination. NKG2D-mediated effects on tumor initiation may represent another factor in the observed overall enhancement of tumor development. Altogether, these results may have an impact on immunotherapy approaches, which currently do not account for such NKG2D effects in cancer patients and thus could be misdirected as underlying assumptions are incomplete.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: El-Gazzar
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cai
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Reeves
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Caballero-Benitez
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: McDonald
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Vazquez
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Gooley
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Sale
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Spies
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Groh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D064593:Heterografts; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference
chemical_list: D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C488760:RAET1E protein, human