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      Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells 1 2

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          Abstract

          Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D + cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states. NKG2D + ovarian cancer cell populations harbor substantially greater capacities for self-renewing in vitro sphere formation and in vivo tumor initiation in immunodeficient (NOD scid gamma) mice than NKG2D controls. Sphere formation and tumor initiation are impaired by NKG2D silencing or ligand blockade using antibodies or a newly designed pan ligand-masking NKG2D multimer. In further support of pathophysiological significance, a prospective study of 47 high-grade serous ovarian cancer cases revealed that the odds of disease recurrence were significantly greater and median progression-free survival rates higher among patients with above and below median NKG2D + cancer cell frequencies, respectively. Collectively, our results define cancer cell NKG2D as an important regulator of tumor initiation in ovarian cancer and presumably other malignancies and thus challenge current efforts in immunotherapy aimed at enhancing NKG2D function.

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          Most cited references37

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          The emerging role of EpCAM in cancer and stem cell signaling.

          Initially discovered as a dominant antigen on colon carcinomas, the epithelial cell adhesion molecule (EpCAM) was considered a mere cell adhesion molecule and reliable surface-binding site for therapeutic antibodies. Recent findings can better explain the relevance of EpCAM's high-level expression on human cancers and cancer propagating cells, and its negative prognostic potential for survival of patients with certain cancers. EpCAM has oncogenic potential and is activated by release of its intracellular domain, which can signal into the cell nucleus by engagement of elements of the wnt pathway.
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            Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival.

            Markers that reliably identify cancer stem cells (CSC) in ovarian cancer could assist prognosis and improve strategies for therapy. CD133 is a reported marker of ovarian CSC. Aldehyde dehydrogenase (ALDH) activity is a reported CSC marker in several solid tumors, but it has not been studied in ovarian CSC. Here we report that dual positivity of CD133 and ALDH defines a compelling marker set in ovarian CSC. All human ovarian tumors and cell lines displayed ALDH activity. ALDH(+) cells isolated from ovarian cancer cell lines were chemoresistant and preferentially grew tumors, compared with ALDH(-) cells, validating ALDH as a marker of ovarian CSC in cell lines. Notably, as few as 1,000 ALDH(+) cells isolated directly from CD133(-) human ovarian tumors were sufficient to generate tumors in immunocompromised mice, whereas 50,000 ALDH(-) cells were unable to initiate tumors. Using ALDH in combination with CD133 to analyze ovarian cancer cell lines, we observed even greater growth in the ALDH(+)CD133(+) cells compared with ALDH(+)CD133(-) cells, suggesting a further enrichment of ovarian CSC in ALDH(+)CD133(+) cells. Strikingly, as few as 11 ALDH(+)CD133(+) cells isolated directly from human tumors were sufficient to initiate tumors in mice. Like other CSC, ovarian CSC exhibited increased angiogenic capacity compared with bulk tumor cells. Finally, the presence of ALDH(+)CD133(+) cells in debulked primary tumor specimens correlated with reduced disease-free and overall survival in ovarian cancer patients. Taken together, our findings define ALDH and CD133 as a functionally significant set of markers to identify ovarian CSCs.
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              Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB.

              Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens that are recognized by a subset of gamma delta T cells expressing the variable region Vdelta1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where MICA and, presumably, MICB are mainly expressed. However, increased frequencies of Vdelta1 gamma delta T cells have been observed in various epithelial tumors; moreover, MICA/B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of MICA/B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for MICA/B, the frequencies of Vdelta1 gamma delta T cells were significantly higher than in those that were negative. Vdelta1 gamma delta T cell lines and clones derived from different tumors recognized MICA/B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, MICA/B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating gamma delta T cells. These results raise the possibility that an induced expression of MICA/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.
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                Author and article information

                Contributors
                Journal
                Neoplasia
                Neoplasia
                Neoplasia (New York, N.Y.)
                Neoplasia Press
                1522-8002
                1476-5586
                09 May 2017
                June 2017
                09 May 2017
                : 19
                : 6
                : 471-482
                Affiliations
                [* ]Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98112, USA
                []Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98112, USA
                []Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98112, USA
                Author notes
                [* ]Address all correspondence to: Veronika Groh, MD, and Thomas Spies, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA.Clinical Research DivisionFred Hutchinson Cancer Research Center1100 Fairview Ave. N.SeattleWA98109USA vgroh@ 123456fredhutch.org
                [3]

                These authors contributed equally to this work.

                Article
                S1476-5586(17)30086-6
                10.1016/j.neo.2017.03.005
                5429243
                28499126
                ab2c9380-df1c-458d-9872-73cde6ec3e1e
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 14 February 2017
                : 20 March 2017
                : 24 March 2017
                Categories
                Original article

                dap10, dnax-activating protein 10,eoc, epithelial ovarian cancer,hgs, high-grade serous,mica and micb, mhc class i-related chains a and b,nkg2dl, nkg2d ligands,ulbp, ul-16 binding protein

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