A Novel Secreted Tumor Antigen with a Glycosylphosphatidylinositol-Anchored Structure Ubiquitously Expressed in Human Cancers

Onda, Haruo; Ohkubo, Shoichi; Shintani, Yasushi; Ogi, Kazuhiro; Kikuchi, Kuniko; Tanaka, Hideyuki; Yamamoto, Kōji; Tsuji, Isamu; Ishibashi, Yoshihiro; Yamada, Takao; Kitada, Chieko; Suzuki, Nobuhiro; Sawada, Hideki; Nishimura, Osamu; Fujino, Masahiko

doi:10.1006/bbrc.2001.5149

Cited by 30 publications

(27 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, we investigated tumor cell shedding of ULBP2 as a representative of GPI-anchored NKG2DL. A previous study reported release of ULBP2 by several tumor cell lines and proposed shedding by phospholipases (18). We however find that ULBP2 shedding is, at least for the most part, executed by metalloproteases and not by phospholipases.…”

Section: Discussioncontrasting

confidence: 61%

“…In contrast to MIC molecules, ULBP1-3 have been shown to be linked to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor similarly to their mouse counterparts, the RAE-1 molecules (5,17). Previously, release of soluble ULBP2 (sULBP2)/ALCAN from some tumor cells in vitro has been reported (18), but neither the molecular mechanism of ULBP2 release nor its functional implications have been addressed. Here, we report that ULBP2 molecules are released from tumor cells by metalloproteases and can be detected in sera of patients with hematopoietic malignancies.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells

2006

View full text Add to dashboard Cite

The MHC class I-related ligands of the immunoreceptor NKG2D are frequently expressed by tumor cells and stimulate tumor immunity mediated by CD8 T cells and natural killer (NK) cells. In humans, NKG2D ligands (NKG2DL) are encoded by the MHC-encoded MIC and non-MHC-encoded UL16-binding protein (ULBP) families of proteins. Recently, we and others showed that tumor cells release soluble MICA (sMICA), thereby counteracting NKG2D-mediated tumor immunosurveillance. Here, we now report that ULBP2 molecules are likewise released from tumor cells in a processed soluble form, and that soluble ULBP2 (sULBP2) can be detected in sera of some patients with hematopoietic malignancies. Tumor cell-derived sULBP2 as opposed to cell-bound ULBP2 does not down-regulate NKG2D on NK cells. Unexpectedly, the glycosylphosphatidylinositol-anchored ULBP2 molecules are not released by phospholipases but by the action of metalloproteases. Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity. Shedding of MICA and ULBP2 can be blocked by the same inhibitors, suggesting the involvement of related metalloproteases. Thus, our data suggest that reducing NKG2DL surface densities is due to a common cleavage process executed by metalloproteases that promotes escape of tumors from NKG2D-mediated immunosurveillance. (Cancer Res 2006; 66(5): 2520-6)

show abstract

Section: Discussioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells

2006

View full text Add to dashboard Cite

show abstract

“…However, there is substantial evidence that human NK cells can recognize and destroy transformed tumor cells. This evidence is not simply the lysis of tumor cell lines in cell culture, but includes an understanding of the molecular display of DNA damaged tumor cells that express genotoxic, danger signals recognized by NK cells (Cosman, et al, 2001;Gasser, et al, 2005;Onda, et al, 2001;Oppenheim, et al, 2005;Radosavljevic, et al, 2002;Smyth et al, 2005a). The clinical significance of immune modulation during cancer is supported in several ways.…”

Section: Discussionmentioning

confidence: 99%

Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer

Witek-Janusek

Albuquerque

Chroniak

et al. 2008

Brain, Behavior, and Immunity

393

324

View full text Add to dashboard Cite

This investigation used a non-randomized controlled design to evaluate the effect and feasibility of a mindfulness based stress reduction (MBSR) program on immune function, quality of life (QOL), and coping in women recently diagnosed with breast cancer. Early stage breast cancer patients, who did not receive chemotherapy, self-selected into an 8-week MBSR program or into an assessment only, control group. Outcomes were evaluated over time. The first assessment was at least 10 days after surgery and prior to adjuvant therapy, as well as before the MBSR start-up. Further assessments were mid-MBSR, at completion of MBSR, and at 4-weeks post MBSR completion. Women with breast cancer enrolled in the control group (Non-MBSR) were assessed at similar times. At the first assessment (i.e., before MBSR start), reductions in peripheral blood mononuclear cell NK cell activity (NKCA) and IFN gamma production with increases in IL-4, IL-6, and IL-10 production and plasma cortisol levels were observed for both the MBSR and Non-MBSR groups of breast cancer patients. Over time women in the MBSR group re-established their NKCA and cytokine production levels. In contrast, breast cancer patients in the Non-MBSR group exhibited continued reductions in NKCA and IFN gamma production with increased IL-4, IL-6, and IL-10 production. Moreover, women enrolled in the MBSR program had reduced cortisol levels, improved QOL, and increased coping effectiveness compared to the Non-MBSR group. In summary, MBSR is a program that is feasible for women recently diagnosed with early stage breast cancer and the results provide preliminary evidence of beneficial effects of MBSR on immune function, QOL, and coping effectiveness.

show abstract

“…ADAMs 10 and 17 have been shown to be involved in proteolytic cleavage of ULBP2 (22), but nothing else is known about the shedding of other ULBPs. Indeed, in general, little is known about the biochemistry and cell biology of the ULBPs other than that they have signals for a GPI anchor (24,25) and that ULBP3 can associate with microdomains of the membrane rich in sphingolipids and cholesterol (detergent-resistant membranes) (26).…”

mentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

141

166

View full text Add to dashboard Cite

Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.NKG2D is an activating immune receptor that can be expressed by most cytotoxic lymphocytes, including NK and CD8ϩ T cells (1). Engagement of NKG2D by its ligands leads to the activation or co-stimulation of lysis and cytokine secretion (for review, see Ref. 2). In humans, NKG2D ligands (NKG2D-L) 5 occur in two families of proteins: the polymorphic family of MHC-I-related chain A/B (MICA/B) and the multigene family of UL16-binding proteins (ULBPs, also known as RAET1A-E). In total, 10 members of this gene family have been described, of which six can be expressed as functional proteins (3). Two members of the ULBP family have a transmembrane region (ULBP4 and -5), like MICA/B, whereas the other ULBP molecules are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. The existence of such a large number of ligands for a single receptor is not fully understood but may reflect a differential role for different ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer.In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas. An additional complication is that mRNA can be found in many cells that do not express protein suggesting post-transcriptional regulation of NKG2D-L expression (8 -10).Mice deficient in NKG2D expression show an enhanced susceptibility to the development of tumors (11). However, shedding NKG2D-L as soluble molecules allows tumor cells to evade NKG2D surveillance. Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12, 13). In fact, the sustained presence in vivo of NKG2D-L down-modulates...

show abstract

A Novel Secreted Tumor Antigen with a Glycosylphosphatidylinositol-Anchored Structure Ubiquitously Expressed in Human Cancers

Cited by 30 publications

References 28 publications

Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells

Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells

Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Contact Info

Product

Resources

About