Expression of an antigen homologous to the human CO17-1A/GA733 colon cancer antigen in animal tissues

Žaloudík, Jan; Basak, Sayan; Nesbit, Mark E.; Speicher, DW; Wunner, William H.; Miller, Ewa; Ernst-Grotkowski, C.; Kennedy, Ralph M.; Bergsagel, Leif; Koido, Takashi; Herlyn, Dorothee

doi:10.1038/bjc.1997.483

Cited by 15 publications

(9 citation statements)

References 26 publications

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“…A search for physiological expression of the molecule revealed that it was strongly expressed on epithelial cells (Claas et al, 1996). The same pattern of expression has been described for the panepithelial glycoprotein EGP of the mouse and the human epithelial glycoprotein antigen/major gastrointestinal tumor-associated protein GA733-2/EGP314 (Bergsagel et al, 1992;Momburg et al, 1987;Zaloudik et al, 1997). Since expression of GA733-2/EGP314 is used as diagnostic and therapeutic tool (Fagerberg et al, 1995;Li et al, 1997), it was of interest to evaluate, whether D5.7A is, indeed, the rat ortholog, which would o er a possibility to elaborate functional activities of the molecule.…”

Section: Resultsmentioning

confidence: 55%

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314

Würfel

Rösel

Seiter³

et al. 1999

Oncogene

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Screening for surface molecules expressed by metastasizing rat tumors had revealed evidence for metastasisassociation of a molecule also expressed on epithelial cells. The similarity to the expression pro®le of the panepithelial glycoprotein EGP314 prompted us to isolate and sequence the gene and to explore functional features of the molecule in transfected tumor lines. The molecule D5.7A, named according to the antibody, D5.7, used for selection, indeed, is the ortholog of EGP314 with 92% and 80% identity to the murine and the human molecules. Like EGP314, D5.7A has a particular cleavage site, a small cleavage product being resolved under reducing conditions from the membrane anchored part of the molecule. Transfection of a low metastasizing ®brosarcoma, pheochromoblastoma and adenocarcinoma revealed that expression of D5.7A facilitates tumor progression. Depending on the origin of the tumor, D5.7A transfectants either metastasized via the lymphatic system (pheochromoblastoma, adenocarcinoma) or hematogeneously (®brosarcoma). Particularly after proteolytic cleavage, D5.7A facilitated cell ± cell adhesion and provided a proliferative signal upon crosslinking. Thus, the rat ortholog of EGP314 is involved in metastasis formation. Importantly, its functional activities apparently rely on proteolytic cleavage. These ®ndings provide a ®rst evidence on how a panepithelial marker can be involved in tumor progression.

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Section: Resultsmentioning

confidence: 55%

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314

Würfel

Rösel

Seiter³

et al. 1999

Oncogene

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“…VV GA733-2 also prevents growth of syngeneic Ag -positive tumor cells in mice. The high amino acid sequence homology between the mouse and human GA733 Ag in normal tissues, 23 and the similarity in normal tissue distribution 24 makes the mouse a relevant model for experimental active immunotherapy against the GA733 Ag.…”

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confidence: 99%

Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice

Žaloudík

Jacob

et al. 2002

Cancer Gene Ther

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The human colorectal carcinoma ( CRC ) -associated GA733 antigen ( Ag ), also named CO17 -1A / EpCAM / KSA / KS1 -4, has been a useful target in passive immunotherapy of CRC patients with monoclonal antibody ( mAb ) and in active immunotherapy with antiidiotypic antibodies or with recombinant protein. These approaches have targeted single epitopes ( monoclonal anti -GA733 antibodies and anti -idiotypic antibodies ) or extracellular domain epitopes ( recombinant protein ), primarily by B cells. To determine whether a reagent that induces immunity to a larger number of both B -and T -cell epitopes might represent a superior vaccine, we analyzed the capacity of full -length GA733 Ag expressing multiple potentially immunogenic epitopes and encoded by recombinant vaccinia virus ( VV GA733 -2 ) to induce humoral, cellular, and / or protective immunity in mice. VV GA733 -2 induced Ag -specific antibodies that reacted predominantly to unknown epitopes on the Ag and lysed Ag -positive CRC targets in conjunction with murine peritoneal macrophages as effector cells. Immunized mice developed Ag -specific, proliferative and delayed -type hypersensitive lymphocytes. VV GA733 -2 inhibited growth of ras -transformed syngeneic tumor cells expressing the human GA733 Ag in mice. These results suggest the potential of VV GA733 -2 as a candidate vaccine for patients with CRC, possibly in combination with recombinant GA733 -2 -expressing adenovirus, which has been shown to induce cytolytic antibodies and T cells as well as tumor protective effects in mice. The combined vaccine approach may be superior to the use of either vaccine alone in patients who are pre -immune to both viruses.

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“…Moreover, the comparison to control adenovirus-transduced controls rules out any nonspecific effects of adenovirus infection. DC are known to effectively internalize cellular fragments from apoptotic or necrotic cells and process these proteins for presentation by MHC class I and class II molecules (25,35). Should tumor infiltrating DC internalize such fragments from mEGP-expressing tumor cells in vivo, DC presentation of TAA would be expected to be inhibited by the internalized mEGP.…”

Section: Discussionmentioning

confidence: 99%

“…When expressed ectopically in fibroblasts or epithelial cells, GA733-2 has been shown to mediate homotypic cell:cell interactions and to interfere with adhesion mediated by conventional adhesion molecules (23,24), but its physiological function is not known. mEGP bears 81% amino acid identity to GA733-2, has a similar expression profile in normal tissues (19,25), and is similarly overexpressed in some murine tumor cell lines. As part of an effort to establish a murine model for anti-carcinoma immune responses, we attempted to immunize mice with DC-expressing mEGP.…”

mentioning

confidence: 99%

A Tumor-Associated Glycoprotein That Blocks MHC Class II-Dependent Antigen Presentation by Dendritic Cells

Gutzmer¹,

Li²,

Sutterwala

et al. 2004

The Journal of Immunology

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Tumors evade immune surveillance despite the frequent expression of tumor-associated Ags (TAA). Tumor cells escape recognition by CD8+ T cells through several mechanisms, including down-regulation of MHC class I molecules and associated Ag-processing machinery. However, although it is well accepted that optimal anti-tumor immune responses require tumor-reactive CD4+ T cells, few studies have addressed how tumor cells evade CD4+ T cell recognition. In this study, we show that a common TAA, GA733-2, and its murine orthologue, mouse epithelial glycoprotein (mEGP), function in blocking MHC class II-restricted Ag presentation by dendritic cells. GA733-2 is a common TAA that is expressed normally at low levels by some epithelial tissues and a subset of dendritic cells, but at high levels on colon, breast, lung, and some nonepithelial tumors. We show that ectopic expression of mEGP or GA733-2, respectively, in dendritic cells derived from murine bone marrow or human monocytes results in a dose-dependent inability to stimulate proliferation of Ag-specific or alloreactive CD4+ T cells. Dendritic cells exposed to cell debris from tumors expressing mEGP are similarly compromised. Furthermore, mice immunized with dendritic cells expressing mEGP from a recombinant adenovirus vector exhibited a muted anti-adenovirus immune response. The inhibitory effect of mEGP was not due to down-regulation of functional MHC class II molecules or active suppression of T cells, and did not extend to T cell responses to superantigen. These results demonstrate a novel mechanism by which tumors may evade CD4+ T cell-dependent immune responses through expression of a TAA.

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Expression of an antigen homologous to the human CO17-1A/GA733 colon cancer antigen in animal tissues

Cited by 15 publications

References 26 publications

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314

Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice

A Tumor-Associated Glycoprotein That Blocks MHC Class II-Dependent Antigen Presentation by Dendritic Cells

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