Syncytin immunoreactivity in colorectal cancer: Potential prognostic impact

Larsen, Julie M.; Christensen, Ib Jarle; Nielsen, Hans Jørgen; Hansen, Ulla; Bjerregaard, Bolette; Talts, Jan F.; Larsson, Lars‐Inge

doi:10.1016/j.canlet.2009.02.008

“…Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs (Chen et al, 2004; Cohen et al, 1988; Larsen et al, 2009; Larsson et al, 2007; Rycaj et al, 2014; Strick et al, 2007; Strissel et al, 2012; Wang-Johanning et al, 2001; Wang-Johanning et al, 2007) while others maintain silencing. Aza can induce specific ERV transcripts in melanoma, choriocarcinoma, and endometrial cancer cells (Laska et al, 2013; Ruebner et al, 2013; Stengel et al, 2010) (Strissel et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli

¹

,

Strissel

²

,

Desrichard

³

et al. 2015

Cell

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Summary We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

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“…Many tumor cells are fusogenic, and the fusion rate in experimental tumors is estimated at 1% (Duelli and Lazebnik 2003). Moreover, fused cells have been observed in cancer specimens (Duelli and Lazebnik 2007;Strick et al 2007;Larsen et al 2009). Despite the oncogenic potential of cell fusion, however, most cases of cell fusion do not lead to cell transformation (Harris et al 1969;Ogle et al 2005;Duelli and Lazebnik 2007).…”

Section: Discussionmentioning

confidence: 99%

“…ERVWE1 is one of the proteins that is expressed in cancer cells of multiple origins and mediates fusion of cells in human tumors (Larsson et al 2007;Strick et al 2007;Larsen et al 2009). Interestingly, both ERVWE1 and MV have been proposed as candidates for the local treatment of cancer via induction of cell fusion (Msaouel et al 2009;Lin et al 2010).…”

Section: Fusion Of Cancer Cells Leads To Cellular Senescencementioning

confidence: 99%

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

Chuprin

¹

,

Gal

²

,

Biron‐Shental

³

et al. 2013

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Cellular senescence limits proliferation of potentially detrimental cells, preventing tumorigenesis and restricting tissue damage. However, the function of senescence in nonpathological conditions is unknown. We found that the human placental syncytiotrophoblast exhibited the phenotype and expressed molecular markers of cellular senescence. During embryonic development, ERVWE1-mediated cell fusion results in formation of the syncytiotrophoblast, which serves as the maternal/fetal interface at the placenta. Expression of ERVWE1 caused cell fusion in normal and cancer cells, leading to formation of hyperploid syncytia exhibiting features of cellular senescence. Infection by the measles virus, which leads to cell fusion, also induced cellular senescence in normal and cancer cells. The fused cells activated the main molecular pathways of senescence, the p53-and p16-pRbdependent pathways; the senescence-associated secretory phenotype; and immune surveillance-related proteins. Thus, fusion-induced senescence might be needed for proper syncytiotrophoblast function during embryonic development, and reuse of this senescence program later in life protects against pathological expression of endogenous fusogens and fusogenic viral infections.

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“…Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing. Aza can induce specific ERV transcripts in melanoma, choriocarcinoma, and endometrial cancer cells (Laska et al, 2013;Ruebner et al, 2013;Stengel et al, 2010) (Strissel et al, 2012).…”

Section: Aza-induced Human Endogenous Retrovirus (Erv) Transcripts Camentioning

confidence: 99%

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli¹,

Strissel²,

Desrichard³

et al. 2017

Cell

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SummaryWe show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Correspondence should be addressed to Reiner.Strick@uk-erlangen.de and sbaylin@jhmi.edu.. 7 Co-first authors. 8 Co-senior authors.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions KBC, PLS, AD, TM, JW, TAC, SBB, and RS designed experiments, performed data analyses, and wrote the manuscript. KBC, PLS, CH, AD, AH, BA, and SB performed experiments. NSR provided ERV-3 env cDNA plasmid and DS provided ovarian cancer cell lines. HL, AS, VM, DMP, LMC, MWB, and CAZ assisted with data analyses. TM, TAC, SBB, and RS contributed equally to this work and are co-senior authors. HHS Public Access

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Syncytin immunoreactivity in colorectal cancer: Potential prognostic impact

Cited by 53 publications

References 17 publications

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

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