High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells

Herfs, Michaël; Herman, Ludivine; Hubert, Pascale; Minner, Frédéric; Arafa, Mohammad; Roncarati, Patrick; Henrotin, Yves; Boniver, Jacques; Delvenne, Philippe

doi:10.1007/s00262-008-0584-4

Cited by 59 publications

(46 citation statements)

References 60 publications

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“…Previous results have demonstrated that a high epithelial expression of PGE 2 enzymatic pathways (COX-2 and mPGES-1) is correlated with a lower density of LC in cervical (pre)neoplastic lesions [16]. In agreement with these results, the conditioned media of HPV16 VLP-incubated keratinocytes contained higher levels of PGE 2 than those from untreated keratinocytes.…”

Section: Discussionsupporting

confidence: 83%

“…One random field was counted per well using an eyepiece with a calibrated grid to evaluate the number of fully migrated cells. PGE 2 radioimmunoassay PGE 2 was detected in supernatants of keratinocytes treated or not by VLP according to a previously described RIA [16] using a polyclonal rabbit antiserum, which does not cross react with other prostanoids (thromboxane B2 (TxB 2 ), 6-keto-PGF1a, PGA 2 ) or fatty acids (arachidonic, linoleic, oleic).…”

Section: Chemotaxis Assaymentioning

confidence: 99%

“…As previous studies reported that prostaglandin E2 (PGE 2 ) could influence APC function [16], we determined whether HPV16 VLP could affect the level of PGE 2 produced by normal keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

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The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Herman¹,

Hubert²,

Herfs³

et al. 2010

Eur J Immunol

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Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/ Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-jB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE 2 ), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells.Key words: APC . Cell trafficking . Chemokines . HPV16 VLP Supporting Information available online IntroductionMore than 90% of cervical cancers and precursor lesions (squamous intraepithelial lesions, SIL) may be attributed to the infection by oncogenic types of human papillomavirus (HPV) [1]. However, HPV alone is not sufficient for tumor progression [2]. Additional environmental and/or host factors are probably involved in malignant progression as suggested by the small proportion of infected individuals developing cervical cancer and the relatively long latency period before cancer emergence [3]. The importance of the immune system in the control of HPV infection and lesion development is shown, indirectly, by the high Eur. J. Immunol. 2010. 40: 3075-3084 DOI 10.1002 Immunity to infection 3075 prevalence and persistence of HPV infections in immunosuppressed individuals [4] and by the fact that an increased cellular immune response is correlated with a good clinical prognosis [5]. The DC lineage is a family of professional APC. On exposure to danger signals such as pathogens, immature DC are able to process antigens and to mature through a dramatic change in their cell surface markers [6]. The migration of maturing DC to the draining lymph nodes results in the interactions between DC and naive T cells and in the initiation of an antigen-specific immune response [7]. Furthermore, the signals induced within draining lymph nodes can cause the expansion of lymphatic vessels, sustaining and amplifying the effective homing of DC [8]. Indeed, migration of DC from the site of antigen capture to secondary lymphoid organs is a crucial event in the initiation and amplification of immune responses. In turn, inflammatory sites can recruit circulating...

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Section: Discussionsupporting

confidence: 83%

Section: Chemotaxis Assaymentioning

confidence: 99%

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The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Herman¹,

Hubert²,

Herfs³

et al. 2010

Eur J Immunol

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“…15 Briefly, paraffin sections were deparaffinized, rehydrated in graded alcohols, and antigens were retrieved in EDTA or in citrate buffer, whereas frozen sections were fixed with 4% paraformaldehyde and nonspecific binding sites were blocked by a 2% BSA solution. Antibodies anti-p63 (clone 7JUL; Novocastra, Newcastle, UK) recognizing all p63 isoforms, anti-Snail (Abcam, Cambridge, UK), and anti-Slug (Abcam) were used for the primary reaction.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Regulation of p63 Isoforms by Snail and Slug Transcription Factors in Human Squamous Cell Carcinoma

Herfs

Hubert

Suarez-Carmona

et al. 2010

The American Journal of Pathology

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TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (⌬Np63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of ⌬N and TAp63 isoforms were, respectively, down-and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of ⌬Np63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that ⌬Np63 silencing reduced cellcell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness.

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“…One important mechanism by which tumor-derived PGE 2 suppresses immune responses is the induction of APC dysfunction in vivo resulting in an inhibition of T cell responses against the tumor. This has been demonstrated for human epithelial cancers such as head and neck and cervical cancer (31,32). Several mechanisms by which PGE 2 -induced tolerogenic DCs prevent tumoricidal immune reactions have been discovered: they promote T helper type 2 (Th2) instead of T helper type 1 (Th1) responses and they attract regulatory T cells (33).…”

Section: Discussionmentioning

confidence: 99%

The properties of human CD40-activated B cells as antigen-presenting cells are not affected by PGE2

Shimabukuro‐Vornhagen

Draube

Liebig

et al. 2012

Oncology Reports

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Abstract. Tumor vaccination represents a promising immunotherapeutic strategy in cancer. However, the inherent ability of many tumors to evade immune responses by suppression of immune cell function represents a major barrier. Prostaglandin E 2 (PGE 2 ) has been shown to be a critical tumor-derived immunosuppressive factor. It affects a broad range of immune cells including T cells, macrophages and dendritic cells (DCs). CD40-activated B cells are being studied as a potential alternative to DCs as antigen-presenting cells for immunotherapy. So far, it is not known whether PGE 2 affects their antigen presenting capacity. We, therefore, investigated the influence of PGE 2 on the phenotype, migratory potential and antigen-presenting function of CD40-activated human B cells. Here, we demonstrate that the immunostimulatory properties of CD40-activated B cells are not affected by PGE 2 . These results support the use of CD40-activated B cells as cellular adjuvants, especially in settings where PGE 2 is present in the tumor microenvironment.

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High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells

Cited by 59 publications

References 60 publications

The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Regulation of p63 Isoforms by Snail and Slug Transcription Factors in Human Squamous Cell Carcinoma

The properties of human CD40-activated B cells as antigen-presenting cells are not affected by PGE2

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