Expression of Toll-like Receptor 9 Increases with Progression of Cervical Neoplasia in Tunisian Women - A Comparative Analysis of Condyloma, Cervical Intraepithelial Neoplasia and Invasive Carcinoma

International audienceToll-like receptors (TLRs) are expressed in immune and tumor cells and recognize pathogen-associated molecular patterns. Cervical cancer (CC) is directly linked to a persistent infection with high risk human papillomaviruses (HR-HPVs) and could be associated with alteration of TLRs expression. TLR9 plays a key role in the recognition of DNA viruses and better understanding of this signaling pathway in CC could lead to the development of novel immunotherapeutic approaches. The present study was undertaken to determine the level of TLR9 expression in cervical neoplasias from Tunisian women with 53 formalin-fixed and paraffin-embedded specimens, including 22 samples of invasive cervical carcinoma (ICC), 18 of cervical intraepithelial neoplasia (CIN), 7 of condyloma and 6 normal cervical tissues as control cases. Quantification of TLR9 expression was based on scoring four degrees of extent and intensity of immunostaining in squamous epithelial cells. TLR9 expression gradually increased from CIN1 (80% weak intensity) to CIN2 (83.3% moderate), CIN3 (57.1% strong) and ICC (100% very strong). It was absent in normal cervical tissue and weak in 71.4% of condyloma. The mean scores of TLR9 expression were compared using the Kruskall-Wallis test and there was a statistical significance between normal tissue and condyloma as well as between condyloma, CINs and ICC. These results suggest that TLR9 may play a role in progression of cervical neoplasia in Tunisian patients and could represent a useful biomarker for malignant transformation of cervical squamous cells

TLR9 and Glioma: Friends or Foes?

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma

TLR9 and Glioma: Friends or Foes?

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma

Prevalence, Genotype Distribution and Risk Factors for Cervical Human Papillomavirus Infection in the Grand Tunis Region, Tunisia.

Implementation of Human Papillomavirus (HPV) vaccination should be considered a key cervical cancer prevention strategy in Tunisia, where Pap smear screening is not efficient. This study aims to estimate the prevalence and to identify risk factors associated with HPV infection among women from Grand Tunis, Tunisia. We conducted a cross-sectional study, between December 2012 and May 2013. Eligible women for this study were those aged 18-65 years, sexually active, who sought medical attention at their primary health care centre or clinic in Grand Tunis, Tunisia and who gave written consent. A liquid-based Pap smear sample was obtained from all women using a cervical brush. Only women with betaglobin positive test were further analysed for HPV detection and typing. A nested-PCR of the L1 region was performed followed by reverse line blot hybridization to facilitate the specific detection of 31 HPV genotypes. Multiple logistic regression modeling was used for the analysis of associations between variables with some considered possible confounders after checking for interactions. A total of 391 women were enrolled in this study and 325 out of the 391 cervical samples were positive for the betaglobin test. Overall HPV prevalence was 13.2% [9.8%-17.5%], with the following most prevalent HPV genotypes: HPV6 (40%), HPV40 (14%), HPV16 (12%), HPV52 (9%), HPV31 and HPV59 (7%), followed by HPV68 (4%). Mean age of HPV positive women was 40.7±0.92 years. Independently associated risk factors of HPV infection were smoking (OR:2.8 [0.8-9.6]), low income (OR:9.6 [1.4-63.4), bad housing type (OR:2.5 [1-6.8]), partner with multiple sexual relationship (OR:4.5 [0.9-22.9]) and single women (widowed, divorced, separated, never married) (OR:6.9 [1.1-42.2]). This study provides the first national-based estimate of HPV prevalence in Tunisia. Our findings contribute to the evidence on the current burden of HPV infection, the critical role of sexual behaviour and socioeconomic status and call for increased support for the screening program in Tunisia to prevent cervical cancer. These results allow us to evaluate the cost-effectiveness of vaccine program implementation in Tunisia in future

The Prevalence, Genotype Distribution and Risk Factors of Human Papillomavirus in Tunisia: A National-Based Study

There are limited national population-based studies on HPV genotypes distribution in Tunisia, thus making difficult an assessment of the burden of vaccine-preventable cervical cancer. In this context, we conducted a national survey to determine the HPV prevalence and genotypes distribution and the risk factors for HPV infections in Tunisian women. This is a cross-sectional study performed between December 2012 and December 2014. A liquid-based Pap smear sample was obtained from all women and samples’ DNAs were extracted. Only women with betaglobin-positive PCR were further analysed for HPV detection and typing by a nested-PCR of the L1 region followed by next-generation sequencing. A multiple logistic regression model was used for the analysis of associations between the variables. A total of 1517 women were enrolled in this study, and 1229 out of the 1517 cervical samples were positive for the betaglobin control PCR and tested for HPV. Overall HPV infection prevalence was measured to be 7.8% (96/1229), with significant differences between the grand regions, ranging from 2% in the North to 13.1% in Grand Tunis. High-risk HPV genotypes accounted for 5% of the infections. The most prevalent genotypes were HPV 31 (1%), 16 (0.9%), 59 (0.7%). HPV18 was detected only in four cases of the study population. Potential risk factors were living in Grand Tunis region (OR: 7.94 [2.74–22.99]), married status (OR: 2.74 [1.23–6.13]), smoking habit (OR: 2.73 [1.35–5.51]), occupation (OR: 1.81 [1.09–3.01]) and women with multiple sexual partners (OR: 1.91 [1.07–3.39]). These findings underscore the need to evaluate the cost effectiveness of HPV vaccine implementation, contribute to the evidence on the burden of HPV infections, the critical role of sexual behaviour and socioeconomic status, and call for increased support to the preventive program of cervical cancer in Tunisia

Sample size of each governorate included in the study.

<p>Sample size of each governorate included in the study.</p

Map showing the 4 governorates of the Grand Tunis region.

<p>Map showing the 4 governorates of the Grand Tunis region.</p

HPV Type prevalence in Grand Tunis Region.

<p>HPV Type prevalence in Grand Tunis Region.</p

Multivariable analysis of associated factors with HPV infection (N = 219).

<p>Multivariable analysis of associated factors with HPV infection (N = 219).</p

HPV type distribution according to age groups.

<p>HPV type distribution according to age groups.</p