DENDRITIC CELLS IN BARRETT’S ESOPHAGUS CARCINOGENESIS: AN INADEQUATE MICROENVIRONMENT FOR ANTITUMOR IMMUNITY?

in American Journal of Pathology (in press)

Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms

in Journal of Leukocyte Biology (2013), 93

Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their ... [more ▼]

Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their capacity to bring together innate and adaptive immunity and to secrete soluble factors controlling cancer development, these cells could represent important actors in antitumor immunity. However, accumulating evidence suggests that pDCs recruited to the tumor microenvironment often display a nonactivated state and are associated with the development and maintenance of immunosuppression. Here, we present an overview of neoplastic lesions associated with an infiltration of immunosuppressive/ tolerogenic pDC. Moreover, as the proper response of pDC against cancer depends on a critical balance between immune-activating and immune-suppressing mechanisms, we summarize current knowledge about the molecular pathways developed by tumors to prevent antitumoral pDC immune responses. A better understanding of the mechanisms regulating pDC function in tumors could aid in the development of new therapies. Indeed, effective cancer vaccines or therapies could combine immunoactivating strategies (i.e., TLR agonists) with elimination of immune-suppressing mechanisms, leading to pDC reprogramming and thus, allowing tumor rejection in a clinical setting. [less ▲]

Giant Condyloma of the Cervix: An Uncommon Entity Associated With Low-risk Human Papilloma Virus Infection.

in American Journal of Surgical Pathology (2013), 37(2), 300-4

"Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were ... [more ▼]

"Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were predominantly young and presented with a cervical lesion producing bleeding or a mass effect. Biopsy/excision revealed a uniformly bland, exophytic squamous epithelial proliferation with viral cytopathic changes and absence of stromal invasion. Human papilloma virus types 6 and 11 were detected in all cases. Follow-up was uneventful without recurrence or spread. Giant condylomas of the cervix as defined in this report signify a benign albeit extensive variant of low-risk human papilloma virus infection. This term is proposed as a specific descriptor for such lesions and should be considered in the setting of any large well-differentiated exophytic cervical squamous lesion in young or immunosuppressed women. The term "giant condyloma of Buschke and Loewenstein" should be discontinued given the lack of specificity. [less ▲]

A novel blueprint for "top down" differentiation defines the cervical squamocolumnar junction during development, reproductive life and neoplasia.

in Journal of Pathology (The) (2013), 229(3), 460-8

The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this ... [more ▼]

The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodeling and neoplasia is unclear. In the present study, we analyzed the SC junction immunophenotype during pre and postnatal human and mouse development and in the adult, processes of metaplastic evolution of SC junction, microglandular change and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the SC junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic/SC junction cells gave rise to subjacent metaplastic basal/reserve cells with a switch from the SC junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or "top down" differentiation. A similar pattern was noted in high grade squamous intraepithelial lesions (HSIL), suggesting HPV infection of the cuboidal SC junction cells initiated outgrowth of basally-oriented neoplastic progeny. The progressive loss of the embryonic/SC junction markers occurred with top-down differentiation during development, remodeling and early neoplasia. Interestingly, most low grade SILs were SC junction negative, implying infection of metaplastic progeny rather than the original SC junction cells. This proposed model of "top down" differentiation resolves the mystery of how SC junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the SC junction is uniquely susceptible to carcinogenic HPV infection. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [less ▲]

Implication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia

Conference (2012, May)

A candidate cell of origin for cervical cancer

in Modern Pathology : An Official Journal of the United States & Canadian Academy of Pathology, Inc (2012, February), 25(2), 4-552

Mucosal junctions: open doors to HPV and HIV infections?

in Trends in microbiology (2011), 19(3), 114-120

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at ... [more ▼]

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies. [less ▲]

Les cellules souches cancereuses.

in Bulletin et Mémoires de l'Académie Royale de Médecine de Belgique (2011), 166(3-4), 141-5146

In tumours, a significant fraction of neoplastic cells are engaged in the cell cycle (growth fraction) and are therefore targets for radiation therapy and chemotherapy. Unfortunately, in most disseminated ... [more ▼]

In tumours, a significant fraction of neoplastic cells are engaged in the cell cycle (growth fraction) and are therefore targets for radiation therapy and chemotherapy. Unfortunately, in most disseminated cancers, such treatments cannot lead to complete cure. Many different mechanisms have been described to explain this resistance. The hypothesis of the existence of "cancer stem cells "has been recently proposed. Indeed, the tumour would contain a small subpopulation of cancer cells displaying the phenotypical characteristics of multipotential stem cells. Since such cells display different signalling pathways compared with more differentiated cells, this might explain at least partially the resistance to treatments. Chronic myeloid leukaemia is a good model in favour of cancer stem cells, but the presence of such cells in all types of cancers is still a matter of debate. Several questions emerge: is the multipotential stem cell, the cell of origin of cancer? What is the relevance of the cancer stem cell paradigm for understanding cancer cell biology and to envision new therapeutic, hopefully curative, therapies? The case of chronic myeloid leukaemia is used to discuss these questions. [less ▲]

Implication of plasmacytoid dendritic cells in the malignant transformation of cervical epithelial metaplasia

Poster (2011)

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

in American Journal of Pathology (2010), 176(4), 1941-1949

TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the ... [more ▼]

TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) 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 DeltaN 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 DeltaNp63, 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 DeltaNp63 silencing reduced cell-cell 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. [less ▲]