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See detailMicroanatomy of the cervical and anorectal squamocolumnar junctions: a proposed model for anatomical differences in HPV-related cancer risk
Yang, Eric J; Quick, Charles M; Hanamornroongruang, Suchanan et al

in Modern Pathology : An Official Journal of the United States & Canadian Academy of Pathology, Inc (in press)

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See detailCarcinogenic HPV infection in the cervical squamo-columnar junction
Mirkovic, Jelena; Howitt, Brooke; RONCARATI, Patrick ULg et al

in Journal of Pathology (The) (in press)

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and ... [more ▼]

Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to 1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and 2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analyzed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16ink4, Ki67 and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from 8 of 10 with visible SCJ cells, 6 of which were HPV16/18 DNA positive. In 5 of these latter cases, the SCJ cells were positive for p16ink4 and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in micro-dissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16ink4 immunoreactivity, elevated proliferative index and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16ink4 expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ. [less ▲]

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See detailDefensins: « simple » antimicrobial peptides or broad-spectrum molecules ?
Suarez-Carmona, Meggy ULg; Hubert, Pascale ULg; Delvenne, Philippe ULg et al

in Cytokine & Growth Factor Reviews (2015), 26

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See detailUnique recurrence patterns of cervical intraepithelial neoplasia following excision of the squamo-columnar junction.
Herfs, Michael ULg; SOMJA, Joan ULg; Howitt, Brooke E. et al

in International journal of cancer. Journal international du cancer (2015), 136

Recent studies have identified a putative cell of origin for cervical intraepithelial neoplasia (CIN) and cervical cancer at the squamo-columnar junction (SCJ) and suggest that these cells may not ... [more ▼]

Recent studies have identified a putative cell of origin for cervical intraepithelial neoplasia (CIN) and cervical cancer at the squamo-columnar junction (SCJ) and suggest that these cells may not regenerate following excision (LEEP). This study addressed the impact of SCJ excision on the temporal dynamics, histologic and viral (HPV) characteristics of recurrent CIN. One hundred thirty one consecutive patients treated by excision and attending follow-up visits were enrolled. We compared recurrent and initial CIN with attention to excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype, and SCJ immunophenotype. During the follow-up period (up to four years), sixteen (12.2%) recurrences were identified. Four (25%) were identified at the first follow-up visit, closely resembled the initial CIN 2/3 in grade and HPV type, and were typically SCJ marker positive [SCJ(+)], suggesting non-excised (residual) disease. Twelve (75%) manifested after the first postoperative visit and all were in the ectocervix or in mature metaplastic epithelium. All of the 12 delayed recurrences were classified as CIN 1 and were SCJ (-). Nine of 11 SCJ (-) recurrences (82%) followed regressed spontaneously. Taken together, these results show that new lesions developing from any HPV infection are delayed and occur within the ectocervix or metaplastic epithelium. This dramatically lower risk of CIN 2/3 following successful SCJ excision suggests that removal of the SCJ could be a critical variable in reducing the risk of subsequent CIN 2/3 and cervical cancer. (c) 2014 Wiley Periodicals, Inc. [less ▲]

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See detailThe PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
Ning, Gang; Bijron, Jonathan G.; Yamamoto, Yusuke et al

in The Journal of pathology (2014), 234

The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are gamma-H2AXp - and TP53 mutation-positive. Although they express wild-type p53 ... [more ▼]

The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are gamma-H2AXp - and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2n ). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7p /PAX2n /EZH2p and underwent ciliated (PAX2n /EZH2n /FOXJ1p ) and basal (Krt7n /EZH2n /Krt5p ) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2n SCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1n and beta-cateninmem (membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p , ALDH1p , beta-cateninnc (nuclear and cytoplasmic), stathminp , LEF1p , RCN1p , and RUNX2p expression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2n , ALDH1n , beta-cateninmem , but highly expressed EZH2p , LEF1p , RCN1p , and stathminp . This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [less ▲]

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See detailSquamocolumnar junction cells and HPV infection
Herfs, Michael ULg

Scientific conference (2014, October)

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See detailDefensins in (lymph)angiogenesis
Herfs, Michael ULg

Conference (2014, May)

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See detailImplication of squamocolumnar junction cells in the pathogenesis of cervical cancer
Herfs, Michael ULg

Scientific conference (2014, January)

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See detailDeltaNp63 isoform-mediated beta-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.
Suarez-Carmona, Meggy ULg; Hubert, Pascale ULg; Gonzalez, Arnaud ULg et al

in Oncotarget (2014), 5(7), 1856-1868

Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype ... [more ▼]

Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HbetaDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HbetaDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that DeltaNp63 proteins (alpha, beta, gamma) induce HbetaD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that DeltaNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HbetaDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HbetaDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HbetaDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that DeltaNp63-regulated HbetaD could promote tumor (lymph)angiogenesis in SCC microenvironment. [less ▲]

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See detailAltered alpha-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment.
Hubert, Pascale ULg; Herman, Ludivine; RONCARATI, Patrick ULg et al

in Journal of Pathology (The) (2014), 234(4), 464-77

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical ... [more ▼]

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical HPV infections into (pre)neoplastic lesions suggests that viral antigens are not adequately recognized by innate immunity or presented to the adaptive immune system. Members of the defensin family have recently been found to inhibit viral and bacterial pathogens, to stimulate the migration of immune cells and to play a role in anticancer responses. In the present study, we focused on the poorly characterized human alpha-defensin 5 (HD-5) and its possible role in these processes. We showed that HD-5 was able to prevent HPV virion entry into cervical keratinocytes and to influence adaptive immunity. Indeed, this peptide specifically induced the chemoattraction and proliferation of both activated T lymphocytes and immature dendritic cells in a CCR2/CCR6-dependent manner and stimulated the infiltration of these professional antigen-presenting cells in a (pre)neoplastic epithelium transplanted in vivo in immunodeficient mice. No chemotactic effect was observed with plasmacytoid dendritic cells, macrophages or natural killer cells. Proliferative and angiogenic effects of HD-5 were also assessed in vitro and in vivo. However there was a striking regional disparity in expression of HD-5, being prominent in ectocervical, vaginal and vulvar neoplasia, while absent, or nearly so, in the cervical SC junction. Taken together, these results suggest one possible explanation for why the SC junction is uniquely vulnerable to both high-risk HPV infection (via reduced HD-5 expression and viral entry) and progression of neoplasia (via altered cell-mediated immune responses and altered microenvironment). Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [less ▲]

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See detailHMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells
Demoulin, Stéphanie ULg; Herfs, Michael ULg; SOMJA, Joan ULg et al

in International Journal of Cancer = Journal International du Cancer (2014)

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See detailResponse to "Two major pathways of recurrent high-grade squamous intraepithelial lesions of the cervix"
Herfs, Michael ULg; Crum, Christopher P.

in International journal of cancer. Journal international du cancer (2014)

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See detailHedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.
FRANCHIMONT, Claudine ULg; Hermanns-Lê, Trinh ULg; PAQUET, Philippe ULg et al

in Current approaches to basal cell carcinoma (2014)

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in patched homologue 1 (PTCH 1) or smoothened (SMO), two conducting proteins of the Hedgehog (Hh ... [more ▼]

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in patched homologue 1 (PTCH 1) or smoothened (SMO), two conducting proteins of the Hedgehog (Hh) pathway. They rarely progress deeply and metastasize; however, if they do, these advanced BCC become amenable to treatment by inhibiting the Hedgehog and the P13K–mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development. [less ▲]

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See detailThrough the glass darkly: intraepithelial neoplasia, top-down differentiation and the road to ovarian cancer.
Crum, Christopher P.; Herfs, Michael ULg; Ning, Gang et al

in The Journal of pathology (2013), 231

It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of ... [more ▼]

It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta catenin, EZH2 and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Mullerian epithelium, essentially requiring mesothelial to Mullerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immuno-phenotypically distinct progeny under stromal influences via "top down" differentiation. Similarly, biphasic cell differentiation can be seen in the endometrium with a parallel in the juxtaposition of mesothelial and mullerian differentiation in the ovary. An abrupt mesothelial-Mullerian transition remains to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumor cells in HGSC and pinpointing where initial transformation and trans-differentiation occurs if the POSE is an origin. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention. [less ▲]

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See detailLaboratory management of cervical intraepithelial neoplasia: proposing a new paradigm
Herfs, Michael ULg; Crum, Christopher

in Advances in Anatomic Pathology (2013), 20

Since the discovery of human papillomavirus (HPV) type 16 in early 80’s, the link between HPV and cervical cancer has been established with certainty, a function of the discovery and cloning of a range of ... [more ▼]

Since the discovery of human papillomavirus (HPV) type 16 in early 80’s, the link between HPV and cervical cancer has been established with certainty, a function of the discovery and cloning of a range of HPV types associated with both cancer precursors (cervical intraepithelial neoplasia or CIN) and carcinomas and extensive epidemiologic, clinical, pathologic and experimental data. These accumulated results have culminated in new paradigms of cancer prevention through screening and triage. Despite this, the management of women with CIN is still suboptimal and the over-treatment of these conditions still occurs, largely due to the lack of clarity regarding which precancerous lesions are most likely to progress in grade. Recently, a discrete population of cuboidal cells was discovered at the cervical squamocolumnar junction, the anatomical site where the large majority of HPVrelated (pre)neoplastic lesions develop. These cells appear to be embryonic in nature and participate both in benign metaplasias and the initial phase of precancer development. This review summarizes the historical evolution of precursor management, assesses the potential role of this and other discoveries in segregating lower from higher risk precursors and examines their potential impact on the management of women with real or potential cervical cancer precursors. [less ▲]

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See detailTumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms
Demoulin, Stéphanie ULg; Herfs, Michael ULg; Delvenne, Philippe ULg et al

in Journal of Leukocyte Biology (2013), 93(3), 343-352

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 ▲]

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