Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.

in Blood (2012), 119(21), 5048-56

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to ... [more ▼]

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density and cross-linking). Transmission electron microscopy (TEM) and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LEC associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LEC negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis. [less ▲]

Aberrant promoter methylation and expression of UTF1 during cervical carcinogenesis.

in PLoS ONE (2012), 7(8), 42704

Promoter methylation profiles are proposed as potential prognosis and/or diagnosis biomarkers in cervical cancer. Up to now, little is known about the promoter methylation profile and expression pattern ... [more ▼]

Promoter methylation profiles are proposed as potential prognosis and/or diagnosis biomarkers in cervical cancer. Up to now, little is known about the promoter methylation profile and expression pattern of stem cell (SC) markers during tumor development. In this study, we were interested to identify SC genes methylation profiles during cervical carcinogenesis. A genome-wide promoter methylation screening revealed a strong hypermethylation of Undifferentiated cell Transcription Factor 1 (UTF1) promoter in cervical cancer in comparison with normal ectocervix. By direct bisulfite pyrosequencing of DNA isolated from liquid-based cytological samples, we showed that UTF1 promoter methylation increases with lesion severity, the highest level of methylation being found in carcinoma. This hypermethylation was associated with increased UTF1 mRNA and protein expression. By using quantitative RT-PCR and Western Blot, we showed that both UTF1 mRNA and protein are present in epithelial cancer cell lines, even in the absence of its two main described regulators Oct4A and Sox2. Moreover, by immunofluorescence, we confirmed the nuclear localisation of UTF1 in cell lines. Surprisingly, direct bisulfite pyrosequencing revealed that the inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine was associated with decreased UTF1 gene methylation and expression in two cervical cancer cell lines of the four tested. These findings strongly suggest that UTF1 promoter methylation profile might be a useful biomarker for cervical cancer diagnosis and raise the questions of its role during epithelial carcinogenesis and of the mechanisms regulating its expression. [less ▲]

Radiothérapie dans le cadre d’une maladie de Paget touchant la région génitale

in Revue Médicale de Liège (2012), 67(2), 61-63

Une maladie de Paget urogénitale est habituellement traitée par chirurgie. Cependant, dans certains cas, que ce soit dans le contexte d’une récidive ou à l’évocation d’une chirurgie mutilante, la ... [more ▼]

Une maladie de Paget urogénitale est habituellement traitée par chirurgie. Cependant, dans certains cas, que ce soit dans le contexte d’une récidive ou à l’évocation d’une chirurgie mutilante, la radiothérapie peut être une alternative. Nous relatons le cas d’une patiente traitée avec succès par radiothérapie. [less ▲]

Whole Slide Quantification of Stromal Lymphatic Vessel Distribution and Peritumoral Lymphatic Vessel Density in Early Invasive Cervical Cancer: A Method Description

in ISRN Obstetrics and Gynecology (2011), 2011

Peritumoral Lymphatic Vessel Density (LVD) is considered to be a predictive marker for the presence of lymph node metastases in cervical cancer. However, when LVD quantification relies on conventional ... [more ▼]

Peritumoral Lymphatic Vessel Density (LVD) is considered to be a predictive marker for the presence of lymph node metastases in cervical cancer. However, when LVD quantification relies on conventional optical microscopy and the hot spot technique, interobserver variability is significant and yields inconsistent conclusions. In this work, we describe an original method that applies computed image analysis to whole slide scanned tissue sections following immunohistochemical lymphatic vessel staining. This procedure allows to determine an objective LVD quantification as well as the lymphatic vessel distribution and its heterogeneity within the stroma surrounding the invasive tumor bundles. The proposed technique can be useful to better characterize lymphatic vessel interactions with tumor cells and could potentially impact on prognosis and therapeutic decisions. [less ▲]

Prise en charge des consequences de la carence oestrogenique apres cancer du sein.

in Revue Médicale de Liège (2011), 66(5-6), 385-92

The prevention and the treatment of oestrogen deficiency induced by breast cancer treatments are crucial in the management of patients. The impacts of this deficiency must not be neglected: quality of ... [more ▼]

The prevention and the treatment of oestrogen deficiency induced by breast cancer treatments are crucial in the management of patients. The impacts of this deficiency must not be neglected: quality of life impairments inducing eventually premature withdrawal of hormonotherapies, and excess of bone and cardio-vascular morbidities and mortalities, especially in good prognosis young women. Management strategies of short and long term effects of this deficiency are reviewed and discussed here. [less ▲]

Current concepts in the pathology and epigenetics of endometrial carcinoma.

in Pathology (2010), 42(7), 613-7

In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are ... [more ▼]

In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are recognised: the oestrogen-related (type I, endometrioid) and the non-oestrogen related (type II, non-endometrioid). This article reviews the epidemiology, risk factors, genetic alterations during endometrial carcinogenesis, features of tumours and precursors and early detection of the disease. Insights into the epigenetic alterations, with emphasis on DNA methylation during endometrial carcinogenesis, and their diagnostic value are also provided. [less ▲]

High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarinoma

in Histopathology (2008), 53(5), 525-532

Aims: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis. <br />Methods and results: Archival biopsy specimens of ... [more ▼]

Aims: To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis. <br />Methods and results: Archival biopsy specimens of 39 EECs, 14 cases of atypical hyperplasia (AH), 11 histologically normal endometrial tissues adjacent to EECs and 24 normal control endometrial samples were retrieved. The cases were tested by quantitative methylation-specific polymerase chain reaction with primers hybridizing in the promoter regions of five genes frequently methylated in human cancer (RASSF1A, RARb2, P16, MGMT and GSTPi). Twenty-nine of 39 (74%) EECs and 7/14 (50%) AHs were methylated for the RASSF1A gene, whereas 17/39 (44%) EECs and 6/14 (43%) AHs were positive for the methylation of the RARb2 gene. No significant results were obtained for the other genes (P16, MGMT and GSTPi). Interestingly, 4/11 (36%) and 6/11 (55%) histologically normal endometrial tissues adjacent to EEC showed, respectively, RASSF1A and RARb2 gene methylation. Furthermore, these 11 specimens were microsatellite stable and showed similar proliferative, cell cycle and apoptotic mean labelling indices as the normal endometrial control tissues. <br />Conclusions: Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis. [less ▲]

Peut-on sortir de l'embrouillamini relatif aux contraceptifs oraux et aux cancers cutanés?

in Revue Médicale de Liège (2007), 62(5-6), 463-6

Skin contains various hormonal receptors, particularly those for estrogens, progesterone and androgens. Steroid hormones of oral contraceptives affect the skin, in particular the control of the cell cycle ... [more ▼]

Skin contains various hormonal receptors, particularly those for estrogens, progesterone and androgens. Steroid hormones of oral contraceptives affect the skin, in particular the control of the cell cycle, DNA replication, apoptosis and other cellular functions. Some estrogen-responsive pathways have the potential to promote tumor development. The question of whether oral contraceptives increase the risk for the development of skin cancer, particularly melanoma, remains an area of concern. There is some evidence that steroid hormones present in oral contraceptives do not significantly increase the risk of developing skin cancer when estrogen exposure is not excessive. [less ▲]

Le cancer du col de l'utérus: du virus au traitement

in Revue Médicale de Liège (2007), 62(S1)

Squamous cell cancer of the uterine cervix is associated with a high morbidity and mortality worldwide and in Belgium. New therapeutic approaches have been recently proposed. The development of this ... [more ▼]

Squamous cell cancer of the uterine cervix is associated with a high morbidity and mortality worldwide and in Belgium. New therapeutic approaches have been recently proposed. The development of this cancer is related to the infection by oncogenic human papillomavirus (HPV) types. The link between cervical cancer and HPV has, in recent years, generated, a great interest for studies aiming to better understand the role of the immune system in the control of these infections and for the development of prophylactic anti-HPV vaccines. [less ▲]

Staging of primary cervical cancers: the role of nuclear medicine

in Critical Reviews in Oncology/Hematology (2003), 46(3), 275-284

In nuclear medicine, [F-18]-fluorodeoxyglucose positron emission tomography ((18)FDG PET) and lymphatic mapping and sentinel lymphadenectomy (LM/SL) may significantly improve the staging of primary ... [more ▼]

In nuclear medicine, [F-18]-fluorodeoxyglucose positron emission tomography ((18)FDG PET) and lymphatic mapping and sentinel lymphadenectomy (LM/SL) may significantly improve the staging of primary cervical cancers. Indeed, the disease progresses in a 'level by level' fashion to regional nodes through the lymphatic channels, and also to extra-nodal sites via the hematogenous stream. Additionally, the sub-optimal efficacy of routine radiological protocols, while new combined therapies are proving to be more efficient, stresses the need for alternative staging procedures. Current data suggest that LM/SL accurately reflects the regional lymph node status in early stage cervical cancers, and thus could avoid unnecessary complete lymphadenectomies. Also, whole body (18)FDG PET may provide valuable insights on extra-pelvic and distant tumor spreading, with a significant impact on treatment choices. If these promising results are confirmed on large controlled trials, LM/SL and (18)FDG PET imaging could be incorporated in the routine staging work-up of primary cervical cancers. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]