Academic literature on the topic 'Sein – Cancer – Cytopathologie'

Objective: Oral cancer accounts for almost 40% of all cancers in the Indian subcontinent. Techniques like oral scrape cytology are helpful in early diagnosis of premalignant lesion and thus prevention of malignant transformation. The purpose of this study is to evaluate the performance of cytotechnologists in assessing the adequacy and preliminary diagnostic accuracy of oral brush liquid-based cytology. Study Design: 110 oral brush liquid-based cytology smears were prospectively screened by a cytotechnologist for adequacy assessment, and a preliminary diagnosis was recorded. Smears were subsequently studied by the reporting cytopathologist for the final diagnosis. The performance of the cytotechnologist in the assessment of adequacy and the preliminary diagnosis were compared with the final interpretation rendered by the cytopathologist. Results: There was no significant difference in adequacy assessment between both observers, and good concordance was observed in the identification of frankly malignant lesions; however, in premalignant cases, complete agreement in all the cases was not observed. Maximum numbers of discrepant cases were seen in high-grade squamous intraepithelial lesions, 4/17 were downgraded to low-grade squamous intraepithelial lesions and 2/17 to negative for intraepithelial lesion or malignancy, respectively. Conclusion: Trained cytotechnologists are capable of assessing the adequacy and identifying the malignancy in oral brush liquid-based cytology smears, and hence there is potential for them to perform initial screening of such cases.

<p><strong>Introduction:</strong> Urological dogma dictates that washings collected from the urinary tract for cytological assessment must be performed without interference from contrast agents that may alter cellular integrity and diagnostic interpretation. In practice, the initial contrast used to outline the upper tracts is commonly discarded with subsequent saline washings sent for cytology. We hypothesize that contrast washings do not affect the morphology of urothelial carcinoma cells or the integrity of cytology interpretation.</p><p><strong>Methods:</strong> Samples obtained from (1) human bladder cell lines; (2) urine from a human xenograft bladder cancer model using UC-3 cells; and (3) patients with urothelial carcinoma were subjected to various experimental solutions (water, saline, urine, and dilutions of contrast media) for different exposure times. After exposure to various different solutions, samples underwent cytological analysis to assess morphologic and degenerative changes.</p><p><strong>Results:</strong> No cytological differences were seen when cells were exposed to ionic, hyperosmolar, or non-ionic low-osmolar contrast agents for any exposures up to five minutes. Cells exposed to mixtures of contrast agents and urine also demonstrated no evidence of degenerative change. Cells exposed to water for greater than one minute demonstrated significant hydropic degeneration impacting cytological interpretation. At 40 minutes or later, all reagents caused severe degeneration when evaluating urine samples from the mouse bladder cancer model and from patients undergoing urothelial carcinoma.</p><p><strong>Conclusions:</strong> Commonly used contrast agents have no effect on urinary cytology up to five minutes. Contrast washings of the urinary tract should not be discarded and can be sent for cytological diagnosis if fixed within this time period.</p>

Laryngeal SCCA usually presents with hoarseness when the glottis is involved, dysphagia if the supraglottis is involved, and difficulty of breathing and stridor in subglottic invovlement. A neck mass as an initial presentation of laryngeal carcinoma is commonly linked to the involvement of the supraglottis due to its rich lymphatic drainage. About 70% of supraglottic tumours present with advanced disease (stages III-IV),1 while 75% of glottic tumours present with localized disease (stages I-II).1 Smoking and alcohol consumption are considered highly significant etiologic factors but evidence has suggested a possible role for human papilloma virus (HPV) infection, ras oncogene activation, and gastroesophageal reflux as well.2 To the best of our knowledge, laryngeal squamous cell carcinoma has not been associated with herpes simplex virus (HSV). We report a case of laryngeal squamous cell carcinoma with an unusual presentation and peculiar histopathology, and discuss its potential association with herpes simplex virus. CASE REPORT A 67-year-old man consulted for a right lateral neck mass that gradually started enlarging eight months prior to consult. There was no fever, cough, nasal discharge or congestion, hoarseness, dysphagia, difficulty of breathing, weight loss, oral ulcers, difficulty opening and closing the mouth, or facial asymmetry, and he did not consult a health professional or take any medication. He was a smoker but did not drink alcoholic beverages. He finally consulted due to the gradual increase in size of the neck mass. Physical examination revealed a 6 x 7 cm hard, fixed, right neck mass involving levels II, and III. Flexible endoscopy showed an enlarged right arytenoid with normal-looking mucosa. (Figure 1 A, B). A CT scan of the neck revealed a 2.8 x 3.8 x 6.3 cm supraglottic/glottic soft tissue mass and right-sided cervical lymphadenopathies suggestive of metastasis. (Figure 2 A, B) Direct laryngoscopy with biopsy of the (arytenoid) supraglottic mass and panendoscopy surprisingly revealed only an enlarged right arytenoid and no lesions in the false and true vocal folds or oral, nasopharyngeal, oropharyngeal, tracheal, and esophageal mucosa. Histopathology showed focal moderate dysplasia with cytopathic changes probably Herpes Simplex virus infection with probable involvement of the submucosal layer requiring deeper bites for further diagnosis. At this point, although the working impression was a benign lesion, we still considered the possibility that this was a malignancy because of the dysplastic changes noted on the histopathology report. A repeat laryngoscopy with biopsy of the supraglottic mass and fine needle aspiration biopsy of the neck mass yielded a histopathologic diagnosis of moderately differentiated squamous cell carcinoma and level II lymph node metastatic SCCA. With a diagnosis of laryngeal SCCA stage IVA (T3 N2b M0), a total laryngectomy with bilateral neck dissection (radical on the right and modified radical on the left) and total thyroidectomy was performed. There was a submucosal lesion confined to the supra and glottic area on the right side of the posterior aspect of the cut larynx. (Figure 3) Final histopathology showed moderately differentiated, keratinizing invasive squamous cell carcinoma with viral cytopathic changes. (Figure 4) DISCUSSION In this case, the patient initially presented with a lateral neck mass without associated signs and symptoms. This made it more difficult to diagnose, since neck masses can have varying etiologies involving a large number of different structures of the head and neck. Squamous cell carcinoma on physical examination usually presents with an ulcerative, exophytic, or polypoid lesion.2 This patient initially showed an enlarged right arytenoid with normal-looking mucosa and no involvement of the false and true vocal folds, consistent with the absence of symptoms of hoarseness or dysphagia. Considering the patient’s age and the history of smoking, a malignant neoplasm was still the most plausible explanation for the lateral neck mass and supraglottic bulge. Imaging was important to evaluate deeper structures that might be involved. Computed tomography is an indispensable tool for evaluating submucosal laryngeal masses or otherwise unexplainable symptoms (usually hoarseness) that might herald such a mass.3 CT scans showed involvement of the supraglottis and glottis, inconsistent with the patient’s history and physical examination findings. Our patient was diagnosed to have transglottic SCCA with paraglottic space (PGS) involvement. Paraglottic space involvement in either a glottic or supraglottic tumor is staged as T3 and is significant because the extent of the PGS means that tumors in this space may spread to involve any or all of the three regions of the larynx.2 The PGS lies lateral to the true and false vocal folds and extends laterally to the thyroid cartilage.2 Anteriorly, each PGS is continuous with the paraepiglottic space, and tumors may spread along this pathway.2 Transglottic tumors are an important subset of laryngeal tumors with aggressive behavior and high risk of lymphatic metastasis. The term transglottic was first used by McGavran and associates in 1961.4 It is not used in the American Joint Commission and associates for Cancer (AJCC) staging system and is defined by Kirchner and colleagues as a tumor that crosses the ventricle in a vertical direction.4 Tumors can become transglottic in four ways: by crossing the ventricle directly; by crossing at the anterior commissure; by spreading through the paraglottic space; and by spreading along the arytenoid cartilage posterior to the ventricle. The latter form of spread does not predict deep invasion: in Kirchner's series of 50 transglottic tumors studied in whole organ preparations, none of the 8 tumors with transglottic spread along the arytenoid demonstrated laryngeal cartilage invasion.4 In the same series, invasion of the laryngeal framework was seen in over half of transglottic tumors over 2 cm. Cervical metastases were seen in 30% of cases; and in primary tumors greater than 4 cm in dimension, 55% of tumors had nodal metastases.4 The biopsy showed moderate dysplasia with viral cytopathic changes suggestive of submucosal rather than mucosal involvement, and this was consistent with our intraoperative findings. In general, squamous cell carcinomas histologically involve the epithelial layer of a certain structure. However, in a specific type of laryngeal carcinoma -- ventriculosaccular squamous cell carcinoma -- epithelial lesions are not visibly apparent.2 Our case may have been similar to ventriculosaccular SCCA in this regard. The histopathologic slides of our patient revealed multinucleated giant cells, which resulted from fusion of cell membranes bearing viral glycoproteins. (Figure 4) Alterations in the cell nuclei and cytoplasmic tails between the cells were seen. These cytopathic effects (CPE) are seen in HSV-infected cells. This is another issue because Herpes viruses are less likely linked to laryngeal malignancies. Herpes simplex virus (HSV) is less strongly correlated with the development of oral carcinomas than EBV or HPV.5 On the other hand, serologic studies have shown that patients with head and neck cancer have higher levels of IgM antibody to HSV type one than control ‘subjects.6,7 HSV can transform cells in vitro to a malignant phenotype. This may be due to an HSV-encoded peptide that increases mutagenicity of infected cells. In one series of 31 young adults with head and neck cancer, antipeptide antibody levels were significantly higher in the patients than in control subjects.8 However, most of the studies generalized the association of viruses with malignancies of the oral cavity in general, not with laryngeal carcinoma alone. The question regarding which caused which is left; did the Herpes virus cause the laryngeal SCCA or was it a superimposed infection due to the patient’s immunocompromised state? Head and neck carcinomas are closely linked to Epstein-Barr and Human Papilloma viruses, particularly carcinoma of the nasopharynx and the oral cavity respectively. At present, accepted causal associations between viruses and human cancer include HPV and cervical cancer; human T-lymphotrophic virus type-1 (HTLV-1) and adult T-cell leukemia and lymphoma; hepatitis B and C and liver cancer, Epstein–Barr virus (EBV) and nasopharyngeal cancer, Burkitt’s and Hodgkin’s lymphomas, and some non-Hodgkin’s lymphomas; and human herpes virus 8 (HHV-8) and Kaposi’s sarcoma.9 There may or may not be an association between herpes simplex virus and laryngeal SCCA, but our experience suggests that the matter is worth investigating. The clinical history and physical examination findings may not always reveal the true extent of disease, and imaging modalities may mislead, but the complementary nature of all these should be considered vis-à-vis intraoperative findings and final histopathologic results.

Background: Around 2.5% of male cancer in Turkey, 12% of female cancers include cancers of the thyroid. Early diagnosis and correct treatment of thyroid cancers is therefore important. However, in addition to preventing the complications, patients not to be subjected to unnecessary thyroid procedure depend on the pre-detection of that whether the nodules are benign or malign. The objectives of the study were to investigate whether fine needle aspiration (FNA) cytology of thyroid nodules is sufficient for diagnosis. Thyroid FNA result is based on the standardized Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).Methods: FNA cytology reports of 1808 patients for the period between January 2011 and December 2017 in Atatürk City Hospital, which is located in Balıkesir province, in the western part of Turkey, were retrospectively analyzed. Cytology results were reported as follows: non-diagnostic, benign, atypia (AUS) or follicular lesion (FLUS) of undetermined significance, follicular neoplasm or suspected follicular neoplasm (FN), suspected malignity and malign. They were compared with postoperative histopathology result.Results: According to the thyroid FNA cytology, 409 patients were operated on, and the obtained specimens were histopathologically analyzed. The histopathological malignity rates of patients were detected to be as follows: 0.0%, 2.0%, 3.0%, 12.1%, 31.3% and 51.5%. It was detected that malign thyroid cancer was detected to be seen more in women and the age group of 31-60. The sensitivity value of the research was detected to be 92%, which was a significantly high ratio. Positive and negative predictive values were detected to be 97% and 92%, respectively.Conclusions: Where FNA cytology result is insufficient, FNA procedure should be repeated. FNA must be repeated with USG for cases with suspected AUS, FLUS and follicular neoplasm.

AbstractThe role of endoscopic ultrasound (EUS) and guided biopsies has been well established for the locoregional staging of esophageal cancers. However, their role in posttreatment surveillance is unclear. Here, we describe a case of a pancreatic mass diagnosed on the follow-up positron emission tomography scan, concerning for a metastatic lesion. EUS-guided fine-needle aspiration (FNA) helped in establishing the diagnosis of neuroendocrine tumor, which tends to have a similar sonographic appearance. Therefore, it is imperative to evaluate a suspicious mass seen on computed tomography/positron emission tomography scan. EUS and EUS-guided FNA can serve as useful modalities to confirm the diagnosis by cytopathology.

Introduction: The International System for Reporting Serous Fluid Cytopathology (ISRSFC) has recently been announced. Pericardial effusion (PE) is a clinical manifestation of a large variety of both neoplastic and non-neoplastic conditions. Herein, we have applied the ISRSFC on reporting PE cytopathology and report our experience in a large academic institution. Method and Materials: After the Institutional Research Board approval, the electronic pathology database of a large academic institution was queried for PEs collected from January 2014 to January 2019. The diagnosis, patient demographics, and specimen volume were recorded for each case. The ISRSFC was applied and the cases were divided into 5 categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of uncertain significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). Each category was evaluated separately. Results: A total of 299 cases were identified, 162 females and 137 males. The age of the subjects ranged from less than a year to 89 years (average 51.25 years). The volume ranged from 3 to 1,700 mL (average 298 mL). There were 252 NFM (84.3%), 13 AUS (4.3%), 4 SFM (1.3%), and 30 MAL (10%) cases. Metastatic lung cancer followed by metastatic breast cancer were the most common malignancies involving pericardial fluid (PF). No cases were diagnosed as ND. However, no mesothelial cells were seen in 97 specimens (38% of the negative cases). None of these patients developed malignant PE in at least 6 months of follow-up. Conclusion: The ISRSFC is a user-friendly reporting system which is easily applicable on serous fluid including PF. The vast majority of PEs was benign (84.3%). Our study shows that the presence of mesothelial cells is not necessary for specimen adequacy in serous effusions as no mesothelial cells were identified in 38% of the negative cases. Metastatic lung carcinoma was the most common diagnosis of malignant effusions.

Background: Approximately 10% of breast masses are breast cancer. It is important for women with a breast lump to receive appropriate evaluation. Mammography has been the “gold standard” in breast cancer detection for >40 years. Ultrasonography is non-invasive easily available, cheaper and accurate tool while Fine needle aspiration cytology has a high diagnostic accuracy rate in hands of experienced cytopathologist. Materials and methods: This was a retrospective and prospective study of 173 women attending radiology department in Manipal Teaching Hospital, Pokhara for mammography during a period of 18 months from January 2011 to June 2012.The age ranged from 20yrs to 75yrs. BIRADS score was given for both mammography and sonomammography. All malignant and suspicious cases had undergone fine needle aspiration cytology. Cytology reports were correlated with imaging study. Results: The most common age group for the breast lump was 40-49 years showing 65(37.57%) cases. Most lumps were seen on the left side 54.3% (94/ 173) cases and were seen in upper outer quadrant of the breast (74 cases). 11 cases each were given the BIRADS score of 4 in both mammography and sonomammography. Sensitivity and specificity of mammography and sonomammography were compared to cytologyreports. The sensitivity for mammogram was 73.7% while specificity was 96.3%. The sensitivity and specificity for sonomammogram was 78.9% and 95% respectively. Conclusion: Quadruple assessment i.e. clinical assessment, mammography, sonomammography and cytological study are the new “gold standard” in the investigation of breast disease. DOI: http://dx.doi.org/10.3126/jpn.v4i8.11499 Journal of Pathology of Nepal; Vol.4,No. 8 (2014) 630-634

The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled ‘Other encapsulated follicular-patterned thyroid tumours’, in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word ‘carcinoma’ from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with ‘very low malignant potential’. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because RAS mutations and PAX8-PPARg rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features.

Abstract Background: ATA guidelines recommend evaluation of hyperthyroidism with radioiodine scan and consideration of FNA for non-toxic nodules with suspicious sonographic features. However, there is no standard evidence-based approach to performing ultrasound in patients with toxic nodules. Recent studies have shown increased rates of thyroid cancer in patients with hyperthyroidism and has been shown to demonstrate aggressive histologic features. Clinical Case: A 41-year-old female presented to primary care provider for annual physical exam, found to have intermittent bigeminy and enlarged thyroid on exam. EKG notable for multiple premature ventricular complexes. Evaluation revealed suppressed TSH &lt;0.01 µIU/mL (0.27-4.20), normal free T4 1.27 ng/dL (0.80-1.80), slightly elevated free T3 4.84 pg/mL (2.57-4.43) and elevated TSI 238% (&lt;122). Methimazole was started for treatment of hyperthyroidism. Thyroid sonogram was ordered for abnormal exam, that showed 2.7 cm TIRADS 4 left thyroid nodule with microcalcifications. I-131 uptake values were 20% and 49% at 4-hours and 24-hours, respectively. Technetium-99M scan showed toxic autonomous nodule in the left thyroid lobe corresponding to the one seen on sonogram. The remainder of the thyroid gland showed heterogeneously suppressed uptake. FNA of the thyroid nodule was done due to the presence of microcalcifications and the cytopathology was suspicious for papillary carcinoma. She underwent total thyroidectomy with central neck dissection involving pre-tracheal and paratracheal lymph nodes (level VI). Pathology showed 1.4 cm papillary carcinoma with lymphovascular space invasion and multifocal papillary microcarcinomas in the left thyroid lobe, 0.2 cm papillary microcarcinoma in right thyroid lobe, metastatic papillary carcinoma in 2 out of 5 lymph nodes, largest metastatic deposit 0.1 cm in the largest dimension with no extra nodal extension. There was also follicular hyperplasia noted consistent with Graves’ disease. Post-operatively, she had thyrogen-stimulated adjuvant RAI treatment, dose 107.4 mCi. Post therapy scan did not show evidence of distant metastases. Conclusion: This case demonstrates the identification of a metastatic papillary thyroid carcinoma based on suspicious ultrasound features requiring total thyroidectomy, central neck dissection and adjunct radioactive iodine in a patient with hyperthyroidism from co-existent toxic thyroid nodule and Graves’ disease.

L'objectif de ce travail est d'analyser l'hétérogénéité de la distribution spatiale de différents marqueurs dans des tumeurs mammaires et, plus particulièrement, dans des carcinomes canalaires infiltrants. Nous avons étudié par microscopie confocale et analyse d'images la variabilité d'expression de deux marqueurs de prolifération (Ki-67 et PCNA), de l'oncogène c-erbB-2 et de la PS2, protéine œstrogène-dépendante. De plus, nous avons corrélé le contenu en ADN des cellules et l'expression de ces marqueurs. Pour chaque tumeur, un échantillonnage en cascade a été réalisé : plusieurs blocs dans une même tumeur, plusieurs régions et sous-régions, en périphérie ou au centre de la tumeur. Une analyse de variance emboîtée a permis de montrer que l'hétérogénéité de distribution de différents marqueurs se retrouve aux différents niveaux de l'échantillonnage. De plus, la distance entre les blocs ou entre les régions accroît la variabilité d'expression des marqueurs. Ces résultats suggèrent que différents blocs d'une même tumeur doivent être étudiés afin d'améliorer le diagnostic individuel des patientes et les procédures thérapeutiques. Ces résultats doivent être confirmés par l'étude d'un plus grand nombre de cas.

Plusieurs pathologies humaines sont associées à l'altération de l'expression ou de la fonction de facteurs de transcription GATA. L'hyperméthylation, l'hypoacétylation ou la surexpression des gènes GALA sont observées dans plusieurs types de cancers. Des mutations ponctuelles des gènes GATA sont aussi à l'origine de graves maladies congénitales. Plus de 60% des tumeurs du sein sont dépendantes des estrogènes et produisent elles-mêmes les hormones nécessaires à leur croissance. Cette production aberrante d'estrogènes est causée par la surexpression de l'enzyme aromatase, codée par le gène CYP19A1. L'utilisation ectopique dans les tumeurs du sein du promoteur PII du gène CYP19A1, normalement spécifique à l'ovaire et régulé par la voie de signalisation AMPc/PKA, est reconnue comme étant responsable de la surexpression de l'enzyme et de la production inappropriée d'estrogènes par les tumeurs. Les facteurs GATA sont impliqués dans la régulation du promoteur PII de CYP19A1 dans les gonades. J'ai démontré que GATA3 et/ou GATA4 sont exprimés dans plusieurs lignées cellulaires de cancer du sein. En réponse à l'activation de la voie de signalisation AMPc/PKA, GATA3/4 et le récepteur nucléaire LRH1 coopèrent de façon synergique pour moduler l'activité du promoteur PII dans les cellules de cancer du sein MCF-7. Ces résultats fournissent un nouveau mécanisme dépendant de GATA pour expliquer l'expression aberrante de l'enzyme aromatase dans les tumeurs du sein. Les mutations hétérozygotes connues de GATA4 ségrègent avec de graves défauts cardiaques congénitaux. GATA4 est un important régulateur du développement cardiaque mais aussi un marqueur précoce du développement gonadique. Toutefois, aucune des mutations connues de GATA4 n'affecte le développement ou la fonction gonadique des individus porteurs. L'effet des différentes mutations de ce facteur sur la régulation de l'expression de ses cibles gonadiques demeurait par contre inconnu. J'ai étudié cinq mutations différentes du facteur GATA4. J'ai démontré que certaines de ces mutations affectent significativement la fonction de GATA4 dans un contexte de régulation de l'expression de gènes gonadiques. Mes résultats démontrent que malgré l'absence d'un phénotype observable, la plupart des mutations de GATA4 réduisent significativement sa capacité d'activer l'expression de ses gènes cibles sans affecter sa capacité à se lier à l'ADN ou celle de recruter ses co-activateurs transcriptionnels. Dans l'ensemble, les résultats présentés dans ma thèse démontrent comment les facteurs GATA exprimés dans un contexte tumoral contribuent à l'expression aberrante de CYP19A1 dans les cellules cancéreuses du sein selon un mécanisme rappelant celui menant à l'expression gonadique de ce gène et d'autre part comment l'altération de la séquence peptidique du facteur GATA4, telle qu'observée dans de nombreuses malformations cardiaques congénitales, affecte la fonction de ce facteur de transcription dans la régulation de l'expression de ses cibles gonadiques.

Les phosphatases CDC25 sont des enzymes clés qui interviennent dans la progression du cycle cellulaire en régulant l’activité des kinases dépendantes des cyclines (Cdk) par déphosphorylation. Ces phosphatases sont des cibles thérapeutiques intéressantes car leur surexpression, notamment dans le cancer du sein, a pu être corrélée au développement de résistance à certains agents anticancéreux ainsi qu’à un mauvais pronostic.Ce projet vise à évaluer le système des phosphatases CDC25 en tant que cibles intéressantes dans le traitement du cancer du sein.Lors de cette étude, nous nous sommes intéressés à deux composés organosoufrés naturellement présents dans l’ail et l’oignon, les diallyl- (DAS4) et dipropyl- (DPS4) tétrasulfures. Nous avons montré que ces composés étaient capables d’inhiber, de manière irréversible, les phosphatases CDC25A et C in vitro. Le potentiel anticancéreux des composés DAS4 et DPS4 a été confirmé sur des cellules d’adénocarcinome mammaire humain : MCF-7 et MDA-MB-231 (lignées sensibles) et Vcr-R (lignée résistante). Leur croissance est apparue significativement altérée par ces deux composés qui a pu être associée à un blocage du cycle cellulaire en phase G2/M. Par ailleurs, nos résultats ont également suggéré l’existence d’une activité pro-apoptotique des composés DAS4 et DPS4 qui est indépendante de la production d’espèces réactives oxygénées. L’étude de l’induction de l’apoptose dans le cas des cellules MCF-7 a révélé l’implication des protéines de la famille Bcl-2.Ces résultats suggèrent que l’inhibition des phosphatases CDC25A et C serait un des mécanismes qui contribuerait à l’activité anticancéreuse des composés organosoufrés
The CDC25 phosphatases are important regulators of eukaryotic cell cycle progression and play a crucial role in the activation of cyclin-dependent kinases (Cdk) by dephosphorylation. CDC25s are attractive targets in cancer therapy because their over-expression was reported in various types of human malignancies, including breast cancer, and this has been correlated with either poor prognosis or tumor aggressiveness.Our study aims to evaluate the CDC25s as interesting targets in breast cancer treatment. This study reports the inhibitory activity of two tetrasulfides : diallyl- (DAS4) and dipropyl- (DPS4) tetrasulfides naturally occurring in garlic and onion, towards the human cell division cycle (CDC) 25 phosphatases. Both compounds have emerged as interesting irreversible inhibitors of the CDC25 isoforms A and C in vitro.Then, we have investigated the anticancer properties of DAS4 et DPS4 on both sensitive (MCF-7 and MDA-MB-231) and resistant (Vcr-R) human breast carcinoma cell lines. Experiments performed on cultured cells have showed that growth of both sensitive and resistant cells was significantly decreased by these tetrasulfides and appeared to be associated with a G2/M cell cycle arrest. In addition, our results also suggested that DAS4 and DPS4 induce apoptotis in MCF-7 cells without affecting reactive oxygen species production. Analysis of mechanisms implicated in apoptosis induction in MCF-7 cells after treatment with DAS4 et DPS4 have suggested the involvement of the Bcl-2 family members. Taken together, these results suggest phosphatases CDC25A and C as possible targets of naturally occuring polysulfides contributing to their anticancer properties

Le cancer de la prostate est un réel problème de santé publique, essentiellement dû à une rechute des patients par échappement hormonal après traitement. Lors de sa progression, le cancer de la prostate, initialement androgéno-dépendant, évolue vers un état androgéno-indépendant supposant que des facteurs autres que les androgènes régulent la croissance et la survie des cellules cancéreuses. Il existe des évidences de l’implication des neurotransmetteurs et leurs récepteurs couplés aux protéines G dans le cancer de la prostate. De plus, la cavéoline-1, constituant majeur des cavéoles membranaires, a été associée à la progression maligne du cancer de la prostate. La localisation privilégiée des récepteurs couplés aux protéines G au sein des cavéoles favoriserait la transmission des signaux aboutissant à l’échappement hormonal des cellules cancéreuses androgéno-indépendantes. Je me suis alors intéressée à la localisation et au rôle du récepteur adrénergique a1A dans les cellules prostatiques androgéno-indépendantes DU145. J’ai tenté de mettre en évidence l’implication des cavéoles dans une fonction de survie et/ou de croissance du récepteur. Nos résultats démontrent que le récepteur adrénergique a1A peut être associé à la cavéoline-1, au sein de cavéoles dans les cellules androgéno-indépendantes. Nous avons aussi mis en évidence que la stimulation du récepteur participe à la protection de ces cellules vis-àvis de stimuli apoptotiques et ce via les cavéoles. Enfin, le profil d’expression du récepteur a1A et de la cavéoline-1 suggère qu’il y ait une corrélation positive avec l’état pathologique de la prostate
Prostate cancer has become a real public health issue, mainly due to patients’ relapse by hormone-refractory disease after treatment. During its progression, initially androgendependent prostate cancer evolves in an androgen-independent state supposing that factors others than androgens regulate growth and survival of cancer cells. There is growing evidence concerning the involvement of neurotransmitters and their G-protein coupled receptors in prostate cancer. Moreover, overexpression of a major caveolae constituent, caveolin-1 has been associated with aggressive prostate cancer. Privileged localisation of G-protein coupled receptors in caveolae could enhance signalling pathways leading to hormone-refractory mechanisms in androgen-independent prostate cancer cells. I was therefore interested in determining the localisation and functional role of the a1A-adrenoceptor in the DU145 androgen-independent prostate cells. I attempted to demonstrate the involvement of caveolae in a growth/survival function of this receptor. Our results showed that the a1A-adrenoceptor can be associated with caveolin-1 in caveolae of these androgen-independent cells. We also demonstrated that a1A-adrenoceptor stimulation mediated through caveolae contributes to the protection of these cells from apoptotic stimuli. Finally, the expression of a1A-adrenoceptor and caveolin-1 seems to be positively correlated with prostate pathological state