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2.
Front Oncol ; 12: 804868, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35847954

RESUMO

Luminal breast cancers represent 70% of newly diagnosed breast cancers per annum and have a relatively good prognosis compared with triple-negative breast cancers. Luminal tumors that are responsive to hormonal therapy are particularly associated with a favorable prognosis. Nonetheless, the absolute number of metastatic relapses in luminal cancers is larger than in triple-negative breast cancers. A better understanding of the biology of luminal cancers, control of metastases formation, and identification of predictive markers of their evolution are therefore still necessary. In this context, we previously disclosed the key role of NFAT3 in regulating luminal breast cancer invasion. We have now identified a specific inhibitory region, in the C-terminal part of NFAT3, required for the inhibition of invasion of the human luminal breast cancer cell line T-47D. Indeed, we showed that this 85 amino acid C-terminal region acts as a dominant negative form of NFAT3 and that its overexpression in the T-47D cell line led to increased cell invasion. Mechanistically, we have revealed that this region of NFAT3 interacts with the small Ras GTPase RERG (RAS like estrogen regulated growth inhibitor) and shown that RERG expression is required for NFAT3 to impede T-47D cell invasion. We have validated the association of NFAT3 with RERG in human luminal breast cancer tissues. We have shown an increase of the quantity of the NFAT3/RERG complexes in patients without axillary lymph node colonization and therefore proposed that the detection of this complex may be a non-invasive marker of axillary lymph node colonization.

3.
Cancer Med ; 11(24): 4865-4879, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35593199

RESUMO

BACKGROUND: The COVID-19 pandemic led to a widely documented disruption in cancer care pathway. Since a resurgence of the pandemic was expected after the first lockdown in France, the global impact on the cancer care pathway over the year 2020 was investigated. AIMS: This study aimed to describe the changes in the oncology care pathway for cancer screening, diagnosis, assessment, diagnosis annoucement procedure and treatment over a one-year period. MATERIALS & METHODS: The ONCOCARE-COV study was a comprehensive, retrospective, descriptive, and cross-sectional study comparing the years 2019 and 2020. All key indicators along the cancer care pathway assessing the oncological activity over four periods were described. This study was set in a high-volume, public, single tertiary care center divided in two complementary sites (Reims University Hospital and Godinot Cancer Institute, Reims, France) which was located in a high COVID-19 incidence area during both peaks of the outbreak. RESULTS: A total of 26,566 patient's files were active during the year 2020. Breast screening (-19.5%), announcement dedicated consultations (-9.2%), Intravenous and Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPECs) (-25%), and oncogeriatric evaluations (-14.8%) were heavily disrupted in regard to 2020 activity. We identified a clear second outbreak wave impact on medical announcement procedures (October, -14.4%), radiotherapy sessions (October, -16%), number of new health record discussed in multidisciplinary tumor board meeting (November, -14.6%) and HIPECs (November, -100%). Moreover, 2020 cancer care activity stagnated compared to 2019. DISCUSSION: The oncological care pathway was heavily disrupted during the first and second peaks of the COVID-19 outbreak. Between lockdowns, we observed a remarkable but non-compensatory recovery as well as a lesser impact from the pandemic resurgence. However, in absence of an increase in activity, a backlog persisted. CONCLUSION: Public health efforts are needed to deal with the consequences of the COVID-19 pandemic on the oncology care pathway.


Assuntos
COVID-19 , Neoplasias , Humanos , Pandemias , COVID-19/epidemiologia , Estudos Transversais , SARS-CoV-2 , Procedimentos Clínicos , Estudos Retrospectivos , Controle de Doenças Transmissíveis , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia
4.
Cancer Immunol Immunother ; 71(11): 2731-2742, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35428910

RESUMO

Melanoma is responsible for 90% of skin cancer-related deaths. Major therapeutic advances have led to a considerable improvement in the prognosis of patients, with the development of targeted therapies (BRAF or MEK inhibitors) and immunotherapy (anti-CTLA-4 or -PD-1 antibodies). However, the tumor constitutes an immunosuppressive microenvironment that prevents the therapeutic efficacy and/or promotes the development of secondary resistances. CD160 is an activating NK-cell receptor initially described as delineating the NK and CD8+ T-cell cytotoxic populations. Three forms of CD160 have been described: (1) the GPI isoform, constitutively expressed and involved in the initiation of NK-cells' cytotoxic activity, (2) the transmembrane isoform, neo-synthesized upon cell activation, allowing the amplification of NK cells' cytotoxic functions and (3) the soluble form, generated after cleavage of the GPI isoform, which presents an immuno-suppressive activity. By performing immunohistochemistry analyses, we observed a strong expression of CD160 at the primary cutaneous tumor site of melanoma patients. We further demonstrated that melanoma cells express CD160-GPI isoform and constitutively release the soluble form (sCD160) into the tumor environment. sCD160 was shown to inhibit the cytotoxic activity of NK-cells towards their target cells. In addition, it was found in the serum of melanoma patients and associated with increased tumor dissemination. Altogether these results support a role for sCD160 in the mechanisms leading to the inhibition of anti-tumor response and immune surveillance in melanoma.


Assuntos
Melanoma , Receptores Imunológicos , Antígenos CD , Proteínas Ligadas por GPI , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , Receptor de Morte Celular Programada 1 , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas B-raf , Receptores Imunológicos/metabolismo , Microambiente Tumoral
5.
Sci Rep ; 11(1): 22278, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782679

RESUMO

Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann-Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.


Assuntos
Aorta/metabolismo , Aorta/fisiopatologia , Apelina/deficiência , Matriz Extracelular/metabolismo , Rigidez Vascular/genética , Animais , Apelina/genética , Apelina/metabolismo , Biomarcadores , Pressão Sanguínea , Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Elastase Pancreática/genética , Elastase Pancreática/metabolismo
6.
Breast J ; 27(7): 595-602, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34251074

RESUMO

INTRODUCTION: The Grisotti technique consists to excise central breast tumor with nipple areolar and mobilize a dermo-glandular flap which is de-epithelized in order to reshape the breast and recreate an areola. The objective was to assess oncological results, postoperative side-effects, and patient and surgeon satisfaction rates resulting from this technique. MATERIALS AND METHODS: From September 2016 to December 2019, 38 patients have been treated with a central breast tumor using the Grisotti technique. RESULTS: The mean age was 61.6 ± 11. The median body mass index was 27 kg/m² [20-42]. Thirty one patients benefited from a sentinel lymph node dissection. Preoperative histology found a majority of invasive ductal carcinomas (IDC) (71%). There were no intraoperative complications, and the average operating time was 90 min [60-200]. Postoperative histology found IDC associated with ductal carcinoma in situ in 28 patients. The surgical margins were invaded in two patients (reoperated by mastectomy after adjuvant treatment) and invasion of a margin of less than 1 mm in another six patients (supplemented by re-excision). The main postoperative complications were an abscess of the operating site and a partial necrosis of the neo-areola. The appearance of the breasts after radiotherapy gives a high satisfaction rate, both for patients and for surgeons. CONCLUSION: The Grisotti technique is an easily reproducible procedure without major complications. It makes it possible to perform a carcinological satisfactory central lumpectomy, correction of the central glandular defect, and reconstruction of a new areola.


Assuntos
Neoplasias da Mama , Mamoplastia , Idoso , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mamoplastia/efeitos adversos , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Mamilos/cirurgia , Estudos Retrospectivos
7.
Int J Surg Case Rep ; 78: 270-273, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33373921

RESUMO

INTRODUCTION: Synovial sarcoma (SS) is a mesenchymal neoplasm that is characterized by its unique histological pattern and is most commonly found near the joints of the extremity. Stomach involvement is very rare. This work aimed to present the case of a patient with gastric SS. We also conducted a review of 39 gastric SS cases reported in the literature. PRESENTATION OF CASE: Here we report a case of primary gastric synovial sarcoma in a 32-year-old male patient revealed by gastric reflux. Partial gastrectomy was performed showing a 35 mm lesion with a high spindle cell component. Immunohistochemistry revealed 18q11.2 translocation expression in most of the cells asserting a diagnosis of SS. No local or distant recurrence occurred at 8 months post-operative follow-up. DISCUSSION: The majority of SS occurs in the extremities and is most often associated with tendons in the large articulations of young adults. Gastric SS are very scarce and a molecular biology approach to detect the SYT-SSX fusion gene is required for conclusive diagnosis. We carried out a clinical review of the 40 cases of primary gastric SS, including our case. They all underwent an excisional surgery, most of them by partial gastectomy or wedge resection. Recurrences were rare and early when they occurred. CONCLUSION: Gastric SS is a very uncommon neoplasia although it is henceforth a described entity. Immunohistochemical detection of a pathognomonic translocation is needed to make the diagnosis of SS. Best therapeutic approach for these tumors remains surgical resection with no specific excisional technique recommended.

8.
Cancer Immunol Immunother ; 69(7): 1337-1352, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32219500

RESUMO

Cleavage of the MUC1 glycoprotein yields two subunits, an extracellular alpha-subunit bound to a smaller transmembrane beta-subunit. Monoclonal antibodies (mAbs) directed against the MUC1 alpha-beta junction comprising the SEA domain, a stable cell-surface moiety, were generated. Sequencing of all seven anti-SEA domain mAbs showed that they clustered into four groups and sequences of all groups are presented here. mAb DMB5F3 with picomolar affinity for the MUC1 SEA target was selected for further evaluation. Immunohistochemical staining of a series of malignancies with DMB5F3 including lung, prostate, breast, colon, and pancreatic carcinomas revealed qualitative and qualitative differences between MUC1 expression on normal versus malignant cells: DMB5F3 strongly stained malignant cells in a near-circumferential pattern, whereas MUC1 in normal pancreatic and breast tissue showed only weak apical positivity of ductal/acinar cells. Humanized chimeric DMB5F3 linked to ZZ-PE38 (ZZ IgG-binding protein fused to Pseudomonas exotoxin) induced vigorous cytotoxicity of MUC1+ malignant cells in vitro. The intensity of cell killing correlated with the level of MUC1 expression by the target cell, suggesting a MUC1 expression threshold for cell killing. MUC1+ Colo357 pancreatic cancer cells xenotransplanted into nude and SCID mice models were treated with the chDMB5F3:ZZ-PE38 immunocomplex. In both transplant models, chDMB5F3:ZZ-PE38 exhibited significant in vivo anti-tumor activity, suppressing up to 90% of tumor volume in the SCID model compared with concomitant controls. The efficacy of chDMB5F3:ZZ-PE38 immunotoxin in mediating tumor killing both in vitro and in vivo strongly suggests a clinical role for anti-MUC1 SEA antibody in the treatment of MUC1-expressing malignancies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Imunotoxinas/imunologia , Mucina-1/química , Mucina-1/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Domínios Proteicos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Ann Pathol ; 39(6): 383-398, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31257035

RESUMO

Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Linfonodos/patologia , Terapia Neoadjuvante , Manejo de Espécimes/normas , Biomarcadores Tumorais , Biópsia/métodos , Biópsia/normas , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/normas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , França , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/cirurgia , Prontuários Médicos/normas , Microscopia , Neoplasia Residual/patologia , Prognóstico , Biópsia de Linfonodo Sentinela/métodos , Manejo de Espécimes/métodos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
10.
Int J Mol Sci ; 19(12)2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30518157

RESUMO

Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.


Assuntos
Neoplasias da Mama/metabolismo , Interleucina-17/metabolismo , Animais , Feminino , Humanos , Modelos Biológicos , Transdução de Sinais
11.
FEBS Open Bio ; 8(9): 1395-1404, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30186741

RESUMO

Elastin is a long-lived extracellular matrix protein responsible for the structural integrity and function of tissues. Breast cancer elastosis is a complex phenomenon resulting in both the deposition of elastotic masses and the local production of elastin fragments. In invasive human breast cancers, an increase in elastosis is correlated with severity of the disease and age of the patient. Elastin-derived peptides (EDPs) are a hallmark of aging and are matrikines - matrix fragments having the ability to regulate cell physiology. They are known to promote processes linked to tumor progression, but their effects on breast cancer cells remain unexplored. Our data show that EDPs enhance the invasiveness of MDA-MB-231 breast cancer cells through the engagement of matrix metalloproteases 14 and 2. We therefore suggest that elastosis and/or an aged stroma could promote breast cancer cell invasiveness.

12.
Invest Ophthalmol Vis Sci ; 59(7): 2679-2686, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860454

RESUMO

Purpose: Anti-angiogenic agents stand first in the treatment of neovascular diseases of the retina. CD160 appeared in several experimental studies as a marker of activated endothelial cells, suggesting it could represent a promising target for novel anti-angiogenic therapies. The aim of the present study was to assess the distribution of CD160 in the human eye, and to search for a possible correlation with retinal neovascular diseases. Methods: The physiological distribution of CD160 in the normal eye was assessed with immunolabeling in 10 human donor eyes. Then, in a retrospective cohort of 75 surgical retinal specimens, the density of CD160+ microvessels was evaluated, along with immunolabeling on serial sections against ERG (pan-endothelial cell marker), CD105 (activated endothelial cell marker), and α-SMA (pericyte cell marker). The cohort was divided into two groups: 29 patients with neovascular disease (NV+) and 46 control patients (NV-). Results: CD160 was physiologically expressed by several cell types: endothelial cells of retinal blood vessels, ganglion cells, macrophages, epithelial cells of the conjunctiva, ciliary body, and retinal pigment epithelium. In the patient cohort, the percentage of CD160+ vessels in the retina was significantly and independently higher in patients suffering from neovascular diseases (P = 0.04). On the contrary, the expression of CD105 was correlated neither with retinal neovascular diseases, nor with CD160 expression. Conclusions: CD160 was expressed in some retinal vessels in both normal and pathologic eyes. CD160 expression by endothelial cells of retinal vessels was correlated with ocular neovascular diseases. CD160 could therefore represent an interesting target for novel anti-angiogenic therapies.


Assuntos
Antígenos CD/metabolismo , Receptores Imunológicos/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/metabolismo , Actinas/metabolismo , Idoso , Biomarcadores/metabolismo , Corpo Ciliar/metabolismo , Túnica Conjuntiva/metabolismo , Endoglina/metabolismo , Endotélio Vascular/metabolismo , Células Epiteliais/metabolismo , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Células Ganglionares da Retina/metabolismo , Estudos Retrospectivos , Doadores de Tecidos , Regulador Transcricional ERG/metabolismo
13.
Cancer Manag Res ; 10: 1051-1059, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29765252

RESUMO

INTRODUCTION: Breast cancers develop different patterns of sialylation to modulate their tumor-infiltrating lymphocyte (TIL) environment. We studied the relationship between α-2,6 sialyltransferases and the TIL in different breast cancer molecular subgroups. MATERIALS AND METHODS: Immunohistochemical preparations were made from 39 luminal (LUM), 13 human epidermal growth factor receptor 2-overexpressing (HER2) and 47 triple-negative (TN) breast carcinomas. Targeted proteins included ST6Gal-I, ST6Gal-II, ST6GalNac-I, CD8, CD4 and granzyme-B in both cytotoxic T lymphocytes and NK lymphocytes (CTL/NK). RESULTS: CTL/NK populations were significantly more frequent in TN than LUM (P <0.001). TN showed a lower level of ST6Gal-I expression than LUM or HER2 (both P > 0.001). ST6GalNac-I expression was lower in LUM than in TN or HER2 (P = 0.002 and P = 0.02, respectively). In HER2, a significant association was found between a low level of ST6Gal-I expression and a high TIL level. In TN, a significant association was observed between a high level of ST6Gal-II expression and a high TIL level. CONCLUSION: An increase in infiltrating lymphocytes could be influenced by low expression of ST6Gal-I in HER2 and by high expression of ST6Gal-II in TN breast cancers. Thus, targeting these sialylation pathways could modulate the levels of TIL.

14.
Sci Rep ; 7(1): 7201, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-28775276

RESUMO

Autophagy is one of the chemotherapy resistance mechanisms in breast cancer. The aim of this study was to determine the level of recruitment of the autophagy pathway in the triple-negative breast cancer (TNBC) cell line MDA-MB231 compared with that in the control luminal breast cancer cell line MCF7 before and after treatment with chemotherapy drugs. Furthermore, we investigated the relationship between autophagy and EGFR, MUC1 and IL17-receptors as activators of autophagy. Immunohistochemistry was performed in cell culture blocks using LC3b, MUC1-C, EGFR, IL17A, IL17-RA and IL17-RB antibodies. We found that the basal autophagy level in MDA-MB231 was high, whereas it was low in MCF7. However, in contrast to MDA-MB231, the autophagy level was increased in MCF7 upon treatment with chemotherapy agents. Interestingly, we observed that the expression levels of MUC1-C, EGFR, IL17-RA, and IL17-RB were not modified by the same treatments. Furthermore, the chemotherapy treatments did not increase autophagy in TNBC cells without affecting the expression levels of MUC1-C, EGFR, IL17-RA or IL17-RB.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Autofagia/genética , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Células MCF-7 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
15.
PLoS One ; 11(10): e0165031, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27768738

RESUMO

Translation of mRNA in alternate reading frames (ARF) is a naturally occurring process heretofore underappreciated as a generator of protein diversity. The MUC1 gene encodes MUC1-TM, a signal-transducing trans-membrane protein highly expressed in human malignancies. Here we show that an AUG codon downstream to the MUC1-TM initiation codon initiates an alternate reading frame thereby generating a novel protein, MUC1-ARF. MUC1-ARF, like its MUC1-TM 'parent' protein, contains a tandem repeat (VNTR) domain. However, the amino acid sequence of the MUC1-ARF tandem repeat as well as N- and C- sequences flanking it differ entirely from those of MUC1-TM. In vitro protein synthesis assays and extensive immunohistochemical as well as western blot analyses with MUC1-ARF specific monoclonal antibodies confirmed MUC1-ARF expression. Rather than being expressed at the cell membrane like MUC1-TM, immunostaining showed that MUC1-ARF protein localizes mainly in the nucleus: Immunohistochemical analyses of MUC1-expressing tissues demonstrated MUC1-ARF expression in the nuclei of secretory luminal epithelial cells. MUC1-ARF expression varies in different malignancies. While the malignant epithelial cells of pancreatic cancer show limited expression, in breast cancer tissue MUC1-ARF demonstrates strong nuclear expression. Proinflammatory cytokines upregulate expression of MUC1-ARF protein and co-immunoprecipitation analyses demonstrate association of MUC1-ARF with SH3 domain-containing proteins. Mass spectrometry performed on proteins coprecipitating with MUC1-ARF demonstrated Glucose-6-phosphate 1-dehydrogenase (G6PD) and Dynamin 2 (DNM2). These studies not only reveal that the MUC1 gene generates a previously unidentified MUC1-ARF protein, they also show that just like its 'parent' MUC1-TM protein, MUC1-ARF is apparently linked to signaling and malignancy, yet a definitive link to these processes and the roles it plays awaits a precise identification of its molecular functions. Comprising at least 524 amino acids, MUC1-ARF is, furthermore, the longest ARF protein heretofore described.


Assuntos
Núcleo Celular/metabolismo , Mucina-1/genética , Biossíntese de Proteínas , RNA Mensageiro/genética , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Códon , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Camundongos , Mucina-1/metabolismo , Neoplasias Pancreáticas/metabolismo
16.
Int J Mol Sci ; 17(9)2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27589729

RESUMO

The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors.


Assuntos
Imunoterapia/métodos , Interleucina-17/metabolismo , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Interleucina-17/genética , Neoplasias/classificação , Neoplasias/terapia , Linfócitos T Auxiliares-Indutores/imunologia
17.
Oncotarget ; 7(33): 53350-53361, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27462789

RESUMO

Estrogen receptor-, progesterone receptor- and HER2-negative breast cancers, also known as triple-negative breast cancers (TNBCs), have poor prognoses and are refractory to current therapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors. Resistance to anti-EGFR therapeutic agents is often associated with sustained kinase phosphorylation, which promotes EGFR activation and translocation to the nucleus and prevents these agents from acting on their targets. The mechanisms underlying this resistance have not been fully elucidated. In addition, the IL-17E receptor is overexpressed in TNBC tumors and is associated with a poor prognosis. We have previously reported that IL-17E promotes TNBC resistance to anti-mitotic therapies. Here, we investigated whether IL-17E promotes TNBC resistance to anti-EGFR therapeutic agents by exploring the link between the IL-17E/IL-17E receptor axis and EGF signaling. We found that IL-17E, similarly to EGF, activates the EGFR in TNBC cells that are resistant to EGFR inhibitors. It also activates the PYK-2, Src and STAT3 kinases, which are essential for EGFR activation and nuclear translocation. IL-17E binds its specific receptor, IL-17RA/IL17RB, on these TNBC cells and synergizes with the EGF signaling pathway, thereby inducing Src-dependent EGFR transactivation and pSTAT3 and pEGFR translocation to the nucleus. Collectively, our data indicate that the IL-17E/IL-17E receptor axis may underlie TNBC resistance to EGFR inhibitors and suggest that inhibiting IL-17E or its receptor in combination with EGFR inhibitor administration may improve TNBC management.


Assuntos
Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Interleucina-17/farmacologia , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Humanos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transporte Proteico/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
18.
Cancer Cytopathol ; 124(8): 573-80, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27136615

RESUMO

BACKGROUND: The liquid-based cytology Papanicolaou (Pap) test has gradually replaced the conventional Pap test, as it seems to be more efficient, in part because it uses computer assistance. However, Pap test diagnoses are still subjective and are cost-consuming or time-consuming. The authors describe a new digital holographic microscopy instrument and accompanying software. This technology provides an instantaneous, 3-dimensional image reconstruction of cells directly from the uterine cervical sample vial. METHODS: Analyses were performed using the proprietary digital holographic microscopy (DHM) instrument, computer, and software. Residual materials from 3 randomly chosen laboratories were analyzed and subjected to DHM, and the sensitivity and specificity of DHM were calculated for the detection neoplasia. RESULTS: In 41 specimens that yielded normal Pap test results, 1333 cells were analyzed using DHM; and, in 30 specimens that yielded abnormal Pap test results, 494 cells were analyzed using DHM. Available histologic correlation was as follows: 4 histologic samples were diagnosed as grade 1 cervical intraepithelial neoplasia (corresponding to 2 cytologic diagnoses of low-grade squamous intraepithelial lesion and 2 cytologic diagnoses of atypical squamous cells of undetermined significance), 4 histologic samples were diagnosed as grade 3 cervical intraepithelial neoplasia (corresponding to 2 cytologic diagnoses of low-grade squamous intraepithelial lesion and 2 cytologic diagnosis of atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion), and 11 lesions were diagnosed as benign. Receiver operating characteristic curve analysis indicated that the best criteria were the nuclear-to-cytoplasmic ratio (area under the curve, 0.88; 95% confidence interval, 0.68-1.00) and the greatest nuclear dimension (area under the curve, 0.85; 95% confidence interval, 0.66-1.00). CONCLUSIONS: This preliminary study demonstrated for the first time that the DHM technique is suitable for the processing of gynecologic cervical samples. Nevertheless, DHM criteria and parameters could be better defined. Hopefully, holographic analysis will be performed automatically and will provide an instantaneous, cost-effective diagnosis from a closed vial with the preservation of all cellular material. Cancer Cytopathol 2016;124:573-80. © 2016 American Cancer Society.


Assuntos
Células Escamosas Atípicas do Colo do Útero/patologia , Holografia/métodos , Microscopia/métodos , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Feminino , Seguimentos , Humanos , Gradação de Tumores , Teste de Papanicolaou , Prognóstico , Estudos Retrospectivos , Esfregaço Vaginal
19.
Clin Nucl Med ; 41(6): 512-3, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26914574

RESUMO

A 70-year-old man with prostate cancer and increased prostate-specific antigen level of 55 ng/mL underwent staging F-fluorocholine PET/CT, which demonstrated the primary prostate tumor and a focal area corresponding to a 2-cm hypodense nodule in the left thyroid lobe. Fine-needle aspiration and subsequent total thyroidectomy with central lymph node dissection showed an oxyphilic papillary thyroid carcinoma and a medullary microcarcinoma. Oxyphilic tumors represent a significant proportion of the few case reports of incidental focal thyroid fluorocholine thyroid uptake.


Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Idoso , Biópsia por Agulha Fina , Carcinoma/patologia , Carcinoma/cirurgia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Carcinoma Papilar , Colina/análogos & derivados , Humanos , Achados Incidentais , Masculino , Esvaziamento Cervical , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico , Compostos Radiofarmacêuticos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia
20.
Int J Clin Exp Pathol ; 8(5): 4344-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26191126

RESUMO

Triple-negative breast carcinoma (TN) is a heterogeneous cancer type expressing EGFR in 75% of cases. MUC1 is a large type I sialylated glycoprotein comprising two subunits (α and ß chains, also called respectively MUC1-VNTR and MUC1-CT), which was found to regulate EGFR activity through endocytic internalisation. Endocytosis and autophagy use the lysosome pathway involving NEU1. Recently, a molecular EGFR-MUC1-NEU1 complex was suggested to play a role in EGFR pathway. In the aim to understand the relationship between EGFR-MUC1-NEU1 complex and autophagy in breast carcinoma, we compared triple negative (TN) showing a high-EGFR expression with luminal (LUM) presenting low-EGFR level. We studied the expression of MUC1-VNTR, MUC1-CT and NEU1 in comparison with those of two molecular actors of autophagy, PI3K (p110ß) and Beclin1. A total of 87 breast cancers were split in two groups following the immunohistochemical classification of breast carcinoma: 48 TN and 39 LUM. Our results showed that TN presented a high expression of EGFR and a low expression of MUC1-VNTR, MUC1-CT, NEU1, Beclin-1 and PI3Kp110ß. Moreover, in TN, a positive statistical correlation was observed between Beclin-1 or PI3Kp110ß and MUC1-VNTR or NEU1, but not with EGFR. In conclusion, our data suggest that autophagy is reduced in TN leading likely to the deregulation of EGFR-MUC1-NEU1 complex and its associated cellular pathways.


Assuntos
Autofagia/fisiologia , Receptores ErbB/metabolismo , Mucina-1/metabolismo , Neuraminidase/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estudos Retrospectivos , Transdução de Sinais/fisiologia , Análise Serial de Tecidos , Neoplasias de Mama Triplo Negativas/metabolismo
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