Histology and histopathology Vol.32, nº9 (2017)
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- PublicationOpen AccessRelevance of in vitro 3-D skin models in dissecting cytokine contribution to psoriasis pathogenesis(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Chiricozzi, A.; Romanelli, M.; Panduri, S.; Donetti, E.; Prignano, F.Psoriasis is a chronic skin disease characterized by the activation of various T cell subsets secreting IFNγ, IL-17, and IL-22, dendritic cells producing TNFα and IFNα, and other immune cells including neutrophils and mast cells. Keratinocytes respond to different cytokine signals orchestrating innate and adaptive immune responses. In vitro studies sought to clarify the cytokine effects on keratinocytes in order to evaluate the centrality of these mediators in psoriasis pathogenesis. The aim of this review is to highlight the relevance of this peculiar in vitro approach in investigating cytokine effects on skin or multilayered epidermis. Particularly, we reported keynfinding
- PublicationOpen AccessVascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Angara, Kartik; Rashid, Mohammad H.; Shankar, Adarsh; Ara, Roxan; Iskander, Asm; Borin, Thaiz F.; Jain, Meenu; Achyut, Bhagelu R.; Arbab, Ali S.Glioblastoma (GBM) is one hypervascular and hypoxic tumor known among solid tumors. Antiangiogenic therapeutics (AATs) have been tested as an adjuvant to normalize blood vessels and control abnormal vasculature. Evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance to AATs. Here, we identified that GBM following AAT (Vatalanib) acquired an alternate mechanism to support tumor growth, called vascular mimicry (VM). We observed that Vatalanib induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer-side. The PAS+ matrix is positive for basal laminae (laminin) indicating vascular structures. Vatalanib treated GBM displayed various stages of VM such as initiation (mosaic), sustenance, and full-blown VM. Mature VM structures contain red blood cells (RBC) and bear semblance to the functional blood vessel-like structures, which provide all growth factors to favor tumor growth. Vatalanib treatment significantly increased VM especially in the core of the tumor, where HIF-1α was highly expressed in tumor cells. VM vessels correlate with hypoxia and are characterized by co-localized MHC-1+ tumor and HIF-1α expression. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at periphery of the tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by tumors to make functional vessels by transdifferentiation of tumor cells into endothelial-like cells to supply nutrients in the event of hypoxia. AAT induced VM is a potential therapeutic target of the novel formulation of HET0016. Our present study suggests that HET0016 has a potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.
- PublicationOpen AccessMyoepithelial tumor of soft tissue and bone: A current perspective(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Verma, Anuj; Rekhi, BharatMyoepithelial tumor (MET) of soft tissue and bone is an unusual tumor of uncertain differentiation and histogenesis, but lately has been recognized as a distinct tumor entity. This tumor forms a morphologic continuum with a mixed tumor and a parachordoma, but is different from an extra-axial chordoma or chordoma periphericium. METs display a range of histopathologic features, including architectural arrangements/growth patterns, cell types and intervening stroma, leading to their several differential diagnoses. Presently, moderate nuclear atypia is the acceptable criterion to differentiate a myoepithelial carcinoma from a myoepithelioma. Immunohistochemical (IHC) stains, including epithelial antibody markers, along with S100 protein and GFAP are necessary in confirming a diagnosis of a MET. Certain METs are associated with loss of INI1/SMARCB1. Lately, certain specific “molecular signatures” been described underlying METs, identification of which that can further aid in their accurate diagnosis and in differentiating these tumors from their diagnostic mimics. Complete surgical resection forms the treatment mainstay, irrespective of a myoepithelioma or a myoepithelial carcinoma. This review will focus upon clinicopathologic, immunohistochemical and molecular features of METs of soft tissue and bone, along with their differential diagnoses and diagnostic implications.
- PublicationOpen AccessEthanol enhances thymocyte apoptosis and autophagy in macrophages of rat thymi(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Betsuyaku, Tsubasa; Eid, Nabil; Ito, Yuko; Tanaka, Yoshihisa; Otsuki, Yoshinori; Kondo, YoichiTingible body macrophages (TBMs) play essential roles in the phagocytosis of apoptotic lymphocytes, specifically under exposure to various stressors. Although excessive ethanol consumption may enhance thymocyte apoptosis, reports investigating the autophagic response of the thymus to ethanol toxicity are still lacking. We investigated apoptosis and autophagy in thymi of an animal model of binge ethanol exposure. Adult male Wistar rats were injected intraperitoneally either with 5 g/kg ethanol or phosphate buffer saline (for the control group) and sacrificed 0, 3, 6 and 24 hours after injection. Light and transmission electron microscopy (TEM) studies revealed enhanced formation of TBMs phagocytosing many apoptotic thymocytes in the thymic cortex of the ethanol-treated rats (ETRs), and this formation was particularly marked at 24 h. The macrophages showed signs of activation under TEM and immunofluorescence double labeling with RM4 (a macrophage marker) and iNOS. Additionally, in comparison to the control group, autophagy was enhanced in ETR thymic TBMs as evidenced ultrastructurally by accumulation of autophagic vacuoles, immunohistochemical increases in LC3 puncta, Western blot analysis of the latter protein, and colocalization of LC3 and RM4 in immunofluorescence double labeling. Immunoelectron microscopy also revealed LC3-labeled autophagic vacuoles and apoptotic cell phagosomes in ETR TBMs, suggesting the possibility of LC3-related phagocytosis. This was confirmed by enhanced colocalization of LC3 with lysosomal cathepsins in double labeling. These results indicate that enhanced autophagy in ETR thymic TBMs is not only a cytoprotective mechanism but could also be involved in the clearance of apoptotic thymocytes, thus preventing autoimmune reactions and suppressing inflammatory response.
- PublicationOpen AccessThe circumventricular organs(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Kaur, Charanjit; Ling, Eng AngThe circumventricular organs (CVOs) are midline structures located around the third and fourth ventricles that are characterized by a lack of blood-brain barrier. The pineal gland, median eminence, neurohypophysis and the subcommisural organ are classified as secretory, whereas the subfornical organ, area postrema and the organum vasculosum of the lamina terminalis as the sensory CVOs. Glial cells consisting of astrocytes and microglia/macrophages are present in all these organs. The pineal gland, neurohypophysis and the median eminence lack the presence of neurons that are present in the rest of the CVOs. Most of the CVOs are lined by ependymal cells except for the pineal and the neurohypophysis. Modified ependymal cells known as tanycytes are present in the ependymal lining. These organs are important sites for communication with the cerebrospinal fluid as well as between the brain and peripheral organs via blood-borne products as they lack the blood-brain barrier.
- PublicationOpen AccessChitooligosaccharide promotes immune organ development in broiler chickens and reduces serum lipid levels(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Shenghe, Li; Erhui, Jin; Enmei, Qiao; Guozhong, Wu; Kui, LiThis study investigated the effects of chitooligosaccharide on lipid metabolism, immune organ development, and lymphocyte apoptosis in broiler chickens. A total of 480 one-day-old broiler chickens (Arbor Acres) were randomly and evenly assigned to control group and experimental groups I, II, and III. The control group was given a basic diet, while experimental groups I, II, and III were given basic diets for 42 days, supplemented with 50 mg/kg chlortetracycline, 20, and 40 mg/kg chitooligosaccharide, respectively. We found levels of serum triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) to be significantly reduced in experimental group II after 21 days, while the periarterial lymphatic sheath area of the spleens and the average number of bursa of Fabricius nodes were markedly increased. The serum total protein (TP) and high density lipoprotein cholesterol (HDL-C) levels, bursa of Fabricius index, and bursa of Fabricius lobule areas were additionally increased in experimental group III. After 42 days, the serum TP content had also increased and the bursa of Fabricius lobule area was augmented as well in experimental group II. Moreover, the splenic periarterial lymphatic sheath areas and the average numbers of bursa of Fabricius nodes were significantly increased in experimental group III. At both 21 and 42 days, numbers of Caspase-3 positive cells in spleen and bursa of Fabricius were significantly decreased in experimental groups II and III. Our results show that appropriate supplementation of chitooligosaccharide may improve lipid metabolism, promote immune organ development, and inhibit lymphocyte apoptosis in broilers.
- PublicationOpen AccessTargeting miR-155 suppresses proliferation and induces apoptosis of HL-60 cells by targeting Slug/PUMA signal(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Liang, Hui; Dong, Ziyan; Liu, Jiang Feng; Chuang, Wei; Gao, Li Zhen; Ren, Yu GuoRecent studies have shown that high miR155 expression was associated with poor prognosis in patients with acute myelogeneous leukemia (AML). Furthermore, targeting miR-155 results in monocytic differentiation and apoptosis. However, the exact role and mechanisms of miR-155 in human AML remains speculative. HL-60 cells were treated with anti-miR-155 for 72 h. Cell growth and apoptosis in vitro were detected by MTT, BrdU proliferation, colony formation and flow cytometry assay. The effect of anti-miR-155 on growth of HL-60 cells was also evaluated in a leukemia mouse model. Slug cDNA and PUMA siRNA trannsfection was used to assess the signal pathway. Different protein expression was detected by western blot assay and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay. The results shown that targeting miR-155 resulted in a 24-fold decrease of miR-155 expression compared to negative control in the HL-60 cells. Targeting miR-155 significantly downregulated Slug and upregulated PUMA expression, and decreased HL-60 cell growth by 70% , impaired colony formation by approximately 60%, and increased HL-60 cell apoptosis by 45%. Targeting PUMA reversed miR-155 sliencing-induced proliferation and apoptosis of HL-60 cells. Restoration of Slug decreased PUMA expression. In murine engraftment models of HL-60 cells, we showed that targeting miR-155 was able to reduce tumor growth. This was accompanied with decreased Slug expression and increased PUMA expression in these tumors. Collectively, our findings strongly suggest targeting miR-155 exhibited in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of Slug expression and increase of PUMA expression.
- PublicationOpen AccessMicro-RNA signature of lymphovascular space involvement in type 1 endometrial cancer(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Canlorbe, Geoffroy; Castela, Mathieu; Bendifallah, Sofiane; Wang, Zhe; Lefevre, Marine; Chabbert Buffet, Nathalie; Aractingi, Selim; Daraï, Emile; Méhats, Céline; Ballester, MarcosObjective. Lymphovascular space involvement (LVSI) is a major prognostic factor in type 1 endometrial cancer (EC). However, its use has been criticized because of poor subjectivity. MicroRNA signatures have recently been linked to EC pathologic characteristics. The aim of this study was to evaluate whether microRNA profiles of type 1 EC can be related to LVSI status and used as a tool to adapt therapy. Study Design. MicroRNA expression was assessed by chip analysis and qRT-PCR in 12 formalin-fixed paraffin-embedded grade 2 EC specimens with positive LVSI and in 12 specimens with negative LVSI. Various statistical analyses, including enrichment analysis and a minimum p-value approach, were performed. Results. The expression levels of microRNAs 34c5p, -23b-5p, and 23c were significantly lower in the EC with positive LVSI compared to those with negative LVSI. Women with a microRNA-34c-5p fold change <0.15 were more likely to have positive LVSI status (92.3%) compared with those with a microRNA-34c-5p fold change >0.15 (0.0%), p<0.001. Furthermore, women with a microRNA-23b-5p fold change <0.51 were more likely to have positive LVSI status (90.0%) compared with those with a microRNA-23b-5p fold change >0.51 (21.4%), p=0.003. Conclusion. This was the first study to investigate the relative expression of microRNA in type 1 EC according to LVSI status. This microRNA expression profile may provide a basis for further study of the microRNA function in EC, and be used as a diagnostic tool for LVSI status.
- PublicationOpen AccessDevelopment of biological tools to assess the role of TMPRSS4 and identification of novel tumor types with high expression of this prometastatic protein(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Villalba, Maria; Lopez, Lissett; Redrado, Miriam; Ruiz, Tamara; de Aberasturi, Arrate L.; de la Roja, Nuria; Garcia, David; Exposito, Francisco; de Andrea, Carlos; Álvarez Fernández, Emilio; Montuenga, Luis; Rueda, Paloma; Rodriguez, Maria Jose; Calvo, AlfonsoMetastatic spread is responsible for the majority of cancer deaths and identification of metastasisrelated therapeutic targets is compulsory. TMPRSS4 is a pro-metastatic druggable transmembrane type II serine protease whose expression has been associated with the development of several cancer types and poor prognosis. To study the role and expression of this protease in cancer, we have developed molecular tools (active recombinant proteins and a polyclonal antibody) that can be used for diagnostic purposes and for testing anti-TMPRSS4 drugs. In addition, we have evaluated TMPRSS4 protein expression in several cancer tissue microarrays (TMAs). Full length and truncated TMPRSS4 recombinant proteins maintained the catalytic activity in two different expression systems (baculovirus and E. coli). Sensitivity of the rabbit polyclonal antisera against TMPRSS4 (ING-pAb) outperformed the antibody most commonly used in clinical settings. Analysis by immunohistochemistry in the different TMAs identified a subset of adenocarcinomas, squamous carcinomas, large cell carcinomas and carcinoids of the lung, in which TMPRSS4 expression may define aggressive tumors. In conclusion, our biological tools will help the characterization of TMPRSS4 activity and protein expression, as well as the evaluation of anti-TMPRSS4 drugs. Future studies should determine the clinical value of assessing TMPRSS4 levels in different types of lung cancer.
- PublicationOpen AccessNovel biomarkers in primary breast core biopsies to predict poor response to neoadjuvant chemotherapy and appearance of metastases(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Novell, Anna; Morales, Serafin; Valls, Joan; Panadés, Maria José; Salud, Antonieta; Iglesias, Edelmiro; Vilardell, Felip; Matias Guiu, Xavier; Llombart Cussac, AntonioDrug resistance has been one of the major obstacles limiting the success of cancer chemotherapy. In two thirds of breast cancer patients, large (>1cm) residual tumors are present after neoadjuvant chemotherapy (NCT). The residual tumor and involved nodes have been indicators of relapse and survival very important in breast cancer. The goal of this preliminary study was to assess the predictive significance of a panel of molecular biomarkers, related with the response to treatment or drug resistance to NCT, as determined on the diagnostic tumor. The expression of 22 proteins was examined using immunohistochemistry in tissue microarrays (TMA) from 115 patients of stage II-III breast cancer, treated with NCT. Among studied proteins, there are some that are anti-apoptotic, pro-proliferative, cancer stem cell markers and the Vitamin D Receptor. Other proteins are involved in the identification of molecular subtype, cell cycle regulation or DNA repair. Next, a predictive signature of poor response was generated from independent markers of predictive value. Tumors that expressed four or five conditions (biomarkers of chemoresistance with a determinated cutoff) were associated with a 9-fold increase in the chances of these patients of having a poor response to NCT. Additionally, we also found a worse prognostic signature, generated from independent markers of prognostic value. Tumors which expressed two or three conditions of worst prognostic, were associated with a 6-fold reduction in Distant Disease Free Survival. In conclusion, finding biomarkers of chemoresitance (ypTNM II-III) and metastases can become a stepping stone for future studies that will need to be assessed in a bigger scale.