Histology and histopathology Vol.24, nº2 (2009)
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- PublicationOpen AccessAberrant nuclear beta-catenin expression in the spindle or corded cells in so-called corded and hyalinized endometrioid carcinomas. Another critical role of the unique morphological feature(Murcia : F. Hernández, 2009) Wani, Yoji; Saegusa, Makoto; Notohara, KenjiCorded and hyalinized endometrioid carcinoma (CHEC), showing spindle and/or corded (SPICO) cells often in the background of hyalinized stroma, is a rare variant of uterine endometrioid carcinomas. The aim of our study was to explore the status of cell-adhesion molecules (beta-catenin, Ecadherin) in CHECs and to survey whether immunostains for beta-catenin and p53 can help to distinguish CHECs from their morphological mimics: malignant mixed mullerian tumors (MMMTs) and uterine tumors resembling ovarian sex-cord tumors (UTROSCTs). Immunohistochemistry was performed and scored for each element as follows: 0: negative, 1+: <10% positive cells, 2+: 10-30%, 3+: >30%. The SPICO patterns were classified as spindle/fusiform; 3, corded; 1, and both; 2. SPICO components consisted of <10%: 4, 10-30%: 1, >30%: 1. Five contained squamous components. In SPICO elements of all CHECs, nuclear beta-catenin expression (score: 1+; 1, 2+; 2, 3+; 3) and complete loss of membranous expression of E-cadherin was observed. In contrast, comparable components (sarcomatous ones for eight MMMTs or sex-cord-like ones for six UTROSCTs) showed no nuclear positivity for beta-catenin. p53 expression was observed in SPICO (64.7%), sarcomatous (87.5%), and sex-cord-like (50%) components, and sarcomatous areas of most MMMTs notably showed diffuse and intense staining. Sequence analysis of PCR amplification products of exon 3 of the beta-catenin gene revealed mutation in all cases, except two lacking SPICO components represented on microdissected areas. Our results suggest that alterations in beta-catenin/E-cadherin complex play a critical role in SPICO features. Immunostain for beta-catenin and p53 is a promising approach for distinguishing CHECs from MMMTs and UTROSCTs
- PublicationOpen AccessReceptor activator of nuclear factor-kappa B ligand (RANKL) stimulates bone-associated tumors through functional RANK expressed on bone-associated cancer cells?(Murcia : F. Hernández, 2009) Mori, K.; Ando, K.; Heymann, D.; Rédini, F.Primary and secondary bone tumors clearly deteriorate quality of life and the activity of daily living of patients. These undesirable diseases become a major social and economic burden. As both primary and secondary bone tumors develop in the unique bone tissue, it is therefore necessary to understand bone cell biology in tumor bone environment. Recent findings of the Receptor Activator of Nuclear Factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) molecular triad, the key regulators of bone remodeling, opened new era of bone research. Although RANK is an essential receptor for osteoclast formation, activation and survival, functional RANK expression has been recently identified on several bone-associated tumor cells. When RANK is expressed on secondary bone tumor cells, it is implicated in tumor cell migration, whereas this is not the case for primary bone tumors. In any case, RANK is not involved in RANK-positive cell proliferation or death. In two models of bone metastases secondary to melanoma or prostate carcinoma, in vivo neutralization of RANKL by OPG resulted in complete protection from paralysis, due to metastases of vertebral body, and a marked reduction in tumor burden in bones, but not in other organs. OPG also decreased tumor formation and tumor burden in a mouse model of primary bone tumor, osteosarcoma. In all these models, tumor cells express RANK. These data revealed that local differentiation factors, such as RANKL, play an important role in cell migration in a metastatic tissue-specific manner. These findings substantiate the novel direct role of RANKL/RANK in bone-associated tumors, and its capability of representing new therapeutic targets.
- PublicationOpen AccessRole of fatty acids in malignancy and visual impairment, Epidemiological evidence and experimental studies(Murcia : F. Hernández, 2009) Tsubura, A.; Yuri, T.; Yoshizawa, K.; Uehara, N.; Takada, H.International variation in breast and colon cancer incidence is positively related to total fat intake. However, total fat consists of different fatty acid families, e.g., saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and n-3 and n-6 polyunsaturated fatty acids (PUFAs). Epidemiological evidence and experimental studies suggest that these fatty acid families have different effects on breast and colon carcinogenesis. Therefore the action of each fatty acid on carcinogenesis should be evaluated separately. Although it is difficult to establish firm conclusions on the effect of each fatty acid in human epidemiological studies, experimental studies on animals and cultured cells suggest that n-6 PUFAs (linoleic acid and arachidonic acid) may have a tumor promoting effect, while n-3 PUFAs (eicosapentaenoic acid, docosahexaenoic acid and a-linolenic acid) and conjugated fatty acids (CFAs; a mixture of positional and geometric isomers of PUFAs with conjugated double bonds) exert an inhibitory effect on tumor growth. SFAs such as palmitic acid and stearic acid show little or no tumor promoting effect, and the action of oleic acid, a MUFA, is inconclusive. In addition to regulation of abnormal cell growth seen in cancers, fatty acids also control cell loss seen in degenerative eye diseases, such as degeneration of lens material in cataract and degeneration of photoreceptor cells in retinitis pigmentosa. Experiments suggest that n-6 PUFAs cause deleterious effects, while n-3 PUFAs result in beneficial effects on the lens and retina. In particular, docosahexaenoic acid is known to be effective in rescuing photoreceptor cells from damage. Thus, understanding the function of each fatty acid is likely to be important for making progress in treating these and other diseases.
- PublicationOpen AccessTracing the accumulation and effects of mercury uptake in the previtellogenic ovary of crucian carp Carassius auratus gibelio by autometallography and caspase-3 immunohistochemistry(Murcia : F. Hernández, 2009) Zarnescu, OtiliaThe aims of the present study were to apply the AMG technique for localization of mercury at the light and electron microscopic level in the ovary of crucian carp after exposure to mercuric chloride and to find out if this heavy metal induces expression of caspase-3. Depending on the stage of ovarian follicle development, two patterns of mercury accumulation have been found in previtellogenic ovary of crucian carp. The first mercury accumulation pattern has been found in the early previtellogenic oocyte without zona radiata. In these oocytes, mercury accumulates into an ooplasmic region that seems to correspond to the Balbiani body (32-65 μm oocyte diameter), throughout the cytoplasm (84-116 μm oocyte diameter) and in the cortical cytoplasm (~180 μm oocyte diameter). The second mercury accumulation pattern has been found in the late previtellogenic oocyte with cortical alveoli (229- 330 μm oocyte diameter). Ultrastructural observations have shown grains of silver-enhanced mercury inside coated vesicles, the cortical lysosome-like bodies or multivesicular bodies and cortical alveoli. Immunohistochemistry reaction for caspase-3 was positive in nuclei of the early previtellogenic oocyte and Balbiani body.
- PublicationOpen AccessGlucose transporter-1 expression and prognostic significance in pancreatic carcinogenesis(Murcia : F. Hernández, 2009) Pizzi, Sara; Porzionato, Andrea; Pasquali, Claudio; Guidolin, Diego; Sperti, Cosino; Fogar, Paola; Macchi, Verónica; De Caro, Raffaelle; Pedrazzoli, Sergio; Parenti, AnnaThe purposes of this study were to evaluate the prognostic significance of Glut-1 expression in patients with pancreatic ductal adenocarcinoma, and to analyse its expression in pancreatic intraepithelial neoplasias (PanIN) and non invasive intraductal papillary mucinous neoplasms (IPMN). Glut-1 expression was studied by immunohistochemistry in 60 pancreatic ductal adenocarcinomas and scored on a 4- point scale (1: <25%; 2: 25-50%; 3: 50-75%; 4: >75%). Relationships between Glut-1 score, histological grade and MIB-1 score were evaluated by the Spearman rank correlation test. Significant correlations were found between Glut-1 expression and histological grade (P<0.001) and MIB-1 score (P<0.01). Significant prognostic factors by univariate analysis were stage (P<0.0001), histological grade (P<0.001) and Glut-1 expression (P<0.005). Independent prognostic factors after multivariate analysis were stage (P<0.001) and Glut-1 expression (P<0.05), stratified as <50% and >50%. The correlation of Glut-1 score with histological grade and MIB-1 score indicated a higher glucose uptake in poorly differentiated and highly proliferative pancreatic cancer cells. Glut-1 immunohistochemical expression provides a useful prognostic factor in pancreatic ductal adenocarcinoma. Glut-1 expression was not found in PanINs 1 but in 27.8% and 43.8% of PanINs 2 and 3, and was not found in IPMNs with lowand moderate-grade dysplasia but in 60% of IPMNs with high-grade dysplasia, indicating Glut-1 involvement in a relatively early phase of pancreatic carcinogenesis.
- PublicationOpen AccessIntracellular signalling pathways regulating the adaptation of skeletal muscle to exercise and nutritional changes(Murcia : F. Hernández, 2009) Matsakas, Antonios; Patel, KetanThe focus of the present review is to assimilate current knowledge concerning the differing signalling transduction cascades that control muscle mass development and affect skeletal muscle phenotype following exercise or nutritional uptake. Effects of mechanical loading on protein synthesis are discussed. Muscle growth control is regulated by the interplay of growth promoting and growth suppressing factors, which act in concert. Much emphasis has been placed on understanding how increases in the rate of protein synthesis are induced in skeletal muscle during the adaptive process. One key point to emerge is that protein synthesis following resistance exercise or increased nutrient availability is mediated through changes in signal transduction involving the phosphorylation of mTOR and sequential activation of downstream targets. On the other hand, AMPK activation plays an important role in the inhibition of protein synthesis by suppressing the function of multiple translation regulators of the mTOR signalling pathway in response to cellular energy depletion and low metabolic conditions. The effects of exercise and/or nutritional uptake on the activation of signalling molecules that regulate protein synthesis are highlighted, providing a better understanding of the molecular changes in the cell.
- PublicationOpen AccessCritical role of IkB kinase alpha in embryonic skin development and skin carcinogenesis(Murcia : F. Hernández, 2009) Zhu, Feng; Park, Eunmi; Liu, Bigang; Xia, Xiaojun; Fischer, Susan M.; Hu, YinlingIκB kinase alpha (IKKα), IKKß, and IKKγ/NEMO form the IKK complex, which is essential for NF-κB activation. However, genetic studies have shown that the role of IKKα is distinct from that of IKKß or IKKγ in the development of the mouse embryonic skin. Loss of IKKα has been shown to cause epidermal hyperplasia, prevent keratinocyte terminal differentiation, and impair the formation of the skin, resulting in the deaths of IKKα-deficient (Ikkα -/-) mice soon after birth. Recent experimental data from several laboratories have revealed that IKKα functions as a tumor suppressor in human squamous cell carcinomas (SCCs) of skin, lungs, and head and neck. Chemical carcinogenesis studies using mice have shown that reduction in IKKα expression increases the number and size of Ras-initiated skin tumors and promotes their progression, indicating that reduced IKKα expression provides a selective growth advantage that cooperates with Ras activity to promote skin carcinogenesis. In this review, we will summarize these findings from our and other studies on the role that IKKα plays in development of the mouse embryonic skin and skin carcinogenesis
- PublicationOpen AccessMultiple kallikrein (KLK 5, 7, 8, and 10) expression in squamous cell carcinoma of the oral cavity(Murcia : F. Hernández, 2009) Pettus, Jason R.; Johnson, Jeffrey J.; Shi, Zonggao; Davis, J.Wade; Koblinski, Jennifer; Ghosh, Supurna; Liu, Yueying; Ravosa, Matthew J.; Frazier, Shellaine; Stack, M. SharonOral squamous cell carcinoma (OSCC) represents 3% of all cancer deaths in the U.S. and is ranked one of the top 10 cancers worldwide. The 5-year survival rate has remained at a low 50% for the past several decades, necessitating discovery of novel biomarkers of aggressive disease and therapeutic targets. As overexpression of urinary type plasminogen activator and receptor (uPA/R) in OSCC is associated with malignant progression and poor outcome, cell lines were generated with either overexpression (SCC25-uPAR+) or silencing (SCC25-uPAR-KD) of uPAR. As SCC25- uPAR+ tumors behaved more aggressively both in vitro and in vivo, comparative cDNA microarray analysis was used to identify additional genes that may be associated with aggressive tumors. Four members of the human tissue kallikrein family (KLK 5, 7, 8, and 10) were identified and real-time RT-PCR (qPCR) was used to verify and quantify gene expression. qPCR analysis revealed 2.8-, 5.3-, 4.0-, and 3.5-fold increases in gene expression for KLK5, 7, 8, and 10, respectively, in SCC25-uPAR+ versus SCC25-uPAR-KD. Immunohistochemical analysis demonstrated strong reactivity for KLKs 5, 7, 8 and 10 in both orthotopic murine tumors and human OSCC tissues. Control experiments show lack of reactivity against KLK3 (prostate specific antigen). These results demonstrate that kallikreins 5, 7, 8, and 10 are abundantly expressed in human OSCC and may be implicated in malignant progression.
- PublicationOpen AccessDistribution of cytoskeletal and adhesion proteins in adult zebrafish skeletal muscle(Murcia : F. Hernández, 2009) Câmara-Pereira, E.S.; Campos, L.M.; Vannier-Santos, M.A.; Mermelstein, C.S.; Costa, M.L.The organization of cytoskeletal and adhesion proteins in skeletal muscle is critical for its contractile function. Zebrafish has become a paramount model for studies of vertebrate biology, including muscle. However, only a few studies have been published using immunolabeling to specifically localize proteins in adult zebrafish muscle. To fully appreciate the distribution of cytoskeletal and adhesion proteins, and therefore to better correlate the adult muscle with its myogenesis, we used indirect immunofluorescence microscopy of frozen adult zebrafish skeletal muscle sections. Here we describe the fish muscle cytoskeletal architecture and location of the major myofibrillar proteins desmin, alpha-actinin, myosin, titin, troponin, tropomyosin and nebulin, the adhesion proteins vinculin and paxillin, and the extracellular matrix proteins laminin and fibronectin. Electron microscopical analysis in ultra-thin sections of adult zebrafish skeletal muscle showed bundles of collagen fibers and fibroblastic cells in the extracellular space of the myosepta.
- PublicationOpen Access5-Fluorouracil-induced histopathological changes in the central nervous system of rat fetuses(Murcia : F. Hernández, 2009) Yamaguchi, Y.; Aoki, A.; Fukunaga, Y.; Matsushima, K.; Ebata, T.; Ikeya, M.; Tamura, K.5-Fluorouracil (5-FU), a thymidylate synthesis inhibitor, has been well known to induce developmental anomalies in the craniofacial tissues and limb buds. Recently it was reported that microencephaly was also induced in rat neonates after 5-Fu-treatement in late phase of pregnancy (Kumar et al., 2006). In this study, pregnant rats were treated with 5-Fu (15, 30 or 50 mg/kg) on day 13 of gestation, and their fetuses were examined for histopathological changes, especially in the fetal central nervous system (CNS) at 12, 24 and 48 hours after treatment (HAT). At 12 HAT, an enhancement of pyknosis of neuronal progenitor cells and subsequent loss of dead cells were detected in the CNS in a dose-dependent manner. The severity of such histopathological changes in the CNS was most prominent in the telencephalon (middle and dorsal layers of the ventricular zone) and spinal cord (dorsal area). Pyknotic cells decreased towards 48 HAT in the brain while they increased towards 48 HAT in the spinal cord. Almost all of the nuclei of pyknotic cells were positively stained by TUNEL method and showed characteristics of apoptotic cells under electron microscopy. Therefore, these pyknotic cells were considered to be apoptotic ones. Enhanced apoptosis and reduced mitosis in neuronal progenitor cells in the telencephalon seem to be responsible for the later induction of microencephaly reported by Kumar et al. (2006).