Histology and histopathology Vol.25, nº8 (2010)
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- PublicationOpen AccessInvolvement of endogenous prostaglandin E2 in tubular epithelial regeneration through inhibition of apoptosis and epithelial-mesenchymal transition in cisplatin-induced rat renal lesions(Murcia : F. Hernández, 2010) Yamamoto Emi; Izawa, Takeshi; Juniantito, Vetnizah; Kuwamura, Mitsuru; Sugiura, Kikuya; Takeuchi, TadayoshiIn the kidney, prostaglandin (PG) E2 is the main PG, playing important roles in maintaining homeostasis or development of pathological settings. Roles of PGE2 in renal lesions remain to be clarified. The expression patterns of PGE2 synthesis enzymes such as cyclooxygenase (COX)-1, COX-2 and microsomal PGE synthase (mPGES)-1, and PGE2 receptors (EP2 and EP4) were examined in cisplatin-induced rat renal failure. The immunoexpressions for COX-1, mPGES-1 and EP4 receptor were increased exclusively in the affected renal tubules, but those of COX-2 and EP2 receptor were not detected; increased expression of COX-1 was confirmed at mRNA level. Using rat renal epithelial cell line (NRK-52E), the effects of PGE2 on cell proliferation were investigated. The addition of PGE2 or 11-deoxy-PGE1 (EP4 receptor agonist) to NRK-52E increased the cell number, indicating the effects of PGE2 via EP4 receptor. Furthermore, 11- deoxy-PGE1-treated NRK-52E cells underwent the G0/G1 arrest and decreased apoptosis. NRK-52E treated with transforming growth factor (TGF)-ß1, an inducer of epithelial-mesenchymal transition (EMT), in the presence of 11-deoxy-PGE1 decreased the mRNA expression of α-smooth muscle actin (a marker of myofibroblasts). Collectively, the present study shows that COX-1 plays more important roles than dose COX- 2 in cisplatin-induced rat renal failure; the product, PGE2, may regulate renal epithelial regeneration via EP4 receptor through inhibition of apoptosis and EMT.
- PublicationOpen AccessImmunohistochemical analysis of steroid receptors in ovaries of postmenopausal women - effects of aging and hormone status(Murcia : F. Hernández, 2010) Brodowska, A.; Laszczynska, M.; Starczewski, A.; Brodowski, J.; Masiuk, M.; Domagała, W.Current knowledge on immunolocalization and immunoexpression of steroid hormone receptors, especially estrogen receptor alpha (ER-α), progesterone receptor (PR) and androgen receptor (AR) in normal ovaries in postmenopausal women is not complete. The recognition of localization of these receptors in postmenopausal women is crucial, as many of these women receive estro-progestagene therapy, and its participation in the pathogenesis of ovarian cancer should be carefully studied. In our paper we present the results of immunohistochemical studies performed on samples from 100 post-menopausal women (aged: 48 to 60 years) who did not use hormonal therapy. The ovaries were removed during elective operation due to uterine leiomyoma, endometriosis and/or prolapsed uterine. PR, ER-α and AR were detected in the normal ovaries of postmenopausal women in stroma and in ovarian surface epithelium, as well as in its invagination and in epithelial inclusion cysts. The expression of PR and AR did not change, while the expression of ER-α decreased in time from menopause, and it was also detected in patients more than 10 years after menopause. Women older than 60 were not included in the study. The concentration of selected hormones was measured in the serum. The immunohistochemical expression of PR and AR were similar in all examined patients and did not correlate with FSH, LH, T, A, DHEAS concentrations in serum, while immunohistochemical expression of ER-α correlated with FSH, LH, T, A, DHEAS concentrations in serum. The significant correlation of decreasing expression of ER-α in normal ovarian tissue and decreasing concentrations of T, A and DHEAS in serum were found, as well as increasing serum concentrations of FSH and LH.
- PublicationOpen AccessP-cadherin, Vimentin and CK14 for identification of basal-like phenotype in breast carcinomas: an immunohistochemical study(Murcia : F. Hernández, 2010) Sousa, Bárbara; Paredes, Joana; Milanezi, Fernanda; Lopes, Nair; Martins, Diana; Dufloth, Rozany; Vieira, Daniella; Albergaria, André; Veronese, Luiz; Carneiro, Vitor; Carvalho, Silvia; Costa, José Luis; Zeferino, Luiz; Schmitt, FernandoIntroduction: The most suitable immunohistochemical criterion to identify basal-like breast carcinomas (BLBC), a molecular subgroup of breast cancer associated with poor prognosis, is the triple negative phenotype along with CK5 and/or EGFR immunoreactivity. However, several putative basal markers have been suggested as alternatives to identify BLBC with more accuracy. Experimental Design: The expression of CK5, EGFR, P-cadherin, CK14, Vimentin and p63 were evaluated in 462 invasive breast carcinomas to determine their sensitivity and specificity for BLBC identification. Results: P-cadherin and CK5 showed higher sensitivity values, while EGFR, Vimentin and CK14 were the most specific markers. The combination of CK5 with P-cadherin, Vimentin or CK14 proved to be a reliable option for distinguishing the basal phenotype, compared to the “gold standard” pair CK5/EGFR. Furthermore, P-cadherin was still able to recognize a large number of putative BLBC among the “unclassified” group (ER-/PR-/HER2-/CK5-/EGFR-). Conclusions: P-cadherin, Vimentin and CK14 can recognize BLBC already identified in triple negative/ CK5 and/or EGFR+ tumors, and due to P-cadherin sensitivity for BLBC identification this marker can reliably recruit a large number of breast carcinomas with basal phenotype among immunohistochemistry triple negative/ CK5 and/or EGFR - pool of tumors. Although they need GEP validation, our results can introduce the idea of these markers as additional options in the daily workup of breast pathology laboratories to identify BLBC.
- PublicationOpen AccessSudan Black B treatment reduces autofluorescence and improves resolution of in situ hybridization specific fluorescent signals of brain sections(Murcia: F. Hernández, 2010) Oliveira, V.C.; Carrara, R.C.V.; Simoes, D.L.C.; Saggioro, F.P.; Carlotti, C.G.; Covas, D.T., Jr.; Neder, L.Interference by autofluorescence is one of the major concerns of immunofluorescence analysis of in situ hybridization-based diagnostic assays. We present a useful technique that reduces autofluorescent background without affecting the tissue integrity or direct immunofluorescence signals in brain sections. Using six different protocols, such as ammonia/ethanol, Sudan Black B (SBB) in 70% ethanol, photobleaching with UV light and different combinations of them in both formalin-fixed paraffin-embedded and frozen human brain tissue sections, we have found that tissue treatment of SBB in a concentration of 0.1% in 70% ethanol is the best approach to reduce/eliminate tissue autofluorescence and background, while preserving the specific fluorescence hybridization signals. This strategy is a feasible, non-time consuming method that provides a reasonable compromise between total reduction of the tissue autofluorescence and maintenance of specific fluorescent labels.
- PublicationOpen AccessNew advances on critical implications of tumorand metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence(Murcia: F. Hernández, 2010) Mimeault, M.; Batra, Surinder K.Accumulating lines of experimental evidence have revealed that the malignant transformation of multipotent tissue-resident adult stem/progenitor cells into cancer stem/progenitor cells endowed with a high self-renewal capacity and aberrant multilineage differentiation potential may be at origin of the most types of human aggressive and recurrent cancers. Based on new cancer stem/progenitor cell concepts of carcinogenesis, it is suggested that a small subpopulation of highly tumorigenic and migrating cancer stem/progenitor cells, also designated as cancer- and metastasis-initiating cells, can provide critical roles for primary tumor growth, metastases at distant tissues and organs, treatment resistance and disease relapse. Particularly, cancer initiation and progression to locally invasive and metastatic stages is often associated with a persistent activation of distinct developmental signaling pathways in these immature cells during epithelialmesenchymal transition program. The signaling cascades that are often deregulated in cancer stem/progenitor cells include hedgehog, epidermal growth factor receptor (EGFR), Wnt/ß-catenin, NOTCH, polycomb gene product BMI-1 and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). Importantly, the results from recent investigations have also indicated that different cancer subtypes may harbor distinct subsets and/or number of cancer-initiating cells during cancer progression as well as before or after therapy initiation and disease recurrence. Therefore, the identification of the molecular transforming events that frequently occur in cancer- and metastasis-initiating cells versus their differentiated progenies is of immense interest to develop new targeting approach for improving current therapies against aggressive, metastatic, recurrent and lethal cancers.
- PublicationOpen AccessThe kinetics and distribution of different macrophage populations in the developing rat skin(Murcia : F. Hernández, 2010) Juniantito, Vetnizah; Izawa, Takeshi; Yamamoto Emi; Kuwamura, Mitsuru; Yamate, JyojiMacrophages play important roles in host defense and homeostasis. In contrast to adulthood, far less is known about macrophage populations in fetuses and neonates. Macrophages were evaluated in the developing rat skin at different anatomical sites (head, anterior dorsal, posterior dorsal, and abdomen) of F344 rats obtained on gestational days 18 and 20, on neonatal days 1-21, and at adult weeks 5-15. The numbers of macrophages in the epidermis, dermis or perifollicular areas that were positive for ED1 (exudative macrophages with activated phagocytosis), ED2 (resident macrophages), and OX6 (antigen-presenting cells) were evaluated. There were no differences in macrophage numbers among the anatomical sites. In the epidermis, only OX6 cells were seen, with gradually increased numbers in neonates and adults. In the dermis, many ED1 cells were already seen in fetuses, and the number peaked on neonatal day 4, and remained at that level until adulthood. By contrast, ED2 and OX6 cells began to be seen after birth and their numbers continued to increase until adulthood; ED2 cells were distributed diffusely in the dermis, whereas ED1 and OX6 cells were present exclusively in the upper dermis. In perifollicular areas, ED1, ED2 and OX6 cells began to be seen after birth, and their numbers gradually increased until adulthood. Some macrophages in dermal and perifollicular areas gave double-positive reactions to ED1+ED2+, ED1+OX6+ or OX6+ED2+. Increased mRNA levels of colony stimulating factor-1 and monocyte chemoattractant protein-1 appeared to correspond to the emergence of rat macrophages. Skin macrophages were shown to be heterogeneous in distribution and function; the information from this study should be very useful for future investigations of experimentally induced rat skin lesions.
- PublicationOpen AccessLiver fibrosis: a dynamic and potentially reversible process(Murcia : F. Hernández, 2010) Povero, Davide; Busletta, Chiara; Novo, Erica; Valfrè di Bonzo, Lorenzo; Cannito, Stefania; Paternostro, Claudia; Parola, MaurizioIn any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.e., the dynamic process leading to increased deposition of ECM and much more) can lead to different patterns of fibrosis and is sustained by myofibroblast-like cells (MFs) of different origin, with activated hepatic stellate cells (HSC/MFs) being the major cell type involved. Major pro-fibrogenic mechanisms also include oxidative stress, as well as derangement of epithelial-mesenchymal interactions and, as recently suggested, the process of epithelial to mesenchymal transition (EMT). Liver fibrosis has been considered traditionally as an irreversible process but experimental and clinical literature data published in the last decade have suggested that both the removal of the aetiological agent or condition, as well as an effective therapy, can result in significant regression of liver fibrosis. This is usually associated, particularly in animal models, with induction of apoptosis in MFs but, unfortunately, human HSC/MFs are much more resistant to apoptosis than murine MFs. However, clinical studies provided no unequivocal evidence for a complete reversal of cirrhosis or a significant reversal of vascular changes in conditions of established cirrhosis.
- PublicationOpen AccessAn update on the pathobiological relevance of nuclear receptors for cancers of the head and neck(Murcia : F. Hernández, 2010) Stauber, Roland H.; Wünsch, Desiree; Knauer, Shirley K.; Fetz, VerenaCancers of the head and neck are among the most common neoplasms worldwide, characterized by local tumor aggressiveness, high rate of early recurrence, development of metastasis and second primary tumors. Although disease management of head and neck cancer has improved significantly, overall survival-rates remained largely unchanged over the last decades. Thus, in addition to modern chemo-radiation treatment strategies combined with sophisticated surgery, there is still a need for molecular markers and key regulatory factors exploitable for chemoprevention and targeted therapies. A critical event in carcinogenesis is the uncontrolled modulation of genetic programs, mediated by deregulated signaling cascades, together with downstream transcriptional modulators. Hence, nuclear receptors, belonging to a superfamily of transcription factors implicated in a broad spectrum of physiological and pathophysiological processes, have also been associated with HNC. Enhanced expression of several nuclear receptors has been shown in head and neck cancer cells, and strategies targeting these molecules have been developed and tested in the clinics. In particular, the effects of retinoids targeting nuclear receptors of the thyroid hormone receptor-like receptor subfamily have been vigorously examined in large clinical chemoprevention trials. This review seeks to provide a general overview of nuclear receptors’ molecular functions and summarizes their prognostic/therapeutic relevance, as well as the (pre)clinical studies targeting nuclear receptors in HNC.
- PublicationOpen AccessThe role of focal adhesion Kinase in early development(Murcia : F. Hernández, 2010) Chatzizacharias, Nikolaos A.; Kouraklis, Gregory P.; Theocharis, Stamatios E.FAK is a tyrosine kinase enzyme demonstrated to play an important regulatory role in several basic cellular activities. Scientific evidence have suggested that FAK possessing a central position in the integrin signaling cascade, is responsible, at least in part, for the modulation of cellular proliferation, protection from apoptosis, adhesion, spreading and migration. The role of FAK in the development of different species, including human, is under study. Various published data supported the role of the molecule in the development of the placenta, as well as of several organ systems, like the musculoskeletal, nervous, cardiovascular, genitourinary and respiratory organ systems. Additionally, FAK has been shown to be implicated in the pathophysiology of pregnancy related disorders and congenital neonatal diseases and defects. The purpose of this article is a comprehensive review of the existing literature with a view to the future and the potential conclusions that can be drawn by the study of FAK signaling on the events of early life and species development.
- PublicationOpen AccessImmunohistochemical study of macrophage and cytokine dynamics in the gut of scrapie-infected mice(Murcia : F. Hernández, 2010) Romero-Trevejo, José Lorenzo; Gómez-Villamandos, J. C.; Pedrera, Mirian; Blanco, Alfonso; Bautista, María José; Sánchez-Cordón, Pedro JoséTo study numerical changes in intestinal macrophages and variations in cytokine production by immune cells in the intestine, conventional C57BL/6J mice were orally infected with the Rocky Mountain Laboratory strain of scrapie. Animals were sacrificed at different timepoints, and samples were taken and processed by routine methods for morphological and immunohistochemical analysis. The results point to a possible role for macrophages in the uptake and transport of the infective agent to Peyer’s patches. The observed increase in macrophage numbers in subepithelial sites, taken in conjunction with a drop in tumour necrosis factor-α production at these sites, suggests a possible secretory inhibition that could be induced by the disease-associated prion protein (PrPd). On the other hand, cytokine dynamics indicated the presence of an impaired Th1-Th2 cell mediated response, which could facilitate the spread of PrPd to the central nervous system. Further research is required to confirm these hypotheses.
- PublicationOpen AccessCD34-positive myxoid sarcoma of the retroperitoneum; a dilemma in differential diagnosis of multiple biopsy specimens(Murcia : F. Hernández, 2010) Terada, TadashiThe author reports a case of CD34-positive malignant myxoid sarcoma in the retroperitoneum with a dilemma of differential diagnosis in multiple biopsy specimens of different locations. A 79-year-old man was diagnosed with right renal pelvic carcinoma and nephrectomy was performed. The carcinoma was urothelial carcinoma (2cm in diameter) without invasion. The patient was followed up, and a large retroperitoneal tumor was found two years after the operation. Multiple needle biopsies were performed. The patient then showed a hepatic metastasis, and died of cachexia one year after the detection of the retroperitoneal tumor. The needle biopsy specimens showed spindle cell sarcoma in the myxomatous stroma (80%) and in the nonmyxomatous stroma (20%). Immunohistochemically, the tumor cells were positive for vimentin, CD34, CD99, bcl-2 and p53 protein. They were negative for cytokeratins, desmin, α-smooth muscle actin, S100 protein, melanosome, CEA, neuron specific enolase, CD68, factor VIII-related antigen, CD31, KIT, and PDGFRA. Ki67 labeling was 30%. A genetic analysis for KIT gene (exons 9, 11, 13 and 17) and PDGFRA gene (exons 12 and 18) showed no mutations. Although the differential diagnosis is problematic and difficult, the present case is probably dedifferentiated liposarcoma. The needle biopsy diagnosis of sarcomas is difficult and limited because sarcomas show heterogenous histologies with regard to locations in the same tumor.
- PublicationOpen AccessNeurotrophin-4 dependency of intraepithelial vagal sensory nerve terminals that selectively contact pulmonary NEBs in mice(Murcia : F. Hernández, 2010) Oztay, Fusun; Brouns, Inge; Pintelon, Isabel; Raab, Marion; Neuhuber, Winfried; Timmermans, Jean Pierre; Adriaensen, DirkImportant physiological functions of neurotrophins (NTs) in airways and lungs are the early development, differentiation and maintenance of peripheral sensory neurons. The main pulmonary sensory innervation is of vagal origin, with several nerve fibre populations that selectively contact complex morphologically well-characterized receptor end-organs, called neuroepithelial bodies (NEBs). NEBs in mouse lungs are innervated by at least two separate myelinated vagal sensory nerve fibre populations, of which the neurochemical coding is suggestive of a mechanosensory function. Since neurotrophin-4 (NT-4) has been especially described to be important for the maintenance of mechanosensory nerve terminals, the present study aimed at investigating the NT-4 dependency of the two myelinated vagal sensory nerve fibre populations innervating mouse pulmonary NEBs. Multiple immunostaining in 21-day-old and adult mouse lungs revealed the expression of the NT-4 receptor TrkB on the two different myelinated vagal sensory nerve fibre populations, i.e., the vesicular glutamate transporter/calbindin-positive and the P2X2/3- positive fibres, which selectively contact pulmonary NEBs. Examination of the effect of the lack of NT-4 on these NEB-related nerve fibre populations, by comparing adult NT-4-/- and wild-type mice, revealed that in NT-4-/- mice the percentage of NEBs contacted by P2X2/3+ is reduced by 75%, while the VGLUT+/CB+ population seemed to be unaffected. This study demonstrated that although mouse pulmonary NEBs are contacted by two distinct TrkB expressing populations of vagal myelinated afferents, only one is distinctly reduced in NT-4 deficient mice, suggesting the involvement of NTs. In view of the growing evidence for the involvement of NTs in neuronal plasticity associated with airway diseases, pulmonary NEBs innervated by NT-sensitive vagal afferents may play a significant role.