Histology and histopathology Vol.22, nº 3 (2007)
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- PublicationOpen AccessExpression of TGF-ß signaling proteins in normal placenta and gestational trophoblastic disease(Murcia : F. Hernández, 2007) Xuan, Y.H.; Choi, Y.L.; Shin, Y.K.; Ahn, G.H.; Kim, Kyung Hee; Kim, W.J.; Lee, H.C.; Kim, S.H.The transforming growth factor ß (TGF-ß) is a vital regulator of placental development and functions. TGF-ß exerts several modulatory effects on trophoblast cells, such as inhibition of proliferation and invasiveness, and stimulation of differentiation by inducing multinucleated cell formation. In this study, we determine the expression patterns of TGF-ß signaling molecules in normal trophoblast, various hydatidiform mole types and choriocarcinoma. A total of 132 cases, including 51 normal placenta (20 first trimester, 11 second trimester, and 20 third trimester) and 81 gestational trophoblastic diseases (17 choriocarcinoma, and 64 hydatidiform moles: 39 complete, 6 partial, and 19 invasive) were immunohistochemically analyzed with anti-TGF ß1/2, TGF-ß receptor type I (TßRI), TßRII, Smad 2/3, and Smad 4 antibodies on paraffin blocks. In the case of normal placenta, maximal levels of all TGF-ß signaling molecules were observed in villous trophoblast in the first trimester, which decreased with gestational age. Expression of all the TGF-ß signaling proteins except Smad2/3, was significantly enhanced in various moles, relative to normal trophoblast. Moreover, TGF-ß signaling molecules were significantly downregulated in choriocarcinoma, compared to moles. In particular, TßRI and Smad2/3 levels were lower in choriocarcinoma than normal villous trophoblast (TßRI: p<0.025, Smad2/3: p<0.001). In conclusion, the TGF-ß signaling pathway plays an important role in the pathogenesis and progression of gestational trophoblastic disease, and may thus be employed as a potential therapeutic target and a diagnostic biomarker
- PublicationOpen AccessIn vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin(Murcia : F. Hernández, 2007) Ribatti, Doménico; Nico, Beatrice; Mangieri, Doménica; Longo, V.; Sansonno, D.; Vacca, A.; Dammacco, F.This paper illustrates the use of the chick embryo chorioallantoic membrane (CAM) assay to determine the single and combined antiangiogenic effects of very low doses of vinblastine (VBL) and rapamycin (RAP) in human hepatocellular carcinoma (HCC). The angiogenic response induced by human HCC biopsy specimens was inhibited by each drug and sinergistically by their combination. Morever, immunohistochemical detection of microvessels with anti-CD31 mAB showed that their area was significantly lower in specimens treated with VBL and RAP in combination. Sinergy on the part of these well-known drugs when used in combination as antiangiogenics at very low doses may be of significance in the designing of new ways of treating HCC.
- PublicationOpen AccessExpression of the serine protease, matriptase, in breast ductal carcinoma of Chinese women: Correlation with clinicopathological parameters(Murcia : F. Hernández, 2007) Jin, J.S.; Cheng, T.F.; Tsai, W.C.; Sheu, L.F.; Chiang, H.; Yu, C.P.Matriptase is a serine protease expressed by cells of surface epithelial origin, including epithelial breast tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine matriptase expression in breast tumors of Chinese women and to identify its clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 251 breast tumors including 30 fibroadenomas, 59 ductal carcinomas in situ (DCIS), 38 grade I invasive ductal carcinomas (IDC), 79 grade II IDC, and 45 grade III IDC. The matriptase scores were significantly higher in the tumors than their non-tumor counterparts (178±12 for fibroadenoma; 275±11 for DCIS; 299±10 for grade I IDC; 251±10 for grade II IDC; and 314±11 for grade III IDC). In cases of IDC, matriptase scores were significantly correlated with tumor staging and nodal staging. Our findings demonstrate that matriptase is over-expressed in breast ductal carcinoma of Chinese women. It therefore may be a good biomarker for diagnosis and treatment of malignant breast tumors
- PublicationOpen AccessMutation, replicative infidelity of DNA and aneuploidy sequentially in the formation of malignant pleomorphic tumors(Murcia : F. Hernández, 2007) Bignold, L.P.Mutations are thought to be involved in tumor formation because (i) tumor cells transmit their abnormalities to their descendants; and (ii) many carcinogens are mutagens. Aneuploidy is thought to be involved in tumor formation because (i) it is a common phenomenon, especially among malignant neoplasms; (ii) certain particular types of tumors are associated with specific karyotypic changes; and (iii) many immortal tumor cell lines are hyperploid. In recent years, acquired somatic cell replicative infidelity of DNA (“mutator phenotype”) has been suggested as a mechanism of tumor formation, because more somatic genomic events occur in malignant tumor cells than could be caused by repeated exogenous mutagenic insults. Previously, theories of the genomic pathogenesis of tumors have involved these mechanisms individually. Here it is suggested that all three mechanisms may play roles in the formation of certain tumor types. For example, a sequence could occur such that first, a mutation affects genomic elements for control of growth, and for replicative fidelity of DNA, leading to “mutator phenotype”. Second, when replicative infidelity of DNA results in mutation of genomic elements for mitotic-andchromosomal stability, aneuploidy develops. Third, an asymmetric mitosis (in the course of the aneuploid stage) could produce occasional cells in which the “bad copy” is lost (or an extra “good copy” is gained) of the original genomic element which had supported replicative fidelity of DNA. These resulting cells would regain fidelity of replication of DNA, and hence could give rise to populations which are relatively genomically stable, hyperploid and immortal.
- PublicationOpen AccessImmunohistochemical characterization of Fas (CD95) and Fas Ligand (FasL-CD95L) expression in the injured brain: Relationship with neuronal cell death and inflammatory mediators(Murcia : F. Hernández, 2007) Grosjean, M.B.; Lenzlinger, P.M.; Stahel, P.F.; Yatsiv, I.; Shohami, E.; Trentz, O.; Kossmann, T.; Morganti-Kossmann, M.C.Traumatic brain injury causes progressive tissue atrophy and consequent neurological dysfunction, resulting from neuronal cell death in both animal models and patients. Fas (CD95) and Fas ligand (FasL/CD95L) are important mediators of apoptosis. However, little is known about the relationship between Fas and FasL and neuronal cell death in mice lacking the genes for inflammatory cytokines. In the present study, double tumor necrosis factor/lymphotoxin-a knockout (–/–) and interleukin-6–/– mice were subjected to closed head injury (CHI) and sacrificed at 24 hours or 7 days postinjury. Consecutive brain sections were evaluated for Fas and FasL expression, in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick end-labeling; TUNEL), morphologic characteristics of apoptotic cell death and leukocyte infiltration. A peak incidence of TUNEL positive cells was found in the injured cortex at 24 hours which remained slightly elevated at 7 days and coincided with maximum Fas expression. FasL was only moderately increased at 24 hours and showed maximum expression at 7 days. A few TUNEL positive cells were also found in the ipsilateral hippocampus at 24 hours. Apoptotic, TUNEL positive cells mostly co-localized with neurons and Fas and FasL immunoreactivity. The amount of accumulated polymorphonuclear leukocytes and CD11b positive cells was maximal in the injured hemispheres at 24 hours. We show strong evidence that Fas and FasL might be involved in neuronal apoptosis after CHI. Furthermore, Fas and FasL upregulation seems to be independent of neuroinflammation since no differences were found between cytokine–/– and wild-type mice.
- PublicationOpen AccessLoss of MUC2 expression correlates with progression along the adenoma-carcinoma sequence pathway as well as de novo carcinogenesis in the colon(Murcia : F. Hernández, 2007) Mizoshita, T.; Tsukamoto, T.; Inada, K.I.; Hirano, N.; Tajika, M.; Nakamura, T.; Ban, H.; Tatematsu, M.Aims: We have previously demonstrated links between clinicopathological findings and phenotypes using several gastric and intestinal phenotypic markers in stomach and pancreatic cancers. However, the clinicopathological significance of the phenotype and Cdx2 expression has hitherto remained unclear in colorectal carcinogenesis. Methods and results: We examined the correlation between gastric and intestinal phenotypic expression in 91 primary early carcinomas of the colon. MUC2 expression demonstrated a significant decrease from tubular/ tubulovillous adenomas with moderate atypia, through intramucosal carcinomas, to cancers with submucosal invasion (P<0.0001). Intramucosal de novo carcinomas (flat type carcinomas without adenomatous components) exhibited a greater decrease of MUC2 than intramucosal lesions with adenomatous components. Expression of MUC5AC also decreased significantly with progression according to the tubular/tubulovillous adenomacarcinoma sequence, carcinomas with villous adenomatous components having a higher level compared with their tubular adenomatous counterparts, suggesting differences in the pathway of malignant transformation. Cdx2 nuclear expression was maintained in all of the adenomas and early carcinomas examined. Conclusions: Our data suggest that the reduction of MUC2 expression may be associated with the occurrence and progression of colorectal carcinomas in both adenoma-carcinoma sequence pathway and de novo carcinogenesis. Tumor-suppressive effects of Cdx2 may be preserved during early stages of colorectal carcinogenesis.
- PublicationOpen AccessGenetic analysis to complement histopathological diagnosis of brain tumors(Murcia : F. Hernández, 2007) Nakamura, M.; Shimada, K.; Ishida, E.; Nakase, H.; Konishi, N.Gliomas, the most frequent tumors originating in the human nervous system, are divided into various subtypes. Currently, microscopic examination alone is insufficient for classification and grading so that genetic profiles are increasingly being emphasized in recognition of the emerging role of molecular diagnostic approaches to glioma classification. Glioblastomas (WHO grade IV) may develop de novo (primary glioblastomas) or through progression from lower-grade astrocytomas (secondary glioblastomas), while both glioblastomas show similar histological features. In contrast, they do constitute distinct disease entities that evolve through different genetic pathways, and are likely to differ in prognosis and response to therapy. Oligodendrogliomas (WHO grade II) account for 2.7% of brain tumors and 5-18% of all gliomas. Since this tumor is recognized as a particular subtype of glioma that shows remarkable responses to chemotherapy, a correct diagnosis is of prime importance. The difficulty is that histological differentiation of oligodendrogliomas from diffuse astrocytomas is highly subjective in cases without typical morphological features and there is a lack of reliable immunohistochemical markers. While histological distinction of low-grade gliomas from reactive astrocytes is also often difficult, reactive astrocytes usually lack genetic alterations. More biological and molecular approaches to glioma classification thus appear warranted to provide improved means to achieve correct diagnoses.
- PublicationOpen AccessGastric and intestinal phenotypic correlation between exocrine and endocrine components in human stomach tumors(Murcia : F. Hernández, 2007) Takenaka, Y.; Tsukamoto, T.; Mizoshita, T.; Ogasawara, N.; Hirano, N.; Otsuka, T.; Ban, H.; Nakamura, T.; Yamamura, Y.; Kaminishi, M.; Tatematsu, M.We have previously suggested that an origin of a stomach cancer is from a progenitor cell specializing toward exocrine cell (Exo-cell) lineages. To clarify whether our hypothesis is correct or not, we analyzed the expression of Exo-cell and endocrine cell (End-cell) markers in a series of lesions for comparison. We evaluated chromogranin A (CgA) expression in 37 early and 73 advanced stomach cancers, in 30 stomach adenomas, in 8 carcinoid tumors, and in 4 endocrine cell carcinomas (ECCs) with assessment of gastric and/or intestinal (G/I) phenotypes in both Exo-cell and End-cell by immunohistochemistry. CgA expression was observed in 10.8% of the early and 16.4% of the advanced stomach cancers, respectively. The End-cell G/I phenotypes were in line with the Exo-cell counterparts in the CgA-positive stomach cancerous areas, and there was strong association between Cdx2 expression and the intestinal End-cell markers. All of the adenoma cases had the intestinal Exo-cell phenotypic expression, with the positive link between Exo-cell and End-cell G/I phenotypes. All stomach carcinoids had CgA expression but no expression of Exo-cell markers. In conclusion, most stomach cancers might develop from a progenitor cell specializing towards Exo-cell lineages, but some cases possessed both Exo-cell and End-cell markers with maturely differentiated phenotypes. In such cases, Exo-cell and End-cell phenotypes were found to correlate strongly, suggesting the possibility of histogenesis from “cancer stem cells”.
- PublicationOpen AccessUltrastructural characterization of calcification onset and progression in subdermally implanted aortic valves. Histochemical and spectrometric data(Murcia : F. Hernández, 2007) Ortolani, F.; Bonetti, A.; Tubaro, F.; Petrelli, L.; Contin, M.; Nori, S.L.; Spina, M.; Marchini, M.Detailed characterization of the subdermal model is a significant tool for better understanding of calcification mechanisms occurring in heart valves. In previous ultrastructural investigation on six-weekimplantated aortic valve leaflets, modified preembedding glutaraldehyde-cuprolinic-blue reactions (GA-CB) enabled sample decalcification with concurrent retention/staining of lipid-containing polyanionic material, which lined cells and cell-derived matrix-vesicle-like bodies (phthalocyanin-positive layers: PPLs) co-localizing with the earliest apatite nucleation sites. Additional post-embedding silver staining (GA-CB-S) revealed PPLs to contain calciumbinding sites. This investigation concerns valve leaflets subjected to shorter implantation times to shed light on the modifications associated with PPLs generation and calcification onset/progression. Spectrometric estimations revealed time-dependent calcium increase, for unreacted samples, and copper modifications indicating an increase in acidic, non-glycanic material, for GA-CB-reacted samples. Two-day-implant thin sections showed emission and subsequent reabsorption of lamellipodium-like protrusions by cells, originating ECM-containing vacuoles, and/or degeneration stages characterized by the appearance of GA-CB-S-reactive, organule-derived dense bodies and progressive dissolution of all cell membranes. In one-week-implants, the first PPL-lined cells were found to co-exist with cells where GA-CB-S-reactive material accumulated, or exudated towards their edges, or outcropped at the ECM milieu, so acquiring PPL features. PPL-derived material was observed increasingly to affect the ECM on thin sections of one-week- to six-week-implants. These results show an endogenous source for PPLs and reveal that a peculiar cascade of cell degenerative steps is associated with valve mineralization in the subdermal model, providing new useful parameters for more reliable comparison of this experimental calcification process versus the physiological and pathological processes.
- PublicationOpen AccessTubular changes in obstructed kidney of adult mice evaluated using immunohistochemistry for segment-specific marker(Murcia : F. Hernández, 2007) Kida, Y.; Sato, T.The main focus of the present investigation is to examine obstructed kidneys due to unilateral ureteral obstruction (UUO) model in adult mice using segmentspecific tubular marker and to confirm the detailed morphological evaluation of UUO that is a typical model for the tubulointerstitial fibrosis which is an endpoint outcome of chronic renal diseases. Adult mice were subjected to UUO, and kidneys were harvested 1, 3, 7 days after surgical operation. Expansion of interstitial space both in the cortex and the medulla was confirmed 3 days after UUO by HE- and azan-staining. Interstitial fibrosis developed especially around dilated tubules. Immunohistochemistry for segment-specific antibodies revealed that the proximal tubules and the descending limb of Henle's loop did not dilate until 7 days after UUO, whereas initial dilation of the ascending limb of Henle's loop appeared to occur one day after surgery. The segment from the distal tubules to the collecting ducts began dilating one day after surgery and afterward significantly dilated. The downstream segment of nephron was involved in dilating earlier than the upstream of nephron in obstructed kidney examined in the present study. Moreover, the tubules accompanying apoptosis of tubular epithelia significantly dilated compared with those without apoptotic tubular epithelia. From the above-mentioned findings, we conclude that tubular dilatation of distal segment (from the ascending limb of Henle's loop to the collecting ducts) of nephron develops tubular epithelial apoptosis caused by accumulated urine, which would link to tubular disappearance and its replacement with fibrous tissue in UUO kidney of adult mice.
- PublicationOpen AccessEgg extracellular coat proteins: From fish to mammals(Murcia : F. Hernández, 2007) Litscher, E.S.; Wassarman, P.M.The extracellular coat surrounding fish (vitelline envelope; VE) and mammalian (zona pellucida; ZP) eggs is composed of long, interconnected filaments. Fish VE and mammalian ZP proteins that make up the filaments are highly conserved groups of proteins that are related to each other, as well as to their amphibian and avian egg counterparts. The rainbow trout (O. mykiss) egg VE is composed of 3 proteins, called VEa (~58 kDa), VEß (~54 kDa), and VEg (~47 kDa). The mouse (M. musculus) egg ZP also is composed of 3 proteins, called ZP1 (~200 kDa), ZP2 (~120 kDa), and ZP3 (~83 kDa). Overall, trout VE and mouse ZP proteins share ~25% sequence identity and have features in common; these include an N-terminal signal sequence, a ZP domain, a consensus furin cleavage-site, and a C-terminal tail. VEa, VEß, and ZP1 also have a trefoil or P-type domain upstream of the ZP domain. VEa and VEß are very similar in sequence (~65% sequence identity) and are related to ZP1 and ZP2, whereas VEg is related to ZP3 (~25% sequence identity). Mouse ZP proteins are synthesized and secreted exclusively by growing oocytes in the ovary. Trout VE proteins are synthesized by the liver under growing oocytes in the ovary. The trout VE is assembled from VEa/g and VEß/g heterodimers. The mouse ZP is assembled from ZP2/3 heterodimers and crosslinked by ZP1. Despite ~400 million years separating the appearance of trout and mice, and the change from external to internal fertilization and development, trout VE and mouse ZP proteins have many common structural features; as do avian and amphibian egg VE proteins. However, the site of synthesis of trout and mouse egg extracellular coat proteins has changed over time from the liver to the ovary, necessitating some changes in the C-terminal region of the polypeptides that regulates processing, secretion, and assembly of the proteins
- PublicationOpen AccessChromatin in embryonic stem cell neuronal differentiation(Murcia : F. Hernández, 2007) Meshorer, E.Chromatin, the basic regulatory unit of the eukaryotic genetic material, is controlled by epigenetic mechanisms including histone modifications, histone variants, DNA methylation and chromatin remodeling. Cellular differentiation involves large changes in gene expression concomitant with alterations in genome organization and chromatin structure. Such changes are particularly evident in self-renewing pluripotent embryonic stem cells, which begin, in terms of cell fate, as a tabula rasa, and through the process of differentiation, acquire distinct identities. Here I describe the changes in chromatin that accompany neuronal differentiation, particularly of embryonic stem cells, and discuss how chromatin serves as the master regulator of cellular destiny.