Histology and histopathology Vol.24, nº7 (2009)
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- PublicationOpen AccessClaudin-5 protein is a new differential marker for histopathological differential diagnosis of canine hemangiosarcoma(Murcia : F. Hernández, 2009) Jakab, Cs.; Halász, J.; Kiss, A.; Schaff, Z.; Rusvai, M.; Gálfi, P.; Abonyi, T.Z.; Kulka, J.Aims: Claudin-5 protein is an endothelspecific claudin, present in tight junctions. To evaluate its usefulness as a differential diagnostic marker of canine hemangiosarcomas, the expression of claudin-5 molecule was studied in different canine tumours of vascular origin. Methods and results: Ninety two canine neoplastic tissue samples obtained from necropsies and biopsy specimens were routinely processed and stained immunhistochemically for claudin-5. The neoplastic endothelial cells of canine hemangiosarcomas, hemangiomas, and lymphangiomas showed a strong membrane immunoreactivity for claudin-5, but the other investigated canine malignant and benign tumours, including fibrosarcomas, myxo-, leiomyo-, cardiac rhabdomyo-, neurofibro-, synovial-, osteo-, and chondrosarcomas, spindle cell melanomas, hemangiopericytomas, benign fibroblast proliferations, and leiomyomas were negative for this endothelial marker. In these non-vascular canine tumours intense immunostaining was detected in the endothelial cells of the incorporated intratumoural vessels and neovasculature. The canine splenic hematomas induced by hemangiosarcomas were distinguished from splenic hematomas induced by non-neoplastic lesions by the means of claudin-5 protein. In hemangiosarcomas the percentage of positive neoplastic endothelial cells was higher, and stronger when using the claudin-5 molecule compared to CD31 and vWf. Conclusion: The results show that claudin-5 molecule can be used as a new differential marker, and could also be of a diagnostic value in the differential diagnosis of canine hemangiosarcomas from sarcomas of other origin with hemorrhages or increased vascularization. Claudin-5 could help to reveal neoplastic proliferation of endothelial cells causing splenic hematomas and differentiate these tumours from non-vascular neoplastic splenic lesion. The immunohistochemical detection of the claudin-5 protein had a higher sensitivity than CD31, and vWf antigen in case of canine hemangiosarcomas.
- PublicationOpen AccessExpression of beta-catenin and its mechanism of delocalization in intestinal-type early gastric cancer based on mucin expression(Murcia : F. Hernández, 2009) Lee, Soo Han; Kang, Hyun Jeong; Shin, Dong-Hun; Cho, Duk-Yeon; Song, Jin Mi; Kim, G.H.; Song, G.A.; So, Mee Young; Kim, J.Y.; Choi, K.U.; Lee, Chian-Her; Huh, G.Y.; Park, D.Y.; Lee, H.C.The biological characteristics of intestinaltype early gastric cancers (ICs) differ based on mucin phenotypes. Beta-catenin delocalization is a predictive marker of aggressive biological behavior (submucosal invasion and lymph node metastasis) of ICs. The presumptive causative genetic alterations leading to delocalization of beta-catenin in ICs are still controversial, and there are only a few reports regarding beta-catenin expression in gastric cancer based on mucin phenotypes. Therefore, in the current study, the expression and mechanisms of delocalization of betacatenin were elucidated on the basis of mucin phenotypes in 109 cases of ICs. There was increased cytoplasmic and nuclear beta-catenin expression (delocalization) in ICs with a predominant intestinal mucin phenotype (ICIP; 46.3% [25/54 cases]) compared to ICs with a predominant gastric mucin phenotype (ICGP; 20% [11/55 cases]). There were no beta-catenin or APC mutations in ICs. APC promoter hypermethylation was present in 49 of 105 (46.7%) cases of ICs. There was a significant relationship between APC promoter hypermethylation and betacatenin delocalization in ICs, especially in ICIPs. There was no relationship between beta-catenin delocalization and APC gene loss of heterozygosity in ICs. In conclusion, we showed that beta-catenin delocalization was more evident in ICIPs, and APC promoter hypermethylation might play a role in delocalization of beta-catenin, especially in ICIPs.
- PublicationOpen AccessImmunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease(Murcia : F. Hernández, 2009) Radaelli, E.; Ceruti, R.; Patton, V.; Russo, M.; Degrassi, A.; Croci, V.; Caprera, F.; Stortini, G.; Scanziani, E.; Pesenti, E.; Alzani, R.Tumorigenesis in human glioblastoma multiforme (GBM) is driven by several genetic abnormalities with disruption of important molecular pathways, such as p53/MDM2/p14ARF and EGFR/PTEN/Akt/mTOR. The malignant progression of human GBM is also primarily associated with a peculiar multistep pathophysiological process characterized by intratumoral ischemic necrosis (i.e. pseudopalisading necrosis) and activation of the hypoxia-inducible factor (HIF)-1a pathway with consequent peritumoral microvascular proliferation and infiltrative behaviour. Predictable preclinical animal models of GBM should recapitulate the main pathobiological hallmarks of the human disease. In this study we describe two murine orthotopic xenograft models using U87MG and U251 human cell lines. Ten Balb/c nude male mice were orthotopically implanted with either U87MG (5 mice) or U251 (5 mice) cell lines. Intracranial tumor growth was monitored through Magnetic Resonance Imaging (MRI). Immunohistopathological examination of the whole cranium was performed 30 days after implantation. U251 orthotopic xenografts recapitulated the salient pathobiological features described for human GBM, including invasive behaviour, wide areas of pseudopalisading necrosis, florid peripheral angiogenesis, GFAP and vimentin expression, nonfunctional p53 expression, striking active-caspase-3 and HIF-1a expression along pseudopalisades. U87MG orthotopic xenografts proved to be very dissimilar from human GBM, showing expansile growth, occasional necrotic foci without pseudopalisades, intratumoral lacunar pattern of angiogenesis, lack of GFAP expression, fuctional p53 expression and inconsistent HIF-1a expression. Expression of pAkt was upregulated in both models. The results obtained suggest that the U251 orthotopic model may be proposed as a predictive and reliable tool in preclinical studies since it recapitulates the most salient pathobiological features reported for human GBM.
- PublicationOpen AccessAnalysis of gene status in cervical dysplastic lesions and squamous cell carcinoma using tissue microarrays(Murcia : F. Hernández, 2009) Costa, C.; Espinet, Blanca; Molina, Miguel A.; Salgado, Rocio; Salido, M.; Baró, Teresa; Fusté, P.; Mancebo, G.; Carreras, R.; Solé, Francesc; Serrano, S.; Alameda, F.Cervical displasia are classified as CIN-I, CIN-II and CIN-III. It has been observed that in at least 60% of CIN-I and CIN-II, the pathology disappears spontaneously, while around 30% persist at 24 months, 10% progress to CIN-III and 1% develops as a SCC. The factors involved in the evolution of the pathology are not defined, although infection of HPV is a necessary condition, but not the only one. For this reason, the identification of genetic changes is an essential element for understanding the carcinogenic process. It can also serve as a helpful tool for identifying patients who may be susceptible to its evolution and treatment, from patients whose lesions could regress spontaneous and for whom periodic follow-ups would be enough. Fiftty three cervical biopsies from patients with dysplasia and ISCC were included in the study. These biopsies were set into nine macroarrays. Eight genes and five proteins were examined in each samples (hTERT, PIK3CA, hTERC, MYC, CCND1, BCL2, ZNF217 and p16) by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC). The results reflected that the genetic alterations of PIK3CA, ZNF217 and CCND1 were associated with the evolution of normal tissue to CIN I, those of hTERC and ERBB with the evolution of LSIL to HSIL, those of hTERT and MYC with the evolution of CIN-II/CIN-III to ISCC, and those of BCL-2 with the inception of ISCC. With regards to proteins, the expression of MYC and CCND1 in the initial stages of the illness would help in the acquisition of the altered cellular phenotype.
- PublicationOpen AccessTumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: prognostic impact(Murcia : F. Hernández, 2009) Hildenbrand, Ralf; Schaaf, Antonela; Dorn-Beineke, Alexandra; Allgayer, Heike; Sütterlin, Marc; Marx, Alexander; Stroebel, PhilippUrokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor PAI-1, play a key role in tumor invasion and metastasis. uPA and PAI-1 were the first novel tumor biological factors to be validated at the highest level of evidence regarding their clinical utility in breast cancer. Their antigens are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA- and PAI-1 in their primary tumor tissue have significantly better survival than patients with high levels of either factor. However, it is unclear whether it is their (relative) levels in the tumor stroma or in the tumor cells themselves that is most relevant to patient outcome. This missing knowledge leads to an uncertainty concerning the management of breast cancer tissue specimens. It is unclear how much tumor stroma is allowed in one tumor tissue specimen for an adequate assessment of the patients' outcome. This is the first study in which tumor cells and stromal tissue of invasive breast carcinomas (n=60) were separated by laser capture microdissection followed by ELISA-based determination of the uPA-, uPAR- and PAI-1-levels. In addition, we have assessed uPA-, uPAR- and PAI-1 distribution in formalin-fixed, paraffin-embedded breast cancer specimens (n=60) by immunohistochemistry. The uPA-, uPAR- and PAI-1 in tumor stroma only, tumor cells only and not separated tumor tissue did not show any significant differences in protein-levels determined by ELISA. Cox regression analysis showed that patients with high uPA-, high uPAR-, and/or high PAI-1-levels, as compared to patients with low levels of either factor, showed a significantly shorter relapse-free survival and overall survival (p=0.000001). These results suggest that a strong expression of uPA, uPAR and PAI-1 in the tumor stroma, as well as in tumor cells, have the same impact on the clinical behaviour of breast cancer. Conclusion: When using uPA- and PAI-1 levels as prognostic and predictive factors in breast cancer the quantity of tumor stroma in the tumor tissue specimen is not relevant for the assessment of the patients' outcome.
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