Histology and histopathology Vol.29, nº 2 (2014)
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- PublicationOpen AccessInsulin-like Growth Factor (IGF) system and gastrointestinal stromal tumours (GIST): present and future(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Nannini, Margherita; Biasco, Guido; Astolfi, Annalisa; Urbini, Milena; Pantaleo, Maria A.In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.
- PublicationOpen AccessCD138 (syndecan-1) expression in health and disease(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Palaiologou, Marina; Delladetsima, Ioanna; Tiniakos, DinaCD138 (syndecan-1, Sdc-1) is a member of the syndecan family that comprises heparan sulfate proteoglycans. CD138 is significant for cell-cell and cell-matrix interactions. In adult human tissues, CD138 is predominantly expressed in epithelial cells and plasmacytes. CD138 immunoexpression is altered in a wide spectrum of benign inflammatory, infectious and fibrotic diseases (colitis, allergic contact dermatitis, fibrosis of various organs, etc) and diabetes mellitus type II. Furthermore, CD138 is involved in molecular pathways that are deregulated during carcinogenesis and are related to cell proliferation, apoptosis, angiogenesis, tumour invasion and metastasis. CD138 tumour cell and stromal immunoexpression is modified in various types of cancer, and is frequently correlated with clinico-pathological parameters and patients’ prognosis. The soluble form of CD138 may be used as a prognostic serum biomarker with promising results in respiratory tract carcinomas. CD138 plays a crucial role in carcinogenesis and is an attractive target for anticancer treatment with heparanase inhibitors and anti-CD138 antibodies for immunotherapy. Histol Histopathol 29, 177-189 (2014)
- PublicationOpen AccessFunctional analysis of NPHS1 mutations in Japanese patients(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Miyai, Takayuki; Aya, Kunihiko; Takaiwa, Masanori; Yan, Kunimasa; Sado, Yoshikazu; Tanaka, Hiroyuki; Morishima, TsuneoBackground: Many mutations in the NPHS1 gene were detected among patients with congenital nephrotic syndrome. Functional analysis of those mutations was done with a stable-expression cell line. Nevertheless, establishing such a cell line is time-consuming. Methods and Results: We established an easier method using automatic counting software for functional analysis with transient-transfection cells rather than a stable-expression cell line. We demonstrated maltrafficking to the plasma membrane of abnormal nephrin for immunostaining on transient-expression cells by comparison without Triton X (detecting proteins on the cell membrane only) and with Triton X (detecting proteins both on the cell membrane and inside the cell cytoplasm). We obtained relevant results with data obtained previously using a stable-expression cell line. Furthermore, we conducted functional analysis of NPHS1 mutations in Japanese patients with congenital nephrotic syndrome using this simple method, which revealed that all pathogenic mutations impaired trafficking to the protein plasma membrane. Conclusions: Functional analysis using transient-expression cells with automatic counting software was useful to demonstrate maltrafficking to the plasma membrane of a protein. All pathogenic mutations detected in Japanese patients impaired trafficking to the protein plasma membrane.
- PublicationOpen AccessDetection of galectin-3 and localization of advanced glycation end products (AGE) in human chronic skin wounds(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Pepe, Daniel; Elliott, Christopher G.; Forbes, Thomas L.; Hamilton, Douglas W.The matricellular protein galectin-3 (Gal-3) is upregulated in excisional skin repair in rats where it has been shown to modulate the inflammatory phase of repair. Recent research into kidney pathology has implicated Gal-3 as a receptor for advanced glycation end products (AGE), resulting in the binding and clearance of these molecules. AGEs are thought to contribute to defective skin repair in diabetic patients as well as a result of the normal aging process. However, the distribution and localization of Gal-3 and AGEs has never been performed in human chronic skin wound tissue. Using immunohistochemistry, the localization of Gal-3 and AGEs in tissue isolated from chronic wounds and non-involved skin from the same patient was investigated. Of the 16 patients from which tissue was isolated, 13 had type II diabetes, one had type I diabetes and 2 patients without diabetes were also examined. In non-involved dermis, Gal-3 was detected strongly in the epidermis and in the vasculature. However, at the wound edge and in the wound bed, the level of Gal-3 labelling was greatly reduced in both the epidermis and vasculature. Labelling of serial sections for Gal-3 and AGE demonstrated that where Gal-3 immunoreactivity is reduced in the epidermis and vasculature, there is a concomitant increase in the level of AGE staining. Interestingly, similar labelling patterns were evident in diabetic and non-diabetic patients. The results from our study demonstrate an inverse correlation between Gal-3 and AGEs localization, suggesting that Gal-3 may protect against accumulation of AGEs in wound healing.
- PublicationOpen AccessLocal extension of HMGB1 in atherosclerotic lesions of human main cerebral and carotid arteries(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Umahara, T.; Uchihara, T.; Koyama, S.; Hashimoto, T.; Akimoto, J.; Haraoka, J.; Iwamoto, T.High mobility group box 1 protein (HMGB1) is a non-histone chromosomal protein which is highly conserved, ubiquitous, and widely distributed. HMGB1 has multiple functions in the nucleus, including the maintenance of nucleosome structure, the regulation of gene transcription, and involvement in DNA recombination. HMBG1 is currently recognized to have a wide range of potential functions and pathological relevance. HMGB1 is released into the extracellular space from necrotic cells and from activated macrophages. HMGB1 binds to the receptor for advanced glycation end products, resulting in the induction of inflammatory cytokines, and to endothelial cell thrombomodulin. HMGB1 neutralization may also reduce the development of atherosclerosis and ameliorate brain infarction. We investigated the immunolocalization of HMGB1 in atherosclerotic lesions of human cerebral and carotid arteries using a specific antibody, and confirmed the detailed expression and cell type localization using double immunofluorolabeling. In the main cerebral arteries, this anti-HMGB1 antibody intensely immunolabeled both normal morphological vascular smooth muscle cells (VSMCs) within the tunica media and infiltrating VSMCs within the intima of thickened fibrous cap plaques. Endothelial cells were also positive for HMGB1. In carotid plaques, HMGB1-like immunoreactivity (IR) was intense in macrophages, although this IR decreased with increasing cell size. Medium-sized foam cells (50-150 µm) were the most intensely stained. This IR was also observed in the nuclei of foam cells and VSMCs. These findings may provide a basis for understanding the association of HMGB1 with atherosclerotic lesions of the cerebral and carotid arteries, and for constructing strategies to counteract atherosclerosis with anti-HMGB1 antibody.
- PublicationOpen AccessThe plexin-B family and its role in cancer progression(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Malik, Muhammad Faraz Arshad; Ye, Lin; Jiang, Wen G.Plexins are transmembrane protein receptors for semaphorin molecules. These molecules are involved in numerous cellular activities related to cell proliferation, adhesion along with the basement membrane, cellular motility and invasive capability. All nine members of Plexins identified in vertebrates have been grouped into subclasses, termed Plexin-A, Plexin-B, Plexin-C and Plexin-D. Plexin-B consists of three members, namely Plexin-B1, Plexin-B2 and Plexin-B3. Plexin-B1 functionally interacts with Sema4A (Yukawa et al., 2010) and can also form heterodimer with Plexin-B2 for Sema4A binding (Nkyimbeng-Takwi and Chapoval, 2011). Plexin-B2 binds with Sema4C. Plexin-B3 mediates interaction with both Sema4G and Sema5A. Some semaphorines exist in a membrane-bound form only, whereas other family members can be found in tissues/fluids in both secreted and membrane-bound forms. This ligand-receptor interaction between sema4D and Plexin-B1 indicated in different signaling pathways results in many intriguing and interesting findings, highlighting its importance in both physiology and pathology. Apart from bidirectional signaling among these molecules, the involvement of Plexin-B1 in the processes described here directly involves a bidirectional singaling between Sema4Dand Plexin-B1. Being a high affinity receptor for both Sema4A and Sema4D, the role played by Plexin-B1 in cancer progression, metastasis and angiogenesis is still an area requiring further research. Activation of Sema4D mediated downstream effectors is largely influenced by cross talk of Plexin-B1 with other molecules, such as Her-2 and Met. In this review, all findings regarding Plexin-B1 upstream and downstream regulation and its putative involvement in relation to the ultimate fate of cancer cells are discussed.
- PublicationOpen AccessPlacental growth factor and soluble Fms-like tyrosine kinase 1 in diabetic pregnancy: A possible relation to distal villous immaturity(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) El-Tarhouny, Shereen A.; Almasry, Shaima M.; Elfayomy, Amr K.; Baghdadi, Hussam; Habib, Fawzia A.This study aimed to describe the prevalence of chorionic distal villous immaturity (DVI) in overt diabetic/gestational diabetic (OD/GD) women compared with normoglycemic ones and to analyze the relation of DVI index (DVII) to placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1). Three groups were studied; normoglycemics (n=21), OD (n=17) and GD (n=20). Maternal blood samples were evaluated regarding serum levels of PlGF and sFlt-1. Immunohistochemical methodologies were employed in term placentae of all subjects to assess DVII and area% of PlGF and sFlt-1 immunostaining. We found that mean Hemoglobin A1c (HbA1c) is 5.22±0.15 in normoglycemics, 6.2±0.3 in OD, and 5.70±0.23 in GD with significant differences between groups (p=0.012). DVII was significantly higher in OD (66.6±4.7) and GD (72.4±4.5) compared to controls (11.6±2.5; p=0.000). Healthy women have significantly lower levels of PlGF (86.6±14.5) compared to OD (166.6±22.4, p=0.000) and GD (150.3±23.97, p=0.000) and their placentae expressed a significantly lower area% of PlGF (6.5±0.8) compared to OD (14.8±1.0, p=0.000) and GD (18.8±1.3, p=0.000). Also, normoglycemic women have significantly lower levels of sFlt-1 (108.9±12.1) compared to OD (226.5±18.6, p=0.000) or GD (197.2±16.8, p=0.000) and their placentae expressed a significantly lower area% of sFlt-1 (3.2±0.3) compared to OD (15.4±1.7, p=0.000) and GD (16.9±1.2, p=0.000). There was significant correlation between DVII and both serum level and area% of PlGF and sFlt-1 expression in the 3 groups. This study provided a new score for evaluating DVI in normal and diabetic placentae and suggested a role for PlGF and sFlt-1 in regulation of DVI in diabetic pregnancies.
- PublicationOpen AccessSomatic mutation of KIT is rare in small cell lung cancer patients from Northeast China(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Xuan, Hong; Jingshu, Geng; Fang, Yang; Na, Li; Xiaolin, Sheng; Zhaoyang, Yang; Meng, Wang; Gongyan, ChenStudies have confirmed that protein overexpression or mutations of KIT are involved in growth and development of a variety of cancers. however, little is known about data of gene mutation and protein expression in small cell lung cancer (SCLC) patients from northeast China.The aim of study is to investigate gene mutation and protein expression in such patients with small cell lung cancer (SCLC) and analyse their clinical significance.The expression of c-Kit protein was analyzed by immunohistochemistry in 77 SCLC samples and 22 normal lung samples. KIT mutations were screened in exons 9, 11, 13, 14, 17 and 18 by DNA direct sequencing.The study showed that positive staining for c-Kit was observed in 28 of 77 SCLC patients . There was no correlations between expression of c-Kit and sex, ages, smoking status, stage. only 1 case was found to have known T801I mutation in exon 17. The median survival (13.9 months) of cases with c-Kit-positive was shorter than that (19.9 months)of cases with c-Kit-negative. The finding revealed that stages was identified as an independent predictive factor for SCLC patients.Our finding reveals that somatic mutation of KIT is rare in SCLC patients from the northeast China and there is no enough evidence comfirming KIT inhibitors for treatment in SCLC.
- PublicationOpen AccessDifferential expression of p53 family proteins in colorectal adenomas and carcinomas: Prognostic and predictive values(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Bahnassy, Abeer A.; Zekri, Abdel-Rahman N.; Salem, Salem E.; Abou-Bakr, Amany A.; Sakr, Mona A.; Abdel-Samiaa, Ayman G.; Al-Bradei, ManalWe studied the contribution of p53 family proteins and their isoforms to the development and progression of colorectal carcinoma in relation to VEGF. Methods: p53, p63, p73 and VEGF proteins were assessed in 45 colorectal adenomas (CRAs), 80 carcinomas (CRCs) and 36 normal colonic tissue samples (NCT) by immunohistochemistry. Different p63 and p73 isoforms were assessed by RT-PCR. Aberrant protein and RNA expressions were correlated to patients' characteristics, disease free and overall survival (DFS& OS). Results: p53, p63, p73 and VEGF proteins were detected in 22.2%, 73.3%, 33.3%, 46.7% CRAs; in 68.8%, 38.8%, 62.5%, 62.5% CRCs and 16.7%, 83.3%; 13.9%, 27.8% NCT (p<0.05 except for VEGF). Commonest isoforms were TAp63a, DNp63, TAp73a in CRA and DNp63, TAp63a, DNp73, TAp73ß in CRC. Significant correlations were found between aggressive tumor phenotypes and aberrations in p73, p53, p63, VEGF. DFS correlated with advanced stage, p73 and VEGF aberrations. While advanced stage, positive lymph nodes, p73 and p53 correlated with OS. Prognosis was worse in patients with aberrant p63& p73 than in those with normal p63& p73 expression regardless of p53 gene status (p<0.05). Conclusions: p53 family proteins and VEGF play a pivotal role in colorectal carcinogenesis. p53 prognostic potential is augmented by p73 and p63 aberrations indicating a synergistic effect between the three family members. Nodal status, stage, p73, VEGF and p53 could be used as predictors of DFS and OS.
- PublicationOpen AccessMorphometric study of uninvolved rectal mucosa 10 cm and 20 cm away from the malignant tumor(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Despotović, Sanja Z.; Milicevic, Novika M.; Milošević, Dragoslav P.; Despotović, Nebojša; Erceg, Predrag; Bojic, Božidar; Bojić, Danijela; Svorcan, Petar; Mihajlović, Gordana; Dordević, Jelena; Lalić, Ivana M.; Milicevic, ŽivanaRecently, many details of the interplay between tumor cells and tumor-associated stromal elements leading to the progression of malignant disease were elucidated. In contrast, little is known about the role of uninvolved stromal tissue in the remote surrounding of the malignant tumor. Therefore, we performed a computer-aided morphometric study of rectal mucosa in samples taken 10 cm and 20 cm away from the malignant tumor during endoscopic examination of 23 patients older than 60 years. The samples of rectal mucosa from 10 healthy persons of corresponding age subjected to diagnostic rectoscopy during active screening for asymptomatic cancer were used as control. All structural elements of the rectal mucosa were studied and the number of nucleated cells in the lamina propria per 0.1 mm2 of tissue was assessed. Our study revealed a reduced number of cells in the lamina propria of the rectal mucosa 10 cm and 20 cm away from the tumor lesion in both male and female patients. The decreased mucosal height and increased crypt number were registered in female patients 10 cm away from the tumor. The connective tissue of lamina propria showed a disorderly organization: the collagen fibers were frail, loosely arranged and signs of tissue edema were present. Small blood vessels and capillaries were much more frequently seen than in healthy tissue. Our results demonstrate the complex interactions between the cancer and remote mucosal tissue of the affected organ.
- PublicationOpen AccessUnique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Nakada, Norihiro; Mikami, Tetuo; Hana, Kiyomi; Ichinoe, Masaaki; Yanagisawa, Nobuyuki; Yoshida, Tsutomu; Endou, Hitoshi; Okayasu, IsaoDysregulated expression of L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids, is a characteristic of various human cancers and possibly offers a molecular target for chemotherapy. LAT2, in contrast, shows lower expression in neoplasms. LAT1 is presumed to be a biomarker of many cancers, suggesting a kind of oncoprotein. However, no precise analysis of LAT1 and LAT2 expression has been performed in systemic normal tissues. To see characteristics of LAT1 and LAT2, immunohisto-chemical expression of LAT1 and LAT2 was assessed and compared in normal human systemic organs and tissues from 3 adults, 3 children and 3 fetuses in the present study. Cardiac muscles, hepatocytes, thymic epithelial cells and primitive neuroectodermal cells in fetus were positive with LAT1, whereas no expression was found in the respective adult tissues, indicating an aspect of oncofetal protein. In adult tissues, LAT1 was found to be expressed proximal to proliferative zones in gastrointestinal mucosa by double immunostaining of LAT1 and Ki-67. Testicular Sertoli cells, ovarian follicular cells, and pancreatic islet cells showed strong expression. Although the systemic capillary endothelium did not express LAT1, but did express LAT2, capillaries corresponding to the blood-brain, blood-follicle, and blood-retinal barriers demonstrated strong LAT1 immunoreactions. In conclusion, LAT1 was expressed in gonad tissues and several kinds of cells having special functions, as well as being discovered to be an aspect of oncofetal protein. In addition, ubiquitous LAT2 expression was confirmed immunohistochemically in systemic tissues, indicating constitutional function.
- PublicationOpen AccessRetrospective study of hepatocellular adenomas based on the phenotypic classification system: A report from China(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Pan, Jinfeng; Chen, Lingli; Fan, Jia; Zhou, Jian; Qin, Lunxiu; Tan, Yun-Shan; Ji, Yuan; Huang, XiaowuA molecular and pathological classification system for hepatocellular adenomas (HCAs) was recently introduced in Europe, resulting in four major identified subgroups. Asian countries have a considerably lower incidence of HCA as well as a different etiology. We aimed to characterize HCAs in a Chinese population based on this new classification system. A series of 30 patients with HCA were analyzed based on the phenotypic classification system using immunohistochemical analysis. Investigated antigens included liver-fatty acid binding protein (L-FABP), glutamine synthetase (GS), ß-catenin, serum amyloid A (SAA), and C-reactive protein (CRP). Of the 30 cases (20 female) included in this study, only one had a history of oral contraceptive use. We identified 9 (30%) hepatocyte nuclear factor (HNF)-1α-inactivated HCAs, 3 (10%) ß-catenin-activated HCAs, 11 (36.7%) inflammatory HCAs, and 7 (23.3%) unclassified HCAs. In the inflammatory HCA group, 2 cases demonstrated concurrent ß-catenin-activation. Homogeneous steatosis (6/9) and microadenomas (2/9) were more frequently observed in HNF1α-inactivated HCAs. A body mass index (BMI) of greater than 25 (5/11), alcohol use (4/11), and steatosis in background liver (3/11) were more frequent in inflammatory HCAs. ß-catenin-activated HCAs were larger than those of other subgroups. Despite obvious differences in etiology and gender proportion compared with Western countries, the clinical and pathological characteristics of HCA subgroups in China are similar to those in Europe. The phenotypic classification system could be reliably applied to Chinese patients as a meaningful tool for HCA management.
- PublicationOpen AccessGenetic aberrations as the targets of oncology research: Involvement of paraffin-embedded tissues(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Dobashi, Yoh; Goto, Akiteru; Endo, Tetsuya; Ooi, AkishiCancer is a complex and heterogeneous group of diseases which have been generally classified by their clinical and histopathological features. The genomes of cancer cells are altered by diverse mechanisms and these genetic aberrations lead to a variety of pathological changes. A number of technological advances have allowed us to analyze the cancer genome by various ‘-omics’ techniques, and have accelerated the exploration for the primary genetic aberrations that drive cancer. The state-of-the-art technologies that have developed over the past few decades have enabled researchers to catalogue these genetic aberrations in detail. These aberrations include changes in gene structure and the copy number, mutation, and modification of DNA. Simultaneously, there have been significant achievements in the translation of the genomic discoveries “from the bench to the bed”, which have provided valuable contributions to the progress in cancer therapy. One technology that has been central to these research efforts has been the histopathology of cancer specimens, particularly the use of formalin-fixed, paraffin-embedded tissues. In this overview, we consider the development of oncology research from the past to current efforts, and highlight the roles of histopathology and paraffin-embedded tissues in these efforts.