Histology and histopathology Vol.30, nº1 (2015)
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- PublicationOpen AccessThe influence of water pH on the genesis of cadmium-induced cancer in a rat model(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Nai, Gisele Alborghetti; Golghetto, Gisele Maria Soria; Estrella, Mariani Paulino Soriano; Teixeira, Larissa Di Santi; Moura, Felipe do Carmo; Bremer Neto, Hermann; Pariz, José Luiz SantosCadmium is a heavy metal that is widely used in industry and can cause tumours in multiple organs. The purpose of our study was to investigate the effect of water pH in the genesis of cadmium-induced cancer. We divided 98 male Wistar rats into 7 groups: group A - 15 rats that received cadmium chloride (CdCl 2 – 400 mg/L) in their drinking water at a neutral pH of 7.0; group B - 15 rats that received CdCl 2 (400 mg/L) in their drinking water at an acidic pH of 5.0; group C - 15 rats that received CdCl 2 (400 mg/L) in their drinking water at a basic pH of 8.0; group D - 15 rats that received water at an acidic pH of 5.0; group E - 15 rats that received water at a basic pH of 8.0; group F - 15 rats that received water at a neutral pH of 7.0; and group G - 8 rats that were subcutaneously injected with a single dose of cyclophosphamide (50 mg/kg). Groups A through F were euthanised 6 months after the start of the experiment and group G was euthanised 24 hours after cyclophosphamide injection. We collected the liver, kidneys, pancreas, prostate, seminal vesicles and testes for histopathological analysis and the bone marrow for micronuclei testing. In all of the groups, neither neoplastic lesions nor an increase in micronuclei (p>0.05) were observed in the liver, kidney, pancreas, seminal vesicles and testes. We found that animals exposed to cadmium had grade one prostatic intraepithelial neoplasia, but this was found more frequently in animals from group B (p<0.05). The acidic pH increased the formation of pre-neoplastic lesions in the prostate glands of cadmium-exposed animals.
- PublicationOpen AccessElucidation of soft tissue flap histologic margins within a canine vocal fold(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Glab, Rachel C.; Gunderson, McLean; Torrealba, José; Bauer, Ben; Dailey, Seth H.Summary. Background: Histologic identification of implanted soft tissues in experimental animal models can be challenging, as donor tissue often strongly resembles the recipient bed. We have encountered this dilemma following implantation of a Composite Thyroid Ala Perichondrium flap (CTAP) into a vocal fold. The CTAP procedure is the first to utilize a vascularized flap for vocal fold reconstruction, making data to confirm or refute its viability critical. The current study evaluated several tissue stains to define precisely the histologic margins of CTAPs at two weeks post-implantation in a canine model. Methods: Initial testing exposed canine cadaveric tissues to four stains (tattoo ink, Congo red, 4’6- diamidino-2-phenylindole, and henna) across four time periods. Tattoo ink alone withstood histologic processing. An exposure of 1 minute adequately delineated CTAP boundaries. The study concluded with a canine in vivo evaluation of a CTAP exposed to tattoo ink for 1 minute. After a two-week recovery period, vocal folds were harvested and evaluated histologically. Results: Tattoo ink proved to be a safe and effective histologic marker in vivo, where the histologic margins of the implanted CTAP were clearly demarcated by a thin band of tattoo ink, soft tissue reactions were minimal, and interference with standard, special, or immunohistochemical stain assessments did not occur. Conclusions: Tattoo ink provides a reliable means of demarcating a CTAP within a vocal fold and demonstrated that CTAPs survive transplantation. Further, tattoo ink demarcation may serve as a useful histologic marker for those wishing to assess tissue implants in other in vivo models.
- PublicationOpen AccessAge-related degeneration of articular cartilage in the pathogenesis of osteoarthritis: molecular markers of senescent chondrocytes(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Musumeci, Giuseppe; Szychlinska, Marta Anna; Mobasheri, AliAging is a natural process by which every single living organism approaches its twilight of existence in a natural way. However, aging is also linked to the pathogenesis of a number of complex diseases. This is the case for osteoarthritis (OA), where age is considered to be a major risk factor of this important and increasingly common joint disorder. Half of the world's population, aged 65 and older, suffers from OA. Although the relationship between the development of OA and aging has not yet been completely understood, it is thought that age-related changes correlate with other risk factors. The most prominent hypothesis linking aging and OA is that chondrocytes undergo premature aging due to several factors, such as excessive mechanical load or oxidative stress, which induce the so called “stress-induced senescent state”, which is ultimately responsible for the onset of OA. This review focuses on molecular markers and mechanisms implicated in chondrocyte aging and the pathogenesis of OA. We discuss the most important age-related morphological and biological changes that affect articular cartilage and chondrocytes. We also identify the main senescence markers that may be used to recognize molecular alterations in the extracellular matrix of cartilage as related to senescence. Since the aging process is strongly associated with the onset of osteoarthritis, we believe that strategies aimed at preventing chondrocyte senescence, as well as the identification of new increasingly sensitive senescent markers, could have a positive impact on the development of new therapies for this severe disease.
- PublicationOpen AccessThe emerging role of exosomes in survivin secretion(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Khan, Salma; Ferguson Bennit, Heather; Wall, Nathan R.The tumor microenvironment plays an integral part in the biology of cancer, participating in tumor initiation, progression, and response to therapy. Factors released by tumor cells themselves contribute in creating an environment mostly favorable but sometimes detrimental to the tumor. Survivin, one of the key members of the inhibitor of apoptosis (IAP) family of proteins, has been shown in the cytoplasm, mitochondria, nucleus, and most recently in the extracellular space, transported via small membrane bound vesicles called exosomes. Exosomes are secreted from hematopoietic, non-hematopoietic, tumor, and nontumor cells, shuttling essential molecules such as proteins, RNAs, and microRNAs, all believed to be important for cell-cell and cell-extracellular communication. In this review, we discuss exosomal Survivin and its role in modifying the tumor microenvironment.
- PublicationOpen AccessThe effect of immunosuppressive therapy on renal cell apoptosis in native rat kidneys(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Kędzierska, Karolina; Sporniak-Tutak, Katarzyna; Kolasa, Agnieszka; Domański, Leszek; Domański, Maciej; Sindrewicz, Krzysztof; Smektała, Tomasz; Bober, Joanna; Safranow, Krzysztof; Osękowska, Bogumiła; Kabat-Koperska, Joanna; Baranowska-Bosiacka, Irena; Parafiniuk, Mirosław; Urasińska, Elżbieta; Ciechanowski, KazimierzAim: To analyse the impact of the most commonly used immunosuppressive drugs on the occurrence of apoptosis in the native kidneys of Wistar rats. Method: The study involved 36 rats. The animals grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporine A, rapamycin and prednisone). The rats in all study groups were treated with a 3-drug protocol for 6 months. The medication dose was adjusted based on available literature data. No drugs were administered to the control group. The rats were then killed. Autopsies of all animals were performed and the kidneys were isolated for histopathology (HE + PAS). To assess cell apoptosis the TUNEL reaction was performed. Blood trough levels of immunosuppressive drugs as well as the parameters of peripheral blood were determined. Results: 1. In rats treated with cyclosporine A distal nephron tubules were characterised by more pronounced apoptosis. 2. In tacrolimus-treated rats a lower intensity of apoptosis was found in the distal tubules. 3. In rapamycin-treated rats the apoptosis was inhibited both in the distal and proximal nephron tubules. 4. In MMF treated rats intense apoptosis was observed in the proximal nephron tubules. 5. There were no significant changes in renal histopathology (HE + PAS). Conclusions: The apoptosis in nephron tubules caused by immunosuppressive therapy is not accompanied by any histopathological changes (eg fibrosis, inflammation, tubular atrophy, vacuolation of the tubular cells) in light microscopy
- PublicationOpen AccessOverexpression of proCOL11A1 as a stromal marker of breast cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Fuentes Martínez, Nelson; García Pravia, Carmen; García Ocaña, Marcos; Menéndez Rodríguez, Primitiva; Del Amo, Jokin; Suárez Fernandez, Laura; Galván, José A.; De los Toyos, Juan R.; Barneo, LuisBackground: Our previous studies demonstrated the expression of procollagen11A1 in fibroblasts of pancreatic cancer desmoplasia and the lack of expression in fibroblasts of pancreatitis by means of the polyclonal antibody (anti-proCOL11A1 pAb) we generated. In a similar way, we decided to compare the expression of procollagen11A1 in fibroblasts of infiltrating ductal carcinoma of the breast and fibroblasts of benign sclerosing lesions of the breast, in order to validate the anti-proCOL11A1 pAb in this setting and to study how proCOL11A1 expression relates to other prognostic and predictive factors, as well as to survival. Methods: 45 core biopsies of sclerosing adenosis and 50 core biopsies of infiltrating ductal carcinoma of the breast were stained with anti-proCOL11A1 pAb, a polyclonal antibody highly specific to the less homologous fraction of proCOL11A1 (in comparison with proCOL5A1 and proCOL11A2). In addition, the expression of the proCOL11A1 gene was measured by RT-qPCR. On the other hand, the expression of proCOL11A1 was compared to the expression of estrogenic receptors, progestagen receptors, the state of the epidermal growth factor receptor 2 (HER2), the histologic grade and the stage of the disease. We also compared the immunohistochemical expression of proCol11A1 to the disease-free interval, and to overall survival. Results: The immunohistochemical analysis showed that proCOL11A1 was expressed in 100% of infiltrating ductal carcinomas, but only focally expressed in 2.2% (1 case) of sclerosing adenosis, in agreement with RT-qPCR results. ProCOL11A1 expression did not prove to have a prognostic value in relation to the disease-free interval or to overall survival in infiltrating ductal carcinoma. Conclusion: The anti-proCOL11A1 pAb is a stromal marker for breast cancer and the expression of proCOL11A1 does not seem to have a prognostic value in infiltrating ductal carcinoma of the breast.
- PublicationOpen AccessTargeting cyclic hypoxia to prevent malignant progression and therapeutic resistance of cancers(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Sun, Qingjia; Li, XiaomingEmerging evidence shows that cyclic hypoxia exists in most solid cancers. It is believed that under cyclic hypoxic conditions cancer cells exhibit more malignant biological behaviors than under chronic hypoxic conditions. In this review, we provide a collection of evidence showing the molecular mechanisms by which cyclic hypoxia induces aggressiveness, malignant progression, and therapeutic resistance in cancers. Moreover, we propose that cyclic hypoxia is responsible for the regulation of cancer stem cells, which possess typical biological characteristics of therapeutic resistance. Based on the present findings, some key factors regulated by cyclic hypoxia may serve as potential targets for the prevention of malignant progression and the treatment of solid cancers. Much research is necessary to gain further insights into the biological aspects of cyclic hypoxia in the development and progression of cancers.
- PublicationOpen AccessThe effect of inhaled nitric oxide on the carrageenan-induced paw edema(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Coelho, Carly Faria; Vieira, Rodolfo P.; Lopes-Martins, Patrícia Sardinha Leonardo; Teixeira, Simone Aparecida; Borbely, Alexandre Urban; Gouvea, Irene María; Frigo, Lucio; Lopes-Martins, Rodrigo Álvaro BrandãoInhaled nitric oxide therapy reaches not only pulmonary vessels, but also other vasculatures, presenting anti-inflammatory effects. Therefore, this study investigated the effects of inhaled nitric oxide on a mice model of carrageenan-induced paw edema. Paw edema was induced in male Swiss mice (20-30 g) by subplantar injection of carrageenan (0.05 ml of a 1% suspension in 0.9% saline). The evaluation of timecourse edema (mililiter) was measured by plethysmometry until 12 h following carrageenan administration. Thirty minutes after carrageenan injection, some groups received inhaled nitric oxide (300 ppm at variable doses and times) or Indometacin (INDO 5 mg/Kg, v.o), while others received sildenafil (1 mg/Kg, i.p) or rolipram (3 mg/Kg, i.p.) with or without inhaled nitric oxide. Paws were assessed for edema levels by plethysmometry, mieloperoxidase activity and histological analysis. Inhaled nitric oxide significantly reduced carrageenan-induced paw edema, mieloperoxidase activity and inflammatory infiltrate, although similar results were also observed in sildenafil and rolipram treated groups. In addition, significant effects between inhaled nitric oxide with pharmacological therapy was observed. Inhaled nitric oxide presents anti-inflammatory effects on carrageenaninduce paw edema, as observed through reduced edema, mieloperoxidase activity and neutrophil infiltration, indicating that inhaled nitric oxide therapy goes beyond lung vascular effects.
- PublicationOpen AccessExpression of matrix Gla protein and osteocalcin in the developing tibial epiphysis of mice(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Liu, Hongrui; Guo, Jie; Wei, Shanliang; Lv, Shengyu; Feng, Wei; Cui, Jian; Hasegawa, Tomoka; Hongo, Hiromi; Yang, Yang; Li, Xiangzhi; Oda, Kimimitsu; Amizuka, Norio; Li, MinqiThis study aimed to investigate the expression of matrix Gla protein (MGP) and osteocalcin (OCN) in the tibial epiphysis of developing mice. At 1, 2, 3, and 4 weeks after birth, tibiae were removed and processed for histochemical observations and western blot analyses under anesthesia. To evaluate bone volume, the specimens were scanned with Micro CT Scanner from the articular cartilage through the growth plate, along the long axis of tibia. At 1 week after birth, OCN reactivity was faint in the region of vascular invasion, while hardly any MGP reactivity was discernible. Subsequently, MGP reactivity was seen on the cartilaginous lacunar walls of hypertrophic chondrocytes, while OCN reactivity was evenly found not only in the bone matrix, but also in the cartilaginous lacunar walls and on the bone surfaces. Furthermore, double-immunostaining clearly showed that MGP reactivity appeared closer to the cartilage matrix than OCN reactivity until postnatal week 3. Interestingly, the immunoreactivities for MGP and OCN both showed tidemarks in the articular cartilage at postnatal week 4, and MGP reactivity was more intense than OCN reactivity. Statistical analyses showed an overall upward trend in MGP and OCN expression levels during tibial epiphysis development, even though OCN was more abundant than MGP at every time-point. Taken together, our findings suggest that the expression of MGP and OCN increased gradually in the murine developing tibial epiphysis, and the two mineral-associated proteins may occur at the same location during a particular period, but at different levels.
- PublicationOpen AccessFibroblast growth factor receptors: multifactorial-contributors to tumor initiation and progression(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Feng, Shachuan; Zhou, Li; Collins Nice, Edouard; Huang, CanhuaFibroblast growth factor receptors (FGFRs), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) are tightly associated with many biological processes such as organ development, cell proliferation and migration. Studies over the past decades have validated the pivotal roles FGFRs play in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. Interestingly, FGFR mutations in somatic cells leading to tumorigenesis and those in germ cells leading to developmental disorders are identical, suggesting that FGFR mutations result in different diseases due to their spatio-temporal expression. Thus, discoveries in developmental biology may also be applicable to cancer. FGFRs regulate the expression and/or the activity of a myriad of molecules (e.g. matrix metalloproteinases (MMPs) and Snail) that are tightly linked to tumorigenesis by four main signaling pathways (RASMAPK, PI3K-AKT, PLCγ-PIP2, and STAT), as well as other minor branches. Epigenetic and genetic alteration of FGFR genes, including DNA methylation, histone remodeling, microRNA regulation, single nucleotide polymorphisms (SNPs), gene missense mutations, amplification, and fusion of FGFRs with other genes, which result in gain or loss of FGFR function, have been identified in many types of cancer. In this review, we focus in particular on recent advances in the relationship between FGFR disorders and tumorigenesis.
- PublicationOpen AccessMicrocirculation density and maturity in uterine and soft tissue leiomyosarcomas: an immunohistochemical study(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Caraffi, Stefano; Corradi, Domenico; Campanini, Nicoletta; Govoni, Paolo; Rocchi, Laura; Perris, Roberto; Mangieri, DomenicaThe role of angiogenesis as a hallmark of tumor progression has been poorly explored in leiomyosarcoma, a rare but aggressive mesenchymal malignancy. We aimed to characterize microvessel distribution and morphology - including pericyte coverage - in a retrospective series of leyomiosarcomas of the soft tissues and the uterus. 41 whole-block tumor slides from formalin-fixed paraffin-embedded tissues were immunostained for endothelial-specific marker CD31 and microvessel density was quantified by assigning a grade to the frequency of CD31 positive microvessels. Vessel morphology and pericyte coverage were investigated by double-labeling for CD31 and either PDGFRβ, αSMA, desmin, CD90, or CD146. We found that microvessel density correlated with tumor grade in leiomyosarcoma of soft tissues, in analogy with what has been established in several types of carcinoma. This did not apply to uterine leiomyosarcoma, possibly due to the abundant myometrial vascularization. The evaluation of perivascular cell markers related to vessel stability revealed immature microvascular networks with aberrant pericyte coverage, irrespective of tumor origin or grade. Our observations substantiate the role of angiogenesis in the progression of soft tissue leiomyosarcoma. A multiple-marker approach to the assessment of pericyte coverage can identify different profiles of vessel immaturity correlated with tumor grade.
- PublicationOpen AccessThe role of proteoglycans in the reactive stroma on tumor growth and progression(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Coulson-Thomas, Yvette May; Gesteira Ferreira, Tarsis; Lawrence Norton, Andrew; W-Y Kao, Winston; Bonciani Nader, Helena; Coulson-Thomas, Vivien JaneThe stroma surrounding tumors can either restrict or promote tumor growth and progression, and both the cellular and non-cellular components of the stroma play an active role. The cellular components in the surrounding stroma include tumor-associated fibroblasts, host tissue cells and immune cells. The noncellular components, which form the extracellular matrix (ECM) scaffold, include proteoglycans, collagen, proteinases, growth factors and cytokines. For tumorigenesis to occur it is necessary for tumor cells to modify the surrounding stroma. Tumor cells have mechanisms for achieving this, such as co-opting fibroblasts and modifying the ECM they produce, degrading the surrounding ECM and/or synthesizing a favorable ECM to support invasion. Proteoglycans are an important component of the ECM and play an active role in tumor growth and progression. The expression and glycosylation patterns of proteoglycans are altered in the stroma surrounding tumors and these molecules may support or restrict tumor growth and progression depending on the type and stage of tumor. In the present review we discuss the difference between the tumor promoting and restricting stromal reactions surrounding tumors and the role proteoglycans play.