Histology and histopathology Vol.35, nº8 (2020)

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Open Access
Diversity of mucins in labial glands of infants
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Stoeckelhuber, Mechthild; Kesting, Marco R.; Loeffelbein, Denys J.; Schmitz, Christoph; Wolff, Klaus-Dietrich
Mucins as highly glycosylated proteins comprise multiple functions like protection, homeostasis, immune defense, cell signaling. Various epithelial tissues including glandular structures express different specific mucin types. We investigated labial salivary glands in infants for the occurrence of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC7 by immunohistochemistry. MUC1 and MUC4 were detected in serous and ductal glandular cells, partially intensified at the apical plasma membrane. MUC3 was found in ductal glandular cells and in myoepithelial cells. MUC5B exhibited a mosaic expression pattern in mucous glandular endpieces. MUC2 and MUC7 were abundant in serous acini. Glandular structures were negative for MUC5AC. A comprehensive study of specific mucins in labial salivary glands of infants was presented for the first time. As a representative of the minor salivary glands, labial glands are, due to their localization, directly exposed to environmental influences. The distribution of a broad spectrum of mucins in infantile labial glands indicates their importance early in human development to sustain oral health.
Open Access
Immunoexpression of adhesion molecules during human fetal hair development
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Andrade Silva, Laura Maria; Hsieh, Ricardo; Lourenço, Silvia Vanessa; Ottoni, Verônica; Valente, Neusa; Dumet Fernandes, Juliana
Introduction. Hair follicles are produced in a cyclical manner and the machinery involved in the reproduction of these follicles is present since the fetal stage. Although extensive research has been done on the human hair follicle, very little is known about the importance of adhesion molecules in its development. Material and methods. We analyzed here, the immunoexpression of beta-1 integrin, p-cadherin, e- cadherin, and beta-catenin in hair follicles from 26 formalin-fixed and paraffin-embedded skin samples from human embryos and fetus between 12-23 weeks of gestational age. Results. The adhesion molecules beta-1 integrin and e-cadherin/p-cadherin were expressed from 12 weeks and seemed to play a role in regulating epidermis invagination. Beta-catenin immunostaining was negative in all cases; down regulation of this protein may be necessary for fetal hair development and thus facilitating hair follicle down growth. Discussion/Conclusion. Adhesion molecules are essential for hair follicle down growth and proliferation; integrins and cadherins play a major role in this process. More studies are needed to describe hair follicle development
Open Access
Cathepsin-B dependent autophagy ameliorates steatoheaptitis in chronic exercise rats
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Guo, Rui; Yu, Qian; Liong, Emily C.; Fung, Man Lung; Tipoe, George L.
Purpose. This study aimed to investigate the role of cathepsin B dependent autophagy induced by chronic aerobic exercise on a high-fat diet (HFD)- induced nonalcoholic steatohepatitis (NASH) in rats. Methods. Healthy female (Sprague-Dawley) SD rats (8- 10 weeks old; 180g-200g; n=6 per group) were divided into: (1) control group; (2) HFD group; (3) Exercise group; (4) HFD + exercise group. Rats were fed with a normal chow or an HFD for 12 weeks. Rats with exercise ran on a rotarod for 30 min per day from weeks 9-12. Results. Exercise training significantly (1) upregulated the levels of autophagy markers Beclin1, ATG5 and LC3II partly through inhibiting the p- AKT/mTOR pathway; (2) ameliorated HFD-mediated accumulation of fat mass by upregulating β-oxidation regulator PPAR-α and downregulating fatty acid synthesis marker SREBP-1c via lipophagy; (3) diminished the HFD-induced hepatic pro-inflammatory mediators TNF-α and IL-1β via NF-κB inactivation; (4) decreased the NASH-induced hepatic apoptotic marker caspase-3 activation caused by the upstream oxidative stress and by cytochrome P450 2E1 (CYP2E1); (5) mitigated the HFD-mediated lysosomal membrane permeabilisation and cathepsin B release partly via the reduction of reactive oxygen species (ROS). Conclusions. Chronic aerobic exercise reduces oxidative stress/ROS and ROS may cause lysosomal membrane destabilisation and disrupts the autophagic process. The beneficial effect of chronic exercise may further inhibit the process of lysosome membrane permeabilisation and facilitate lysosome fusion with autophagosomes to trigger autophagy. This process may possibly contribute to the inhibition of cathepsin B released into cytosol which further reduces inflammation and mitochondrial- dependent apoptosis.
Open Access
Atypical spindle cell/pleomorphic lipomatous tumor
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Lecoutere, Evelyne; Creytens, David
Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently described morphologically low-grade and clinically indolent adipocytic tumor, which will be incorporated as a new tumor entity in the upcoming 5th edition of the WHO Classification of Soft tissue and Bone tumors. Histologically, ASPLTs are characterized by ill-defined tumor margins and the presence of variable proportions of mild-to-moderately atypical spindle cells, adipocytes, lipoblasts, pleomorphic multinucleated cells and a myxoid or collagenous extracellular matrix. ASPLTs can show a wide variety of microscopic appearances and there is histologic overlap with diverse mimics. The diagnosis of ASPLT can therefore be challenging. Molecular studies have shown a consistent absence of MDM2 or CDK4 amplification. On the other hand, deletions or losses of 13q14, including RB1, have been identified in a significant subset of cases. This review provides an overview of the currently known clinical and pathological features of ASPLTs, detailing its most relevant differential diagnoses.
Open Access
Histological villous maturation in placentas of complicated pregnancies
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Vangrieken, Philippe; Vanterpool, Sizzle F.; Schooten, Frederik J. van; Nasiry, Salwan Al; Andriessen, Peter; Degreef, Ellen; Alfer, Joachim; Kramer, Boris W.; Rango, Ulrike von
Chorioamnionitis and preeclampsia account for the majority of preterm births worldwide. Thus far, adequate methods for early detection or prevention of these diseases are lacking. In preeclampsia, accelerated villous maturation is believed to compensate placental insufficiency. However, little is known about the effects of placental inflammation in chorioamnionitis on villous maturation. Therefore, we established a set of morphological parameters to evaluate histological villous maturity in pregnancies complicated by chorioamnionitis and preeclampsia. Preterm placentas complicated by chorioamnionitis or preeclampsia were compared to idiopathic preterm placentas and term controls. Histological villous maturation was analyzed by means of 17 histological markers. Fourteen of these markers provided information on absolute and relative numbers of the terminal villi (TV), the extent of their vascularization (using CD31-stained sections) and their exchange capacity. In addition, the numbers of syncytial bridges, syncytial apoptotic knots and shed syncytiotrophoblasts were counted. Accelerated villous maturation in preeclampsia was demonstrated by means of histological villous remodeling and confirmed by 11 relevant markers. Chorioamnionitis, however, only showed increased area of fetal capillaries. In preeclampsia, placentas may transition from growth to maturation earlier than placentas in normal pregnancies, whereas in chorioamnionitis placental changes are more acute and therefore less elaborated at a structural level. Regression analysis suggests the number of all villi and the number of terminal villi as a percentage of all villi as parameters to evaluate histological villous maturity in preeclamptic placentas and to assist diagnosis. However, we would recommend to analyze all 11 relevant parameters to judge placental maturity in detail.
Open Access
Pancreas is a preeminent source of ghrelin after sleeve gastrectomy in Wistar rats
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Camacho Ramírez, Alonso; Mayo Ossorio, María Ángeles; Pacheco García, José Manuel; Almorza Gomar, David; Ribelles García, Antonio; Belmonte Núñez, Ana; Prada Oliveira, J. Arturo; Pérez Arana, Gonzalo M.
Many surgical techniques are employed in the treatment of severe obesity. A main consequence of these techniques is the improvement of type 2 Diabetes mellitus. Ghrelin is a gut hormone released in the gastric fundus and corpus, which has been related to diabetic improvement as mentioned in these papers. Sleeve gastrectomy and Roux-en Y Gastric Bypass are surgical techniques broadly employed in humans; both severely reduce the gastric surface. Paradoxically, the serum level of ghrelin in patients is preserved. We hypothesized about the role of embryonic pancreatic epsilon cells, which have the capacity to release ghrelin. We studied the changes in the epsilon cells and differentiation markers with immunostaining and ghrelin serum level and after surgery. We employed euglycemic male Wistar rats: two surgical groups (Sleeve gastrectomy and Roux- en Y Gastric Bypass) and two control groups. We reported a significant increase of ghrelin epsilon-cells in the pancreas and basal serum after Sleeve gastrectomy versus the control groups. The epsilon cellular increment was related to neogenesis, as the neurogenin-3 marker revealed. The Roux-en Y Gastric Bypass showed neither epsilon cell increase nor basal serum changes in ghrelin release. As a conclusion, we reported that the severe suppression of the fundus gastric produced the recovery of ghrelin released by the epsilon cells, which was indicative of an ontogenic embryonic pancreatic function
Open Access
Expression of CXCR4 and MMP-2 is associated with poor prognosis in patients with osteosarcoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Gong, Chen; Sun, Kai; Xiong, Hui-hua; Sneh, Tal; Zhang, Jing; Zhou, Xiao; Yan, Peng; Wang, Jian-hua
Backgroud. Osteosarcoma is a primary malignant tumor with a high tendency to form metastasis and poor prognosis. Consequently, finding effective early indicators of metastases is crucial for identifying and treating high-risk patients. CXCR4 and MMP-2 have been found to strongly correlate with invasion and metastasis of malignant tumors, including osteosarcoma. Materials and Methods. Our study evaluated CXCR4 in conjunction with MMP-2 as an important clinicopathological prognostic predictor for metastasis and overall survival of osteosarcoma. 73 patients’ clinical data and pathological samples were retrieved for the study. A median time of 36 months follow-up was performed to evaluate for tumor metastasis and patient survival. CXCR4 and MMP-2 proteins in tumor tissues were detected by immunohistochemistry on paraffin- embedded tissue sections. Results. The positive expression rate of CXCR4 and MMP-2 was 68.5% and 54.8% respectively, and of the 45 patients who developed distal metastasis, 33 and 28 patients had positive expression of CXCR4 and MMP-2 respectively. The median metastasis-free survival was 72.00 months in the CXCR4-negative group and 14.00 months in the CXCR4 positive group. Furthermore, median overall survival was 73.77 and 24.00 months in these same two groups. Further, the median metastasis-free survival was 66.51 months in the MMP-2 negative group and 9.00 months in the MMP-2 positive group. The median overall survival was 75.07 and 19.00 months in these same two groups. MMP2 and metastasis remained the significant and independent prognostic factors for metastasis-free survival and overall survival by using the COX regression model adjusted for the multivariate predictors of survival. Conclusion. Our results suggest that metastasis and MMP-2 are both independent prognostic indicators for metastasis-free and overall survival of osteosarcoma patients.
Open Access
Prognostic value of microRNA-20b expression level in patients with prostate cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Zhang, Rongkui; Li, Fuwei; Wang, Yuchong; Yao, Ming; Chi, Changliang
Background. miR-20b is a member of the miR-106a-363 gene cluster located in the mammalian X chromosome, the larger miR-17 family, and the miR-17- 92 and miR-106b-25 gene clusters. Previous studies have indicated that miR-20b may function as oncogene or tumor suppressor in different types of cancers. The present study analyzed the association between miR-20b and clinicopathological characteristics of patients with prostate cancer. Methods. A total of 127 pairs of prostate cancer tissue samples and adjacent prostate tissue samples were collected from April 2013 to March 2018. The associations between miR-20b expression levels and clinicopathological factors were assessed using the χ 2‑test. Survival was estimated using the Kaplan-Meier method, and the differences in survival according to miR-20b expression were compared using the log-rank test. Prognostic values of miR-20b expression and clinical outcomes were evaluated by Cox regression analysis. Results. The relative expression of miR-20b in prostate cancer tissues was significantly higher than that in adjacent noncancerous prostate tissues (P<0.001). miR-20b expression was observed to be significantly associated with Gleason score (P<0.001), lymph node metastasis (P<0.001), and TNM stage (P=0.002). The log-rank test indicated that patients with increased miR- 20b expression experienced poor overall survival (P=0.037). Multivariate Cox regression analysis showed that miR-20b expression level (HR=2.181, 95% CI: 1.772-9.021, P=0.016) was an independent factor in predicting the overall survival of prostate cancer patients. Conclusion. The present study demonstrated that tissue miR-20b expression level could be a promising biomarker of prognosis in prostate cancer.
Open Access
PVAT: an important guardian of the cardiovascular system
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Liang, Xiuying; Qi, Yan; Dai, Fan; Gu, Jingya; Yao, Wenjuan
Perivascular adipose tissue (PVAT) had long been considered to serve only structural, vessel- supporting purposes, but today PVAT is recognized to be an endocrine organ with important physiological and pathological effects. The expansion of PVAT in vascular homeostasis and vascular disease has attracted much interest. PVAT has been shown to release a wide spectrum of molecules, such as PVAT-derived relaxing factors (PVATRFs) and PVAT-derived contracting factors (PVATCFs). PVAT dysfunction may lead to obesity, atherosclerosis, and other cardiovascular diseases. This review describes recent advances in our understanding of PVAT’s important effects on the cardiovascular system
Open Access
Growth pattern of experimental glioblastoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Ahlstedt, Jonatan; Förnvik, Karolina; Helms, Gunther; Salford, Leif G.; Ceberg, Crister; Skagerberg, Gunnar; Redebrandt, Henrietta Nittby
Glioblastoma multiforme (GBM) is an aggressive primary brain malignancy with a very poor prognosis. Researchers employ animal models to develop potential therapies. It is important that these models have clinical relevance. This means that old models, propagated for decades in cultures, should be questioned. Parameters to be evaluated include whether animals are immune competent or not, the infiltrative growth pattern of the tumor, tumor volume resulting in symptoms and growth rate. We here describe the growth pattern of an experimental glioblastoma model in detail with GFP positive glioblastoma cells in fully immune competent animals and study tumor growth rate and tumor mass as a function of time from inoculation. We were able to correlate findings made with classical immunohistochemistry and MR findings. The tumor growth rate was fitted by a Gompertz function. The model predicted the time until onset of symptoms for 5000 inoculated cells to 18.7±0.4 days, and the tumor mass at days 10 and 14, which are commonly used as the start of treatment in therapeutic studies, were 5.97±0.62 mg and 29.1±3.0 mg, respectively. We want to raise the question regarding the clinical relevance of the outline of glioblastoma experiments, where treatment is often initiated at a very early stage. The approach presented here could potentially be modified to gain information also from other tumor models.
Open Access
MiR-503-5p functions as an oncogene in oral squamous cell carcinoma by targeting Smad7
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Fei, Yifan; Shan, Weilan; Chen, Xiaoqing
Background. Oral squamous cell carcinoma (OSCC) is a common oral malignancy. Previous studies indicated that the level of miR-503-5p was upregulated in OSCC tissues. However, the mechanism by which miR-503-5p regulates the proliferation and invasion of OSCC cells remains unclear. Therefore, this study aimed to investigate the role of miR-503-5p during the progression of OSCC. Methods. The level of miR-503- 5p in Tca8113 cells was detected using RT-qPCR assay. In addition, CCK-8, transwell assays and flow cytometry assays were conducted to detect cell viability, migration, invasion and apoptosis, respectively. Meanwhile, the dual luciferase reporter assay was applied to explore the interaction between miR-503-5p and Smad7 in Tca8113 cells. Results. Overexpression of miR-503-5p significantly promoted the proliferation, migration and invasion of Tca8113 cells, while downregulation of miR- 503-5p markedly inhibited proliferation, migration and invasion of cells. In addition, knockdown of miR-503-5p obviously induced the apoptosis of Tca8113 cells via increasing the levels of Bax and cleaved caspase 3, and decreased the expression of Bcl-2. Moreover, SMAD family member 7 (Smad7) was identified as a direct binding target of miR-503-5p in Tca8113 cells. Overexpression of miR-503-5p significantly downregulated the levels of Smad7 and E-cadherin, but upregulated the levels of N-cadherin and MMP-9 in Tca8113 cells. Conclusion. These results indicated that miR-503-5p might act as an oncogene in OSCC cells by targeting Smad7. Therefore, miR-503-5p might act as a novel and potential therapeutic target for the treatment of OSCC
Open Access
Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) García, Sebastián; Martín Giménez, Virna Margarita; Mocayar Marón, Feres José; Reiter, Russel J.; Manucha, Walter
Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of "neuroinflammaging" has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging. Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuro- inflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases. Some of these neuroprotective effects are fundamentally related to its anti- inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.
Open Access
Tetraspanin CD63 independently predicts poor prognosis in colorectal cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Kaprio, Tuomas; Hagström, Jaana; Andersson, Leif C.; Haglund, Caj
CD63, a member of the tetraspanin family, is expressed in endosomes and enriched in exosomes. Tetraspanins participate in a variety of physiological processes, including cellular differentiation, cell-cell fusion, and cell migration. CD63 reportedly carries both protumorigenic and tumor suppressor properties, and appears to be upregulated in breast cancer, astrocytoma, and melanoma. Yet, the effect of CD63 on cancer prognosis remains unclear, and no previous reports examined it in colorectal cancer (CRC). Identifying novel biomarkers will allow us to better differentiate patients with an increased risk of recurrence and who might benefit from adjuvant therapy. We applied immunohistochemistry with antibodies to human CD63 on 620 consecutive CRC patients treated at the Helsinki University Hospital. We evaluated the associations between CD63 expression and clinicopathological parameters and patient prognosis. We found that CD63 expression associated with an advanced stage, poor differentiation, and mucinous histology. We found no association between CD63 expression and age, sex or tumor location. CD63 expression predicted an unfavorable prognosis in CRC (p=0.00001, log-rank test) and in a subgroup of patients with metastasized CRC (p=0.011). Cox’s multivariate analysis identified CD63 as an independent factor predicting an unfavorable prognosis in CRC and in the subgroup with metastasized disease. We show for the first time that CD63 immunohisto- chemistry expression represents an independent marker of an unfavorable prognosis in CRC and associates with unfavorable clinicopathological parameters. Our results support the hypothesis that a higher tissue expression of CD63 in CRC, indicating an epithelial-to-mesenchymal transition (EMT)-associated secretory phenotype, associated with an adverse outcome.
Open Access
Spatial and phenotypic characterization of pancreatic cancer-associated fibroblasts after neoadjuvant treatment
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Nielsen, Michael Friberg Bruun; Mortensen, Michael Bau; Sörensen, Mia Dahl; Wirenfeldt, Martin; Kristensen, Bjarne Winther; Schröder, Henrik Daa; Pfeiffer, Per; Detlefsen, Sönke
Pancreatic ductal adenocarcinoma (PC) is characterized by a highly fibrotic desmoplastic stroma. Subtypes of cancer-associated fibroblasts (CAFs) have been identified in chemotherapy-naïve PC (CTN-PC), but their precise functions are still unclear. Our knowledge regarding the properties of CAFs in the regressive stroma after neoadjuvant treatment (NAT) of PC (NAT-PC) is particularly limited. We aimed to examine the marker phenotypic properties of CAFs in the regressive stroma of PC. Surgical specimens from patients with CTN-PC (n=10) and NAT-PC (n=10) were included. Juxtatumoural, peripheral, lobular, septal, peripancreatic, and regressive stromal compartments were manually outlined using digital imaging analysis (DIA) for area quantification. The compartment-specific expression of CD271, cytoglobin, DOG-1, miR-21, osteonectin, PDGF-Rβ, and tenascin C was evaluated by immunohistochemistry or in situ hybridization, using manual scoring and automated DIA. The area fraction of the regressive stroma was significantly higher in NAT-PC than in CTN-PC (P=0.0002). CD271 (P<0.01), cytoglobin (P<0.05), DOG1 (P<0.05), miR-21 (P<0.05), and tenascin C (P<0.05) exhibited significant differences in their expression profiles between the juxtatumoural compared to the peripheral and regressive stroma. PDGF-Rβ expression was significantly higher in juxtatumoural than in peripheral CAFs (P<0.05). Our data provide further support of the concept of stromal heterogeneity and phenotypic different CAF subtypes in PC. CAFs in the regressive stroma of NAT- PC show a marker phenotype similar to some (namely, peripheral) and different from other (namely, juxtatumoural) previously defined CAF subtypes. It may be hypothesized that phenotypic CAF subtypes, at least in part, also may share functional properties. Studies examining the precise functional characteristics of CAF subtypes in PC are needed

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