Histology and histopathology Vol.39, nº9 (2024)

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Open Access
Elevated tissue expression of RANKL and RANK is associated with poorer survival rates in pancreatic cancer patients
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Ortega, Miguel A; Jiménez Álvarez, Laura; Fraile Martinez, Oscar; Garcia Montero, Cielo; Leon Oliva, Diego De; Toledo Lobo, M. Val; Palacios, Esther; Granado, Paula; Esteban, Alfonso; Guijarro, Luis G.; Pekarek, Leonel; Asúnsolo, Ángel; Buján, Julia; García Honduvilla, Natalio; Álvarez Mon, Melchor; Saez, Miguel A; Díaz Pedrero, Raúl; López González, Laura
Pancreatic cancer is a highly lethal malignancy with a growing incidence reported worldwide. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, which is often diagnosed at advanced stages, making its prognosis and medical management difficult. The identification of histopathological biomarkers has allowed a more precise stratification of pancreatic cancer patients, providing additional information about their prognosis and offering possible therapeutic targets to be explored. The prognostic value of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been evaluated in breast and prostate tumors, however, their usefulness has not been assessed in pancreatic cancer. In the present work, we analyzed the relationship between the protein expression of RANK and RANKL with the survival of 41 patients with pancreatic cancer followed for 60 months, by performing immunohisto-chemistry and Kaplan-Meier curves. Our results demonstrate a direct association of high expression levels of RANK and RANKL with poorer survival of pancreatic cancer patients in comparison to those with low/medium and null expression levels of both markers. Further studies should be conducted to explore the carcinogenic role of both components in this type of tumor, as well as additional promising translational uses.
Open Access
Myxoid pleomorphic liposarcoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Fadaei, Sharareh; Cordier, Fleur; Ferdinande, Liesbeth; Dorpe, Jo Van; Creytens, David
Myxoid pleomorphic liposarcoma (MPL) is an extremely rare adipocytic tumor, recently recognized as a distinct entity in the 5th edition of the World Health Organization (WHO) Classification of Soft Tissue and Bone Tumors. Predominantly found in the mediastinum of young women, MPLs exhibit a combination of histological features characteristic of myxoid liposarcoma and pleomorphic (lipo)sarcoma. Their unique molecular features distinguish MPLs from other liposarcomas. Unlike myxoid liposarcomas and well-differentiated/dedifferentiated liposarcomas, MPLs lack specific FUS/EWSR1::DDIT3 gene fusions and MDM2/CDK4 gene amplifications, respectively. MPLs are associated with complex karyotypes, further highlighting their distinct genetic profile. They demonstrate aggressive growth patterns, high recurrence rates, and a high tendency to metastasize. These factors contribute to a poor prognosis, with a median survival of approximately 22.6 months. The aim of this review article is to provide a comprehensive summary of previously documented case reports and studies related to MPLs. By shedding light on the intricate details of MPLs, researchers and clinicians can gain valuable insights that may pave the way for improvements in diagnosis, treatment, and patient outcomes in the future.
Open Access
Role of INPP4B in the proliferation, migration, invasion, and survival of human endometrial cancer cells
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Zhao, Jing; Du, Xue-mei; Si, Wen; Zhao, Xian-he; Zhou, Zi-qi
Background. Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a tumor repressor in several human cancers while its role in endometrial cancer has not been investigated yet. Therefore, the current study was designed to determine whether INPP4B participates in the progression of endometrial cancer by utilizing clinical data and experimental determination. Materials and methods. We first include six chemotherapy-treated patients with recurrent and metastatic endometrioid carcinoma to determine the relationship between INPP4B mutation and relative tumor burden. By using siRNA-mediated gene silencing and vector-mediated gene overexpression, we further determined the effect of manipulating INPP4B expression on the proliferation, invasion, and survival of endometrial cancer cells. Furthermore, the repressing effect of INPP4B together with its role in chemotherapy was further validated by xenograft tumor-bearing mice models. Western blot analysis was used to explore further downstream signaling modulated by INPP4B expression manipulation. Results. Two of the patients were found to have INPP4B mutations and the mutation frequency of INPP4B increased during the progression of chemotherapy resistance. Endometrial cancer cells with silenced INPP4B expression were found to have promoted tumor cell proliferation, invasion, and survival. Endometrial cancer cells overexpressing INPP4B were found to have decreased tumor cell proliferation, invasion, and survival. An in vivo study using six xenograft tumor-bearing mice in each group revealed that INPP4B overexpression could suppress tumor progression and enhance chemosensitivity. Furthermore, INPP4B overexpression was found to modulate the activation of Wnt3a signaling. Conclusion. The current study suggested that INPP4B could be a suppressor in endometrial cancer progression and might be a target for endometrial cancer treatment. Also, INPP4B might serve as a predictor of chemosensitivity determination
Open Access
Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Dai, Lu; Huang, Jun; Shen, Kai-Feng; Yang, Xiao-lin; Zhu, Gang; Zhang, Li; Wang, Zhong-ke; Liu, Shi-yong; Liao, Xiang; Xu, Sen-lin; Yang, Hui; Li, Xing-yi; Zhang, Chun-Qing
Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.
Open Access
Neuregulin 1 (NRG1) and its receptors in the enteric nervous system and other parts of the gastrointestinal wall
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Gonkowski, Sławomir
Neuregulin 1 (NRG1) belonging to the transmembrane growth factors family is widespread in living organisms. It acts through ErbB family receptors and first of all takes part in embryogenesis, as well as in developmental, regenerative and adaptive processes occurring in various internal organs and systems. It is known that NRG1 and its receptors are present in various parts of the gastrointestinal (GI) tract. First of all NRG1 and ErbB receptors have been detected in the enteric nervous system (ENS) localized in the wall of the esophagus, stomach and intestine and regulating the majority of the GI tract functions, but also in the mucosal and muscular layers of the GI tract. The NRG1/ErbB pathway is involved in the development and differentiation of the ENS and regulation of the intestinal epithelium functions. Moreover, dysregulation of this pathway results in a wide range of gastrointestinal diseases. However, till now there are no summarizations of previous studies concerning distribution and functions of NRG1 and its receptors in the GI tract. The present review fills this gap.
Open Access
Rapamycin mitigates organ damage by autophagy-mediated NLRP3 inflammasome inactivation in sepsis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Li, Xiaofeng; Zeng, Qingqiu; Yao, Rui; Zhang, Lingyan; Kong, Ying; Shen, Bin
Autophagy activation can alleviate sepsis-induced organ injuries. Rapamycin (Rap) has emerged as an autophagy regulator in multiple forms of organ injuries. This study aimed to assess whether Rap protects rats from cecal ligation and puncture (CLP)-induced sepsis through autophagy-mediated inactivation of the NLRP3 inflammasome. Rats were allocated to the sham, CLP, Rap (10 mg/kg), or 3-Methyladenine (3-MA) (15 mg/kg) groups. A rat CLP model was established. The survival of rats and lung wet-to-dry weight ratio in each group was assessed. Blood biochemical indexes and oxidative stress-related factors were analyzed with an automatic biochemical analyzer. The bacterial counts of blood and organs were monitored. The degrees of myeloperoxidase of the ileum, inflammation-related indexes, and pathological changes in the tissues were detected by ELISA and hematoxylin-eosin staining. The levels of NLRP3 inflammasome and autophagy-related factors were analyzed by Western blot. Rap increased the survival and SOD activity, and repressed ALT, AST, BUN, SCr, MDA, and inflammation-related marker levels in CLP rats, it also restrained the bacterial counts of blood, lung, liver, and kidney in CLP rats; the effects of 3-MA on CLP rats on the above-mentioned indicators were opposite to those of Rap. Additionally, Rap alleviated the pathological injury of the lung, liver, and kidney, which was the opposite to the effect of 3-MA on CLP rats. Furthermore, Rap mitigated the ASC, Pro-caspase 1, and NLRP3 levels and increased the Beclin-1 levels and the LC3II/LC3I ratio in the organ tissues. Collectively, autophagy activation can mitigate organ damage by suppressing the NLRP3 inflammasome in sepsis rats.
Open Access
Astragaloside IV induces endothelial progenitor cell angiogenesis in deep venous thrombosis through inactivation of PI3K/AKT signaling
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Lyu, Xiaojiang; Yi, Zhigang; He, Yun; Zhang, Chunfeng; Zhu, Ping; Liu, Chonghai
Background. Deep vein thrombosis (DVT), referred to as venous thromboembolism, is the third most frequent cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to the recanalization of DVT. Astragaloside IV (AS-IV) has been suggested to have angiogenesis-enhancing effects. Here, we investigate the roles and mechanisms of AS-IV in EPCs and DVT. Methods. The experimental DVT model was established by inferior vena cava stenosis in rats. EPCs were collected from patients with DVT. Transwell assays were performed to detect cell migration. Tube formation was determined using Matrigel basement membrane matrix and ImageJ software. The thrombus weight and length were measured. Pathological changes were examined by hematoxylin-eosin staining. The production of proinflammatory cytokines was estimated by ELISA. The level of PI3K/AKT-related proteins was measured by western blotting. Results. AS-IV administration facilitated the migrative and angiogenic functions of human EPCs in vitro. Additionally, AS-IV inhibited thrombosis and repressed the infiltration of leukocytes into the thrombus and the production of proinflammatory cytokines in rats. Mechanistically, AS-IV inactivated PI3K/AKT signaling in rats. Conclusion. AS-IV prevents thrombus in an experimental DVT model by facilitating EPC angiogenesis and decreasing inflammation through inactivation of PI3K/AKT signaling.
Open Access
Localization of advanced glycation end-products and their receptor in tendinopathic lesions
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Asomugha, Eva; Cho, Young; Paudel, Sharada; Guo, Yi; Schon, Lew; Zhang, Zijun
This study was designed to investigate the accumulation of advanced glycation end-products (AGEs) and the expression of the receptor of AGEs (RAGE) in tendinopathic tissues. In this study, tendinopathic posterior tibial tendons (PTT) were collected from patients (n=6). Redundant autografts of flexor digitorum longus tendon (FDL; n=3) were used for controls. The control and tendinopathic tendon tissues were used for extraction of proteins for western blot and sectioned for histology and immunohisto-chemistry. Tendinopathy of the PTT was confirmed histologically by the presentation of disorderly collagen fibers, high cellularity and increased vascularity. By immunohistochemistry, heterogeneous accumulation of AGEs was detected on the PTT sections and concentrated in areas, where collagen fibers were disorderly and tangled. In the PTT, roundish tenocytes were also AGEs-positive. In contrast, AGEs were diffuse, lightly stained in the FDL. A greater number of tenocytes within the tendinopathic lesions in the PTT were RAGE positive, compared to the tenocytes in the FDL. Western blot confirmed the presence of AGEs and RAGE in both tendinopathic PTT and control FDL but their band densities were not significantly different. The spatial relation of the accumulated AGEs and RAGE- positive tenocytes within the tendinopathic lesions indicates their involvement in the molecular pathology of tendinopathy.
Open Access
Targeting PEAK1 sensitizes anaplastic thyroid carcinoma cells harboring BRAFV600E to Vemurafenib by Bim upregulation
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Wang, Qiuhan; Hao, Fengyun; Ning, Liang; Sun, Chong
Pseudopodium-enriched atypical kinase 1 (PEAK1) has been demonstrated to be upregulated in human malignancies and cells. Enhanced PEAK1 expression facilitates tumor cell survival and chemoresistance. However, the role of PEAK1 inhibition to anaplastic thyroid carcinoma cell (ATC) and vemurafenib resistance is still unknown. Here, we observed that targeting PEAK1 inhibited cell viability and colony formation, but not cell apoptosis in both of the 8505C and Hth74 cells in vitro. Targeting PEAK1 sensitized 8505C and Hth74 cells to Vemurafenib by inducing cell apoptosis, and thereby decreasing cell viability. Mechanistically, Vemurafenib treatment upregulated PEAK1 expression. Combined PEAK1 depletion and Vemurafenib treatment upregulated Bim expression. Targeting PEAK1 sensitized Vemurafenib-induced apoptosis by upregulating Bim. In conclusion, Vemurafenib resistance in ATC cells harboring BRAFV600E is associated with PEAK1 activation, resulting in the inhibition of pro-apoptotic Bim protein. Therefore, targeting PEAK1 may be an effective strategy to sensitize ATC harboring BRAFV600E to Vemurafenib.
Open Access
The application of mesenchymal stem cells in the treatment of traumatic brain injury: Mechanisms, results, and problems
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Zhang, Ying; Zheng, Zejun; Sun, Jinmeng; Xu, Shuangshuang; Wei, Yanan; Ding, Xiaoling; Ding, Gang
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can be derived from a wide variety of human tissues and organs. They can differentiate into a variety of cell types, including osteoblasts, adipocytes, and chondrocytes, and thus show great potential in regenerative medicine. Traumatic brain injury (TBI) is an organic injury to brain tissue with a high rate of disability and death caused by an external impact or concussive force acting directly or indirectly on the head. The current treatment of TBI mainly includes symptomatic, pharmacological, and rehabilitation treatment. Although some efficacy has been achieved, the definitive recovery effect on neural tissue is still limited. Recent studies have shown that MSC therapies are more effective than traditional treatment strategies due to their strong multi-directional differentiation potential, self-renewal capacity, and low immunogenicity and homing properties, thus MSCs are considered to play an important role and are an ideal cell for the treatment of injurious diseases, including TBI. In this paper, we systematically reviewed the role and mechanisms of MSCs and MSC-derived exosomes in the treatment of TBI, thereby providing new insights into the clinical applications of MSCs and MSC-derived exosomes in the treatment of central nervous system disorders
Open Access
Quantification of eosinophils in the lower gastrointestinal tract of adults: a review of surgical specimens with normal histology from the Free State province, South Africa
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Duncan, Jane; Joubert, Gina; Goedhals, Jacqueline
Aim. Eosinophils are normal residents of the gastrointestinal tract (GIT). They are noted in small numbers with significant variation between anatomic locations. An idiopathic increase of eosinophils is known as eosinophilic gastrointestinal disease (EGID). EGIDs are a heterologous group of disorders that produce a range of enteric and colonic syndromes. Their incidence has been increasing worldwide. Our study aimed to quantify eosinophils in each segment of the GIT in surgical specimens with normal histology to facilitate the histological diagnosis of EGID. Similarly, we aimed to describe the effect of race and gender on gastrointestinal eosinophil numbers. Methods. A retrospective, quantitative comparative study was performed. We assessed 360 surgical specimens with normal histology from the lower gastrointestinal tract of African and Caucasian adults from the Free State Province, South Africa. The number of eosinophils per mm2 was counted. Results. Overall, comparable eosinophil values were noted for both males and females, and African and Caucasian South Africans. However, Caucasians recorded a higher concentration of eosinophils in the appendix and the left colon. Eosinophils were most numerous in the lamina propria, with only small numbers present in the epithelium. Our results show that the South African population has similar eosinophil distribution trends to international studies. However, South Africans had far fewer eosinophils than Japanese and North American adults in each segment. Conclusions. Specific eosinophil reference ranges were formulated to quantify reference ranges of eosinophils in the lower GIT, allowing for the accurate diagnosis of EGIDs in our population in future
Open Access
GNA15 facilitates the malignant development of thyroid carcinoma cells via the BTK-mediated MAPK signaling pathway
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Sun, Yihan
G protein subunit alpha 15 (GNA15) is recognized as an oncogene for some cancers, however, its role in thyroid carcinoma (TC) is elusive and is investigated in this study. Concretely, bioinformatics was employed to analyze the GNA15 expression profile in TC. The effect of GNA15 on TC cell functions was examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Transwell assays. Expressions of extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 were determined using Western blot. The involvement of Bruton tyrosine kinase (BTK) in the mechanism of GNA15 was investigated by BTK knockdown and rescue assay. GNA15 presented an overexpression pattern in TC samples, which facilitated the viability, proliferation, migration, and invasion of TC cells; GNA15 silencing led to converse results. Ratios of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 were upregulated by GNA15 overexpression. The BTK deficiency weakened the aforementioned behaviors of TC cells and blocked the MAPK signaling pathway, however, these effects were counteracted by GNA15 overexpression. Collectively, GNA15 contributes to the malignant development of TC cells by binding to BTK and thus activating the MAPK signaling pathway.

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