Pub Date : 2024-10-18DOI: 10.1016/j.prp.2024.155668
Carla Stephan , Majd Al Assaad , Max F. Levine , Aditya Deshpande , Michael Sigouros , Jyothi Manohar , Andrea Sboner , Olivier Elemento , Anna C. Pavlick , Juan Miguel Mosquera
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine neoplasm of the skin. Immunosuppression, ultraviolet radiation and the integration of Merkel cell polyomavirus (MCPyV) have all been shown to be involved in the pathogenesis of this malignancy. We performed whole genome sequencing on two MCPyV-negative cases of MCC that demonstrated very different clinical presentations and outcomes, and mutational profiles. The first case exhibited a highly aggressive clinical course, absence of UV-signature mutations and a low tumor mutational burden. A rearrangement in the tumor suppressor gene SUFU was identified, a likely driver and potential target of the Hedgehog signaling pathway. Meanwhile, the second case exhibited a less aggressive behavior, harbored UV-signature mutations, and a high mutational burden including mutations in TP53 and RB1.
{"title":"Whole genome sequencing elucidates etiological differences in MCPyV-negative Merkel cell carcinoma","authors":"Carla Stephan , Majd Al Assaad , Max F. Levine , Aditya Deshpande , Michael Sigouros , Jyothi Manohar , Andrea Sboner , Olivier Elemento , Anna C. Pavlick , Juan Miguel Mosquera","doi":"10.1016/j.prp.2024.155668","DOIUrl":"10.1016/j.prp.2024.155668","url":null,"abstract":"<div><div>Merkel cell carcinoma (MCC) is an aggressive neuroendocrine neoplasm of the skin. Immunosuppression, ultraviolet radiation and the integration of Merkel cell polyomavirus (MCPyV) have all been shown to be involved in the pathogenesis of this malignancy. We performed whole genome sequencing on two MCPyV-negative cases of MCC that demonstrated very different clinical presentations and outcomes, and mutational profiles. The first case exhibited a highly aggressive clinical course, absence of UV-signature mutations and a low tumor mutational burden. A rearrangement in the tumor suppressor gene <em>SUFU</em> was identified, a likely driver and potential target of the Hedgehog signaling pathway. Meanwhile, the second case exhibited a less aggressive behavior, harbored UV-signature mutations, and a high mutational burden including mutations in <em>TP53</em> and <em>RB1</em>.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155668"},"PeriodicalIF":2.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays a role in the hemostasis of the immune system, inflammation, and cell proliferation. However, it can also have a dark side as it is involved in pro-inflammatory cytokines and pathological processes such as cell growth and death, autoimmunity, and inflammation, leading to a wide range of chronic inflammatory diseases, including digestive cancer. TNF-alpha binds to two distinct receptors, TNFRI and TNFRII. Upon binding of the ligand to these receptors, TNF receptor-associated factors (TRAFs) are recruited to the cytoplasmic receptor, triggering the activation of transcription factors such as NF-kB and Activator protein 1 (AP_1). In contrast, binding of cytokines to certain family members, such as TNF RI and Fas Ligand (Fas L), leads to the secretion and initiation of apoptosis. Gastrointestinal malignancies are among the most common types of cancer globally. Despite extensive research, the exact cause of these tumors remains a mystery. Unfortunately, they often have a poor prognosis and are often detected at a late stage. The global incidence of gastrointestinal cancers, including those of the stomach, esophagus, colon, liver, and pancreas, is on the rise, leading to a surge in both incidence and mortality. Growth factors and cytokines, which are signaling molecules found in the tumor microenvironment, are thought to be major contributors to the development and metastasis of these cancers. In this review, we explored the role of TNF-α, and its receptors in the development of digestive cancers, including its signaling pathways and functions.
{"title":"TNF-α, and TNFRs in gastrointestinal cancers","authors":"Zahra Mozooni , Rezvaneh Ghadyani , Shahrzad Soleimani , Ehsan Rouhollahpour Ahangar , Mojgan Sheikhpour , Mehrdad Haghighi , Marzieh Motallebi , Abolfazl Movafagh , Seyed Mohsen Aghaei-Zarch","doi":"10.1016/j.prp.2024.155665","DOIUrl":"10.1016/j.prp.2024.155665","url":null,"abstract":"<div><div>Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays a role in the hemostasis of the immune system, inflammation, and cell proliferation. However, it can also have a dark side as it is involved in pro-inflammatory cytokines and pathological processes such as cell growth and death, autoimmunity, and inflammation, leading to a wide range of chronic inflammatory diseases, including digestive cancer. TNF-alpha binds to two distinct receptors, TNFRI and TNFRII. Upon binding of the ligand to these receptors, TNF receptor-associated factors (TRAFs) are recruited to the cytoplasmic receptor, triggering the activation of transcription factors such as NF-kB and Activator protein 1 (AP_1). In contrast, binding of cytokines to certain family members, such as TNF RI and Fas Ligand (Fas L), leads to the secretion and initiation of apoptosis. Gastrointestinal malignancies are among the most common types of cancer globally. Despite extensive research, the exact cause of these tumors remains a mystery. Unfortunately, they often have a poor prognosis and are often detected at a late stage. The global incidence of gastrointestinal cancers, including those of the stomach, esophagus, colon, liver, and pancreas, is on the rise, leading to a surge in both incidence and mortality. Growth factors and cytokines, which are signaling molecules found in the tumor microenvironment, are thought to be major contributors to the development and metastasis of these cancers. In this review, we explored the role of TNF-α, and its receptors in the development of digestive cancers, including its signaling pathways and functions.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155665"},"PeriodicalIF":2.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-coding RNAs (lncRNAs) play critical roles in various cellular processes, including a novel form of regulated cell death known as disulfidptosis, characterized by accumulating protein disulfide bonds and severe endoplasmic reticulum stress. This review highlights the therapeutic potential of lncRNAs in regulating disulfidptosis for cancer treatment, emphasizing their influence on key pathway components such as GPX4, SLC7A11, and PDIA family members. Recent studies have demonstrated that targeting specific lncRNAs can sensitize cancer cells to disulfidptosis, offering a promising approach to cancer therapy. The regulation of disulfidptosis by lncRNAs involves various signaling pathways, including oxidative stress, ER stress, and calcium signaling. This review also discusses the molecular mechanisms underlying lncRNA regulation of disulfidptosis, the challenges of developing lncRNA-based therapies, and the future potential of this rapidly advancing field in cancer research.
{"title":"Therapeutic Potential of lncRNAs in Regulating Disulfidptosis for Cancer Treatment","authors":"Abida , Abdulmalik S.A. Altamimi , Nehmat Ghaboura , Ashok Kumar Balaraman , Pranchal Rajput , Pooja Bansal , Sushama Rawat , Fadiyah Jadid Alanazi , Abeer Nuwayfi Alruwaili , Nouf Afit Aldhafeeri , Haider Ali , Pran Kishore Deb","doi":"10.1016/j.prp.2024.155657","DOIUrl":"10.1016/j.prp.2024.155657","url":null,"abstract":"<div><div>Non-coding RNAs (lncRNAs) play critical roles in various cellular processes, including a novel form of regulated cell death known as disulfidptosis, characterized by accumulating protein disulfide bonds and severe endoplasmic reticulum stress. This review highlights the therapeutic potential of lncRNAs in regulating disulfidptosis for cancer treatment, emphasizing their influence on key pathway components such as GPX4, SLC7A11, and PDIA family members. Recent studies have demonstrated that targeting specific lncRNAs can sensitize cancer cells to disulfidptosis, offering a promising approach to cancer therapy. The regulation of disulfidptosis by lncRNAs involves various signaling pathways, including oxidative stress, ER stress, and calcium signaling. This review also discusses the molecular mechanisms underlying lncRNA regulation of disulfidptosis, the challenges of developing lncRNA-based therapies, and the future potential of this rapidly advancing field in cancer research.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155657"},"PeriodicalIF":2.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.prp.2024.155663
Suvesh Munakarmi , Yamuna Gurau , Juna Shrestha , Lokendra Chand , Ho Sung Park , Geum-Hwa Lee , Yeon Jun Jeong
Background
Acute liver injury serves as a crucial marker for detecting liver damage due to toxic, viral, metabolic, and autoimmune exposures. Due to the response to adverse external stimuli and various cellular homeostasis, Endoplasmic reticulum stress (ERS), Oxidative stress, and Inflammation have great potential for treating liver injury. Trans-chalcones (TC) is a polyphenolic compound derived from a natural plant with anti-oxidative and anti-inflammatory abilities. Here, TC was aimed to attenuate liver injury by triggering ER stress, oxidative stress, inflammation, and apoptosis. A single dose of carbon tetrachloride (CCl4) 1 mL/kg was administered intraperitoneally into C57BL6 mice to construct an in vivo NAFLD model, whereas AML12 cells were treated with lipopolysaccharides (LPS) to construct an in vitro NAFLD model. The mice used in the experiment were randomly assigned to two groups: a 12-hour set and a 24-hour set. Forty-nine mice were randomly divided into seven groups, the control group (Group I), TC group (Group II) 10 mg/kg TC, negative control group (Group III) CCl4, TC + CCl4 groups (Groups IV−VI), mice were subcutaneously treated with (5, 10, and 20) mg/kg of TC for three consecutive days before the CCl4 injection and the positive control group (Group VII) received 10 mg/kg Silymarin. After the experiment, serum transaminase, liver histological pathology, hepatic expression levels ERS, oxidative stress, and inflammation-related markers were assessed. TC pre-treatment significantly alleviates the expression of ER stress, oxidative stress, inflammatory cytokines, and apoptosis in both in vivo and in vitro models of liver injury. TC treatment significantly reduced serum transaminase levels (ALT and AST), and improved liver histopathological scores. TC administration also led to a reduction in MDA levels and the suppression of ROS generated by CCl4 in hepatic tissue, which contributed to an increase in GSH levels. The protective effect of TC on the liver injury mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, TC pre-treatment dramatically decreased the protein levels of ER stress indicators such as CHOP, Bip, Ero-Lα, IRE1α, PERK, Calnexin, and PDI when compared to the CCl4-only treated group. TC exerts hepatoprotective effects against CCl4-induced acute liver injuries in mice by modulating ERS, oxidative stress, and inflammation. These results suggest that TC pre-treatment at a dose of (20 mg/kg BW) was as effective as silymarin (10 mg/kg) in preventing CCl4-induced acute liver injury. Further investigations are necessary to elucidate the precise molecular mechanisms underlying the hepatoprotective effects of TC and to explore its therapeutic potential in clinical trials.
{"title":"trans-chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation","authors":"Suvesh Munakarmi , Yamuna Gurau , Juna Shrestha , Lokendra Chand , Ho Sung Park , Geum-Hwa Lee , Yeon Jun Jeong","doi":"10.1016/j.prp.2024.155663","DOIUrl":"10.1016/j.prp.2024.155663","url":null,"abstract":"<div><h3>Background</h3><div>Acute liver injury serves as a crucial marker for detecting liver damage due to toxic, viral, metabolic, and autoimmune exposures. Due to the response to adverse external stimuli and various cellular homeostasis, Endoplasmic reticulum stress (ERS), Oxidative stress, and Inflammation have great potential for treating liver injury. <em>Trans</em>-chalcones (TC) is a polyphenolic compound derived from a natural plant with anti-oxidative and anti-inflammatory abilities. Here, TC was aimed to attenuate liver injury by triggering ER stress, oxidative stress, inflammation, and apoptosis. A single dose of carbon tetrachloride (CCl<sub>4</sub>) 1 mL/kg was administered intraperitoneally into C57BL6 mice to construct an <em>in vivo</em> NAFLD model, whereas AML12 cells were treated with lipopolysaccharides (LPS) to construct an <em>in vitro</em> NAFLD model. The mice used in the experiment were randomly assigned to two groups: a 12-hour set and a 24-hour set. Forty-nine mice were randomly divided into seven groups, the control group (Group I), TC group (Group II) 10 mg/kg TC, negative control group (Group III) CCl<sub>4</sub>, TC + CCl<sub>4</sub> groups (Groups IV−VI), mice were subcutaneously treated with (5, 10, and 20) mg/kg of TC for three consecutive days before the CCl<sub>4</sub> injection and the positive control group (Group VII) received 10 mg/kg Silymarin. After the experiment, serum transaminase, liver histological pathology, hepatic expression levels ERS, oxidative stress, and inflammation-related markers were assessed. TC pre-treatment significantly alleviates the expression of ER stress, oxidative stress, inflammatory cytokines, and apoptosis in both <em>in vivo</em> and <em>in vitro</em> models of liver injury. TC treatment significantly reduced serum transaminase levels (ALT and AST), and improved liver histopathological scores. TC administration also led to a reduction in MDA levels and the suppression of ROS generated by CCl4 in hepatic tissue, which contributed to an increase in GSH levels. The protective effect of TC on the liver injury mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, TC pre-treatment dramatically decreased the protein levels of ER stress indicators such as CHOP, Bip, Ero-Lα, IRE1α, PERK, Calnexin, and PDI when compared to the CCl4-only treated group. TC exerts hepatoprotective effects against CCl<sub>4</sub>-induced acute liver injuries in mice by modulating ERS, oxidative stress, and inflammation. These results suggest that TC pre-treatment at a dose of (20 mg/kg BW) was as effective as silymarin (10 mg/kg) in preventing CCl4-induced acute liver injury. Further investigations are necessary to elucidate the precise molecular mechanisms underlying the hepatoprotective effects of TC and to explore its therapeutic potential in clinical trials.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155663"},"PeriodicalIF":2.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Indoleamine 2,3-Dioxygenase 1 (IDO1)-mediated tryptophan degradation, which is the rate-limiting enzyme of tryptophan/kynurenine pathway, may cause immune suppression in the tumor microenvironment, while potentiating proliferative and metastatic activity in the tumor focus, Phase studies of IDO1 inhibitors are ongoing, and our study aims to evaluate the potential contribution of IDO1 gene expression to the tryptophan/kynurenine pathway in tumor and tumor microenvironment foci in gastric cancer (GC) on a clinicopathological axis,
Method
In the case-control study design, the determination of tryptophan and its metabolites in the serum of 51 GC and 49 healthy controls was made using High Pressure Liquid Chromatography-Fluorescence Detector (HPLC-FD). IDO1 expression in a total of 102 tissues with tumor and tumor microenvironment was detected by quantitative PCR (q-PCR).
Results
In gastric tumors, 3,25-fold decreased expression of IDO1 was detected according to the tumor microenvironment (p=0,05), IDO1 expression was found to be more than 2 times higher in signet ring cell carcinoma (SRCC) and poorly differentiated tumors without distant organ metastasis (p<0,05), In GC, tryptophan level was found to be 1,6 times lower than in control (AUC:0889; cut off≤21,57; p<0001), Low tryptophan level was found in advanced tumor stage compared to early stage and in the presence of perineural invasion compared to its absence (p<0,05) The level of kynurenine was found to be approximately 1,8 times lower in SRCC (p=0,04),
Conclusion
Increased tryptophan accumulation in the gastric tumor and its microenvironment, when catabolized via IDO1, exhibits histological type, tumor differentiation, and metastasis-promoting effects more prominently in aggressive subtypes such as SRCC,
{"title":"IDO1-mediated catabolism of tryptophan in gastric tumors: Its potential role in the axis of histopathology, differentiation and metastasis","authors":"Cem Horozoglu , Mehmet Tolgahan Hakan , Dilara Sonmez , Asli Yildiz , Seyda Demirkol , Fikret Aktas , Sidar Bagbudar , Ozlem Kucukhuseyin , Soykan Arikan , Filiz Akyuz , Ilhan Yaylim","doi":"10.1016/j.prp.2024.155655","DOIUrl":"10.1016/j.prp.2024.155655","url":null,"abstract":"<div><h3>Background</h3><div>Indoleamine 2,3-Dioxygenase 1 (IDO1)-mediated tryptophan degradation, which is the rate-limiting enzyme of tryptophan/kynurenine pathway, may cause immune suppression in the tumor microenvironment, while potentiating proliferative and metastatic activity in the tumor focus, Phase studies of IDO1 inhibitors are ongoing, and our study aims to evaluate the potential contribution of IDO1 gene expression to the tryptophan/kynurenine pathway in tumor and tumor microenvironment foci in gastric cancer (GC) on a clinicopathological axis,</div></div><div><h3>Method</h3><div>In the case-control study design, the determination of tryptophan and its metabolites in the serum of 51 GC and 49 healthy controls was made using High Pressure Liquid Chromatography-Fluorescence Detector (HPLC-FD). IDO1 expression in a total of 102 tissues with tumor and tumor microenvironment was detected by quantitative PCR (q-PCR).</div></div><div><h3>Results</h3><div>In gastric tumors, 3,25-fold decreased expression of IDO1 was detected according to the tumor microenvironment (p=0,05), IDO1 expression was found to be more than 2 times higher in signet ring cell carcinoma (SRCC) and poorly differentiated tumors without distant organ metastasis (p<0,05), In GC, tryptophan level was found to be 1,6 times lower than in control (AUC:0889; cut off≤21,57; p<0001), Low tryptophan level was found in advanced tumor stage compared to early stage and in the presence of perineural invasion compared to its absence (p<0,05) The level of kynurenine was found to be approximately 1,8 times lower in SRCC (p=0,04),</div></div><div><h3>Conclusion</h3><div>Increased tryptophan accumulation in the gastric tumor and its microenvironment, when catabolized via IDO1, exhibits histological type, tumor differentiation, and metastasis-promoting effects more prominently in aggressive subtypes such as SRCC,</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155655"},"PeriodicalIF":2.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Solid pseudopapillary neoplasm (SPN) is a tumor of young females with gain-of-function mutation in catenin beta 1 gene involved in Wnt signal transduction pathway. Beta-catenin immunohistochemistry (IHC) is used to diagnose SPN. Lymphoid enhancer-binding factor 1 (LEF-1) has been recognized in the transactivation of Wnt pathway. We aim to study LEF-1 IHC in SPN and other pancreatic tumors and compare it with beta-catenin IHC.
Methods
We retrieved cases of SPN, pancreatic neuroendocrine tumor (PanNET), serous cystadenoma (SCA), ductal adenocarcinoma (PDAC) and acinar cell carcinoma (ACC) from 2011 to 2023. Formalin-fixed, paraffin-embedded blocks with adequate tumor were cut and stained with beta-catenin (B-Catenin-1 clone) and LEF-1 (EP310 clone) IHC. Cases were reviewed by two pathologists independently. Nuclear staining with LEF-1 and beta-catenin was considered as positive.
Results
Our cohort consisted of 111 cases [SPN = 59 (42 resections, 11 FNA, 6 biopsies), PDAC = 24, PanNET = 22, SCA = 5, ACC = 1]. For SPN cases male to female ratio was1:8. Age ranged from 9 to 81 years (average: 32 years). Pancreatic tail was the most common location (47 %) followed by head (28 %), body (19 %) and neck (6 %). Tumor size ranged from 1.0 to 12.2 cm (average: 5 cm). Among the SPN cases 57/59 demonstrated strong nuclear LEF-1 staining. 2/49 cases were negative for LEF-1 (both pathologist in agreement). All SPN tumors demonstrated nuclear staining with beta-catenin. Among the non-SPN tumors, beta-catenin showed nuclear staining in 2/52 cases (2 PDAC). The remaining 50 cases were negative for nuclear beta-catenin and demonstrated variable staining pattern with interpretation variability between the two pathologists. The sensitivity and specificity for LEF-1 were 97 % and 100 %, respectively, while for beta-catenin, they were 100 % and 96 % respectively.
Conclusion
Crisp nuclear staining of LEF-1 without background staining makes diagnostic interpretation relatively easy and accurate compared to beta-catenin IHC. This is further helpful for small biopsy samples to help differentiate SPN from mimickers such as PanNET. None of the non-SPN cases displayed nuclear LEF-1 rendering it a valuable adjunct to beta-catenin in the diagnostic evaluation of SPN.
{"title":"Application of LEF-1 immunohistochemical staining in the diagnosis of solid pseudopapillary neoplasm of the pancreas","authors":"Saroja Devi Geetha , Atif Khan , Anam Khan , Yonah Ziemba , Karen Chau , Sunder Sham , Silvat Sheikh-Fayyaz , Arvind Rishi , Deepika Savant","doi":"10.1016/j.prp.2024.155662","DOIUrl":"10.1016/j.prp.2024.155662","url":null,"abstract":"<div><h3>Introduction</h3><div>Solid pseudopapillary neoplasm (SPN) is a tumor of young females with gain-of-function mutation in catenin beta 1 gene involved in Wnt signal transduction pathway. Beta-catenin immunohistochemistry (IHC) is used to diagnose SPN. Lymphoid enhancer-binding factor 1 (LEF-1) has been recognized in the transactivation of Wnt pathway. We aim to study LEF-1 IHC in SPN and other pancreatic tumors and compare it with beta-catenin IHC.</div></div><div><h3>Methods</h3><div>We retrieved cases of SPN, pancreatic neuroendocrine tumor (PanNET), serous cystadenoma (SCA), ductal adenocarcinoma (PDAC) and acinar cell carcinoma (ACC) from 2011 to 2023. Formalin-fixed, paraffin-embedded blocks with adequate tumor were cut and stained with beta-catenin (B-Catenin-1 clone) and LEF-1 (EP310 clone) IHC. Cases were reviewed by two pathologists independently. Nuclear staining with LEF-1 and beta-catenin was considered as positive.</div></div><div><h3>Results</h3><div>Our cohort consisted of 111 cases [SPN = 59 (42 resections, 11 FNA, 6 biopsies), PDAC = 24, PanNET = 22, SCA = 5, ACC = 1]. For SPN cases male to female ratio was1:8. Age ranged from 9 to 81 years (average: 32 years). Pancreatic tail was the most common location (47 %) followed by head (28 %), body (19 %) and neck (6 %). Tumor size ranged from 1.0 to 12.2 cm (average: 5 cm). Among the SPN cases 57/59 demonstrated strong nuclear LEF-1 staining. 2/49 cases were negative for LEF-1 (both pathologist in agreement). All SPN tumors demonstrated nuclear staining with beta-catenin. Among the non-SPN tumors, beta-catenin showed nuclear staining in 2/52 cases (2 PDAC). The remaining 50 cases were negative for nuclear beta-catenin and demonstrated variable staining pattern with interpretation variability between the two pathologists. The sensitivity and specificity for LEF-1 were 97 % and 100 %, respectively, while for beta-catenin, they were 100 % and 96 % respectively.</div></div><div><h3>Conclusion</h3><div>Crisp nuclear staining of LEF-1 without background staining makes diagnostic interpretation relatively easy and accurate compared to beta-catenin IHC. This is further helpful for small biopsy samples to help differentiate SPN from mimickers such as PanNET. None of the non-SPN cases displayed nuclear LEF-1 rendering it a valuable adjunct to beta-catenin in the diagnostic evaluation of SPN.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155662"},"PeriodicalIF":2.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1016/j.prp.2024.155658
Jie Zhou , Zhu Zhu , Xi Zhang , Wenli Peng , Yongpeng He , Qing Zhang
Background
CircRNA has emerged as a significant player in human malignancies, including hepatocellular carcinoma (HCC). Hsa_circ_0004277 (circWDR37) is abnormally up-regulated in HCC. But, its function and underlying mechanism in HCC progression are largely unknown.
Methods
qRT-PCR and western blot assays were used to measure the expression of circWDR37, miR-646, and TRAF4. Cell malignant phenotypes were assessed via CCK-8, EdU, colony formation, flow cytometry, transwell, and tube formation experiments. The intermolecular interaction between miR-646 and circWDR37 or TRAF4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assay. The in vivo effect of circWDR37 on xenograft tumor growth was also investigated in mice.
Results
Increased CircWDR37 and TRAF4 and decreased miR-646 were found in HCC tissues and cells. Scilencing circWDR37 impeded cell proliferation, migration, invasion, and tube formation, while accelerated apoptosis. CircWDR37 directly bind to miR-646 to suppress miR-646 expression and up-regulate TRAF4 expression. MiR-646 inhibitor partially abated the cell phenotype changes caused by circWDR37 knockdown. Moreover, miR-646 exerted an inhibitory effect on cell malignant phenotypes, which were attenuated due to the increase of TRAF4. Additionally, circWDR37 knockdown blocked HCC tumor growth in vivo.
Conclusion
CircWDR37 exerted an oncogenic effect in HCC by sponging miR-646 to up-regulate TRAF4 expression. Our finding elucidates a novel ‘circWDR37-miR-646-TRAF4’ regulatory axis in HCC and provides a promising target for HCC treatment.
{"title":"CircWDR37 promotes hepatocellular carcinoma tumorigenesis by mediating the miR-646/TRAF4 regulatory pathway","authors":"Jie Zhou , Zhu Zhu , Xi Zhang , Wenli Peng , Yongpeng He , Qing Zhang","doi":"10.1016/j.prp.2024.155658","DOIUrl":"10.1016/j.prp.2024.155658","url":null,"abstract":"<div><h3>Background</h3><div>CircRNA has emerged as a significant player in human malignancies, including hepatocellular carcinoma (HCC). Hsa_circ_0004277 (circWDR37) is abnormally up-regulated in HCC. But, its function and underlying mechanism in HCC progression are largely unknown.</div></div><div><h3>Methods</h3><div>qRT-PCR and western blot assays were used to measure the expression of circWDR37, miR-646, and TRAF4. Cell malignant phenotypes were assessed via CCK-8, EdU, colony formation, flow cytometry, transwell, and tube formation experiments. The intermolecular interaction between miR-646 and circWDR37 or TRAF4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assay. The <em>in vivo</em> effect of circWDR37 on xenograft tumor growth was also investigated in mice.</div></div><div><h3>Results</h3><div>Increased CircWDR37 and TRAF4 and decreased miR-646 were found in HCC tissues and cells. Scilencing circWDR37 impeded cell proliferation, migration, invasion, and tube formation, while accelerated apoptosis. CircWDR37 directly bind to miR-646 to suppress miR-646 expression and up-regulate TRAF4 expression. MiR-646 inhibitor partially abated the cell phenotype changes caused by circWDR37 knockdown. Moreover, miR-646 exerted an inhibitory effect on cell malignant phenotypes, which were attenuated due to the increase of TRAF4. Additionally, circWDR37 knockdown blocked HCC tumor growth <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>CircWDR37 exerted an oncogenic effect in HCC by sponging miR-646 to up-regulate TRAF4 expression. Our finding elucidates a novel ‘circWDR37-miR-646-TRAF4’ regulatory axis in HCC and provides a promising target for HCC treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155658"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
High endothelial venules (HEVs) are vessels specialized in the extravasation of lymphocytes from the blood to the tissue implicated in the immune microenvironment of several tumors. Their presence has been never studied in the pleural tissue.
Material and methods
We retrospectively studied 149 surgical pleural biopsies by immunohistochemistry for MECA-79 expression, a marker specifically recognizing HEVs. The tissues included 44 (44 %) inflammatory and 105 (56 %) neoplastic diseases. The latter corresponded to 34 (22.8 %) mesotheliomas and 71 (47.7 %) metastases from lung (n=50) or breast (n=21) primaries.
Results
HEVs were present in 102 (68 %) of all pleural specimens with a mean number of foci containing HEVs of 13.33 (±20.64). Neoplastic pleural pathologies harbored HEVs in 73.3 % of the cases compared to the non-neoplastic pathologies which harbored HEVs in 56.8 % of the cases (p=0.048). Their presence did not differ between pulmonary or mammary metastasis (p=0.7).
Conclusion
We show for the first time that HEVs are present in the pleural cavity probably participating in the immune microenvironment of inflammatory and neoplastic pleural disease.
{"title":"High endothelial venules in the pleura: MECA-79 expression in mesothelioma, pleural metastasis and pleuritis","authors":"Ikram Kherrour , Mousa Mobarki , Michel Péoc’h , Georgia Karpathiou","doi":"10.1016/j.prp.2024.155661","DOIUrl":"10.1016/j.prp.2024.155661","url":null,"abstract":"<div><h3>Introduction</h3><div>High endothelial venules (HEVs) are vessels specialized in the extravasation of lymphocytes from the blood to the tissue implicated in the immune microenvironment of several tumors. Their presence has been never studied in the pleural tissue.</div></div><div><h3>Material and methods</h3><div>We retrospectively studied 149 surgical pleural biopsies by immunohistochemistry for MECA-79 expression, a marker specifically recognizing HEVs. The tissues included 44 (44 %) inflammatory and 105 (56 %) neoplastic diseases. The latter corresponded to 34 (22.8 %) mesotheliomas and 71 (47.7 %) metastases from lung (n=50) or breast (n=21) primaries.</div></div><div><h3>Results</h3><div>HEVs were present in 102 (68 %) of all pleural specimens with a mean number of foci containing HEVs of 13.33 (±20.64). Neoplastic pleural pathologies harbored HEVs in 73.3 % of the cases compared to the non-neoplastic pathologies which harbored HEVs in 56.8 % of the cases (p=0.048). Their presence did not differ between pulmonary or mammary metastasis (p=0.7).</div></div><div><h3>Conclusion</h3><div>We show for the first time that HEVs are present in the pleural cavity probably participating in the immune microenvironment of inflammatory and neoplastic pleural disease.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155661"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The glycocalyx (GCX) is a glycan structure on the vascular endothelium and cancer cells. It is crucial for blood flow regulation, tumor invasion, and cancer drug resistance. Understanding the role of GCX in human tumors could help develop new cancer biomarkers and therapies.
Aim
This study aimed to demonstrate microstructural changes in human primary and metastatic liver tumors (henceforth termed liver tumors) by visualizing GCX using surgical specimens and comparing formalin-fixed paraffin-embedded sections (FFPEs) with frozen sections. The results of lectin staining were also compared between frozen and FFPE specimens to determine which was more useful for accurately assessing GCX structure and composition.
Methods
Liver tumors and normal tissue samples from three patients were collected and processed into FFPEs and frozen sections, respectively. Lanthanum nitrate staining and scanning electron microscopy (SEM) were used to assess the GCX structures. Twenty lectins were analyzed for their glycan components in the samples.
Results
SEM revealed significant differences in GCX morphology among the cancer specimens. Frozen sections provided a more accurate GCX evaluation than FFPEs, showing distinct glycan compositions in hepatocellular carcinoma, colorectal carcinoma liver metastases, and melanoma liver metastases. Hepatocellular carcinoma samples exhibited a loss of N-acetylgalactosamine-related lectins.
Conclusion
The results revealed that liver tumors have distinct and bulky GCX compared to normal liver tissue, while frozen sections are more reliable for GCX evaluation. These findings highlight glycan alterations in liver tumors and contribute to the development of new cancer therapies targeting GCX on tumor cell surfaces.
{"title":"Evaluating glycocalyx morphology and composition in frozen and formalin-fixed liver tumor sections","authors":"Masashi Kuno , Hiroyuki Tomita , Masahide Endo , Kosuke Mori , Akira Hara , Takeshi Horaguchi , Ryoma Yokoi , Keita Matsumoto , Hirokatsu Hayashi , Masahiro Fukada , Chika Takao , Yuta Sato , Ryuichi Asai , Itaru Yasufuku , Jesse Yu Tajima , Shigeru Kiyama , Yoshihiro Tanaka , Nobuhisa Matsuhashi","doi":"10.1016/j.prp.2024.155660","DOIUrl":"10.1016/j.prp.2024.155660","url":null,"abstract":"<div><h3>Background</h3><div>The glycocalyx (GCX) is a glycan structure on the vascular endothelium and cancer cells. It is crucial for blood flow regulation, tumor invasion, and cancer drug resistance. Understanding the role of GCX in human tumors could help develop new cancer biomarkers and therapies.</div></div><div><h3>Aim</h3><div>This study aimed to demonstrate microstructural changes in human primary and metastatic liver tumors (henceforth termed liver tumors) by visualizing GCX using surgical specimens and comparing formalin-fixed paraffin-embedded sections (FFPEs) with frozen sections. The results of lectin staining were also compared between frozen and FFPE specimens to determine which was more useful for accurately assessing GCX structure and composition.</div></div><div><h3>Methods</h3><div>Liver tumors and normal tissue samples from three patients were collected and processed into FFPEs and frozen sections, respectively. Lanthanum nitrate staining and scanning electron microscopy (SEM) were used to assess the GCX structures. Twenty lectins were analyzed for their glycan components in the samples.</div></div><div><h3>Results</h3><div>SEM revealed significant differences in GCX morphology among the cancer specimens. Frozen sections provided a more accurate GCX evaluation than FFPEs, showing distinct glycan compositions in hepatocellular carcinoma, colorectal carcinoma liver metastases, and melanoma liver metastases. Hepatocellular carcinoma samples exhibited a loss of N-acetylgalactosamine-related lectins.</div></div><div><h3>Conclusion</h3><div>The results revealed that liver tumors have distinct and bulky GCX compared to normal liver tissue, while frozen sections are more reliable for GCX evaluation. These findings highlight glycan alterations in liver tumors and contribute to the development of new cancer therapies targeting GCX on tumor cell surfaces.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155660"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver cancer is a major health epidemic worldwide, mainly due to its high mortality rates and limited treatment options. The association of cellular senescence to tumorigenesis and the cancer hallmarks remains a subject of interest in cancer biology. The p53-p21 signalling axis is an important regulator in restoring the cell’s balance by supporting tumor suppression and tumorigenesis in liver cancer. We review the novel molecular mechanisms that p53 and its downstream effector, p21, employ to induce cellular senescence, making it last longer, and halt the proliferation of damaged hepatocytes to become tumorous cells. We also examine how dysregulation of this pathway contributes to HCC pathogenesis, proliferation, survival, acquired resistance to apoptosis, and increased invasiveness. Furthermore, we comprehensively describe the molecular cross-talk between the p53-p21 signalling axis and major cell cycle signalling pathways, including Wnt/β-catenin, PI3K/Akt, and TGF-β in liver cancer and provide an overview of promising candidates for chemoprevention and future therapeutic strategies. This review article explores the roles of the p53-p21 pathway in liver cancer, examining its function in promoting cellular senescence under normal conditions and its potential role in cancer progression. It also highlights novel therapeutic drugs and drug targets within the pathway and discusses the implications for treatment strategies and prognosis in liver cancer.
{"title":"Targeting the p53-p21 axis in liver cancer: Linking cellular senescence to tumor suppression and progression","authors":"Lakshmi Thangavelu , Abdulmalik S.A. Altamimi , Nehmat Ghaboura , M. Arockia Babu , R. Roopashree , Pawan Sharma , Pusparghya Pal , Chhavi Choudhary , G.V. Siva Prasad , Aashna Sinha , Ashok Kumar Balaraman , Sushama Rawat","doi":"10.1016/j.prp.2024.155652","DOIUrl":"10.1016/j.prp.2024.155652","url":null,"abstract":"<div><div>Liver cancer is a major health epidemic worldwide, mainly due to its high mortality rates and limited treatment options. The association of cellular senescence to tumorigenesis and the cancer hallmarks remains a subject of interest in cancer biology. The p53-p21 signalling axis is an important regulator in restoring the cell’s balance by supporting tumor suppression and tumorigenesis in liver cancer. We review the novel molecular mechanisms that p53 and its downstream effector, p21, employ to induce cellular senescence, making it last longer, and halt the proliferation of damaged hepatocytes to become tumorous cells. We also examine how dysregulation of this pathway contributes to HCC pathogenesis, proliferation, survival, acquired resistance to apoptosis, and increased invasiveness. Furthermore, we comprehensively describe the molecular cross-talk between the p53-p21 signalling axis and major cell cycle signalling pathways, including Wnt/β-catenin, PI3K/Akt, and TGF-β in liver cancer and provide an overview of promising candidates for chemoprevention and future therapeutic strategies. This review article explores the roles of the p53-p21 pathway in liver cancer, examining its function in promoting cellular senescence under normal conditions and its potential role in cancer progression. It also highlights novel therapeutic drugs and drug targets within the pathway and discusses the implications for treatment strategies and prognosis in liver cancer.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"263 ","pages":"Article 155652"},"PeriodicalIF":2.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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