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Chung EYM, Wang YM, Keung K, Hu M, McCarthy H, Wong G, Kairaitis L, Bose B, Harris DCH, Alexander SI. Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment. Front Immunol 2022; 13:1036249. [PMID: 36405681 PMCID: PMC9667740 DOI: 10.3389/fimmu.2022.1036249] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/19/2022] [Indexed: 11/07/2022] Open
Abstract
Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.
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Affiliation(s)
- Edmund Y. M. Chung
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Yuan M. Wang
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Karen Keung
- Department of Nephrology, Prince of Wales Hospital, Randwick, NSW, Australia
| | - Min Hu
- The Centre for Transplant and Renal Research, Westmead Institute of Medical Research, Westmead, NSW, Australia
| | - Hugh McCarthy
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- Department of Nephrology, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- Department of Nephrology, Sydney Children’s Hospital, Randwick, NSW, Australia
| | - Germaine Wong
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- Department of Nephrology, Westmead Hospital, Westmead, NSW, Australia
| | - Lukas Kairaitis
- Department of Nephrology, Blacktown Hospital, Blacktown, NSW, Australia
| | - Bhadran Bose
- Department of Nephrology, Nepean Hospital, Kingswood, NSW, Australia
| | - David C. H. Harris
- The Centre for Transplant and Renal Research, Westmead Institute of Medical Research, Westmead, NSW, Australia
- Department of Nephrology, Westmead Hospital, Westmead, NSW, Australia
| | - Stephen I. Alexander
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- Department of Nephrology, The Children’s Hospital at Westmead, Westmead, NSW, Australia
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Rong C, Grünow J, Thierauf J, Lucena-Porcel C, Major G, Holzinger D, Dyckhoff G, Kern J, Lammert A, Scherl C, Rotter N, Plinkert PK, Affolter A. Conjoint analysis of OPRPN and SMR3A protein expression as potential predictive biomarkers for head and neck squamous cell carcinoma after radiotherapy. Oncol Rep 2022; 48:159. [PMID: 35856431 DOI: 10.3892/or.2022.8374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 05/26/2022] [Indexed: 11/06/2022] Open
Abstract
Increased submaxillary gland androgen‑regulated protein 3A (SMR3A) expression was previously shown to serve as an independent risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and as a surrogate biomarker for active estrogen receptor 2 signaling in radioresistant tumor cells. In the present study, it was aimed to unravel the expression and clinical significance of another member of the opiorphin family, opiorphin prepropeptide (OPRPN), in the radiotherapy for head and neck squamous cell carcinoma (HNSCC). Expression of SMR3A and OPRPN were analyzed for the prior and post fractionated irradiation (4x2 Gy) by double immunofluorescence staining in established HNSCC cell lines as well as by immunohistochemical (IHC) staining in ex vivo tumor tissues. Next, in a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n=96), who received definitive surgery and adjuvant radiotherapy were reviewed, and expression levels of OPRPN protein were detected by IHC. Immunoreactivity scores (IRS) were associated with pathological and clinical risk factors by Chi‑square analysis. Survival analysis was performed by using the Kaplan‑Meier plot, log‑rank test and Cox regression analysis. The expression levels of OPRPN and SMR3A protein were both induced by fractionated irradiation in vitro and ex vivo. In primary tumor samples, IRS of OPRPN was significantly higher than scores of SMR3A expression and positively correlated with expression patterns of SMR3A. SMR3A was confirmed to serve as an unfavorable factor, while OPRPN protein had no significant association with the clinical outcome of patients with OPSCC. A combinational analysis revealed that the subgroup with SMR3AhighOPRPNlow staining pattern had the worst clinical outcome among the various subgroups. Multivariate Cox regression analyses indicated that high expression of SMR3A serves as an independent unfavorable biomarker, while increased expression of OPRPN appears to exert protective function. In summary, the present study indicated that SMR3A and OPRPN serve as potential prognostic markers for HNSCC after radiotherapy.
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Affiliation(s)
- Chao Rong
- Department of Pathology, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, P.R. China
| | - Jennifer Grünow
- Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
| | - Julia Thierauf
- Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
| | | | - Gerald Major
- Department of Radiation Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
| | - Dana Holzinger
- Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), D‑69120 Heidelberg, Germany
| | - Gerhard Dyckhoff
- Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
| | - Johann Kern
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim of Heidelberg University, D‑68167 Mannheim, Germany
| | - Anne Lammert
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim of Heidelberg University, D‑68167 Mannheim, Germany
| | - Claudia Scherl
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim of Heidelberg University, D‑68167 Mannheim, Germany
| | - Nicole Rotter
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim of Heidelberg University, D‑68167 Mannheim, Germany
| | - Peter K Plinkert
- Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
| | - Annette Affolter
- Department of Otorhinolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
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Role of B Cell Development Marker CD10 in Cancer Progression and Prognosis. Mol Biol Int 2016; 2016:4328697. [PMID: 27965895 PMCID: PMC5124668 DOI: 10.1155/2016/4328697] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 10/07/2016] [Accepted: 10/17/2016] [Indexed: 12/03/2022] Open
Abstract
The human CD10 antigen is a single pass, type II transmembrane, 100 kD cell surface glycoprotein belonging to peptidase M13 family. Identified in common acute lymphoblastic leukemia as a cancer specific antigen, CD10 is a cell surface ectoenzyme widely expressed on different types of cells. Earlier, it was used only as a cell surface marker to identify and differentiate between haematological malignancies. Later, reported to be present in various malignancies, it is thought to play significant role in cancer development and progression. Regulated expression of CD10 is necessary for angiogenesis and so forth. However its expression level is found to be deregulated in different cancers. In some cancers, it acts as tumor suppressor and inhibits tumor progression whereas in others it has tumor promoting tendency. However, its role in tumorigenesis remains unclear. This review summarises structural features, functions, and probable role of CD10 in cancer development.
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Ieni A, Barresi V, Todaro P, Caruso RA, Tuccari G. Cell-block procedure in endoscopic ultrasound-guided-fine-needle-aspiration of gastrointestinal solid neoplastic lesions. World J Gastrointest Endosc 2015; 7:1014-1022. [PMID: 26322154 PMCID: PMC4549658 DOI: 10.4253/wjge.v7.i11.1014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 07/01/2015] [Accepted: 08/03/2015] [Indexed: 02/05/2023] Open
Abstract
In the present review we have analyzed the clinical applications of endoscopic ultrasound-guided-fine-needle-aspiration (EUS-FNA) and the methodological aspects obtained by cell-block procedure (CBP) in the diagnostic approach to the gastrointestinal neoplastic pathology. CBP showed numerous advantages in comparison to the cytologic routine smears; in particular, better preservation of cell architecture, achievement of routine haematoxylin-eosin staining equivalent to histological slides and possibility to perform immunohistochemistry or molecular analyses represented the most evident reasons to choose this method. Moreover, by this approach, the differential diagnosis of solid gastrointestinal neoplasias may be more easily achieved and the background of contaminant non-neoplastic gastrointestinal avoided. Finally, biological samples collected by EUS-FNA CBP-assisted should be investigated in order to identify and quantify further potential molecular markers.
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Ieni A, Todaro P, Crino SF, Barresi V, Tuccari G. Endoscopic ultrasound-guided fine-needle aspiration cytology in pancreaticobiliary carcinomas: diagnostic efficacy of cell-block immunocytochemistry. Hepatobiliary Pancreat Dis Int 2015; 14:305-12. [PMID: 26063033 DOI: 10.1016/s1499-3872(15)60367-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Endoscopic ultrasound-guided fine-needle aspiration cytology was demonstrated to be a useful tool for the diagnosis and staging of pancreaticobiliary neoplastic lesions. Nonetheless, the diagnostic value of this procedure may be limited by low cellularity of the specimen, contamination of intestinal cells and unfeasibility of ancillary immunocytochemical procedures. The present study was to evaluate its usefulness in the diagnosis of neoplastic lesions. METHODS A series of 46 pancreaticobiliary carcinomas with available cell block preparations was submitted to immunocytochemistry against cytokeratins, carcinoembryonic antigen, E-cadherin, CD10 and p53. The sensitivity, specificity, positive and negative predictive values of the cytological smear in the discrimination of malignant lesions were calculated and compared with those of cell block preparation with the immunocytochemical stains against p53 and CD10. RESULTS According to our findings, the use of cell block preparations together with immunostains against p53 and CD10 allowed to discriminate malignant versus benign specimens with higher sensitivity than the only cytological examination. In detail, CD10 immunostaining was of significant help for the discrimination between cytological contaminants, such as benign gastrointestinal cells, and the neoplastic elements of pancreaticobiliary well differentiated adenocarcinomas. Also, intense nuclear immunoreactivity for p53 was encountered in about 2/3 of the cases and identified pancreatic malignancy with high sensitivity. CONCLUSIONS We suggest that immunocytochemistry against both CD10 and p53 could be applied case by case, mainly to differentiate gastrointestinal and pancreatic benign cellular contaminants showing hyperplasia or reactive changes from differentiated pancreaticobiliary adenocarcinomas.
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Affiliation(s)
- Antonio Ieni
- Department of Human Pathology "Gaetano Barresi", Section of Pathological Anatomy, Azienda Ospedaliera Universitaria "Policlinico G. Martino", University of Messina, Messina 98125, Italy.
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Vigliar E, Troncone G, Bracale U, Iaccarino A, Napolitano V, Bellevicine C. CD10 is useful to identify gastrointestinal contamination in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology from pancreatic ductal adenocarcinoma. Cytopathology 2015; 26:83-7. [PMID: 24754336 DOI: 10.1111/cyt.12148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2014] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology is an effective tool to diagnose pancreatic ductal adenocarcinoma (PDA). Standard morphological criteria are usually reliable. When contaminating gastrointestinal (GI) epithelial cells are prevalent among neoplastic cells, these can be highlighted by carcinoembryonic antigen (CEA) staining. CD10 is a cell-surface metallopeptidase normally expressed by the GI epithelial apical border, whose expression is decreased or lost in PDA. We included CD10 in a panel, together with CEA, to discriminate the GI contaminant cells from PDA cells on cell blocks. METHODS Eight cases of EUS-FNA of PDA, featuring both contaminating GI cells and neoplastic cells, whose corresponding cell blocks were available for immunostaining, were selected. CD10 and CEA were stained on cell blocks by standard methods. RESULTS CD10 strongly labelled only the GI cells, with a well-defined apical membrane signal; conversely, GI cells did not show CEA staining; benign duodenal cells were faintly labelled in only one case. Malignant cells were positive for CEA and negative for CD10, with the exception of one case with labelled neoplastic cells with weak diffuse cytoplasmic positivity. CD10 apical membrane staining was a feature only seen in benign GI cells. CONCLUSIONS As a loss of CD10 is a consistent feature of PDA, this marker can be useful, together with CEA, to aid the cytopathologist to identify neoplastic cells in a background rich in GI contaminant cells.
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Affiliation(s)
- E Vigliar
- Department of Public Health, University Federico II, Napoli, Italy
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Zhu J, Guo X, Qiu B, Li Z, Xia N, Yang Y, Liu P. Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection. Onco Targets Ther 2014; 7:297-304. [PMID: 24570591 PMCID: PMC3933717 DOI: 10.2147/ott.s57355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim The aim of this study was to investigate the relationship between the expression of neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP IV) proteins, and the clinical significance of the two proteins in patients with intrahepatic cholangiocarcinomas (IHCC). Methods Expression patterns and subcellular localizations of NEP and DPP IV proteins in 186 primary IHCC and 60 noncancerous liver tissue specimens were detected by immunohistochemistry. Results Both the expression of NEP and DPP IV proteins in IHCC tissues were significantly higher than those in noncancerous liver tissues (both P<0.001). Of 186 patients with IHCC, 128 (68.82%) highly expressed both NEP and DPP IV proteins. In addition, the coexpression of NEP and DPP IV proteins was significantly associated with advanced tumor stage (P=0.009), positive lymph node metastasis (P=0.016) and distant metastasis (P=0.013), and the presence of recurrence (P=0.027). Moreover, Kaplan–Meier analysis showed that IHCC patients with high NEP expression, high DPP IV expression, and combined overexpression of NEP and DPP IV proteins all had poorer overall survival and early recurrence after surgery. Furthermore, Cox analysis suggested that NEP expression, DPP IV expression, and combined expression of NEP and DPP IV proteins were all independent prognostic markers for overall survival and recurrence-free survival in patients with IHCC. Conclusion Our data suggest, for the first time, that both the expression of NEP and DPP IV proteins may be upregulated in human IHCC tissues and the combined expression of NEP and DPP IV proteins may play important roles in progression and prognosis of patients with IHCC.
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Affiliation(s)
- Jianyong Zhu
- Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China
| | - Xiaodong Guo
- 302 Hospital of PLA, Beijing, People's Republic of China
| | - Baoan Qiu
- Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China
| | - Zhiyan Li
- 302 Hospital of PLA, Beijing, People's Republic of China
| | - Nianxin Xia
- Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China
| | - Yingxiang Yang
- Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China
| | - Peng Liu
- Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China
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Jang TJ, Park JB, Lee JI. The Expression of CD10 and CD15 Is Progressively Increased during Colorectal Cancer Development. KOREAN JOURNAL OF PATHOLOGY 2013; 47:340-7. [PMID: 24009629 PMCID: PMC3759633 DOI: 10.4132/koreanjpathol.2013.47.4.340] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 07/10/2013] [Accepted: 07/12/2013] [Indexed: 12/14/2022]
Abstract
Background The aim of this study was to examine the expression of CD10 and CD15 in tumor cells, stromal cells and infiltrating inflammatory cells during colorectal carcinoma (CRC) development and to investigate their expression levels between the tumor center and invasive front and compare them to clinicopathological parameters in invasive CRC. Methods We performed immunohistochemical staining for CD10, CD15, and E-cadherin in 42 cases of CRC, 49 of tubular adenoma, 15 of hyperplastic polyp, and 17 of non-neoplastic colon. Results CD10 was expressed in tumor cells (tCD10), stromal cells (sCD10) and infiltrating inflammatory cells (iCD10), and CD15 was expressed in tumor cells (tCD15) and infiltrating inflammatory cells (iCD15). Their expressions were progressively increased during CRC development and the iCD10 expression level was significantly correlated with the iCD15 expression level in invasive CRC. Invasive front revealed a higher expression level of iCD10 and iCD15 than the tumor center. Moreover, the iCD15 expression level of invasive front was significantly correlated with the degree of tumor budding and tCD15 in whole tissue sections was closely associated with tumor depth. Conclusions The present study suggests that the expression of CD10 and CD15 is associated with the development and progression of CRC.
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Affiliation(s)
- Tae Jung Jang
- Department of Pathology, Dongguk University College of Medicine, Gyeongju, Korea
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Koutsounas I, Giaginis C, Patsouris E, Theocharis S. Current evidence for histone deacetylase inhibitors in pancreatic cancer. World J Gastroenterol 2013; 19:813-28. [PMID: 23430136 PMCID: PMC3574878 DOI: 10.3748/wjg.v19.i6.813] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 10/18/2011] [Accepted: 01/05/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.
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Jang TJ. CD10 Is Again Expressed at a Certain Stage during the Neoplastic Process of Bladder Transitional Cell Carcinomas. Cancer Res Treat 2012; 44:262-6. [PMID: 23341790 PMCID: PMC3546273 DOI: 10.4143/crt.2012.44.4.262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 10/25/2012] [Indexed: 12/01/2022] Open
Abstract
Purpose CD10, a membrane-bound zinc-dependent metallopeptidase, is normally expressed in many tissues. Accordingly, the derangement of CD10 expression may be related to development or progression in a variety of tumors. The aim of this study is to examine any association between CD10 expression and clinicopathological parameters in bladder transitional cell carcinomas (TCCs) and the relationship between expression of E-cadherin and CD10. Materials and Methods Immunohistochemical staining was performed for CD10 and E-cadherin in tissues of 94 TCCs and 10 non-neoplastic bladder mucosa. Results Positive immunoreactivity for CD10 was observed in non-neoplastic urothelium at a proportion of 80% and TCCs were observed at a rate of 23%. A positive rate of CD10 expression was observed in 10% of total cases of a low grade tumor and in 35% of those of a high grade tumor. It was also observed in 15% of pTa tumors, 13% of pT1 tumors, and 48% of pT2 tumors. In addition, CD10 expression showed reciprocal correlation with expression of membranous E-cadherin in tumors. Conclusion CD10 is again expressed at a certain stage during the neoplastic process of TCCs and could play some roles intheir carcinogenesis.
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Affiliation(s)
- Tae Jung Jang
- Department of Pathology, Dongguk University College of Medicine, Gyeongju, Korea
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Koffler J, Holzinger D, Sanhueza GA, Flechtenmacher C, Zaoui K, Lahrmann B, Grabe N, Plinkert PK, Hess J. Submaxillary gland androgen-regulated protein 3A expression is an unfavorable risk factor for the survival of oropharyngeal squamous cell carcinoma patients after surgery. Eur Arch Otorhinolaryngol 2012; 270:1493-500. [PMID: 23053383 DOI: 10.1007/s00405-012-2201-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 09/19/2012] [Indexed: 11/29/2022]
Abstract
Recently, increased expression of the submaxillary gland androgen-regulated protein 3A (SMR3A) was found in recurrent tumors of an orthotopic floor-of-mouth mouse tumor model after surgery. However, SMR3A expression in the pathogenesis of human malignancy and its correlation with the clinical outcome have not been addressed so far. We analyzed tissue microarrays with specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 157) by immunohistochemistry and compared SMR3A expression with clinical and pathological features by statistical analysis. Strong SMR3A expression was found in almost 36 % of all primary OPSCCs. Although, SMR3A protein levels were not associated with any clinical or histopathological feature tested, univariate Kaplan-Meier analysis revealed a significant correlation between high SMR3A protein expression and poor progression-free (p = 0.02) and overall survival (p = 0.03). Furthermore, high SMR3A expression was an independent marker for poor clinical outcome [HR (SMR3A(high) vs. SMR3(low)) = 2.32; 95 % CI = 1.03-5.23] concerning overall survival in a multivariate analysis of OPSCC patients with surgery as primary therapy (n = 100). Our data demonstrate for the first time increased SMR3A protein expression in the pathogenesis of OPSCC, which serves as an unfavorable risk factor for patient survival.
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Affiliation(s)
- Jennifer Koffler
- Experimental Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
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Mass Spectrometry-Based (GeLC-MS/MS) Comparative Proteomic Analysis of Endoscopically (ePFT) Collected Pancreatic and Gastroduodenal Fluids. Clin Transl Gastroenterol 2012; 3:e14. [PMID: 23238231 PMCID: PMC3367612 DOI: 10.1038/ctg.2012.7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES: The secretin-stimulated endoscopic pancreatic function test (ePFT) allows for the safe collection of gastroduodenal and pancreatic fluid from the duodenum. We test the hypothesis that these endoscopically collected fluids have different proteomes. As such, we aim to show that the ePFT method can be used to collect fluid enriched in pancreatic proteins to test for pancreatic function. METHODS: Gastroduodenal and pancreatic fluid were collected sequentially from chronic pancreatitis patients undergoing an ePFT. Proteins from each fluid type were extracted using previously published optimized methods and subjected to GeLC-MS/MS analysis for protein identification and bioinformatics analysis. RESULTS: Mass spectrometry analysis identified proteins that were exclusive in either gastroduodenal (46) or pancreatic fluid (234). Subsequent quantitative analysis revealed proteins that were differentially abundant with statistical significance. As expected, proteolytic enzymes and protease inhibitors were among the differentially detected proteins. The proteases pepsinogens and gastrin were enriched in gastroduodenal fluid, while common pancreatic enzymes (e.g., aminopeptidase N, chymotrypsin C, elastase-3A, trypsin, and carboxypeptidase A1, and elastase 2B) were found in greater abundance in pancreatic fluid. Similarly for protease inhibitors, members of the cystatin family were exclusive to gastroduodenal fluid, while serpins A11, B4, and D1 were exclusive to pancreatic fluid. CONCLUSIONS: We have shown that ePFT collection coupled with mass spectrometry can be used to identify differentially detected proteins in gastroduodenal and pancreatic fluids. The data obtained using GeLC-MS/MS techniques provide further evidence supporting the feasibility of using ePFT-collected fluid to study specific diseases of the upper gastrointestinal tract, such as chronic pancreatitis.
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Paulo JA, Kadiyala V, Lee LS, Banks PA, Conwell DL, Steen H. Proteomic analysis (GeLC-MS/MS) of ePFT-collected pancreatic fluid in chronic pancreatitis. J Proteome Res 2012; 11:1897-912. [PMID: 22243521 DOI: 10.1021/pr2011022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Chronic pancreatitis is characterized by inflammation, fibrosis, pain, and loss of exocrine function of the pancreas. We aimed to identify differentially expressed proteins in the ePFT-collected pancreatic fluid from individuals with chronic pancreatitis (CP; n = 9) and controls with chronic abdominal pain not associated with the pancreas (NP; n = 9). Using GeLC-MS/MS techniques, we identified a total of 1391 different proteins in 18 pancreatic fluid samples. Of these proteins, 257 and 413 were identified exclusively in the control and chronic pancreatitis cohorts, respectively, and 721 were identified in both cohorts. Spectral counting and statistical analysis thereof revealed an additional 38 and 77 proteins that were up- or down-regulated, respectively, in the pancreatic fluid from individuals with chronic pancreatitis. As expected, gene ontology analysis illustrated that the largest percentage of differentially regulated proteins was secreted/extracellular in origin. In addition, proteins that were down-regulated with statistical significance in the chronic pancreatitis cohort were determined to have biological function of proteases, corresponding to the canonical pancreatic insufficiency associated with chronic pancreatitis. Proteins enriched in the pancreatic fluid of chronic pancreatitis patients had roles in fibrosis, inflammation, and pain, whereas digestive enzymes were significantly less abundant. Our workflow provided a mass spectrometry-based approach for the further study of the pancreatic fluid proteome, which may lead to the discovery potential biomarkers of chronic pancreatitis.
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Affiliation(s)
- Joao A Paulo
- Department of Pathology, Children's Hospital Boston , Boston, Massachusettes, United States
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High CD10 expression predicts favorable outcome in surgically treated lymph node-positive bladder cancer patients. Hum Pathol 2011; 43:269-75. [PMID: 21835428 DOI: 10.1016/j.humpath.2011.04.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 04/16/2011] [Accepted: 04/21/2011] [Indexed: 11/21/2022]
Abstract
CD10 predicts survival in different cancers. The prognostic significance in bladder cancer still has to be documented. One hundred fifty lymph node-positive bladder cancer patients were treated by cystectomy and standardized pelvic lymphadenectomy in curative intent. CD10 expression was evaluated in tissue microarrays (TMAs) constructed from histopathological normal urothelium, primary tumor (tumor center and invasion front), and corresponding lymph node metastases and correlated with tumor characteristics (stage, extracapsular extension, number, and total diameter of metastases) and survival. CD10 expression was successively lost from normal urothelium to primary tumor to metastases (P < .05) and decreased from the tumor center to the invasion front (P < .002). High CD10 expression in tumor center or invasion front (P < .05) but not in the metastases predicted favorable outcome; the prognostic information in the tumor center was independent from tumor stage and lymph node parameters. High CD10 expression level was not associated with specific tumor characteristics. A well-defined sampling strategy for TMAs allows detection of specific biomarker expression patterns and may generate prognostic information inherent in particular tumor areas. The favorable outcome in bladder cancer patients with high CD10 expression might suggest a tumor suppressive function of CD10.
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High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death. Virchows Arch 2011; 458:741-8. [PMID: 21538124 DOI: 10.1007/s00428-011-1084-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 03/24/2011] [Accepted: 04/10/2011] [Indexed: 10/18/2022]
Abstract
Patients with nodal positive prostate cancers are an important cohort with poorly defined risk factors. CD10 is a cell surface metallopeptidase that has been suggested to play a role in prostate cancer progression. CD10 expression was evaluated in 119 nodal positive prostate cancer patients using tissue microarrays constructed from primary tumors and lymph node metastases. All patients underwent radical prostatectomy and standardized extended lymphadenectomy. They had no neoadjuvant therapy and received deferred androgen deprivation. In the primary tumor, high CD10 expression was significantly associated with earlier death from disease when compared with low CD10 expression (5-year survival 73.7% vs. 91.8%; p = 0.043). In the metastases, a high CD10 expression was significantly associated with larger total size of metastases (median 11.4 vs. 6.5 mm; p = 0.015), earlier death of disease (5-year survival 71.5% vs. 87.3%; p = 0.017), and death of any cause (5-year survival 70.0% vs. 87.2%; p = 0.001) when compared with low CD10 expression. CD10 expression in the metastases added independent prognostic information for overall survival (p = 0.029) after adjustment for Gleason score of the primary tumor, nodal tumor burden, and resection margins. In conclusion, a high CD10 expression in prostate cancer predicts early death. This information is inherent in the primary tumors and in the lymph node metastases and might help to personalize patient management.
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Maguer-Satta V, Besançon R, Bachelard-Cascales E. Concise Review: Neutral Endopeptidase (CD10): A Multifaceted Environment Actor in Stem Cells, Physiological Mechanisms, and Cancer. Stem Cells 2011; 29:389-96. [DOI: 10.1002/stem.592] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, Wirths O, Bayer TA. Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem 2010; 285:10678-89. [PMID: 20145244 PMCID: PMC2856276 DOI: 10.1074/jbc.m109.057836] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Revised: 02/05/2010] [Indexed: 11/06/2022] Open
Abstract
The beta-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APPalpha. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP down-regulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy.
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Affiliation(s)
- Vivek Venkataramani
- From the Department of Molecular Psychiatry, Alzheimer Ph.D. Graduate School, and
| | - Christian Rossner
- From the Department of Molecular Psychiatry, Alzheimer Ph.D. Graduate School, and
| | - Lara Iffland
- From the Department of Molecular Psychiatry, Alzheimer Ph.D. Graduate School, and
| | - Stefan Schweyer
- Department of Pathology, University of Goettingen, 37075 Goettingen and
| | - Irfan Y. Tamboli
- the Department of Molecular Cell Biology, University of Bonn, 53127 Bonn, Germany
| | - Jochen Walter
- the Department of Molecular Cell Biology, University of Bonn, 53127 Bonn, Germany
| | - Oliver Wirths
- From the Department of Molecular Psychiatry, Alzheimer Ph.D. Graduate School, and
| | - Thomas A. Bayer
- From the Department of Molecular Psychiatry, Alzheimer Ph.D. Graduate School, and
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Fleischmann A, Schlomm T, Huland H, Köllermann J, Simon P, Mirlacher M, Salomon G, Chun FHK, Steuber T, Simon R, Sauter G, Graefen M, Erbersdobler A. Distinct subcellular expression patterns of neutral endopeptidase (CD10) in prostate cancer predict diverging clinical courses in surgically treated patients. Clin Cancer Res 2009; 14:7838-42. [PMID: 19047112 DOI: 10.1158/1078-0432.ccr-08-1432] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Neutral endopeptidase (CD10), an ectopeptidase bound to the cell surface, is thought to be a potential prognostic marker for prostate cancer. EXPERIMENTAL DESIGN Prostate cancer patients (N = 3,261) treated by radical prostatectomy at a single institution were evaluated by using tissue microarray. Follow-up data were available for 2,385 patients. The cellular domain (membranous, membranous-cytoplasmatic, and cytoplasmatic only) of CD10 expression was analyzed immunohistochemically and correlated with various clinical and histopathologic features of the tumors. RESULTS CD10 expression was detected in 62.2% of cancer samples and occurred preferentially in higher Gleason pattern (P < 0.0001). CD10 expression positively correlated with adverse tumor features such as elevated preoperative prostate-specific antigen (PSA), higher Gleason score, and advanced stage (P < 0.0001 each). Survival analyses showed that PSA recurrence was significantly associated with the staining pattern of CD10 expression. Outcome significantly declined from negative over membranous, membranous-cytoplasmatic, to exclusively cytoplasmatic CD10 expression (P < 0.0001). In multivariate analysis, CD10 expression was an independent predictor for PSA failure (P = 0.0343). CONCLUSIONS CD10 expression is an unfavorable independent risk factor in prostate cancer. The subcellular location of CD10 protein is associated with specific clinical courses, suggesting an effect on different important biological properties of prostate cancer cells. The frequent expression of CD10 in prostate cancer and the strong association of CD10 with unfavorable tumor features may qualify this biomarker for targeted therapies.
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Affiliation(s)
- Achim Fleischmann
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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