Neprilysin: Difference between revisions

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__NOTOC__
{{Infobox_gene}}
{{CMG}}
{{protein
|Name=membrane metallo-endopeptidase
|caption=The structure of the neprilysin ectodomain in complex with a [[zinc]]-[[chelation|chelating]] inhibitor. The zinc atom is shown as a gray sphere and the inhibitor is shown in green.
|image=Neprilysin 1r1h.png
|width=240
|HGNCid=7154
|Symbol=MME
|AltSymbols=
|EntrezGene=4311
|OMIM=120520
|RefSeq=NM_000902
|UniProt=P08473
|PDB=
|ECnumber=3.4.24.11
|Chromosome=3
|Arm=q
|Band=21
|LocusSupplementaryData=-q27
}}
{{SI}}
==Overview==
'''Neprilysin''', also known as '''neutral endopeptidase''' ('''NEP'''), '''[[cluster of differentiation|CD10]]''', and '''common [[acute lymphoblastic leukemia]] antigen''' ('''CALLA'''), is a [[zinc]]-dependent [[metalloprotease]] [[enzyme]] that degrades a number of small [[secrete]]d peptides, most notably the [[amyloid beta]] peptide whose abnormal [[protein folding|misfolding]] and aggregation in [[neural tissue]] has been implicated as a cause of [[Alzheimer's disease]]. Synthesized as a [[membrane protein|membrane-bound protein]], the neprilysin ectodomain is released into the extracellular domain after it has been transported from the [[Golgi apparatus]] to the cell surface. In [[neuron]]s, neprilysin is regulated by the protein [[nicastrin]], a component of the [[gamma secretase]] complex that performs a necessary step in processing [[amyloid precursor protein]] to amyloid beta.<ref name="Pardossi">{{cite journal| last=Pardossi-Piquard|first= R.| coauthors=Dunys J., Yu G., St George-Hyslop P., Alves da Costa C. and Checler F.|title=Neprilysin activity and expression are controlled by nicastrin| journal=Journal of Neurochemistry| month=May| year=2006|volume=97| issue=4|pages=1052-6| pmid=16606360|doi=10.1111/j.1471-4159.2006.03822.x}}</ref>


==Amyloid beta regulation==
'''Neprilysin''' ({{IPAc-en|ˌ|n|ɛ|p|r|ᵻ|ˈ|l|aɪ|s|ᵻ|n}})<ref>{{cite web|url=https://cofactor.io/ora/neprilysin|title=Neprilysin - Cofactor Ora|website=cofactor.io|accessdate=November 24, 2017}}</ref>, also known as '''membrane metallo-endopeptidase''' ('''MME'''), '''neutral endopeptidase''' ('''NEP'''), '''cluster of differentiation 10''' ('''CD10'''), and '''common acute lymphoblastic leukemia antigen''' ('''CALLA''') is an [[enzyme]] that in humans is encoded by the ''MME'' gene. Neprilysin is a [[zinc]]-dependent [[metalloprotease]] that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including [[glucagon]], [[enkephalin]]s, [[substance P]], [[neurotensin]], [[oxytocin]], and [[bradykinin]].<ref name="entrez">{{cite web | title = Entrez Gene: Membrane metallo-endopeptidase | url = https://www.ncbi.nlm.nih.gov/gene/4311 }}</ref> It also degrades the [[amyloid beta]] peptide whose abnormal [[protein folding|misfolding]] and aggregation in [[neural tissue]] has been implicated as a cause of [[Alzheimer's disease]]. Synthesized as a [[membrane protein|membrane-bound protein]], the neprilysin ectodomain is released into the extracellular domain after it has been transported from the [[Golgi apparatus]] to the cell surface.
Mutations in the neprilysin gene have been associated with familial forms of Alzheimer's disease,<ref name="Helisalmi">{{cite journal |last=Helisalmi |first=S coauthors= M. Hiltunen, S. Vepsäläinen, S. Iivonen, A. Mannermaa, M. Lehtovirta, A. M. Koivisto, I. Alafuzoff and H. Soininen |year=2004 |title=Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients |journal=Journal of Neurology Neurosurgery and Psychiatry |volume=75 |issue=12 |pages=1746-8 |pmid=15548496 |url=http://jnnp.bmj.com/cgi/content/full/75/12/1746 |accessdate=2007-03-11 }}</ref> and neprilysin-deficient [[knockout mouse|knockout mice]] show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,<ref name="Madani">{{cite journal |last=Madan |first=Rime |coauthors=Raphael Poirier, David P. Wolfer, Hans Welzl, Peter Groscurth, Hans-Peter Lipp, Bao Lu, Mohammed El Mouedden, Marc Mercken, Roger M. Nitsch and M. Hasan Mohajeri |year=2006 |month=December |title=Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo |journal=Journal of Neuroscience Research |volume=84 |issue=8 |pages=1871-8 |pmid=16998901 |doi=10.1002/jnr.21074}}</ref> providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the [[rate-limiting step]] in amyloid beta degradation,<ref name="Iwata1">{{cite journal |last=Iwata |first=Nobuhisa |coauthors=Satoshi Tsubuki, Yoshie Takaki, Kaori Watanabe, Misaki Sekiguchi, Emi Hosoki, Maho Kawashima-Morishima, Hahn-Jun Lee, Emi Hama, Yoko Sekine-Aizawa and Takaomi C. Saido |year=2000 |month=February |title=Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition |journal=Nature Medicine |volume=6 |issue=2 |pages=143-50 |pmid=10655101 |doi= 10.1038/72237}}</ref> it has been considered a potential therapeutic target; compounds such as the [[peptide hormone]] [[somatostatin]] have been identified that increase the enzyme's activity level.<ref name="Iwata">{{cite journal |last=Iwata |first=Nobuhisa |coauthors=Makoto Higuchi and Takaomi C. Saido |year=2005 |month=November |title=Metabolism of amyloid-beta peptide and Alzheimer's disease |journal=Pharmacology & Therapeutics |volume=108 |issue=2 |pages=129-48 |pmid=16112736 |doi=10.1016/j.pharmthera.2005.03.010 }}</ref> One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.<ref name="Hama">{{cite journal |last=Hama |first=Emi |coauthors=Takaomi C. Saido |year=2005  |title=Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide |journal=Medical Hypotheses |volume=65 |issue=3 |pages=498-500 |pmid=15921860 |doi=10.1016/j.mehy.2005.02.045 }}</ref> Declining neprilysin activity with increasing age may also be explained by [[oxidative]] damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.<ref name="Wang">{{cite journal |last=Wang |first=Deng-Shun |coauthors=Nobuhisa Iwata, Emi Hama, Takaomi C. Saido and Dennis W. Dickson |year=2003 |month=October |title=Oxidized neprilysin in aging and Alzheimer's disease brains |journal=Biochemical and Biophysical Research Communications |volume=310 |issue=1 |pages=236-41 |pmid=14511676 |doi=10.1016/j.bbrc.2003.09.003 }}</ref>


==Signaling peptides==
Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common [[acute lymphocytic leukemia]] antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.<ref name="entrez"/>
===Fluid balance===
Neprilysin is highly expressed in [[kidney]] and [[lung]] tissues. Inhibitors are [[Natriuretic peptides|natriuretic]] and [[antihypertensive]] agents that act by preventing neprilysin's activity against signaling peptides such as [[endothelin]], and [[atrial natriuretic factor]].<ref name="Sahli">{{cite journal |last=Sahli |first=Stefan B|coauthors= ernhard Stump, Tobias Welti, W. Bernd Schweizer, François Diederich, Denise Blum-Kaelin, Johannes D. Aebi  and Hans-Joachim Böhm|year= 2005|month=April |title=A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold |journal=Helvetica Chimica Acta |volume=88 |issue=4 |pages=707-730 |doi=10.1002/hlca.200590050 }}</ref><ref name="Oefner">{{cite journal |last=Oefner |first=C. |coauthors= B. P.  Roques, M.-C.  Fournie-Zaluski and G. E.  Dale|year= 2004|month=February |title=Structural analysis of neprilysin with various specific and potent inhibitors |journal=Acta Crystallographica Section D Biological Crystallography |volume=60, prt 2 |pages=392-396 |pmid=14747736 |doi=10.1107/S0907444903027410 }}</ref>


[[Randomized control trial]]s have found that [[sacubitril]], a neprilysin inhibitor that increases levels of [[natriuretic peptides]], can reduce death and of hospitalization for heart failure. <ref name="pmid25176015">{{cite journal| author=McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al.| title=Angiotensin-neprilysin inhibition versus enalapril in heart failure. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 11 | pages= 993-1004 | pmid=25176015 | doi=10.1056/NEJMoa1409077 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25176015  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25686189 Review in: Ann Intern Med. 2015 Feb 17;162(4):JC2]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25659916 Review in: Evid Based Med. 2015 Apr;20(2):61] </ref>
Hematopoetic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells.<ref>{{cite journal | pmid = 7584137 | volume=3 | issue=4 | title=Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. | date=Oct 1995 | journal=Immunity | pages=459–73 | doi=10.1016/1074-7613(95)90175-2}}</ref> CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node [[germinal centers]].<ref name="urlCD Markers - CD10">{{cite web | url = http://www.pathologyoutlines.com/topic/cdmarkerscd10.html | title = CD10 | author = Singh C | date = 2011-02-25 | work = CD Markers | publisher = PathologyOutlines.com, Inc. }}</ref> Hematologic diseases in which it is positive include ALL, [[angioimmunoblastic T cell lymphoma]], [[Burkitt lymphoma]],  [[chronic myelogenous leukemia]] in blast crisis (90%),  [[diffuse large B-cell lymphoma]] (variable),  follicular center cells (70%),  [[hairy cell leukemia]] (10%), and myeloma (some). It tends to be negative in [[acute myeloid leukemia]], [[chronic lymphocytic leukemia]], [[mantle cell lymphoma]], and [[marginal zone lymphoma]]. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.<ref name="pmid20051779">{{cite journal |vauthors=Papandreou CN, Nanus DM | title = Is methylation the key to CD10 loss? | journal = J. Pediatr. Hematol. Oncol. | volume = 32 | issue = 1 | pages = 2–3 |date=January 2010 | pmid = 20051779 | doi = 10.1097/MPH.0b013e3181c74aca  }}</ref>


===Pain===
== Amyloid beta regulation ==
Neprilysin inhibitors have been designed with [[analgesic]] properties that inhibit neprilysin's activity against signaling peptides such as [[enkephalin]]s and [[substance P]].<ref name="Sahli">{{cite journal | author = Sahli S, Stump B, Welti T, Schweizer WB, Diederich R, Blum-Kaelin D, Aebi JD, Böhm H-J |date=April 2005 |title=A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold |journal=[[Helvetica Chimica Acta]] |volume=88 |issue=4 |pages=707–730 |doi=10.1002/hlca.200590050 }}</ref><ref name="Oefner">{{cite journal | author = Oefner C, Roques BP, Fournie-Zaluski MC, Dale GE | title = Structural analysis of neprilysin with various specific and potent inhibitors | journal = Acta Crystallogr. D Biol. Crystallogr. | volume = 60 | issue = Pt 2 | pages = 392–6 |date=February 2004 | pmid = 14747736 | doi = 10.1107/S0907444903027410 }}</ref>
Neprilysin-deficient [[knockout mouse|knockout mice]] show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,<ref name="Madani">{{cite journal |vauthors=Madani R, Poirier R, Wolfer DP, Welzl H, Groscurth P, Lipp HP, Lu B, El Mouedden M, Mercken M, Nitsch RM, Mohajeri MH | title = Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo | journal = J. Neurosci. Res. | volume = 84 | issue = 8 | pages = 1871–8 |date=December 2006 | pmid = 16998901 | doi = 10.1002/jnr.21074 }}</ref> providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the [[rate-limiting step]] in amyloid beta degradation,<ref name="Iwata1">{{cite journal |vauthors=Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC | title = Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition | journal = Nat. Med. | volume = 6 | issue = 2 | pages = 143–50 |date=February 2000 | pmid = 10655101 | doi = 10.1038/72237 }}</ref> it has been considered a potential therapeutic target; compounds such as the [[peptide hormone]] [[somatostatin]] have been identified that increase the enzyme's activity level.<ref name="Iwata">{{cite journal |vauthors=Iwata N, Higuchi M, Saido TC | title = Metabolism of amyloid-beta peptide and Alzheimer's disease | journal = Pharmacol. Ther. | volume = 108 | issue = 2 | pages = 129–48 |date=November 2005 | pmid = 16112736 | doi = 10.1016/j.pharmthera.2005.03.010 }}</ref> One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.<ref name="Hama">{{cite journal |vauthors=Hama E, Saido TC | title = Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide | journal = Med. Hypotheses | volume = 65 | issue = 3 | pages = 498–500 | year = 2005 | pmid = 15921860 | doi = 10.1016/j.mehy.2005.02.045 }}</ref> Declining neprilysin activity with increasing age may also be explained by [[oxidative]] damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.<ref name="Wang">{{cite journal |vauthors=Wang DS, Iwata N, Hama E, Saido TC, Dickson DW | title = Oxidized neprilysin in aging and Alzheimer's disease brains | journal = Biochem. Biophys. Res. Commun. | volume = 310 | issue = 1 | pages = 236–41 |date=October 2003 | pmid = 14511676 | doi = 10.1016/j.bbrc.2003.09.003 }}</ref>


===Tumor growth===
== Signaling peptides ==
Associations have been observed between neprilysin expression and various types of [[cancer]]; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer [[biomarker]] studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as [[metastatic]] [[carcinoma]] and some advanced [[melanoma]]s, neprilysin is overexpressed;<ref name="Velazquez">{{cite journal |last=Velasquez |first=Elsa F.|coauthors=Molly Yancovitz, Anna Pavlick, Russell Berman, Richard Shapiro, Dusan Bogunovic, David O'Neill, Yi-Lo Yu, Joanna Spira, Paul J Christos, Xi Kathy Zhou, Madhu Mazumdar4, David M Nanus, Leonard Liebes, Nina Bhardwaj, David Polsky and Iman Osman |year=2007 |month=January |title=Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma |journal=Journal of Translational Medicine |volume=5 |issue=2 |pmid=17207277 |doi=10.1186/1479-5876-5-2 }}</ref> in other types, most notably [[lung cancer]]s, neprilysin is downregulated, and thus unable to modulate the pro-growth [[autocrine]] signaling of cancer cells via secreted peptides such as mammalian [[homology (biology)|homologs]] related to [[bombesin]].<ref name="Cohen">{{cite journal |last=Cohen |first=Andrea J. |coauthors=  Paul A. Bunn, Wilbur Franklin, Catherine Magill-Solc, Christa Hartmann, Barbara Heifrich, Laura Gilman, Joy Folkvord, Karen Helm, and York E. Miller|year=1996 |month=February |title=Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux |journal=Cancer Research |volume=56 |issue=4 |pages=831-9 |pmid=8631021 |url=http://cancerres.aacrjournals.org/cgi/reprint/56/4/831 |accessdate=2006-03-11 }}</ref>
[[Image:Kidney cd10 ihc.jpg|thumb|Neprilysin immunohistochemical staining of normal [[kidney]].]]
Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in [[kidney]] and [[lung]] tissues. Inhibitors have been designed with the aim of developing [[analgesic]] and [[antihypertensive]] agents that act by preventing neprilysin's activity against signaling peptides such as [[enkephalin]]s, [[substance P]], [[endothelin]], and [[atrial natriuretic factor]].<ref name="Sahli">{{cite journal |vauthors=Sahli S, Stump B, Welti T, Schweizer WB, Diederich R, Blum-Kaelin D, Aebi JD, Böhm HJ |date=April 2005 |title=A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold |journal=[[Helvetica Chimica Acta]] |volume=88 |issue=4 |pages=707–730 |doi=10.1002/hlca.200590050 }}</ref><ref name="Oefner">{{cite journal |vauthors=Oefner C, Roques BP, Fournie-Zaluski MC, Dale GE | title = Structural analysis of neprilysin with various specific and potent inhibitors | journal = Acta Crystallogr. D | volume = 60 | issue = Pt 2 | pages = 392–6 |date=February 2004 | pmid = 14747736 | doi = 10.1107/S0907444903027410 }}</ref>


==References==
Associations have been observed between neprilysin expression and various types of [[cancer]]; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer [[biomarker]] studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as [[metastatic]] [[carcinoma]] and some advanced [[melanoma]]s, neprilysin is overexpressed;<ref name="Velazquez">{{cite journal |vauthors=Velazquez EF, Yancovitz M, Pavlick A, Berman R, Shapiro R, Bogunovic D, O'Neill D, Yu YL, Spira J, Christos PJ, Zhou XK, Mazumdar M, Nanus DM, Liebes L, Bhardwaj N, Polsky D, Osman I | title = Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma | journal = J Transl Med | volume = 5 | issue = 1| pages = 2 | year = 2007 | pmid = 17207277 | pmc = 1770905 | doi = 10.1186/1479-5876-5-2 }}</ref> in other types, most notably [[lung cancer]]s, neprilysin is downregulated, and thus unable to modulate the pro-growth [[autocrine]] signaling of cancer cells via secreted peptides such as mammalian [[homology (biology)|homologs]] related to [[bombesin]].<ref name="Cohen">{{cite journal |vauthors=Cohen AJ, Bunn PA, Franklin W, Magill-Solc C, Hartmann C, Helfrich B, Gilman L, Folkvord J, Helm K, Miller YE | title = Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux | journal = Cancer Res. | volume = 56 | issue = 4 | pages = 831–9 |date=February 1996 | pmid = 8631021 | doi = | url = http://cancerres.aacrjournals.org/cgi/reprint/56/4/831 }}</ref>
<div class="references-2column">
Some plant extracts (methanol extracts of ''[[Ceropegia]] rupicola'', ''[[Kniphofia]] sumarae'', '' [[Plectranthus]] cf barbatus'', and an aqueous extract of ''[[Pavetta]] longiflora'') were found able to inhibit the enzymatic activity of neutral endopeptidase.<ref name="pmid18271311">{{cite journal |vauthors=Alasbahi R, Melzig MF | title = Screening of some Yemeni medicinal plants for inhibitory activity against peptidases | journal = Pharmazie | volume = 63 | issue = 1 | pages = 86–8 |date=January 2008 | pmid = 18271311 | doi = }}</ref>
<references/>
</div>


==External links==
== Inhibitors ==
Inhibitors have been designed with the aim of developing [[analgesic]] and [[antihypertensive]] agents that act by preventing neprilysin's activity against signaling peptides such as [[enkephalin]]s, [[substance P]], [[endothelin]], and [[atrial natriuretic factor]].<ref name="Sahli"/><ref name="Oefner"/>
 
Some are intended to treat [[heart failure]].<ref name=McMurray2014/>
 
* [[Sacubitril/valsartan]] (Entresto/LCZ696), which has been tested against [[enalapril]] in patients with heart failure.<ref name=McMurray2014>{{cite journal | vauthors = McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR | title = Angiotensin-neprilysin inhibition versus enalapril in heart failure | journal = The New England Journal of Medicine | volume = 371 | issue = 11 | pages = 993–1004 | date = Sep 2014 | pmid = 25176015 | doi = 10.1056/NEJMoa1409077 | url = http://www.nejm.org/doi/full/10.1056/NEJMoa1409077 }}</ref>
* [[Sacubitril]] (AHU-377), a [[prodrug]] which is a component of [[sacubitril/valsartan]]
* [[Sacubitrilat]] (LBQ657), the active form of sacubitril
* [[RB-101]], an enkephalinase inhibitor, used in scientific research.
* [[UK-414,495]]
* [[Omapatrilat]] (dual inhibitor of NEP and [[angiotensin-converting enzyme]]) developed by BMS did not receive FDA approval due to [[angioedema]] safety concerns.
* [[Ecadotril]]
 
Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.<ref>{{cite journal |author=Venugopal J |title=Pharmacological modulation of the natriuretic peptide system |journal=Expert Opinion on Therapeutic Patents |volume=13 |issue=9 |pages=1389–1409 |year=2003 |url=http://www.expertopin.com/doi/abs/10.1517/13543776.13.9.1389 |doi=10.1517/13543776.13.9.1389}}</ref>
 
== Immunochemistry ==
CD10 is used in clinical pathology for diagnostic purpose.
 
=== In lymphomas and leukemias ===
* [[Acute lymphoblastic leukemia]] (ALL) cells are CD10<sup>+</sup>.
* [[Follicular lymphoma]] (follicle centre cell lymphoma) are CD10<sup>+</sup>.
* Burkitt Lymphoma cells are CD10<sup>+</sup>.
* CD10<sup>+</sup> diffuse large B cell lymphoma (CD10<sup>+</sup> DLBLC)<ref name="pmid22431545">{{cite journal |vauthors=McGowan P, Nelles N, Wimmer J, Williams D, Wen J, Li M, Ewton A, Curry C, Zu Y, Sheehan A, Chang CC | title = Differentiating between Burkitt lymphoma and CD10+ diffuse large B-cell lymphoma: the role of commonly used flow cytometry cell markers and the application of a multiparameter scoring system | journal = Am. J. Clin. Pathol. | volume = 137 | issue = 4 | pages = 665–70 | year = 2012 | pmid = 22431545 | doi = 10.1309/AJCP3FEPX5BEEKGX }}</ref>
** Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,<ref name="pmid15920553">{{cite journal |vauthors=Berglund M, Thunberg U, Amini RM, Book M, Roos G, Erlanson M, Linderoth J, Dictor M, Jerkeman M, Cavallin-Ståhl E, Sundström C, Rehn-Eriksson S, Backlin C, Hagberg H, Rosenquist R, Enblad G | title = Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis | journal = Mod. Pathol. | volume = 18 | issue = 8 | pages = 1113–20 | year = 2005 | pmid = 15920553 | doi = 10.1038/modpathol.3800396 }}</ref><ref name="pmid20309427">{{cite journal |vauthors=Höller S, Horn H, Lohr A, Mäder U, Katzenberger T, Kalla J, Bernd HW, Went P, Ott MM, Müller-Hermelink HK, Rosenwald A, Ott G | title = A cytomorphological and immunohistochemical profile of aggressive B-cell lymphoma: high clinical impact of a cumulative immunohistochemical outcome predictor score | journal = J Hematop | volume = 2 | issue = 4 | pages = 187–94 | year = 2009 | pmid = 20309427 | pmc = 2798934 | doi = 10.1007/s12308-009-0044-x }}</ref> but CD10<sup>+</sup>, [[BCL2]]<sup>+ </sup>tumors could have poorer survival.<ref name="pmid11488064">{{cite journal |vauthors=Xu Y, McKenna RW, Molberg KH, Kroft SH | title = Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2 | journal = Am. J. Clin. Pathol. | volume = 116 | issue = 2 | pages = 183–90 | year = 2001 | pmid = 11488064 | doi = 10.1309/J7RN-UXAY-55GX-BUNK }}</ref> For some authors, CD10 expression in DLBCL does not influence survival.<ref name="pmid15517363">{{cite journal |vauthors=Fabiani B, Delmer A, Lepage E, Guettier C, Petrella T, Brière J, Penny AM, Copin MC, Diebold J, Reyes F, Gaulard P, Molina TJ | title = CD10 expression in diffuse large B-cell lymphomas does not influence survival | journal = Virchows Arch. | volume = 445 | issue = 6 | pages = 545–51 | year = 2004 | pmid = 15517363 | doi = 10.1007/s00428-004-1129-7 }}</ref>
* [[Angioimmunoblastic T cell lymphoma]] (AITL) are CD10<sup>+</sup><ref name="pmid21499231">{{cite journal |vauthors=Baseggio L, Traverse-Glehen A, Berger F, Ffrench M, Jallades L, Morel D, Goedert G, Magaud JP, Salles G, Felman P | title = CD10 and ICOS expression by multiparametric flow cytometry in angioimmunoblastic T-cell lymphoma | journal = Mod. Pathol. | volume = 24 | issue = 7 | pages = 993–1003 | year = 2011 | pmid = 21499231 | doi = 10.1038/modpathol.2011.53 }}</ref><ref name="pmid16084948">{{cite journal |vauthors=Yuan CM, Vergilio JA, Zhao XF, Smith TK, Harris NL, Bagg A | title = CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10+ T cells by flow cytometry | journal = Hum. Pathol. | volume = 36 | issue = 7 | pages = 784–91 | year = 2005 | pmid = 16084948 | doi = 10.1016/j.humpath.2005.05.008 }}</ref> and distinguishes AITL from other T cell lymphomas (CD10<sup>−</sup>)<ref name="pmid14707864">{{cite journal |vauthors=Attygalle AD, Diss TC, Munson P, Isaacson PG, Du MQ, Dogan A | title = CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma | journal = Am. J. Surg. Pathol. | volume = 28 | issue = 1 | pages = 54–61 | year = 2004 | pmid = 14707864 | doi = 10.1097/00000478-200401000-00005}}</ref>
** Some benign T cells can be CD10<sup>+</sup><ref name="pmid13679451">{{cite journal |vauthors=Cook JR, Craig FE, Swerdlow SH | title = Benign CD10-positive T cells in reactive lymphoid proliferations and B-cell lymphomas | journal = Mod. Pathol. | volume = 16 | issue = 9 | pages = 879–85 | year = 2003 | pmid = 13679451 | doi = 10.1097/01.MP.0000084630.64243.D1 }}</ref>
 
=== In epithelial tumors ===
* [[Clear cell renal cell carcinoma]] (Clear cell RCC)
** CD10<sup>+</sup> distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers. Chromophobe carcinoma and oncocytoma are CD10<sup>−</sup>.<ref name="pmid22417859">{{cite journal |vauthors=Yasir S, Herrera L, Gomez-Fernandez C, Reis IM, Umar S, Leveillee R, Kava B, Jorda M | title = CD10<sup>+</sup> and CK7/RON- immunophenotype distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers | journal = Appl. Immunohistochem. Mol. Morphol. | volume = 20 | issue = 5 | pages = 454–61 | year = 2012 | pmid = 22417859 | doi = 10.1097/PAI.0b013e31823fecd3 }}</ref>
* [[Pancreatic tumor]]s
** [[Solid pseudopapillary tumour]]s are CD10<sup>+</sup>.<ref name="pmid11023097">{{cite journal |vauthors=Notohara K, Hamazaki S, Tsukayama C, Nakamoto S, Kawabata K, Mizobuchi K, Sakamoto K, Okada S | title = Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10 | journal = Am. J. Surg. Pathol. | volume = 24 | issue = 10 | pages = 1361–71 | year = 2000 | pmid = 11023097 | doi = 10.1097/00000478-200010000-00005}}</ref>
** CD10<sup>+</sup> differentiates [[mucinous cystic neoplasm]]s (CD10<sup>+</sup>/CK20+) from [[intraductal papillary mucinous neoplasm]] of branch duct type (CD10<sup>−</sup>/CK20-).<ref name="pmid11023097"/>
* [[Cutaneous tumor]]s
** CD10 may differentiate [[basal cell carcinoma]] (CD10 epithelial staining) from [[trichoblastoma]] (CD10 peritumoral stromal staining), basal cell carcinoma with follicular differentiation (CD10 stromal and epithelial staining)<ref name="pmid19570076">{{cite journal |vauthors=Córdoba A, Guerrero D, Larrinaga B, Iglesias ME, Arrechea MA, Yanguas JI | title = Bcl-2 and CD10 expression in the differential diagnosis of trichoblastoma, basal cell carcinoma, and basal cell carcinoma with follicular differentiation | journal = Int. J. Dermatol. | volume = 48 | issue = 7 | pages = 713–7 | year = 2009 | pmid = 19570076 | doi = 10.1111/j.1365-4632.2009.04076.x }}</ref> and [[squamous cell carcinoma]] (strong stromal staining).<ref name="pmid23825889">{{cite journal |vauthors=Sari Aslani F, Akbarzadeh-Jahromi M, Jowkar F | title = Value of CD10 Expression in Differentiating Cutaneous Basal from Squamous Cell Carcinomas and Basal Cell Carcinoma from Trichoepithelioma | journal = Iran J Med Sci | volume = 38 | issue = 2 | pages = 100–6 | year = 2013 | pmid = 23825889 | pmc = 3700055 | doi = }}</ref>
** CD10 differentiates CD10<sup>+</sup> [[atypical fibroxanthoma]] from CD10<sup>−</sup> spindle cell [[melanoma]] and sarcomatoid [[squamous cell carcinoma]].
* [[Urothelial tumor]]s express CD10 (42-67%).<ref name="pmid16191505">{{cite journal |vauthors=Murali R, Delprado W | title = CD10 immunohistochemical staining in urothelial neoplasms | journal = Am. J. Clin. Pathol. | volume = 124 | issue = 3 | pages = 371–9 | year = 2005 | pmid = 16191505 | doi = 10.1309/04BH-F6A8-0BQM-H7HT }}</ref>
** CD10 expression is strongly correlated with high tumor grade and stage in urothelial carcinoma of the bladder. CD10 may be associated with tumor progression in bladder cancer pathogenesis.<ref name="pmid19917108">{{cite journal |vauthors=Bahadir B, Behzatoglu K, Bektas S, Bozkurt ER, Ozdamar SO | title = CD10 expression in urothelial carcinoma of the bladder | journal = Diagn Pathol | volume = 4 | issue = 1| pages = 38 | year = 2009 | pmid = 19917108 | pmc = 2780995 | doi = 10.1186/1746-1596-4-38 }}</ref>
 
=== In other tumors ===
* CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.<ref name="pmid12218209">{{cite journal |vauthors=Mikami Y, Hata S, Kiyokawa T, Manabe T | title = Expression of CD10 in malignant müllerian mixed tumors and adenosarcomas: an immunohistochemical study | journal = Mod. Pathol. | volume = 15 | issue = 9 | pages = 923–30 | year = 2002 | pmid = 12218209 | doi = 10.1097/01.MP.0000026058.33869.DB }}</ref>
** Normal endometrial stroma<ref name="pmid11532038">{{cite journal |vauthors=McCluggage WG, Sumathi VP, Maxwell P | title = CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms | journal = Histopathology | volume = 39 | issue = 3 | pages = 273–8 | year = 2001 | pmid = 11532038 | doi = 10.1046/j.1365-2559.2001.01215.x}}</ref>
** [[Endometrial stromal sarcoma]] (ESS) are CD10<sup>+</sup> ([[Smooth muscle tumor]]s are usually CD10<sup>−</sup>,<ref name="pmid15867200">{{cite journal |vauthors=Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S | title = Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer | journal = J. Clin. Oncol. | volume = 23 | issue = 16 | pages = 3706–12 | year = 2005 | pmid = 15867200 | doi = 10.1200/JCO.2005.00.232 }}</ref> but can be CD10<sup>+</sup> <ref name="pmid12218209"/>
** [[Malignant müllerian mixed tumor]] (MMMT)
** [[Müllerian adenosarcoma]]
** [[Uterine high-grade leiomyosarcoma]]
** [[Uterine rhabdomyosarcoma]]
* Vascular tumors
** [[Epithelioid hemangioendothelioma]] are mostly CD10<sup>+</sup>.<ref name="pmid19961253">{{cite journal |vauthors=Weinreb I, Cunningham KS, Perez-Ordoñez B, Hwang DM | title = CD10 is expressed in most epithelioid hemangioendotheliomas: a potential diagnostic pitfall | journal = Arch. Pathol. Lab. Med. | volume = 133 | issue = 12 | pages = 1965–8 | year = 2009 | pmid = 19961253 | doi = 10.1043/1543-2165-133.12.1965 }}</ref>
** [[Hemangioblastoma]] is usually CD10<sup>−</sup> (metastatic [[renal cell carcinoma]] is CD10<sup>+</sup>)<ref name="pmid15578072">{{cite journal |vauthors=Jung SM, Kuo TT | title = Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma | journal = Mod. Pathol. | volume = 18 | issue = 6 | pages = 788–94 | year = 2005  | pmid = 15578072 | doi = 10.1038/modpathol.3800351 }}</ref><ref name="pmid22497861">{{cite journal |vauthors=Yin WH, Li J, Chan JK | title = Sporadic haemangioblastoma of the kidney with rhabdoid features and focal CD10 expression: report of a case and literature review | journal = Diagn Pathol | volume = 7 | issue = 1| pages = 39 | year = 2012 | pmid = 22497861 | pmc = 3364142 | doi = 10.1186/1746-1596-7-39 }}</ref>
 
== See also ==
* [[List of histologic stains that aid in diagnosis of cutaneous conditions]]
 
== References ==
{{Reflist|2}}
 
== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M13.001 M13.001]
* {{MeshName|Neprilysin}}
* {{MeshName|Neprilysin}}


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Neprilysin (/ˌnɛprɪˈlaɪsɪn/)[1], also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.[2] It also degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface.

Neprilysin is expressed in a wide variety of tissues and is particularly abundant in kidney. It is also a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). This protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL.[2]

Hematopoetic progenitors expressing CD10 are considered "common lymphoid progenitors", which means they can differentiate into T, B or natural killer cells.[3] CD10 is of use in hematological diagnosis since it is expressed by early B, pro-B and pre-B lymphocytes, and by lymph node germinal centers.[4] Hematologic diseases in which it is positive include ALL, angioimmunoblastic T cell lymphoma, Burkitt lymphoma, chronic myelogenous leukemia in blast crisis (90%), diffuse large B-cell lymphoma (variable), follicular center cells (70%), hairy cell leukemia (10%), and myeloma (some). It tends to be negative in acute myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma. CD10 is found on non-T ALL cells, which derive from pre-B lymphocytes, and in germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.[5]

Amyloid beta regulation

Neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,[6] providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation,[7] it has been considered a potential therapeutic target; compounds such as the peptide hormone somatostatin have been identified that increase the enzyme's activity level.[8] One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin in the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.[9] Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.[10]

Signaling peptides

File:Kidney cd10 ihc.jpg
Neprilysin immunohistochemical staining of normal kidney.

Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic factor.[11][12]

Associations have been observed between neprilysin expression and various types of cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma and some advanced melanomas, neprilysin is overexpressed;[13] in other types, most notably lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to bombesin.[14] Some plant extracts (methanol extracts of Ceropegia rupicola, Kniphofia sumarae, Plectranthus cf barbatus, and an aqueous extract of Pavetta longiflora) were found able to inhibit the enzymatic activity of neutral endopeptidase.[15]

Inhibitors

Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic factor.[11][12]

Some are intended to treat heart failure.[16]

Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.[17]

Immunochemistry

CD10 is used in clinical pathology for diagnostic purpose.

In lymphomas and leukemias

  • Acute lymphoblastic leukemia (ALL) cells are CD10+.
  • Follicular lymphoma (follicle centre cell lymphoma) are CD10+.
  • Burkitt Lymphoma cells are CD10+.
  • CD10+ diffuse large B cell lymphoma (CD10+ DLBLC)[18]
    • Marker for germinal center phenotype (CD10, HGAL, BCL6, CD38) are considered a favorable prognostic factor,[19][20] but CD10+, BCL2+ tumors could have poorer survival.[21] For some authors, CD10 expression in DLBCL does not influence survival.[22]
  • Angioimmunoblastic T cell lymphoma (AITL) are CD10+[23][24] and distinguishes AITL from other T cell lymphomas (CD10−)[25]
    • Some benign T cells can be CD10+[26]

In epithelial tumors

In other tumors

See also

References

  1. ↑ "Neprilysin - Cofactor Ora". cofactor.io. Retrieved November 24, 2017.
  2. ↑ 2.0 2.1 "Entrez Gene: Membrane metallo-endopeptidase".
  3. ↑ "Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset". Immunity. 3 (4): 459–73. Oct 1995. doi:10.1016/1074-7613(95)90175-2. PMID 7584137.
  4. ↑ Singh C (2011-02-25). "CD10". CD Markers. PathologyOutlines.com, Inc.
  5. ↑ Papandreou CN, Nanus DM (January 2010). "Is methylation the key to CD10 loss?". J. Pediatr. Hematol. Oncol. 32 (1): 2–3. doi:10.1097/MPH.0b013e3181c74aca. PMID 20051779.
  6. ↑ Madani R, Poirier R, Wolfer DP, Welzl H, Groscurth P, Lipp HP, Lu B, El Mouedden M, Mercken M, Nitsch RM, Mohajeri MH (December 2006). "Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo". J. Neurosci. Res. 84 (8): 1871–8. doi:10.1002/jnr.21074. PMID 16998901.
  7. ↑ Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (February 2000). "Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition". Nat. Med. 6 (2): 143–50. doi:10.1038/72237. PMID 10655101.
  8. ↑ Iwata N, Higuchi M, Saido TC (November 2005). "Metabolism of amyloid-beta peptide and Alzheimer's disease". Pharmacol. Ther. 108 (2): 129–48. doi:10.1016/j.pharmthera.2005.03.010. PMID 16112736.
  9. ↑ Hama E, Saido TC (2005). "Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide". Med. Hypotheses. 65 (3): 498–500. doi:10.1016/j.mehy.2005.02.045. PMID 15921860.
  10. ↑ Wang DS, Iwata N, Hama E, Saido TC, Dickson DW (October 2003). "Oxidized neprilysin in aging and Alzheimer's disease brains". Biochem. Biophys. Res. Commun. 310 (1): 236–41. doi:10.1016/j.bbrc.2003.09.003. PMID 14511676.
  11. ↑ 11.0 11.1 Sahli S, Stump B, Welti T, Schweizer WB, Diederich R, Blum-Kaelin D, Aebi JD, Böhm HJ (April 2005). "A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold". Helvetica Chimica Acta. 88 (4): 707–730. doi:10.1002/hlca.200590050.
  12. ↑ 12.0 12.1 Oefner C, Roques BP, Fournie-Zaluski MC, Dale GE (February 2004). "Structural analysis of neprilysin with various specific and potent inhibitors". Acta Crystallogr. D. 60 (Pt 2): 392–6. doi:10.1107/S0907444903027410. PMID 14747736.
  13. ↑ Velazquez EF, Yancovitz M, Pavlick A, Berman R, Shapiro R, Bogunovic D, O'Neill D, Yu YL, Spira J, Christos PJ, Zhou XK, Mazumdar M, Nanus DM, Liebes L, Bhardwaj N, Polsky D, Osman I (2007). "Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma". J Transl Med. 5 (1): 2. doi:10.1186/1479-5876-5-2. PMC 1770905. PMID 17207277.
  14. ↑ Cohen AJ, Bunn PA, Franklin W, Magill-Solc C, Hartmann C, Helfrich B, Gilman L, Folkvord J, Helm K, Miller YE (February 1996). "Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux". Cancer Res. 56 (4): 831–9. PMID 8631021.
  15. ↑ Alasbahi R, Melzig MF (January 2008). "Screening of some Yemeni medicinal plants for inhibitory activity against peptidases". Pharmazie. 63 (1): 86–8. PMID 18271311.
  16. ↑ 16.0 16.1 McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (Sep 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015.
  17. ↑ Venugopal J (2003). "Pharmacological modulation of the natriuretic peptide system". Expert Opinion on Therapeutic Patents. 13 (9): 1389–1409. doi:10.1517/13543776.13.9.1389.
  18. ↑ McGowan P, Nelles N, Wimmer J, Williams D, Wen J, Li M, Ewton A, Curry C, Zu Y, Sheehan A, Chang CC (2012). "Differentiating between Burkitt lymphoma and CD10+ diffuse large B-cell lymphoma: the role of commonly used flow cytometry cell markers and the application of a multiparameter scoring system". Am. J. Clin. Pathol. 137 (4): 665–70. doi:10.1309/AJCP3FEPX5BEEKGX. PMID 22431545.
  19. ↑ Berglund M, Thunberg U, Amini RM, Book M, Roos G, Erlanson M, Linderoth J, Dictor M, Jerkeman M, Cavallin-Ståhl E, Sundström C, Rehn-Eriksson S, Backlin C, Hagberg H, Rosenquist R, Enblad G (2005). "Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis". Mod. Pathol. 18 (8): 1113–20. doi:10.1038/modpathol.3800396. PMID 15920553.
  20. ↑ Höller S, Horn H, Lohr A, Mäder U, Katzenberger T, Kalla J, Bernd HW, Went P, Ott MM, Müller-Hermelink HK, Rosenwald A, Ott G (2009). "A cytomorphological and immunohistochemical profile of aggressive B-cell lymphoma: high clinical impact of a cumulative immunohistochemical outcome predictor score". J Hematop. 2 (4): 187–94. doi:10.1007/s12308-009-0044-x. PMC 2798934. PMID 20309427.
  21. ↑ Xu Y, McKenna RW, Molberg KH, Kroft SH (2001). "Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2". Am. J. Clin. Pathol. 116 (2): 183–90. doi:10.1309/J7RN-UXAY-55GX-BUNK. PMID 11488064.
  22. ↑ Fabiani B, Delmer A, Lepage E, Guettier C, Petrella T, Brière J, Penny AM, Copin MC, Diebold J, Reyes F, Gaulard P, Molina TJ (2004). "CD10 expression in diffuse large B-cell lymphomas does not influence survival". Virchows Arch. 445 (6): 545–51. doi:10.1007/s00428-004-1129-7. PMID 15517363.
  23. ↑ Baseggio L, Traverse-Glehen A, Berger F, Ffrench M, Jallades L, Morel D, Goedert G, Magaud JP, Salles G, Felman P (2011). "CD10 and ICOS expression by multiparametric flow cytometry in angioimmunoblastic T-cell lymphoma". Mod. Pathol. 24 (7): 993–1003. doi:10.1038/modpathol.2011.53. PMID 21499231.
  24. ↑ Yuan CM, Vergilio JA, Zhao XF, Smith TK, Harris NL, Bagg A (2005). "CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10+ T cells by flow cytometry". Hum. Pathol. 36 (7): 784–91. doi:10.1016/j.humpath.2005.05.008. PMID 16084948.
  25. ↑ Attygalle AD, Diss TC, Munson P, Isaacson PG, Du MQ, Dogan A (2004). "CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma". Am. J. Surg. Pathol. 28 (1): 54–61. doi:10.1097/00000478-200401000-00005. PMID 14707864.
  26. ↑ Cook JR, Craig FE, Swerdlow SH (2003). "Benign CD10-positive T cells in reactive lymphoid proliferations and B-cell lymphomas". Mod. Pathol. 16 (9): 879–85. doi:10.1097/01.MP.0000084630.64243.D1. PMID 13679451.
  27. ↑ Yasir S, Herrera L, Gomez-Fernandez C, Reis IM, Umar S, Leveillee R, Kava B, Jorda M (2012). "CD10+ and CK7/RON- immunophenotype distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers". Appl. Immunohistochem. Mol. Morphol. 20 (5): 454–61. doi:10.1097/PAI.0b013e31823fecd3. PMID 22417859.
  28. ↑ 28.0 28.1 Notohara K, Hamazaki S, Tsukayama C, Nakamoto S, Kawabata K, Mizobuchi K, Sakamoto K, Okada S (2000). "Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10". Am. J. Surg. Pathol. 24 (10): 1361–71. doi:10.1097/00000478-200010000-00005. PMID 11023097.
  29. ↑ Córdoba A, Guerrero D, Larrinaga B, Iglesias ME, Arrechea MA, Yanguas JI (2009). "Bcl-2 and CD10 expression in the differential diagnosis of trichoblastoma, basal cell carcinoma, and basal cell carcinoma with follicular differentiation". Int. J. Dermatol. 48 (7): 713–7. doi:10.1111/j.1365-4632.2009.04076.x. PMID 19570076.
  30. ↑ Sari Aslani F, Akbarzadeh-Jahromi M, Jowkar F (2013). "Value of CD10 Expression in Differentiating Cutaneous Basal from Squamous Cell Carcinomas and Basal Cell Carcinoma from Trichoepithelioma". Iran J Med Sci. 38 (2): 100–6. PMC 3700055. PMID 23825889.
  31. ↑ Murali R, Delprado W (2005). "CD10 immunohistochemical staining in urothelial neoplasms". Am. J. Clin. Pathol. 124 (3): 371–9. doi:10.1309/04BH-F6A8-0BQM-H7HT. PMID 16191505.
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