Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Inflammation Research
Published in: Inflammation Research 3-4/2015

01-04-2015 | Original Research Paper

Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells

Authors: Adrian J. Maurer, Phillip A. Bonney, Lucas C. Toho, Chad A. Glenn, Shweta Agarwal, James D. Battiste, Kar-Ming Fung, Michael E. Sughrue

Published in: Inflammation Research | Issue 3-4/2015

Login to get access

Abstract

Objective and design

We sought to determine the effect of necrosis-induced activation of the complement protein C3 in medulloblastoma.

Materials/methods

Twelve medulloblastoma surgical specimens were evaluated for complement activation using immunohistochemistry, with H&E stains performed on adjacent tissue sections to determine the relationship of complement activation to necrotic tissue. Flow cytometry and Western blot were performed on three established medulloblastoma lines and one surgically-procured cell culture to determine expression of C3a receptor (C3aR) in medulloblastoma. In vitro proliferation of siRNA C3aR knockdown cells was compared to that of control siRNA cells with cell line Daoy.

Results

Three surgical specimens were found to have necrosis on H&E sections. In each case, iC3b staining was identified on adjacent sections, limited to the necrotic region. In no case did necrosis occur without iC3b staining on adjacent sections. C3aR protein was demonstrated on both the three established cell lines and on the surgical culture. Proliferation assays of Daoy cells with siRNA knockdown vs. control siRNA revealed significantly reduced proliferation at 72 h (p = 0.001).

Conclusions

Necrosis is associated with complement activation in medulloblastoma. Medulloblastoma cells express C3aR, and siRNA-mediated knockdown of C3aR inhibits proliferation of these cells in vitro.
Literature
1.
Proctor LM, Arumugam TV, Shiels I, Reid RC, Fairlie DP, Taylor SM. Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. Br J Pharmacol. 2004;142:756–64.CrossRefPubMedCentralPubMed
2.
Elsner J, Oppermann M, Czech W, Kapp A. C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins. Blood. 1994;83:3324–31.PubMed
3.
4.
5.
Gasque P, Singhrao SK, Neal JW, Gotze O, Morgan BP. Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. Am J Pathol. 1997;150:31–41.PubMedCentralPubMed
6.
Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology. 2000;49:171–86.CrossRefPubMed
7.
Ciurana CL, Zwart B, van Mierlo G, Hack CE. Complement activation by necrotic cells in normal plasma environment compares to that by late apoptotic cells and involves predominantly IgM. Eur J Immunol. 2004;34:2609–19.CrossRefPubMed
8.
Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: the immune system in health and disease. London: Churchill Livingstone; 2001.
9.
10.
Mastellos D, Lambris JD. Complement: more than a ‘guard’ against invading pathogens? Trends Immunol. 2002;23:485–91.CrossRefPubMed
11.
Rutkowski MJ, Sughrue ME, Kane AJ, Ahn BJ, Fang S, Parsa AT. The complement cascade as a mediator of tissue growth and regeneration. Inflamm Res. 2010;59:897–905.CrossRefPubMedCentralPubMed
12.
Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Fang S, Parsa AT. Complement and the central nervous system: emerging roles in development, protection and regeneration. Immunol Cell Biol. 2010;88:781–6.CrossRefPubMed
13.
Gaipl US, Kuenkele S, Voll RE, Beyer TD, Kolowos W, Heyder P, et al. Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ. 2001;8:327–34.CrossRefPubMed
14.
Gasque P, Neal JW, Singhrao SK, McGreal EP, Dean YD, Van BJ, et al. Roles of the complement system in human neurodegenerative disorders: pro-inflammatory and tissue remodeling activities. Mol Neurobiol. 2002;25:1–17.CrossRefPubMed
15.
Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y, et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature. 2000;406:998–1001.CrossRefPubMed
16.
Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y, et al. The C3a receptor antagonist SB 290157 has agonist activity. Immunol Lett. 2005;100:139–45.CrossRefPubMed
17.
Qu H, Magotti P, Ricklin D, Wu EL, Kourtzelis I, Wu YQ, et al. Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency. Mol Immunol. 2011;48:481–9.CrossRefPubMedCentralPubMed
18.
Rahpeymai Y, Hietala MA, Wilhelmsson U, Fotheringham A, Davies I, Nilsson AK, et al. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006;25:1364–74.CrossRefPubMedCentralPubMed
19.
Ricklin D, Lambris JD. Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol. 2008;632:273–92.PubMedCentralPubMed
20.
Speth C, Dierich MP, Gasque P. Neuroinvasion by pathogens: a key role of the complement system. Mol Immunol. 2002;38:669–79.CrossRefPubMed
21.
Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Parsa AT. Cancer and the complement cascade. Mol Cancer Res. 2010;8:1453–65.CrossRefPubMed
22.
Gasque P, Thomas A, Fontaine M, Morgan BP. Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. J Neuroimmunol. 1996;66:29–40.CrossRefPubMed
23.
Kaiser HE, Bodey B. The role of apoptosis in normal ontogenesis and solid human neoplasms. In vivo Athens Greece. 2000;14:789–803.
24.
Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol. 2003;40:109–23.CrossRefPubMed
25.
Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci. 2012;19:1541–4.CrossRefPubMed
26.
McNeil DE, Cote TR, Clegg L, Rorke LB. Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance Epidemiology and End Results. Med Pediatr Oncol. 2002;39:190–4.CrossRefPubMed
27.
Urberuaga A, Navajas A, Burgos J, Pijoan JI. A review of clinical and histological features of Spanish paediatric medulloblastomas during the last 21 years. Child’s Nerv Syst. 2006;22:466–74.CrossRef
28.
Verma S, Tavare CJ, Gilles FH. Histologic features and prognosis in pediatric medulloblastoma. Pediatr Dev Pathol. 2008;11:337–43.CrossRefPubMed
29.
Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer. 2002;94:552–60.CrossRefPubMed
30.
Kopelson G, Linggood RM, Kleinman GM. Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management. Cancer. 1983;51:312–9.CrossRefPubMed
31.
Caputy AJ, McCullough DC, Manz HJ, Patterson K, Hammock MK. A review of the factors influencing the prognosis of medulloblastoma. The importance of cell differentiation. J Neurosurg. 1987;66:80–7.CrossRefPubMed
32.
van Beek J. Complement activation: beneficial and detrimental effects in the CNS. Ernst Schering Research Foundation workshop 2004; 67–85.
33.
van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci. 2003;992:56–71.CrossRefPubMed
34.
Markiewski MM, Mastellos D, Tudoran R, DeAngelis RA, Strey CW, Franchini S, et al. C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J Immunol. 2004;173:747–54 (Baltimore Md: 1950).CrossRefPubMed
35.
Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, et al. Modulation of the antitumor immune response by complement. Nat Immunol. 2008;9:1225–35.CrossRefPubMedCentralPubMed
36.
Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA. 2006;103:2328–33.CrossRefPubMedCentralPubMed
37.
Nataf S, Stahel PF, Davoust N, Barnum SR. Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Trends Neurosci. 1999;22:397–402.CrossRefPubMed
38.
Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, et al. Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J Biol Chem. 1996;271:20231–4.CrossRefPubMed
Metadata
Title
Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells
Authors
Adrian J. Maurer
Phillip A. Bonney
Lucas C. Toho
Chad A. Glenn
Shweta Agarwal
James D. Battiste
Kar-Ming Fung
Michael E. Sughrue
Publication date
01-04-2015
Publisher
Springer Basel
Published in
Inflammation Research / Issue 3-4/2015
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-015-0796-y

Other articles of this Issue 3-4/2015

Inflammation Research 3-4/2015 Go to the issue

Original Research Paper

Anti-inflammatory and chondroprotective effects of atorvastatin in a cartilage explant model of osteoarthritis

Original Research Paper

Histamine receptor expression in human renal tubules: a comparative pharmacological evaluation

Short Communication

Alterations on peripheral blood B cell subsets induced by allergic rhinitis

Original Research Paper

Circulating levels of platelet α-granule cytokines in trauma patients

Original Research Paper

ACE2 and Ang-(1–7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response

Original Research Paper

Methotrexate induced apoptotic and necrotic chromatin changes in rat myeloid leukemia cells
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits