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Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?
BACKGROUND: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020520/ https://www.ncbi.nlm.nih.gov/pubmed/27619675 http://dx.doi.org/10.1186/s12885-016-2764-5 |
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author | Abello-Cáceres, Paula Pizarro-Bauerle, Javier Rosas, Carlos Maldonado, Ismael Aguilar-Guzmán, Lorena González, Carlos Ramírez, Galia Ferreira, Jorge Ferreira, Arturo |
author_facet | Abello-Cáceres, Paula Pizarro-Bauerle, Javier Rosas, Carlos Maldonado, Ismael Aguilar-Guzmán, Lorena González, Carlos Ramírez, Galia Ferreira, Jorge Ferreira, Arturo |
author_sort | Abello-Cáceres, Paula |
collection | PubMed |
description | BACKGROUND: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect. METHODS: Polyclonal anti-rTcCRT F(ab’)(2) Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab’)(2) fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated. RESULTS: The rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab’)(2) Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab’)(2) Ab fragments increased malignancy. CONCLUSION: We have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2764-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5020520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-50205202016-09-14 Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? Abello-Cáceres, Paula Pizarro-Bauerle, Javier Rosas, Carlos Maldonado, Ismael Aguilar-Guzmán, Lorena González, Carlos Ramírez, Galia Ferreira, Jorge Ferreira, Arturo BMC Cancer Research Article BACKGROUND: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect. METHODS: Polyclonal anti-rTcCRT F(ab’)(2) Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab’)(2) fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated. RESULTS: The rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab’)(2) Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab’)(2) Ab fragments increased malignancy. CONCLUSION: We have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2764-5) contains supplementary material, which is available to authorized users. BioMed Central 2016-09-13 /pmc/articles/PMC5020520/ /pubmed/27619675 http://dx.doi.org/10.1186/s12885-016-2764-5 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Abello-Cáceres, Paula Pizarro-Bauerle, Javier Rosas, Carlos Maldonado, Ismael Aguilar-Guzmán, Lorena González, Carlos Ramírez, Galia Ferreira, Jorge Ferreira, Arturo Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title | Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title_full | Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title_fullStr | Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title_full_unstemmed | Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title_short | Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
title_sort | does native trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020520/ https://www.ncbi.nlm.nih.gov/pubmed/27619675 http://dx.doi.org/10.1186/s12885-016-2764-5 |
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