Cargando…

Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization

Human chorionic gonadotropin (hCG) was initially thought to be made only during pregnancy, but is now known to also be synthesized by a variety of cancers and is associated with poor patient prognosis. Transgenic expression of βhCG in mice causes hyper-luteinized ovaries, a loss in estrous cyclicity...

Descripción completa

Detalles Bibliográficos
Autores principales: Sachdeva, Ruchi, Bhardwaj, Neetu, Huhtaniemi, Ilpo, Aggrawal, Usha, Jain, Swatantra Kumar, Zaidi, Rana, Singh, Om, Pal, Rahul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511405/
https://www.ncbi.nlm.nih.gov/pubmed/23226476
http://dx.doi.org/10.1371/journal.pone.0051125
_version_ 1782251600965795840
author Sachdeva, Ruchi
Bhardwaj, Neetu
Huhtaniemi, Ilpo
Aggrawal, Usha
Jain, Swatantra Kumar
Zaidi, Rana
Singh, Om
Pal, Rahul
author_facet Sachdeva, Ruchi
Bhardwaj, Neetu
Huhtaniemi, Ilpo
Aggrawal, Usha
Jain, Swatantra Kumar
Zaidi, Rana
Singh, Om
Pal, Rahul
author_sort Sachdeva, Ruchi
collection PubMed
description Human chorionic gonadotropin (hCG) was initially thought to be made only during pregnancy, but is now known to also be synthesized by a variety of cancers and is associated with poor patient prognosis. Transgenic expression of βhCG in mice causes hyper-luteinized ovaries, a loss in estrous cyclicity and infertility, increased body weight, prolactinomas and mammary gland tumors. Strategies were devised to generate antibody responses against hCG to investigate whether reversal of the molecular processes driving tumorigenesis would follow. hCG-immunized transgenic mice did not exhibit increases in body weight or serum prolactin levels, and gross ovarian and pituitary morphology remained normal. While non-immunized transgenic animals demonstrated heightened levels of transcripts associated with pituitary tumorigenesis (HMG2A, E2F1, CCND1, PRL, GH, GAL, PTTG1, BMP4) and decreased levels of CDK inhibitors CDKN1B (p27), CDKN2A (p16) and CDKN2c (p18), immunization led to a reversal to levels found in non-transgenic animals. Serum derived from transgenic (but not non-transgenic) mice led to enhanced transcription as well as expression of VEGF, IL-8, KC (murine IL-8) and MMP-9 in tumor cells, effects not seen when sera derived from hCG-immunized transgenic mice was employed. As the definitive indication of the restoration of the reproductive axis, immunization led to the resumption of estrous cyclicity as well as fertility in transgenic mice. These results indicate that hCG may influence cancer pathogenesis and progression via several distinct mechanisms. Using a stringent in vivo system in which βhCG acts both a “self” antigen and a tumor-promoting moiety (putatively akin to the situation in humans), the data builds a case for anti-gonadotropin vaccination strategies in the treatment of gonadotropin-dependent or secreting malignancies that frequently acquire resistance to conventional therapy.
format Online
Article
Text
id pubmed-3511405
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-35114052012-12-05 Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization Sachdeva, Ruchi Bhardwaj, Neetu Huhtaniemi, Ilpo Aggrawal, Usha Jain, Swatantra Kumar Zaidi, Rana Singh, Om Pal, Rahul PLoS One Research Article Human chorionic gonadotropin (hCG) was initially thought to be made only during pregnancy, but is now known to also be synthesized by a variety of cancers and is associated with poor patient prognosis. Transgenic expression of βhCG in mice causes hyper-luteinized ovaries, a loss in estrous cyclicity and infertility, increased body weight, prolactinomas and mammary gland tumors. Strategies were devised to generate antibody responses against hCG to investigate whether reversal of the molecular processes driving tumorigenesis would follow. hCG-immunized transgenic mice did not exhibit increases in body weight or serum prolactin levels, and gross ovarian and pituitary morphology remained normal. While non-immunized transgenic animals demonstrated heightened levels of transcripts associated with pituitary tumorigenesis (HMG2A, E2F1, CCND1, PRL, GH, GAL, PTTG1, BMP4) and decreased levels of CDK inhibitors CDKN1B (p27), CDKN2A (p16) and CDKN2c (p18), immunization led to a reversal to levels found in non-transgenic animals. Serum derived from transgenic (but not non-transgenic) mice led to enhanced transcription as well as expression of VEGF, IL-8, KC (murine IL-8) and MMP-9 in tumor cells, effects not seen when sera derived from hCG-immunized transgenic mice was employed. As the definitive indication of the restoration of the reproductive axis, immunization led to the resumption of estrous cyclicity as well as fertility in transgenic mice. These results indicate that hCG may influence cancer pathogenesis and progression via several distinct mechanisms. Using a stringent in vivo system in which βhCG acts both a “self” antigen and a tumor-promoting moiety (putatively akin to the situation in humans), the data builds a case for anti-gonadotropin vaccination strategies in the treatment of gonadotropin-dependent or secreting malignancies that frequently acquire resistance to conventional therapy. Public Library of Science 2012-11-30 /pmc/articles/PMC3511405/ /pubmed/23226476 http://dx.doi.org/10.1371/journal.pone.0051125 Text en © 2012 Sachdeva et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sachdeva, Ruchi
Bhardwaj, Neetu
Huhtaniemi, Ilpo
Aggrawal, Usha
Jain, Swatantra Kumar
Zaidi, Rana
Singh, Om
Pal, Rahul
Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title_full Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title_fullStr Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title_full_unstemmed Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title_short Transgenesis-Mediated Reproductive Dysfunction and Tumorigenesis: Effects of Immunological Neutralization
title_sort transgenesis-mediated reproductive dysfunction and tumorigenesis: effects of immunological neutralization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511405/
https://www.ncbi.nlm.nih.gov/pubmed/23226476
http://dx.doi.org/10.1371/journal.pone.0051125
work_keys_str_mv AT sachdevaruchi transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT bhardwajneetu transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT huhtaniemiilpo transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT aggrawalusha transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT jainswatantrakumar transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT zaidirana transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT singhom transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization
AT palrahul transgenesismediatedreproductivedysfunctionandtumorigenesiseffectsofimmunologicalneutralization