Cargando…

Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer

The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study w...

Descripción completa

Detalles Bibliográficos
Autores principales: Roland, Christina L., Lynn, Kristi D., Toombs, Jason E., Dineen, Sean P., Udugamasooriya, D. Gomika, Brekken, Rolf A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766251/
https://www.ncbi.nlm.nih.gov/pubmed/19888452
http://dx.doi.org/10.1371/journal.pone.0007669
_version_ 1782173205934374912
author Roland, Christina L.
Lynn, Kristi D.
Toombs, Jason E.
Dineen, Sean P.
Udugamasooriya, D. Gomika
Brekken, Rolf A.
author_facet Roland, Christina L.
Lynn, Kristi D.
Toombs, Jason E.
Dineen, Sean P.
Udugamasooriya, D. Gomika
Brekken, Rolf A.
author_sort Roland, Christina L.
collection PubMed
description The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.
format Text
id pubmed-2766251
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-27662512009-11-04 Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer Roland, Christina L. Lynn, Kristi D. Toombs, Jason E. Dineen, Sean P. Udugamasooriya, D. Gomika Brekken, Rolf A. PLoS One Research Article The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients. Public Library of Science 2009-11-03 /pmc/articles/PMC2766251/ /pubmed/19888452 http://dx.doi.org/10.1371/journal.pone.0007669 Text en Roland 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
Roland, Christina L.
Lynn, Kristi D.
Toombs, Jason E.
Dineen, Sean P.
Udugamasooriya, D. Gomika
Brekken, Rolf A.
Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title_full Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title_fullStr Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title_full_unstemmed Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title_short Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer
title_sort cytokine levels correlate with immune cell infiltration after anti-vegf therapy in preclinical mouse models of breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766251/
https://www.ncbi.nlm.nih.gov/pubmed/19888452
http://dx.doi.org/10.1371/journal.pone.0007669
work_keys_str_mv AT rolandchristinal cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer
AT lynnkristid cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer
AT toombsjasone cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer
AT dineenseanp cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer
AT udugamasooriyadgomika cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer
AT brekkenrolfa cytokinelevelscorrelatewithimmunecellinfiltrationafterantivegftherapyinpreclinicalmousemodelsofbreastcancer