Cargando…

Biomarkers for antitumor activity of bevacizumab in gastric cancer models

BACKGROUND: Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer...

Descripción completa

Detalles Bibliográficos
Autores principales: Yamashita-Kashima, Yoriko, Fujimoto-Ouchi, Kaori, Yorozu, Keigo, Kurasawa, Mitsue, Yanagisawa, Mieko, Yasuno, Hideyuki, Mori, Kazushige
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292441/
https://www.ncbi.nlm.nih.gov/pubmed/22273502
http://dx.doi.org/10.1186/1471-2407-12-37
_version_ 1782225271764549632
author Yamashita-Kashima, Yoriko
Fujimoto-Ouchi, Kaori
Yorozu, Keigo
Kurasawa, Mitsue
Yanagisawa, Mieko
Yasuno, Hideyuki
Mori, Kazushige
author_facet Yamashita-Kashima, Yoriko
Fujimoto-Ouchi, Kaori
Yorozu, Keigo
Kurasawa, Mitsue
Yanagisawa, Mieko
Yasuno, Hideyuki
Mori, Kazushige
author_sort Yamashita-Kashima, Yoriko
collection PubMed
description BACKGROUND: Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models. METHODS: Nine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay. RESULTS: Of the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level. CONCLUSIONS: VEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted.
format Online
Article
Text
id pubmed-3292441
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-32924412012-03-03 Biomarkers for antitumor activity of bevacizumab in gastric cancer models Yamashita-Kashima, Yoriko Fujimoto-Ouchi, Kaori Yorozu, Keigo Kurasawa, Mitsue Yanagisawa, Mieko Yasuno, Hideyuki Mori, Kazushige BMC Cancer Research Article BACKGROUND: Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models. METHODS: Nine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay. RESULTS: Of the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level. CONCLUSIONS: VEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted. BioMed Central 2012-01-25 /pmc/articles/PMC3292441/ /pubmed/22273502 http://dx.doi.org/10.1186/1471-2407-12-37 Text en Copyright ©2012 Yamashita-Kashima et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Yamashita-Kashima, Yoriko
Fujimoto-Ouchi, Kaori
Yorozu, Keigo
Kurasawa, Mitsue
Yanagisawa, Mieko
Yasuno, Hideyuki
Mori, Kazushige
Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title_full Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title_fullStr Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title_full_unstemmed Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title_short Biomarkers for antitumor activity of bevacizumab in gastric cancer models
title_sort biomarkers for antitumor activity of bevacizumab in gastric cancer models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292441/
https://www.ncbi.nlm.nih.gov/pubmed/22273502
http://dx.doi.org/10.1186/1471-2407-12-37
work_keys_str_mv AT yamashitakashimayoriko biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT fujimotoouchikaori biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT yorozukeigo biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT kurasawamitsue biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT yanagisawamieko biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT yasunohideyuki biomarkersforantitumoractivityofbevacizumabingastriccancermodels
AT morikazushige biomarkersforantitumoractivityofbevacizumabingastriccancermodels