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Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer
We tested cis-Apc(Δ716)/Smad4(+/−) and cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc(Δ716)/Smad4(+/−) Kras(G12D)...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474657/ https://www.ncbi.nlm.nih.gov/pubmed/32817421 http://dx.doi.org/10.1073/pnas.2008112117 |
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author | Itatani, Yoshiro Yamamoto, Takamasa Zhong, Cuiling Molinolo, Alfredo A. Ruppel, Jane Hegde, Priti Taketo, M. Mark Ferrara, Napoleone |
author_facet | Itatani, Yoshiro Yamamoto, Takamasa Zhong, Cuiling Molinolo, Alfredo A. Ruppel, Jane Hegde, Priti Taketo, M. Mark Ferrara, Napoleone |
author_sort | Itatani, Yoshiro |
collection | PubMed |
description | We tested cis-Apc(Δ716)/Smad4(+/−) and cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc(Δ716)/Smad4(+/−) and cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents. |
format | Online Article Text |
id | pubmed-7474657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-74746572020-09-18 Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer Itatani, Yoshiro Yamamoto, Takamasa Zhong, Cuiling Molinolo, Alfredo A. Ruppel, Jane Hegde, Priti Taketo, M. Mark Ferrara, Napoleone Proc Natl Acad Sci U S A Biological Sciences We tested cis-Apc(Δ716)/Smad4(+/−) and cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc(Δ716)/Smad4(+/−) and cis-Apc(Δ716)/Smad4(+/−) Kras(G12D) mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents. National Academy of Sciences 2020-09-01 2020-08-19 /pmc/articles/PMC7474657/ /pubmed/32817421 http://dx.doi.org/10.1073/pnas.2008112117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Itatani, Yoshiro Yamamoto, Takamasa Zhong, Cuiling Molinolo, Alfredo A. Ruppel, Jane Hegde, Priti Taketo, M. Mark Ferrara, Napoleone Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title | Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title_full | Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title_fullStr | Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title_full_unstemmed | Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title_short | Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer |
title_sort | suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-vegf antibody in a genetic model of colorectal cancer |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474657/ https://www.ncbi.nlm.nih.gov/pubmed/32817421 http://dx.doi.org/10.1073/pnas.2008112117 |
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