Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer.
Aged
Angiogenesis Inhibitors
/ administration & dosage
Animals
Antibodies, Monoclonal, Humanized
/ administration & dosage
Bevacizumab
/ administration & dosage
Biomarkers, Tumor
/ genetics
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
/ genetics
Female
GPI-Linked Proteins
/ genetics
Humans
Isoantigens
/ genetics
Male
Mice
Middle Aged
Neoplasm Metastasis
Neoplastic Stem Cells
/ drug effects
Neovascularization, Pathologic
/ drug therapy
Neutrophils
/ drug effects
Receptors, Cell Surface
/ genetics
Vascular Endothelial Growth Factor A
/ antagonists & inhibitors
Vesicular Transport Proteins
/ genetics
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
27
03
2018
accepted:
04
07
2018
revised:
25
06
2018
pubmed:
1
11
2018
medline:
19
9
2019
entrez:
1
11
2018
Statut:
ppublish
Résumé
Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177- metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.
Sections du résumé
BACKGROUND
Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models.
METHODS
A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry.
RESULTS
The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177- metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance.
CONCLUSIONS
Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.
Identifiants
pubmed: 30377339
doi: 10.1038/s41416-018-0198-3
pii: 10.1038/s41416-018-0198-3
pmc: PMC6325148
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Antibodies, Monoclonal, Humanized
0
Biomarkers, Tumor
0
CD177 protein, human
0
GPI-Linked Proteins
0
Isoantigens
0
Receptors, Cell Surface
0
VEGFA protein, human
0
VPS51 protein, human
0
Vascular Endothelial Growth Factor A
0
Vesicular Transport Proteins
0
Bevacizumab
2S9ZZM9Q9V
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
69-78Références
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