Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer.
Yoshiro ItataniTakamasa YamamotoCuiling ZhongAlfredo A MolinoloJane RuppelPriti HegdeM Mark TaketoNapoleone FerraraPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- vascular endothelial growth factor
- endothelial cells
- epithelial mesenchymal transition
- growth factor
- lps induced
- transforming growth factor
- lipopolysaccharide induced
- end stage renal disease
- stem cells
- oxidative stress
- bone marrow
- dendritic cells
- genome wide
- acute myeloid leukemia
- chronic kidney disease
- dna methylation
- inflammatory response
- newly diagnosed
- mesenchymal stem cells
- cell therapy
- signaling pathway
- prognostic factors
- long non coding rna
- ulcerative colitis
- adipose tissue