Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer.

Published on Sep 1, 2020in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.2008112117
Yoshiro Itatani16
Estimated H-index: 16
(UCSD: University of California, San Diego),
Takamasa Yamamoto5
Estimated H-index: 5
(UCSD: University of California, San Diego)
+ 5 AuthorsNapoleone Ferrara179
Estimated H-index: 179
(UCSD: University of California, San Diego)
We tested cis-ApcΔ716/Smad4+/− and cis-ApcΔ716/Smad4+/−KrasG12D 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-ApcΔ716/Smad4+/−KrasG12D 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-ApcΔ716/Smad4+/− and cis-ApcΔ716/Smad4+/−KrasG12D 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.
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