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

Abstract

We tested <i>cis-Apc</i>^<i>Δ716</i><i>/Smad4</i>^<i>+/-</i> and <i>cis-Apc</i>^<i>Δ716</i><i>/Smad4</i>^<i>+/-</i><i>Kras</i>^<i>G12D</i> 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 <i>cis-Apc</i>^<i>Δ716</i><i>/Smad4</i>^<i>+/-</i><i>Kras</i>^<i>G12D</i> 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 <i>cis-Apc</i>^<i>Δ716</i><i>/Smad4</i>^<i>+/-</i> and <i>cis-Apc</i>^<i>Δ716</i><i>/Smad4</i>^<i>+/-</i><i>Kras</i>^<i>G12D</i> 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.