| First Author | Itatani Y | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 35 | Pages | 21598-21608 |
| PubMed ID | 32817421 | Mgi Jnum | J:295969 |
| Mgi Id | MGI:6454516 | Doi | 10.1073/pnas.2008112117 |
| Citation | Itatani Y, et al. (2020) Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer. Proc Natl Acad Sci U S A 117(35):21598-21608 |
| abstractText | We tested cis-Apc (Delta716) /Smad4 (+/-) and cis-Apc (Delta716) /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 (Delta716) /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 (Delta716) /Smad4 (+/-) and cis-Apc (Delta716) /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. |
