Unknown

Dataset Information

0

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


ABSTRACT: We tested cis-Apc ?716 /Smad4 +/- and cis-Apc ?716 /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 ?716 /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 ?716 /Smad4 +/- and cis-Apc ?716 /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.

SUBMITTER: Itatani Y 

PROVIDER: S-EPMC7474657 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Itatani Yoshiro Y   Yamamoto Takamasa T   Zhong Cuiling C   Molinolo Alfredo A AA   Ruppel Jane J   Hegde Priti P   Taketo M Mark MM   Ferrara Napoleone N  

Proceedings of the National Academy of Sciences of the United States of America 20200819 35


We tested <i>cis-Apc</i><sup><i>Δ716</i></sup><i>/Smad4</i><sup><i>+/-</i></sup> and <i>cis-Apc</i><sup><i>Δ716</i></sup><i>/Smad4</i><sup><i>+/-</i></sup><i>Kras</i><sup><i>G12D</i></sup> 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><sup><i>Δ716</i></sup><i>/Smad4</i><sup><i>+/-</i></sup><i>Kras</i><sup><i>G12D</i></sup> mice, although hi  ...[more]

Similar Datasets

| S-EPMC4323007 | biostudies-other
| S-EPMC4085495 | biostudies-literature
| S-EPMC5830631 | biostudies-literature
| S-EPMC3827603 | biostudies-literature
| S-EPMC6966653 | biostudies-literature
| S-EPMC5347735 | biostudies-literature
| S-EPMC6033358 | biostudies-literature
| S-EPMC3625253 | biostudies-literature
| S-EPMC6774418 | biostudies-literature
| S-EPMC2839169 | biostudies-other