Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer
Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer
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DOI：
10.1073/pnas.2008112117
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发表时间：
2020-09-01
影响因子：
11.1
通讯作者：
Ferrara, Napoleone
中科院分区：
文献类型：
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作者：
Itatani, Yoshiro;Yamamoto, Takamasa;Ferrara, Napoleone
我们测试了顺式apc (Delta 716)/Smad4（+/-）和顺式apc (Delta 716)/Smad4(+/-) Kras（G12D）小鼠对抗vegf治疗的反应性，这些小鼠概括了人类结直肠癌（CRC）肿瘤发生过程中积累的关键遗传异常。我们发现，即使是cis-Apc(Delta 716)/Smad4(+/-) Kras（G12D）小鼠的肿瘤，尽管具有高度侵袭性，但抗vegf治疗也能抑制肿瘤。我们检验了炎症（CRC的主要危险因素和触发因素）可能影响抗vegf反应的假设。顺式- apc (Delta 716)/Smad4（+/-）和顺式- apc (Delta 716)/Smad4(+/-) Kras（G12D）小鼠的化学诱导结肠炎（CIC）促进了结肠肿瘤的发展，这些肿瘤对抗vegf治疗具有很大的抗性。结肠炎诱导后血清中髓样生长因子G-CSF明显升高。阻断G-CSF或其靶点Bv8/PROK2的抗体在cic相关CRC和抗vegf抵抗的CRC肝转移模型中联合抗vegf时，抑制肿瘤进展和髓样细胞浸润。在一系列结直肠癌标本中，肿瘤浸润中性粒细胞强烈表达Bv8/PROK2。结直肠癌患者血浆Bv8/PROK2水平明显高于健康志愿者，且血浆Bv8/PROK2水平与总生存率呈负相关。我们的研究结果证实Bv8/PROK2与抗vegf药物联合在结直肠癌中是一个翻译靶点。
We tested cis-Apc(Delta 716)/Smad4(+/-) and cis-Apc(Delta 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(Delta 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(Delta 716)/Smad4(+/-) and cis-Apc(Delta 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.