A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition.
A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition.
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DOI：
10.1038/bjc.2017.13
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发表时间：
2017-02-28
影响因子：
8.8
通讯作者：
Coutelle O
中科院分区：
文献类型：
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作者：
Schiffmann LM;Brunold M;Liwschitz M;Goede V;Loges S;Wroblewski M;Quaas A;Alakus H;Stippel D;Bruns CJ;Hallek M;Kashkar H;Hacker UT;Coutelle O
以血管内皮生长因子（VEGF）为靶点的药物使肿瘤血管系统正常化，并改善化疗的可及性。然而，过度抑制VEGF并不能改善临床结果，连续的治疗周期导致细胞外基质（ECM）沉积增加，从而限制了灌注和药物传递。我们在这里表明，低剂量的VEGF抑制与PDGF-R抑制相结合，可导致更好的血管正常化，而不会增加ECM沉积，从而维持治疗的可及性。分析了IV型胶原蛋白在结直肠癌（CRC）患者肝转移、人结直肠癌细胞（LS174T）同基因肿瘤（Panc02）和异种移植肿瘤（LS174T）中表达对VEGF抑制的响应。用低剂量（0.5 mg kg - 1体重）或高剂量（5mg kg - 1体重）抗vegf抗体贝伐单抗治疗异种移植物肿瘤，联合或不联合酪氨酸激酶抑制剂伊马替尼。比较肿瘤生长和血管参数的变化，包括微血管密度、周细胞覆盖、渗漏、缺氧、灌注、开放管腔的血管比例和IV型胶原沉积。在患者和肿瘤模型中，标准VEGF抑制后ECM沉积增加。相比之下，低剂量贝伐单抗和伊马替尼治疗产生类似的生长抑制，而不诱导有害的胶原IV沉积，导致更好的血管正常化，减少泄漏，改善氧合，更开放的血管允许灌注和治疗。伊马替尼增强的低剂量贝伐单抗选择成熟，高度正常化和灌注良好的肿瘤血管，而不会诱导通常限制VEGF靶向药物有效性的增量ECM沉积。
Vascular endothelial growth factor (VEGF)-targeting drugs normalise the tumour vasculature and improve access for chemotherapy. However, excessive VEGF inhibition fails to improve clinical outcome, and successive treatment cycles lead to incremental extracellular matrix (ECM) deposition, which limits perfusion and drug delivery. We show here, that low-dose VEGF inhibition augmented with PDGF-R inhibition leads to superior vascular normalisation without incremental ECM deposition thus maintaining access for therapy. Collagen IV expression was analysed in response to VEGF inhibition in liver metastasis of colorectal cancer (CRC) patients, in syngeneic (Panc02) and xenograft tumours of human colorectal cancer cells (LS174T). The xenograft tumours were treated with low (0.5 mg kg−1 body weight) or high (5 mg kg−1 body weight) doses of the anti-VEGF antibody bevacizumab with or without the tyrosine kinase inhibitor imatinib. Changes in tumour growth, and vascular parameters, including microvessel density, pericyte coverage, leakiness, hypoxia, perfusion, fraction of vessels with an open lumen, and type IV collagen deposition were compared. ECM deposition was increased after standard VEGF inhibition in patients and tumour models. In contrast, treatment with low-dose bevacizumab and imatinib produced similar growth inhibition without inducing detrimental collagen IV deposition, leading to superior vascular normalisation, reduced leakiness, improved oxygenation, more open vessels that permit perfusion and access for therapy. Low-dose bevacizumab augmented by imatinib selects a mature, highly normalised and well perfused tumour vasculature without inducing incremental ECM deposition that normally limits the effectiveness of VEGF targeting drugs.