Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts
Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts
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DOI：
10.1158/1535-7163.mct-09-0280
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发表时间：
2009-07-01
影响因子：
5.7
通讯作者：
Brekken, Rolf A.
中科院分区：
文献类型：
--
作者：
Roland, Christina L.;Dineen, Sean P.;Brekken, Rolf A.
血管内皮生长因子是血管生成的主要刺激因子，是一种巨噬细胞趋化蛋白。抑制血管内皮生长因子对某些乳腺癌患者在化疗的同时是有益的。然而，抑制血管内皮生长因子影响肿瘤生长的机制似乎不仅仅涉及它对血管内皮细胞的影响。一般来说，免疫细胞在乳腺肿瘤中的渗入增加会导致较差的预后。我们先前已经证明，2C3，一种阻止血管内皮生长因子与血管内皮生长因子受体2(VEGFR2)结合的鼠单抗，可以减少肿瘤生长，减少血管生成，减少巨噬细胞对胰腺肿瘤的渗透，因此假设r84，一种完全复制2C3的全人免疫球蛋白，也会类似地影响乳腺肿瘤的生长和免疫细胞的渗透。在这项研究中，我们发现，贝伐单抗、2C3或r84的抗血管内皮生长因子治疗抑制了严重联合免疫缺陷(SCID)小鼠已建立的原位MDA-MB-231乳腺肿瘤的生长，降低了肿瘤微血管密度，限制了肿瘤相关巨噬细胞的渗透，但与肿瘤相关中性粒细胞的数量增加有关。此外，我们发现，与对照组动物肿瘤相比，r84治疗减少了肿瘤中CD11b(+)Gr1(+)双阳性细胞的数量。这些结果表明，用抗血管内皮生长因子抗体选择性地抑制VEGFR2足以有效地阻断乳腺癌异种移植瘤中血管内皮生长因子的促肿瘤活性。这些发现进一步定义了肿瘤微环境中复杂的分子相互作用，并提供了一种可能与乳腺癌治疗相关的翻译工具。[摩尔癌症治疗2009；8(7)：1761-71]
Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than its effect on endothelial cells. In general, increased immune cell infiltration into breast tumors confers a worse prognosis. We have shown previously that 2C3, a mouse monoclonal antibody that prevents VEGF from binding to VEGF receptor 2 (VEGFR2), decreases tumor growth, angiogenesis, and macrophage infiltration into pancreatic tumors and therefore hypothesized that r84, a fully human IgG that phenocopies 2C3, would similarly affect breast tumor growth and immune cell infiltration. In this study, we show that anti-VEGF therapy with bevacizumab, 2C3, or r84 inhibits the growth of established orthotopic MDA-MB-231 breast tumors in severe combined immunodeficiency (SCID) mice, reduces tumor microvessel density, limits the infiltration of tumor-associated macrophages, but is associated with elevated numbers of tumor-associated neutrophils. In addition, we found that treatment with r84 reduced the number of CD11b(+)Gr1(+) double-positive cells in the tumor compared with tumors from control-treated animals. These results show that selective inhibition of VEGFR2 with an anti-VEGF antibody is sufficient for effective blockade of the protumorigenic activity of VEGF in breast cancer xenografts. These findings further define the complex molecular interactions in the tumor microenvironment and provide a translational tool that may be relevant to the treatment of breast cancer. [Mol Cancer Ther 2009;8(7):1761-71]