贝伐珠单抗在胃癌模型中抗肿瘤活性的生物标志物。
Biomarkers for antitumor activity of bevacizumab in gastric cancer models.
机构信息
Product Research Department, Chugai Pharmaceutical Co,, Ltd,, Kamakura, Kanagawa, Japan.
出版信息
BMC Cancer. 2012 Jan 25;12:37. doi: 10.1186/1471-2407-12-37.
BACKGROUND
Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models.
METHODS
Nine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay.
RESULTS
Of the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level.
CONCLUSIONS
VEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted.
背景
贝伐珠单抗是人源化单克隆抗体，针对人血管内皮生长因子（VEGF），已用于多种癌症，如结直肠癌、非小细胞肺癌、乳腺癌和胶质母细胞瘤。贝伐珠单抗可能对胃癌有效，因为已有报道称 VEGF 参与了胃癌和其他癌症的发展。另一方面，尽管临床有需求，但仍没有确定的生物标志物来预测贝伐珠单抗的疗效。因此，我们试图通过使用对贝伐珠单抗敏感和不敏感的肿瘤模型来鉴定胃癌患者使用贝伐珠单抗治疗的疗效预测标志物。
方法
对 9 个人胃和 2 个结直肠癌细胞系异种移植瘤进行了贝伐珠单抗敏感性检测。我们通过 ELISA 检测血管生成因子的表达水平，通过加入肿瘤匀浆后 VEGFR2 的磷酸化检测 VEGF 的生物活性，通过 CD31 免疫染色检测肿瘤微血管密度，并通过 HybriProbeTM 检测 VEGF 基因的多态性。
结果
在所使用的 9 个人胃肿瘤异种移植模型中，GXF97、MKN-45、MKN-28、4-1ST、SC-08-JCK 和 SC-09-JCK 对贝伐珠单抗敏感，而 SCH、SC-10-JCK 和 NCI-N87 则不敏感。胃肿瘤模型对贝伐珠单抗的敏感性与组织学类型或 HER2 状态无关。除了一个，即 SC-10-JCK，所有 VEGF 水平较高的肿瘤均对贝伐珠单抗敏感，而该肿瘤的 VEGF 水平较高。对该模型产生抵抗的原因是非磷酸化 VEGFR2 的生物活性和 VEGF 微血管形成，但不能用 VEGF 等位基因或 VEGF165b 来解释。我们还检测了 11 种胃肠道肿瘤组织中其他血管生成因子的表达水平。在包括 SC-10-JCK 在内的耐药模型中，另一种血管生成因子 bFGF 的肿瘤水平相对较高。VEGF/bFGF 比值与贝伐珠单抗敏感性的相关性比 VEGF 水平更密切。
结论
肿瘤中的 VEGF 水平和 VEGF/bFGF 比值与所检测的异种移植瘤对贝伐珠单抗的敏感性相关。进一步的临床研究需要寻找对贝伐珠单抗敏感性有用的预测标志物。
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