Department of Urology, Medical School, University of Pecs, 7602 Pecs, Hungary.
Institute of Human Genetics, Ruhr-University, 44801 Bochum, Germany.
Int J Mol Sci. 2024 Jul 4;25(13):7359. doi: 10.3390/ijms25137359.
It is acknowledged that conventional renal cell carcinoma (cRCC), which makes up 85% of renal malignancies, is a highly vascular tumor. Humanized monoclonal antibodies were developed to inhibit tumor neo-angiogenesis, which is driven by VEGFA/KDR signaling. The results largely met our expectations, and in several cases, adverse events occurred. Our study aimed to analyze the expression of VEGFA and its receptor KDR by immunohistochemistry in tissue multi-array containing 811 cRCC and find a correlation between VEGFA/KDR signaling and new vessel formation. None of the 811 cRCC displayed VEGFA-positive immunostaining. However, each glomerulus in normal kidney showed VEGFA-positive endothelial cells. KDR expression in endothelial meshwork was found in only 9% of cRCC, whereas 2% of the cRCC displayed positive KDR reaction in the cytoplasm of tumor cells. Our results disclose the involvement of VEGFA/KDR signaling in the neo-vascularization of cRCC and explain the frequent resistance to drugs targeting the VEGFA/KDR signaling and the high frequency of adverse events.
人们已经认识到，占肾脏恶性肿瘤 85%的传统肾细胞癌（cRCC）是一种高度血管化的肿瘤。为了抑制由 VEGFA/KDR 信号驱动的肿瘤新生血管形成，开发了人源化单克隆抗体。这些结果在很大程度上达到了我们的预期，并且在某些情况下出现了不良反应事件。我们的研究旨在通过免疫组织化学方法分析 811 例 cRCC 组织中多数组中 VEGFA 及其受体 KDR 的表达，以寻找 VEGFA/KDR 信号与新血管形成之间的相关性。在 811 例 cRCC 中，无一例显示 VEGFA 阳性免疫染色。然而，正常肾脏的每个肾小球均显示出 VEGFA 阳性的内皮细胞。在 cRCC 中，仅 9%的内皮网中存在 KDR 表达，而 2%的 cRCC 中肿瘤细胞的细胞质中显示出 KDR 阳性反应。我们的结果揭示了 VEGFA/KDR 信号在 cRCC 新生血管形成中的参与，并解释了靶向 VEGFA/KDR 信号的药物经常产生耐药性和不良反应频率高的原因。
