Kang Nannan, Liang Xue, Fan Buxi, Zhao Chen, Shen Beiyu, Ji Xuemei, Liu Yu
School of Life Science & Technology, China Pharmaceutical University, Nanjing 211198, China.
Nanjing University of Chinese Medicine, Nanjing 210029, China.
Cancers (Basel). 2022 Nov 18;14(22):5681. doi: 10.3390/cancers14225681.
The development of drug resistance in malignant tumors leads to disease progression, creating a bottleneck in treatment. Bevacizumab is widely used clinically, and acts by inhibiting angiogenesis to "starve" tumors. Continuous treatment can readily induce rebound proliferation of tumor blood vessels, leading to drug resistance. Previously, we found that the fragment crystallizable (Fc) region of bevacizumab cooperates with the Toll-like receptor-4 (TLR4) ligand to induce M2b polarization in macrophages and secrete tumor necrosis factor-α (TNFα), which promotes immunosuppression, tumor metastasis, and angiogenesis. However, the downstream mechanism underlying TNFα-mediated bevacizumab resistance requires further investigation. Our RNA-Seq analysis results revealed that the expression of endothelial cell specific molecule-1 (ESM1) increased significantly in drug-resistant tumors and promoted metastasis and angiogenesis in vitro and in vivo. Furthermore, TNFα induced the upregulation of ESM1, which promotes metastasis and angiogenesis and regulates matrix metalloprotease-9 (MMP9), vascular endothelial growth factor (VEGF), and delta-like ligand-4 molecules (DLL4). Accordingly, the curative effect of bevacizumab improved by neutralizing ESM1 with high-affinity anti-ESM1 monoclonal antibody 1-2B7 in bevacizumab-resistant mice. This study provides important insights regarding the molecular mechanism by which TNFα-induced ESM1 expression promotes angiogenesis, which is significant for elucidating the mechanism of bevacizumab drug resistance and possibly identifying appropriate biosimilar molecules.
恶性肿瘤中耐药性的产生会导致疾病进展，成为治疗的瓶颈。贝伐单抗在临床上广泛应用，其作用机制是通过抑制血管生成来“饿死”肿瘤。持续治疗很容易诱导肿瘤血管的反弹增殖，从而导致耐药性。此前，我们发现贝伐单抗的可结晶片段（Fc）区域与Toll样受体4（TLR4）配体协同作用，诱导巨噬细胞向M2b极化并分泌肿瘤坏死因子-α（TNFα），进而促进免疫抑制、肿瘤转移和血管生成。然而，TNFα介导的贝伐单抗耐药性的下游机制仍需进一步研究。我们的RNA测序分析结果显示，内皮细胞特异性分子1（ESM1）在耐药肿瘤中的表达显著增加，并在体内外促进转移和血管生成。此外，TNFα诱导ESM1上调，从而促进转移和血管生成，并调节基质金属蛋白酶-9（MMP9）、血管内皮生长因子（VEGF）和Delta样配体4分子（DLL4）。因此，在贝伐单抗耐药小鼠中，用高亲和力抗ESM1单克隆抗体1-2B7中和ESM1可提高贝伐单抗的治疗效果。本研究为TNFα诱导的ESM1表达促进血管生成的分子机制提供了重要见解，这对于阐明贝伐单抗耐药机制以及可能识别合适的生物类似分子具有重要意义。
