癌相关成纤维细胞分泌胞外囊泡结合型VEGF降低口腔鳞癌对贝伐单抗敏感性研究

血管新生对肿瘤生长和转移至关重要。重组人源化VEGF单克隆抗体——贝伐单抗是首个FDA批准的抗肿瘤血管新生药物。然而，耐药性、适用群体不明等问题尚待解决，揭示耐药机制、精准识别敏感人群是提高其疗效的关键。我们前期研究发现口腔鳞癌源性癌相关成纤维细胞（CAF）分泌的胞外囊泡（EV）携带VEGF，体内外均可诱导血管新生，对贝伐单抗不敏感。本项目拟深入研究CAF EV携带的VEGF亚型、半衰期、贝伐单抗结合效率等生物学特性，揭示硫酸乙酰肝素蛋白聚糖（HSPG）在EV携带VEGF中的作用，继而靶向HSPG与VEGF之间的结合，探索逆转EV-VEGF对贝伐单抗耐药的有效途径。我们还将对比分析口腔鳞癌和贝伐单抗敏感型结直肠癌患者血浆EV-VEGF水平，为区分药物敏感人群和耐药人群提供生物学指标；考察解离VEGF与HSPG结合能否使患者血浆EV-VEGF重获贝伐单抗敏感性，为耐药群体提供适当的治疗方案。

Angiogenesis is critical in tumor growth and metastasis. Bevacizumab is a humanized antibody to vascular endothelial growth factor (VEGF). Bevacizumab was initially approved by FDA for treatment of metastatic colorectal cancer and subsequently approved for several other solid tumors. However, many problems, such as drug resistance and unclear application groups, remain to be solved. The key to improve the efficacy of anti-tumor angiogenesis is to reveal the mechanism of drug resistance and accurately identify sensitive population. The preliminary research findings of our group demonstrated that carcinoma-associated fibroblasts isolated from oral squamous cell carcinoma (OSCC) secreted extracellular vesicles (EV) that carry VEGF and induced angiogenesis in vitro and in vivo in a bevacizumab-insensitive manner. This project intends to study the biological characteristics of EV-bound VEGF produced by OSCC-derived CAF, including VEGF subtypes, half-life and bevacizumab binding efficiency. We will reveal the interactions of VEGF with HSPG on the EV membrane surface. Then we will explore an effective way to reverse bevacizumab resistance by targeting HSPG-VEGF interactions. We will also analyze the correlations between the plasmal EV-bound VEGF level and the efficacy of bevacizumab in tumor patients, so as to provide biological biomarkers for distinguishing drug sensitive groups from drug resistant groups. Bevacizumab-sensitive colorectal cancer patients will be used as controls. Furthermore, we want to provide appropriate treatment for drug resistant groups. We will test whether dissociation of the binding between VEGF and HSPG can make plasmal EV-VEGF regain bevacizumab sensitivity. This project may gain a new insight into VEGF-induced angiogenesis and result in novel therapeutic strategies for anti-tumor angiogenesis treatment.