Zhang Jiayu, Lu Tong, Lu Shiqi, Ma Shuaijun, Han Donghui, Zhang Keying, Xu Chao, Liu Shaojie, Gan Lunbiao, Wu Xinjie, Yang Fa, Wen Weihong, Qin Weijun
Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, China.
Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
Comput Struct Biotechnol J. 2022 Dec 30;21:665-676. doi: 10.1016/j.csbj.2022.12.049. eCollection 2023.
Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGF/VEGFR therapy; however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGF/VEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.
内皮细胞（ECs）在肿瘤进展中起重要作用。目前，抗血管生成治疗的主要靶点是血管内皮生长因子（VEGF）通路。一些患者确实从抗VEGF/VEGFR治疗中获益；然而，大量患者在治疗后没有反应或产生耐药性。此外，抗VEGF/VEGFR治疗可能因其对正常ECs的作用而导致肾毒性和心血管相关副作用。因此，有必要确定肿瘤ECs特有的靶点，并将其应用于各种癌症类型。我们整合了六种癌症类型的单细胞RNA测序数据，构建了一个多癌种EC图谱，以解读肿瘤ECs的特征。我们发现，类顶端ECs主要存在于肿瘤组织中，而在正常组织中几乎不存在。类顶端ECs参与促进肿瘤血管生成和抑制抗肿瘤免疫反应。此外，肿瘤细胞、髓样细胞和周细胞是促血管生成因子的主要来源。在多种癌症类型中，高比例的类顶端ECs与预后不良相关。我们还确定，前列腺特异性膜抗原（PSMA）是我们研究的所有癌症类型中类顶端ECs的特异性标志物。总之，我们证明类顶端ECs是肿瘤组织和正常组织之间主要的差异EC亚群。类顶端ECs可能通过促进血管生成同时抑制抗肿瘤免疫反应来促进肿瘤进展。PSMA是类顶端ECs的特异性标志物，可作为非前列腺癌诊断和治疗的潜在靶点。
