Translational Research Institute, UQ Diamantina Institute, The University of Queensland, Brisbane, 4102, QLD, Australia.
Institute of Molecular Biosciences, The University of Queensland, Brisbane, 4072, QLD, Australia.
Nat Commun. 2019 Jan 3;10(1):18. doi: 10.1038/s41467-018-07961-w.
Tumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a vasculogenic process as single cells, progressing towards a transit amplifying stage and ultimately differentiating into more mature endothelial phenotypes that comprised arterial, venous and lymphatic subtypes within the core of the tumor. Molecular profiling by RNA sequencing of purified endothelial fractions characterized EVPs as quiescent progenitors remodeling the extracellular matrix with significant paracrine activity promoting growth. Functionally, EVPs did not rely on VEGF-A signaling whereas endothelial-specific loss of Rbpj depleted the population and strongly inhibited metastasis. The understanding of endothelial heterogeneity opens new avenues for more effective anti-vascular therapies in cancer.
肿瘤血管生成是癌症的一个标志，是疾病进展和转移的核心。目前的抗血管生成疗法取得的成功有限，因此需要更好地了解肿瘤血管的细胞起源。通过对黑色素瘤内皮细胞群体进行命运图谱分析，我们报告了在生长中的肿瘤中，内皮前体细胞（EVP）的早期浸润。这些细胞具有自我更新能力，并重新激活 SOX18 转录因子的表达，开始了单个细胞的血管生成过程，进展到过渡扩增阶段，最终分化为更成熟的内皮表型，在肿瘤核心内包含动脉、静脉和淋巴管亚型。通过对纯化的内皮细胞群进行 RNA 测序进行分子谱分析，将 EVPs 鉴定为具有静止潜能的祖细胞，重塑细胞外基质，具有显著的旁分泌活性，促进肿瘤生长。在功能上，EVP 不依赖于 VEGF-A 信号通路，而内皮细胞特异性的 Rbpj 缺失耗尽了该群体，并强烈抑制了转移。对内皮细胞异质性的理解为癌症的更有效抗血管生成治疗开辟了新途径。
