Wiszniak Sophie, Schwarz Quenten
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
Biomolecules. 2021 Jan 19;11(1):128. doi: 10.3390/biom11010128.
Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed "intracrine", and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.
血管内皮生长因子A（VEGF-A或VEGF）是一种高度保守的分泌型信号蛋白，因其在血管发育和血管生成中的作用而最为人所知。随着VEGF及其受体VEGFR1和VEGFR2在许多非血管细胞类型以及各种癌症中表达的发现，VEGF的许多非内皮作用现已得到证实。除了分泌的VEGF在细胞膜的细胞外空间与其受体结合（即旁分泌或自分泌模式）外，细胞内定位的VEGF正成为调节细胞生长、存活和代谢的重要信号分子。这种细胞内信号传导模式被称为“内分泌”，是指信号分子在细胞内直接作用而不被分泌。在这篇综述中，我们描述了内分泌VEGF信号传导在调节细胞生长、分化和存活方面的例子，这些例子既存在于正常细胞稳态和发育过程中，也存在于癌症中。我们进一步讨论了支持VEGF内分泌功能的分子机制的新证据，以及这种VEGF信号传导的细胞内模式可能对抗VEGF癌症治疗的应用和设计产生的影响。
