Abstract
Angiopoietin/tyrosine protein kinase receptor Tie-2 signaling in endothelial cells plays an essential role in angiogenesis and wound healing. Angiopoietin-1 (Ang-1) is crucial for blood vessel maturation while angiopoietin-2 (Ang-2), in collaboration with vascular endothelial growth factor (VEGF), initiates angiogenesis by destabilizing existing blood vessels. In healthy people, the Ang-1 level is sustained while Ang-2 expression is restricted. In cancer patients, Ang-2 level is elevated, which correlates with poor prognosis. Ang-2 not only drives tumor angiogenesis but also attracts infiltration of myeloid cells. The latter rapidly differentiate into tumor stromal cells that foster tumor angiogenesis and progression, and weaken the host’s anti-tumor immunity. Moreover, through integrin signaling, Ang-2 induces expression of matrix metallopeptidases (MMPs) to promote tumor cell invasion and metastasis. Many oncogenic viruses induce expression of Ang-2 to promote development of neoplasia associated with viral infection. Multiple Ang-2 inhibitors exhibit remarkable anti-tumor activities, further highlighting the importance of Ang-2 in cancer development.
Highlights
A hallmark breakthrough in vascular biology during the 1990s was the discovery of angiopoietins, ligands of the tyrosine kinase receptor Tie-2 [1,2,3,4,5]
We attempt to give an update reviewing recent literature on how Ang-1 and Ang-2 contribute to development and progression of cancer in general and neoplasia associated with viral infection
Both hypoxia and cytokines were shown to be strong inducers of Ang-2 expression in cultured endothelial cells [49,50,51,52,53] Hypoxia and cytokines are known to activate transcription factors such as E26 transformation-specific (Ets)-1 involved in Ang-2 transcriptional induction [54,55]
Summary
A hallmark breakthrough in vascular biology during the 1990s was the discovery of angiopoietins, ligands of the tyrosine kinase receptor Tie-2 [1,2,3,4,5]. Cells 2020, 9, 457 demonstrated that Ang-2 destabilization of existing blood vessels depended on Ang-2-mediated activation of integrin-β1 [12] Consistent with this role, Ang-2-deficient mice died early due to failure of angiogenesis [3,13]. It is clear that these molecules contribute to multiple other aspects of biology such as inflammation [17], cell survival [18], and cell migration and invasion [19] Dysregulation of these molecules has been associated with a number of diseases including infection and septic shock [20,21], diabetes [22,23], and cancer [24,25]. We attempt to give an update reviewing recent literature on how Ang-1 and Ang-2 contribute to development and progression of cancer in general and neoplasia associated with viral infection
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