Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

Abstract

Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.teratoma ͉ endothelial cells ͉ VEGF-R2 ͉ VE-PTP

Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency

“…However, like other tumors, their growth is still limited by oxygen and nutrient supply. Teratomas undergo an angiogenic switch that includes differentiation of pluripotent cells within the teratoma to form vessels (Li et al, 2009). However, before this vascularization is achieved areas within the teratoma are under hypoxia conditions.…”

The Complex Role of Angiopoietin-2 in the Angiopoietin-Tie Signaling Pathway

“…Teratomas derived from VE-PTP knockout ES cells have elevated levels of phosphorylated Tie2 and much larger blood vessels than wild-type or VE-PTP heterozygous tumors, consistent with chronic activation of Tie2. Interestingly, treatment of the VE-PTP knockout tumors with an Ang2-selective antibody decreased Tie2 phosphorylation and vessel size, suggesting that Ang2 is functioning as a Tie2 activator in this model (Li et al 2009). This effect of Ang2 blockade on vessel size is consistent with the data from human tumor xenografts mentioned above that demonstrated decreased vessel size following treatment with an Ang2-specific blocker (Falcon et al 2009).…”

“…The extracellular domain of VE-PTP appears to be important for its function because antibodies to this region can cause defects in vascular remodeling similar to those seen with genetic inactivation of VE-PTP (Winderlich et al 2009). The activity of VE-PTP has been linked to its dephosphorylation of Tie2 (Li et al 2009;Winderlich et al 2009) and subsequent downregulation of ERK signaling. Thus, VE-PTP appears to be an essential negative regulator of angiopoietin -Tie signaling.…”

“…Support for this alternate model comes from studies of tumors (teratomas) formed from embryonic stem cells that lack VE-PTP, a Tie2 phosphatase that is specifically expressed in the vasculature (Li et al 2009). When implanted subcutaneously, embryonic stem cells are capable of differentiating into endothelial cells, and they contribute significantly to the vasculature of the teratoma.…”

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

“…Thus, we tested whether the FBW7-mediated degradation of KLF2 is also involved in the development of blood vessels during embryogenesis using a teratoma model, which has been demonstrated as a powerful gene-targeting method to study angiogenesis [30,38]. We first examined the expression of Fbw7 during mouse embryonic stem (ES) cell differentiation using an embryonic body (EB) differentiation model.…”