Abstract
Teratomas are benign tumors that form after ectopic injection of embryonic stem (ES) cells into mice and contain derivatives of all primitive germ layers. To study the role of beta 1 integrin during teratoma formation, we compared teratomas induced by normal and beta1-null ES cells. Injection of normal ES cells gave rise to large teratomas. In contrast, beta 1-null ES cells either did not grow or formed small teratomas with an average weight of <5% of that of normal teratomas. Histological analysis of beta 1-null teratomas revealed the presence of various differentiated cells, however, a much lower number of host-derived stromal cells than in normal teratomas. Fibronectin, collagen I, and nidogen were expressed but, in contrast to normal teratomas, diffusely deposited in beta1-null teratomas. Basement membranes were present but with irregular shape and detached from the cell surface. Normal teratomas had large blood vessels with a smooth inner surface, containing both host- and ES cell-derived endothelial cells. In contrast, beta 1-null teratomas had small vessels that were loosely embedded into the connective tissue. Furthermore, endothelial cells were always of host-derived origin and formed blood vessels with an irregular inner surface. Although beta 1- deficient endothelial cells were absent in teratomas, beta 1-null ES cells could differentiate in vitro into endothelial cells. The formation of a complex vasculature, however, was significantly delayed and of poor quality in beta1-null embryoid bodies. Moreover, while vascular endothelial growth factor induced proliferation of endothelial cells as well as an extensive branching of blood vessels in normal embryoid bodies, it had no effect in beta 1-null embryoid bodies.
Highlights
Normal teratomas had large blood vessels with a smooth inner surface, containing both host- and embryonic stem (ES) cell–derived endothelial cells
We report that vascular endothelial growth factor (VEGF) treatment–induced proliferation of endothelial cells and extensive branching of blood vessels in normal but not in 1-null embryoid bodies
To test whether the lack of 1 integrin has an influence on the development of teratomas normal and 1-null ES cells were injected subcutaneously into syngeneic male mice
Summary
Normal teratomas had large blood vessels with a smooth inner surface, containing both host- and ES cell–derived endothelial cells. While vascular endothelial growth factor induced proliferation of endothelial cells as well as an extensive branching of blood vessels in normal embryoid bodies, it had no effect in 1-null embryoid bodies. Proliferation and survival of tumor cells, determining progression of solid tumors, are independent of signals elicited by interactions with the surrounding extracellular matrix (ECM1; Folkman and Moscona, 1978). Integrins are the most important family of cell surface receptors that mediate cell–matrix interactions (Hynes, 1992). They are heterodimers of noncovalently linked ␣ and  subunits. BrdU, bromodeoxyuridine; ECM, extracellular matrix; ES, embryonic stem; PECAM, platelet/endothelial cell adhesion molecule; VEGF, vascular endothelial growth factor; vWF, von Willebrand Factor
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