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Reduced Blood Vessel Formation and Tumor Growth in 5-Integrin-negative Teratocarcinomas and Embryoid Bodies¹

Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Embryonic stem (ES) cells—wild-type, heterozygous, or null for 5-integrin—were injected ectopically into syngeneic mice to develop teratocarcinomas. 5-null-derived teratocarcinomas were significantly smaller than the wild-type or 5 heterozygous tumors. Histological analysis revealed the presence of tissues derived from all three germ layers, in all tumors. However, 5-null teratocarcinomas displayed less undifferentiated tissue than did the controls. Decreased proliferation and increased apoptosis were observed in the undifferentiated areas of the 5-null teratocarcinomas. The expression of extracellular matrix proteins, fibronectin and tenascin-C, and the basement membrane components, laminin, entactin/nidogen, and collagen IV, was similar in the different tumors, although the deposition of these molecules was more disorganized in 5-null teratocarcinomas. The absence of 5-integrin in the various tissues of the 5-null tumors was confirmed by immunohistochemistry. Many vessels, but not all, stained positively for 5-integrin, showing that they were host derived. Analysis of the area occupied by vessels revealed, on average, an 8-fold decrease in 5-null teratocarcinomas compared with control tumors. Staining for smooth muscle -actin showed that pericytes and smooth muscle cells were recruited around the vessels in all tumors, suggesting similar vessel differentiation. Deposition of EIIIA and EIIIB and fibronectin around the vessels was observed in all tumors. The fact that some, although few, 5-integrin-negative vessels existed in 5-null tumors indicated that 5-/- ES cells could differentiate into endothelial cells. Endothelial cell differentiation and vessel formation were analyzed also in vitro. 5-null ES cells were differentiated into embryoid bodies, although they were delayed in growth and attachment. Differentiation into endothelial cells was achieved, but the organization into a complex vasculature was delayed compared with controls. We conclude that 5ß1-integrin plays a significant role in vessel formation both in ES cell cultures and in teratocarcinomas. Reduced vascularization likely contributed to the reduced proliferation and increased apoptosis observed in 5-null teratocarcinomas.

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