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Human Endocrine Gland-Derived Vascular Endothelial Growth Factor: Expression Early in Development and in Leydig Cell Tumors Suggests Roles in Normal and Pathological Testis Angiogenesis

Departments of Molecular Oncology (M.S., N.F.) and Pathology (F.V.P., G.F.), Genentech, Inc., South San Francisco, California 94080; Institut National de la Santé et de la Recherche Médicale, Unité 435 (M.S.), and Centre Hospitalier Universitaire Ponchaillou Hospital (N.R.-L.), Rennes, France 35042; and Department of Growth and Reproduction, Copenhagen University Hospital (E.R.-D.M.), Copenhagen, Denmark 2100

Address all correspondence and requests for reprints to: Dr. Napoleone Ferrara, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. E-mail: nf{at}gene.com.

Angiogenesis is essential for tumor growth and metastasis. A new human angiogenic mitogen, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), has been recently identified; its expression pattern is restricted to endocrine glands, with the highest expression in testis. We used in situ hybridization and newly generated monoclonal antibodies to investigate the expression of EG-VEGF in normal human prenatal and adult testis and in 48 human testicular tumors of different subtypes. We found that EG-VEGF was expressed from 14 wk until birth in human fetal testis. In the adult testis, EG-VEGF was strongly expressed only in Leydig cells. In testicular tumors, EG-VEGF was expressed specifically in Leydig cell tumors, whereas germ cell-derived neoplasms, including carcinoma in situ, seminoma, and nonseminomatous germ cell tumors, were negative for this antigen. In contrast, VEGF, another powerful angiogenic factor, was expressed in seminoma, but very weakly in Leydig cell tumors. Interestingly, we found that Leydig cell tumors presented vessel surface density 3.2-fold higher than seminoma. These findings argue that human EG-VEGF may play a role in angiogenesis both during the early endocrine development of testis and in the adult testis as well as in Leydig cell tumor growth.

Abbreviations: CIS, Carcinoma in situ; EG-VEGF, endocrine gland-derived vascular endothelial growth factor; FAM, 6-carboxyfluorescein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H&E, hematoxylin and eosin; NSGCT, nonseminomatous germ cell tumor; StAR, steroidogenic acute regulatory protein; TAMRA, tetramethylrhodamine.

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