Abstract
The high degree of vascularisation, accompanied by the low malignancy of human Leydig cell tumours, offers an interesting model to study the neovascularisation and structural stabilisation of the vascular wall. We report here that Leydig cell tumours are characterised by an increased level of vascular endothelial growth factor (VEGF) in testicular veins, the presence of VEGF mRNA and of its receptor, KDR, and an absence of detectable VEGF receptor Flt-1, in blood vessels of tumour marginal zones and of peri-tumour areas. This is in contrast to the capillaries within normal Leydig cell clusters which demonstrate both Flt-1 and KDR. Ultrastructural destabilisation of the vascular wall, evident as a lack of basement membrane and of peri-endothelial cells was also present in nearly 85% of blood vessels of the peri-tumour areas. In contrast, ≈89% of the blood vessels of the tumour centre region demonstrated a stabilised vascular wall including basement membrane and peri-endothelial cells. Local application of VEGF165 to the normal testicular tissue induced significant ultrastructural destabilisation in the capillary walls which only expressed KDR. These results suggest an autocrine role of VEGF on endothelial cells of tumour blood vessels in a region-specific manner and implicate that VEGF interactions with KDR, in the absence of Flt-1, may be involved in vascular destabilisation. In addition, the finding that most (79%) of Leydig tumour blood vessels are stabilised may account for the low malignant potential of these tumours.
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Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–64.
Folkman J. Tumor angiogenesis. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA (eds.) The Molecular Basis of Cancer. Philadelphia: WB Saunders 1995; 206–32.
Folkman J, D'Amore PA. Blood vessel formation: What is its molecular basis? Cell 1996; 87: 1153–5.
Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50.
Senger DR, Galli SJ, Dvorak AM et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–5.
Keck PJ, Hauser SD, Krivi G et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246: 1309–12.
Gospodarowicz D, Abraham JA, Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary derived folliculo stelate cells. Proc Natl Acad Sci USA 1989; 86: 7311–5.
Shibuya M, Yamaguchi S, Yamane A et al. Nucleotide sequence and expression of a novel human receptor type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990; 5: 519–24.
Terman BI, Carrion ME, Kovacs E et al. Identification of new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991; 6: 1677–83.
DeVries C, Escobedo JA, Ueno H et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989–91.
Waltenberger J, Claesson-Welsh L, Siegbahn A et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994; 269: 26988–95.
Klagsbrun M, D'Amore PA. Vascular endothelial growth factor and its receptors. Cytokine-Growth-Factor-Rev 1996; 7: 259–70.
Ergün S, Kilic N, Fiedler W, Mukhopadhyay AK. Vascular endothelial growth factor and its receptors in normal human testicular tissue. Mol Cell Endocrinol 1997; 131: 9–20.
Korpelainen EI, Karkkainen MJ, Tenhunen A et al. Overexpression of VEGF in testis and epididymis causes infertility in transgenic mice: evidence for nonendothelial targets for VEGF. J Cell Biol 1998; 143: 1705–12.
Ergün S, Davidoff M, Holstein AF. Capillaries in the lamina propria of human seminiferous tubules are partly fenestrated. Cell Tissue Res 1996; 286: 93–102.
Czernobilsky H, Czernobilsky B, Schneider HG et al. Characterization of a feminizing testicular Leydig cell tumor by hormonal profile, immunohistochemistry, and tissue culture. Cancer 1985; 56: 1667–76.
Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. Am J Surg Pathol 1985; 9: 177–92.
Schwarzman MI, Russo P, Bossl GJ, Whitmore WF Jr. Hormone secreting metastatic interstitial cell tumor of the testis. J Urol 1989; 141: 620–2.
Damjanov I, Katz SM, Jewett MA. Leydig cell tumors of the testis. Ann Clin Lab Sci 1979; 9: 157–63.
Feldman DS, Kovacs K, Horvath E, Adelson GL. Malignant Leydig cell tumor: Clinical, histologic and electron microscopic features. Cancer 1982; 49: 714–21.
Mostofi FK, Sesterhenn IA. Leydig cell tumour. In Mostofi FK, Sesterhenn IA (eds): Histological Typing of Testis Tumours, WHO International Histological Classification of Tumours. Berlin/Heidelberg/New York: Springer-Verlag 1998; 18–19.
Bao L, Loda M, Janmey PA et al. Thymosin β: A novel regulator of tumor cell motility upregulated in metastatic prostate cancer. Nat Med 1996; 2: 1322–8.
Holstein AF, Wulfhekel U. Die Semidünnschnitt-Technik als Grundlage für eine cytologische Beurteilung der Spermatogenese des Menschen. Andrologia 1971; 3: 65–9.
Freeman MR, Schneck FX, Gagnon ML et al. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: A potential role for T cells in angiogenesis. Cancer Res 1995; 55: 4140–5.
Galaktiniov K, Lee AK, Eckstein J et al. CD25 phosohatases as potential human oncogenes. Science 1995; 269: 1575–7.
Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680–5.
Davidoff MS, Schulze W. Combination of the peroxidase antiperoxidase (PAP)-and avidin-biotin-peroxidase complex (ABC)-techniques: An amplification alternative in immunohistochemical staining. Histochemistry 1990; 93: 531–6.
Ergün S, Luttmer W, Fiedler W, Holstein AF. Functional expression and localization of vascular endothelial growth factor (VEGF) and its receptors in the human epididymis. Biol Reprod 1998; 58: 160–8.
Kolch W, Martiny-Baron G, Kieser A, Marmé D. Regulation of the expression of the VEGF/VPF and its receptors: Role and tumor angiogenesis. Breast Cancer Res Treat 1995; 36: 139–55.
Seghezzi G, Patel S, Ren CJ et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: An autocrine mechanism contributing to angiogenesis. J Cell Biol 1998; 141: 1659–73.
Feng BD, Nagy JA, Hipp J et al. Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 1996; 183: 1981–6.
Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62–6.
Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376: 66–70.
Roberts WG, Palade GE. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 1997; 57: 765–72.
Ahsan Z, Maloney DJL, English PJ. Metastasis to skin from Leydig cell tumour. Br J Urol 1993; 72: 510–11.
O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–28.
O'Reilly MS, Boehm T, Shing Y et al. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–85.
Suri C, Jones PF, Patan S et al. Requisite role of angiopoietin-1, a ligand for the tie2 receptor, during embryonic angiogenesis. Cell 1996; 87: 1171–80.
Maisonpierre PC, Suri C, Jones PF et al. Angiopoietin-2, a natural antagonist for tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55–9.
Hess V, Fiedler W, Kilic N et al. Expression of angiopoietin-1 and tie-2 in normal and tumor tissues of human testis. Eur J Clin Invest (Suppl) 1998; 28: A42.
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Kilic, N., Lauke, H., Fiedler, W. et al. Angiogenic switch and vascular stability in human Leydig cell tumours. Angiogenesis 3, 231–240 (1999). https://doi.org/10.1023/A:1009081101314
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DOI: https://doi.org/10.1023/A:1009081101314