Von Hippel-Lindau Disease: Current Challenges and Future Prospects

Abstract

Understanding of molecular mechanisms of tumor growth has an increasing impact on the development of diagnostics and targeted therapy of human neoplasia. In this review, we summarize the current knowledge on molecular mechanisms and their clinical implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syndrome usually manifests in young adulthood and predisposes affected patients to the development of benign and malignant tumors of different organ systems mainly including the nervous system and internal organs. A consequent screening and timely preventive treatment of lesions are crucial for patients affected by VHL disease. Surgical indications and treatment have been evaluated and optimized over many years. In the last decade, pharmacological therapies have been evolving, but are largely still at an experimental stage. Effective pharmacological therapy as well as detection of biomarkers is based on the understanding of the molecular basis of disease. The molecular basis of von Hippel-Lindau disease is the loss of function of the VHL protein and subsequent accumulation of hypoxia-inducible factor with downstream effects on cellular metabolism and differentiation. Organs affected by VHL disease may develop frank tumors. More characteristically, however, they reveal multiple separate microscopic foci of neoplastic cell proliferation. The exact mechanisms of tumorigenesis in VHL disease are, however, still not entirely understood and knowledge on biomarkers and targeted therapy is scarce.

Keywords: VHL; Von Hippel-Lindau; hemangioblastoma; neuroendocrine tumor; pancreatic tumor; pheochromocytoma; renal cancer; second hit; tumor formation; tumor suppressor gene.

Figure 1

VHL protein functions: HIF independent and HIF dependent. Abbreviations: aPKC, atypical protein kinase C; CA9/12, carbonic anhydrase 9/12; CARD9, caspase recruitment domain-containing protein 9; CDKN1B, cyclin-dependent kinase inhibitor 1B; CK2, protein kinase CK2; CoV, type V collagen; CTGF, connective tissue growth factor; Cul2, Cullin 2; CXCR4, CX chemokine receptor type 4; ECM, extracellular matrix; EGFR, epidermal growth factor; FLK1, fetal liver kinase 1; GLUT1, glucose transporter 1; GSK3B, glycogen synthase kinase 3 beta; HIF, hypoxia-inducible factor; HGFR, hepatocyte growth factor; LOX, lysol oxidase; MDM2, mouse double minute 2 homolog; MMP, matrix metalloproteinases; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS, nitric oxide synthase; PDGF, platelet-derived growth factor; RBX1, ring box protein 1; SDF1, stromal cell-derived factor 1; TCEB1/2, transcription elongation factor B1/2; TGF, transforming growth factor; TWIST, twist related protein; VEGF, vascular endothelial growth factor; 6PFK, 6 phosphofructokinase.

Figure 2

Early VHL pathogenesis in the nervous system: Hemangioblastoma precursors. Histologic examination of grossly normal-appearing nerve root tissue of VHL patients reveals numerous microscopic hemangioblastoma precursor structures within nerve roots. Reprinted with permission from Vortmeyer AO, Tran MG, Zeng W, et al Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006;210(3):374–382.

Figure 3

Hemangioblastoma progression. Proposed structural progression of hemangioblastoma from mesenchymal (A) to epitheloid (B and C) and vasculogenetic architecture/extramedullary erythropoiesis (D–G); (A–D), immunohistochemical stain for CD31; (E–G), (H and E) stain. Immunohistochemistry for CD31 was performed to better differentiate reactive vascular cells (positively staining cells) from neoplastic cells (negatively staining cells). (H and E) stain was performed to demonstrate erythropoiesis within epitheloid and vasculogenetic structures. Reprinted from Exp Mol Pathol, 96(2), Glasker S, Smith J, Raffeld M, Li J, Oldfield EH, Vortmeyer AO, VHL-deficient vasculogenesis in hemangioblastoma 162-167, Copyright (2014), with permission from Elsevier.

Figure 4

Early VHL pathogenesis in the epididymis: cystadenoma precursors. (A–C) Multifocality of cystadenoma precursor structures: “Tumor-free” VHL epididymis contains multifocal microscopic precursors in the efferent ductule compartment of the caput (marked by arrows); e= normal efferent ductules. Republished with permission of John Wiley & Sons-Books, from Epididymal cystadenomas and epithelial tumorlets: Effects of VHL deficiency on human epididymis, Glasker S, Tran MG, Shively SB, et al. J Pathol. 210(1):32–41. permission conveyed through Copyright Clearance Center, Inc. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Figure 5

Papillary cystadenoma of the epididymis. (A), Gross examination of VHL epididymis shows enlargement of the caput epididymis (white arrows). (B), Cystadenomas reveal papillary (pap), tubular (tu) and cystic (cy) architecture. (C), Immunohistochemical staining with anti-CD31 reveals extensive vascularization of the tumor stroma. Numerous reactive vascular cells are in direct contact with overlying neoplastic epithelial cells. Republished with permission of John Wiley & Sons-Books, from Epididymal cystadenomas and epithelial tumorlets: Effects of VHL deficiency on human epididymis, Glasker S, Tran MG, Shively SB, et al J Pathol. 210(1):32–41. permission conveyed through Copyright Clearance Center, Inc. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Figure 6

Molecular targeting in VHL disease: action mechanisms. Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.