1932

Abstract

The von Hippel–Lindau () tumor suppressor gene is mutated as an early event in almost all cases of clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer. In this review we discuss recent advances in understanding how dysregulation of the many hypoxia-inducible factor α–dependent and –independent functions of the VHL tumor suppressor protein (pVHL) can contribute to tumor initiation and progression. Recent evidence showing extensive inter- and intratumoral genetic diversity has given rise to the idea that ccRCC should actually be considered as a series of molecularly related, yet distinct, diseases defined by the pattern of combinatorial genetic alterations present within the cells of the tumor. We highlight the range of genetic and epigenetic alterations that recur in ccRCC and discuss the mechanisms through which these events appear to function cooperatively with a loss of pVHL function in tumorigenesis.

Keyword(s): genomicsHIFαkidney cancerpathologyVHL
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2015-01-24
2024-06-17
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Literature Cited

  1. Moch H. 1.  2014. Kidney cancer. World Cancer Report 2014 BW Stewart, CP Wild 2–9 Lyon, Fr: Int. Agency Res. Cancer/World Health Organ. [Google Scholar]
  2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. 2.  2004. Tumours of the kidney. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs9–88 Lyon, Fr: IARC Press [Google Scholar]
  3. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI. 3.  et al. 2013. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am. J. Surg. Pathol. 37:1469–89 [Google Scholar]
  4. Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS. 4.  et al. 1997. The Heidelberg classification of renal cell tumours. J. Pathol. 183:2131–33 [Google Scholar]
  5. Moch H. 5.  2013. An overview of renal cell cancer: pathology and genetics. Semin. Cancer Biol. 23:13–9 [Google Scholar]
  6. von Teichman A, Comperat E, Behnke S, Storz M, Moch H, Schraml P. 6.  2011. VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma. Mod. Pathol. 24:4571–78 [Google Scholar]
  7. Eble JN, Bonsib SM. 7.  1998. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. Semin. Diagn. Pathol. 15:12–20 [Google Scholar]
  8. Montani M, Heinimann K, Teichman von A, Rudolph T, Perren A, Moch H. 8.  2010. VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von Hippel–Lindau disease. Am. J. Surg. Pathol. 34:6806–15 [Google Scholar]
  9. Thoma CR, Frew IJ, Krek W. 9.  2007. The VHL tumor suppressor: riding tandem with GSK3β in primary cilium maintenance. Cell Cycle 6:151809–13 [Google Scholar]
  10. Latif F, Tory K, Gnarra J, Yao M, Duh FM. 10.  et al. 1993. Identification of the von Hippel–Lindau disease tumor suppressor gene. Science 260:51121317–20 [Google Scholar]
  11. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH. 11.  et al. 1994. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet. 7:185–90First demonstration of biallelic mutations of VHL occurring in ccRCC but not in other common tumors. [Google Scholar]
  12. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y. 12.  et al. 2013. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45:8860–67Comprehensive genome-scale mutational and epigenetic analyses of ccRCC, demonstrating that there are numerous molecular subtypes. [Google Scholar]
  13. Sanjmyatav J, Hauke S, Gajda M, Hartmann A, Moch H. 13.  et al. 2013. Establishment of a multicolour fluorescence in situ hybridisation-based assay for subtyping of renal cell tumours. Eur. Urol. 64:4689–91 [Google Scholar]
  14. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC. 14.  et al. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:6733271–75Discovery that pVHL regulates the oxygen-dependent proteolytic degradation of HIF-α transcription factors. [Google Scholar]
  15. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. 15.  2003. Regulation of microtubule stability by the von Hippel–Lindau tumour suppressor protein pVHL. Nat. Cell Biol. 5:164–70 [Google Scholar]
  16. Thoma CR, Frew IJ, Hoerner CR, Montani M, Moch H, Krek W. 16.  2007. PVHL and GSK3β are components of a primary cilium-maintenance signalling network. Nat. Cell Biol. 9:5588–95Identification of microtubule-dependent role of pVHL in maintaining primary cilia in cooperation with GSK3β. [Google Scholar]
  17. Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD. 17.  2006. P53 stabilization and transactivation by a von Hippel–Lindau protein. Mol. Cell 22:3395–405 [Google Scholar]
  18. Lee S, Nakamura E, Yang H, Wei W, Linggi MS. 18.  et al. 2005. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8:2155–67 [Google Scholar]
  19. Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC. 19.  et al. 2006. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 66:73567–75 [Google Scholar]
  20. Pantuck AJ, An J, Liu H, Rettig MB. 20.  2010. NF-κB-dependent plasticity of the epithelial to mesenchymal transition induced by Von Hippel–Lindau inactivation in renal cell carcinomas. Cancer Res. 70:2752–61 [Google Scholar]
  21. Welford SM, Dorie MJ, Li X, Haase VH, Giaccia AJ. 21.  2010. Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol. Cell. Biol. 30:194595–603 [Google Scholar]
  22. Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L. 22.  et al. 2008. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat. Cell Biol. 10:3361–69 [Google Scholar]
  23. Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ. 23.  et al. 2009. VHL loss causes spindle misorientation and chromosome instability. Nat. Cell Biol. 11:8994–1001Identification of two new pVHL-regulated functions in mitosis: suppression of aneuploidy and mitotic spindle orientation. [Google Scholar]
  24. Kurban G, Duplan E, Ramlal N, Hudon V, Sado Y. 24.  et al. 2008. Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 27:1004–12 [Google Scholar]
  25. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO. 25.  et al. 1998. The von Hippel–Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell 1:7959–68 [Google Scholar]
  26. Hsu T, Adereth Y, Kose N, Dammai V. 26.  2006. Endocytic function of von Hippel–Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility. J. Biol. Chem. 281:1712069–80 [Google Scholar]
  27. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV. 27.  et al. 2008. Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL. Nat. Cell Biol. 10:101208–16 [Google Scholar]
  28. Mikhaylova O, Ignacak ML, Barankiewicz TJ, Harbaugh SV, Yi Y. 28.  et al. 2008. The von Hippel–Lindau tumor suppressor protein and Egl-9-type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mol. Cell. Biol. 28:82701–17 [Google Scholar]
  29. Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS. 29.  et al. 2009. Oxygen-regulated β2-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci. Signal. 2:78ra33 [Google Scholar]
  30. Yang H, Minamishima YA, Yan Q, Schlisio S, Ebert BL. 30.  et al. 2007. PVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-κB agonist Card9 by CK2. Mol. Cell 28:115–27 [Google Scholar]
  31. Iliopoulos O, Kibel A, Gray S, Kaelin WG. 31.  1995. Tumour suppression by the human von Hippel–Lindau gene product. Nat. Med. 1:8822–26 [Google Scholar]
  32. Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A. 32.  et al. 1996. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. PNAS 93:2010589–94 [Google Scholar]
  33. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV. 33.  et al. 2002. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:5459–68Discovery that biallelic loss of VHL function does not automatically initiate tumor formation in the kidney. [Google Scholar]
  34. Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M. 34.  et al. 2008. PVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. 27:121747–57 [Google Scholar]
  35. Gnarra JR, Ward JM, Porter FD, Wagner JR, Devor DE. 35.  et al. 1997. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. PNAS 94:179102–7 [Google Scholar]
  36. Kleymenova E. 36.  2003. Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. Carcinogenesis 25:3309–15 [Google Scholar]
  37. Iguchi M, Kakinuma Y, Kurabayashi A, Sato T, Shuin T. 37.  et al. 2008. Acute inactivation of the VHL gene contributes to protective effects of ischemic preconditioning in the mouse kidney. Nephron Exp. Nephrol. 110:3e82–90 [Google Scholar]
  38. Ma W, Tessarollo L, Hong SB, Baba M, Southon E. 38.  et al. 2003. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res. 63:175320–28 [Google Scholar]
  39. Rankin EB, Tomaszewski JE, Haase VH. 39.  2006. Renal cyst development in mice with conditional inactivation of the von Hippel–Lindau tumor suppressor. Cancer Res. 66:52576–83 [Google Scholar]
  40. Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH. 40.  et al. 2013. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel–Lindau protein. Acta Physiol. 207:3565–76 [Google Scholar]
  41. Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B. 41.  et al. 2012. Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PLOS ONE 7:1e31034 [Google Scholar]
  42. Schley G, Klanke B, Schodel J, Forstreuter F, Shukla D. 42.  et al. 2011. Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury. J. Am. Soc. Nephrol. 22:112004–15 [Google Scholar]
  43. Paraf F, Chauveau D, Chrétien Y, Richard S, Grünfeld JP, Droz D. 43.  2000. Renal lesions in von Hippel–Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins. Histopathology 36:5457–65 [Google Scholar]
  44. Schaub TP, Kartenbeck J, König J, Spring H, Dörsam J. 44.  et al. 1999. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J. Am. Soc. Nephrol. 10:61159–69 [Google Scholar]
  45. Avery AK, Beckstead J, Renshaw AA, Corless CL. 45.  2000. Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms. Am. J. Surg. Pathol. 24:2203–10 [Google Scholar]
  46. Mazal PR, Stichenwirth M, Koller A, Blach S, Haitel A, Susani M. 46.  2004. Expression of aquaporins and PAX-2 compared to CD10 and cytokeratin 7 in renal neoplasms: a tissue microarray study. Mod. Pathol. 18:4535–40 [Google Scholar]
  47. Bakshi N, Kunju LP, Giordano T, Shah RB. 47.  2007. Expression of renal cell carcinoma antigen (RCC) in renal epithelial and nonrenal tumors: diagnostic implications. Appl. Immunohistochem. Mol. Morphol. 15:3310–15 [Google Scholar]
  48. Droz D, Zachar D, Charbit L, Gogusev J, Chrétein Y, Iris L. 48.  1990. Expression of the human nephron differentiation molecules in renal cell carcinomas. Am. J. Pathol. 137:4895–905 [Google Scholar]
  49. Shen SS, Krishna B, Chirala R, Amato RJ, Truong LD. 49.  2005. Kidney-specific cadherin, a specific marker for the distal portion of the nephron and related renal neoplasms. Mod. Pathol. 18:7933–40 [Google Scholar]
  50. Horstmann M, Geiger LM, Vogel U, Schmid H, Hennenlotter J. 50.  et al. 2011. Kidney-specific cadherin correlates with the ontogenetic origin of renal cell carcinoma subtypes: an indicator of a malignant potential?. World J. Urol. 30:4525–31 [Google Scholar]
  51. Kuehn A, Paner GP, Skinnider BF, Cohen C, Datta MW. 51.  et al. 2007. Expression analysis of kidney-specific cadherin in a wide spectrum of traditional and newly recognized renal epithelial neoplasms: diagnostic and histogenetic implications. Am. J. Surg. Pathol. 31:101528–33 [Google Scholar]
  52. Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD. 52.  et al. 2014. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26:319–30 [Google Scholar]
  53. Straube T, Elli AF, Greb C, Hegele A, Elsässer H-P. 53.  et al. 2011. Changes in the expression and subcellular distribution of galectin-3 in clear cell renal cell carcinoma. J. Exp. Clin. Cancer Res. 30:189 [Google Scholar]
  54. Moch H, Schraml P, Bubendorf L, Mirlacher M, Kononen J. 54.  et al. 1999. High-throughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal cell carcinoma. Am. J. Pathol. 154:4981–86 [Google Scholar]
  55. Skinnider BF, Folpe AL, Hennigar RA, Lim SD, Cohen C. 55.  et al. 2005. Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors. Am. J. Surg. Pathol. 29:6747–54 [Google Scholar]
  56. Gröne HJ, Weber K, Gröne E, Helmchen U, Osborn M. 56.  1987. Coexpression of keratin and vimentin in damaged and regenerating tubular epithelia of the kidney. Am. J. Pathol. 129:11–8 [Google Scholar]
  57. Morra L, Rechsteiner M, Casagrande S, Duc Luu V, Santimaria R. 57.  et al. 2011. Relevance of periostin splice variants in renal cell carcinoma. Am. J. Pathol. 179:31513–21 [Google Scholar]
  58. Albers J, Rajski M, Schönenberger D, Harlander S, Schraml P. 58.  et al. 2013. Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO Mol. Med. 5:6949–64 [Google Scholar]
  59. 59. Cancer Genome Atlas Res. Netw 2013. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:745643–49Comprehensive genome-scale mutational and epigenetic analyses of ccRCC, demonstrating that there are numerous molecular subtypes. [Google Scholar]
  60. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A. 60.  et al. 2012. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44:7751–59 [Google Scholar]
  61. Ricketts CJ, Morris MR, Gentle D, Brown M, Wake N. 61.  et al. 2012. Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics 7:3278–90 [Google Scholar]
  62. Morris MR, Ricketts CJ, Gentle D, McRonald F, Carli N. 62.  et al. 2011. Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma. Oncogene 30:121390–401 [Google Scholar]
  63. Varela I, Tarpey P, Raine K, Huang D, Ong CK. 63.  et al. 2011. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469:7331539–42 [Google Scholar]
  64. Keith B, Simon MC. 64.  2007. Hypoxia-inducible factors, stem cells, and cancer. Cell 129:3465–72 [Google Scholar]
  65. Keith B, Johnson RS, Simon MC. 65.  2012. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12:19–22 [Google Scholar]
  66. Wenger RH, Stiehl DP, Camenisch G. 66.  2005. Integration of oxygen signaling at the consensus HRE. Sci. STKE 2005:306re12 [Google Scholar]
  67. Qing G, Simon MC. 67.  2009. Hypoxia inducible factor-2α: a critical mediator of aggressive tumor phenotypes. Curr. Opin. Genet. Dev. 19:160–66 [Google Scholar]
  68. Kondo K, Kim WY, Lechpammer M, Kaelin WGJ. 68.  2003. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLOS Biol. 1:3e83 [Google Scholar]
  69. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ. 69.  et al. 2005. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel–Lindau-associated renal cell carcinoma. Mol. Cell. Biol. 25:135675–86 [Google Scholar]
  70. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. 70.  2004. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL−/− tumors. Mol. Cancer Res. 2:289–95 [Google Scholar]
  71. Mack FA, Patel JH, Biju MP, Haase VH, Simon MC. 71.  2005. Decreased growth of Vhl−/− fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27. Mol. Cell. Biol. 25:114565–78 [Google Scholar]
  72. Mack FA, Rathmell WK, Arsham AM, Gnarra J, Keith B, Simon MC. 72.  2003. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3:175–88 [Google Scholar]
  73. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. 73.  2007. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11:4335–47 [Google Scholar]
  74. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. 74.  2004. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23:91949–56 [Google Scholar]
  75. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B. 75.  et al. 2007. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:5407–20 [Google Scholar]
  76. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN. 76.  et al. 2008. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14:6435–46 [Google Scholar]
  77. Monzon FA, Alvarez K, Peterson L, Truong L, Amato RJ. 77.  et al. 2011. Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod. Pathol. 24:111470–79 [Google Scholar]
  78. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M. 78.  et al. 2011. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1:3222–35 [Google Scholar]
  79. Koh MY, Darnay BG, Powis G. 79.  2008. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1α, leading to its oxygen-independent degradation. Mol. Cell. Biol. 28:237081–95 [Google Scholar]
  80. Koh MY, Lemos R, Liu X, Powis G. 80.  2011. The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 71:114015–27 [Google Scholar]
  81. Mathew LK, Lee SS, Skuli N, Rao S, Keith B. 81.  et al. 2014. Restricted expression of miR-30c-2-3p and miR-30a-3p in clear cell renal cell carcinomas enhances HIF2 activity. Cancer Discov. 4:153–60 [Google Scholar]
  82. Toschi A, Lee E, Gadir N, Ohh M, Foster DA. 82.  2008. Differential dependence of hypoxia-inducible factors 1 α and 2 α on mTORC1 and mTORC2. J. Biol. Chem. 283:5034495–99 [Google Scholar]
  83. Menrad H, Werno C, Schmid T, Copanaki E, Deller T. 83.  et al. 2010. Roles of hypoxia-inducible factor-1α (HIF-1α) versus HIF-2α in the survival of hepatocellular tumor spheroids. Hepatology 51:62183–92 [Google Scholar]
  84. Schulz K, Milke L, Rübsamen D, Menrad H, Schmid T, Brüne B. 84.  2012. HIF-1α protein is upregulated in HIF-2α depleted cells via enhanced translation. FEBS Lett. 586:111652–57 [Google Scholar]
  85. Xu J, Wang B, Xu Y, Sun L, Tian W. 85.  et al. 2012. Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element. Oncogene 31:81065–72 [Google Scholar]
  86. Adam J, Hatipoglu E, O'Flaherty L, Ternette N, Sahgal N. 86.  et al. 2011. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20:4524–37 [Google Scholar]
  87. Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ. 87.  2011. Generation of a mouse model of Von Hippel–Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α. Cancer Res. 71:216848–56 [Google Scholar]
  88. Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ. 88.  2013. Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis. Cancer Res. 73:92916–25 [Google Scholar]
  89. Heiden MG, Cantley LC, Thompson CB. 89.  Vander 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:59301029–33 [Google Scholar]
  90. Semenza GL. 90.  2013. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Investig. 123:93664–71 [Google Scholar]
  91. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E. 91.  et al. 1998. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 α. Genes Dev. 12:2149–62 [Google Scholar]
  92. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. 92.  2006. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3:3187–97 [Google Scholar]
  93. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. 93.  2006. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3:3177–85 [Google Scholar]
  94. Li B, Qiu B, Lee DSM, Walton ZE, Ochocki JD. 94.  et al. 2014. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513:7517251–55 [Google Scholar]
  95. Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J. 95.  et al. 2008. Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Int. J. Cancer 122:112422–28 [Google Scholar]
  96. Luo W, Hu H, Chang R, Zhong J, Knabel M. 96.  et al. 2011. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145:5732–44 [Google Scholar]
  97. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. 97.  2008. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:7184181–86 [Google Scholar]
  98. Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A. 98.  et al. 2010. Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLOS ONE 5:3e9644 [Google Scholar]
  99. Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouysségur J, Mazure NM. 99.  2012. Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Front. Oncol. 2:18 [Google Scholar]
  100. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J. 100.  et al. 2012. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:7381380–84 [Google Scholar]
  101. Mullen AR, Wheaton WW, Jin ES, Chen P-H, Sullivan LB. 101.  et al. 2012. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:7381385–88 [Google Scholar]
  102. Wise DR, Ward PS, Shay JES, Cross JR, Gruber JJ. 102.  et al. 2011. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. PNAS 108:4919611–16 [Google Scholar]
  103. Levine AJ, Puzio-Kuter AM. 103.  2010. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:60091340–44 [Google Scholar]
  104. Sun RC, Denko NC. 104.  2014. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 19:2285–92 [Google Scholar]
  105. Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G. 105.  et al. 2012. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol. Cell 48:5681–91 [Google Scholar]
  106. Gatto F, Nookaew I, Nielsen J. 106.  2014. Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma. PNAS 111:9E866–75 [Google Scholar]
  107. Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW. 107.  et al. 2011. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med. 3:9494ra70 [Google Scholar]
  108. Velickovic M, Delahunt B, McIver B, Grebe SK. 108.  2002. Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Mod. Pathol. 15:5479–85 [Google Scholar]
  109. Shin Lee J, Seok Kim H, Bok Kim Y, Cheol Lee M, Soo Park C. 109.  2003. Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. J. Surg. Oncol. 84:3166–72 [Google Scholar]
  110. Horiguchi A, Oya M, Uchida A, Marumo K, Murai M. 110.  2003. Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma. J. Urol. 169:2710–13 [Google Scholar]
  111. Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT. 111.  et al. 2007. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 109:112257–67 [Google Scholar]
  112. Li L, Shen C, Nakamura E, Ando K, Signoretti S. 112.  et al. 2013. SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell 24:6738–50 [Google Scholar]
  113. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E. 113.  et al. 2006. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat. Med. 12:1122–27 [Google Scholar]
  114. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R. 114.  et al. 2007. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356:222271–81 [Google Scholar]
  115. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C. 115.  et al. 2010. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:184256–65 [Google Scholar]
  116. Thoma CR, Matov A, Gutbrodt KL, Hoerner CR, Smole Z. 116.  et al. 2010. Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. J. Cell Biol. 190:6991–1003 [Google Scholar]
  117. Mans DA, Lolkema MP, van Beest M, Daenen LG, Voest EE, Giles RH. 117.  2008. Mobility of the von Hippel–Lindau tumour suppressor protein is regulated by kinesin-2. Exp. Cell Res. 314:61229–36 [Google Scholar]
  118. Schermer B, Ghenoiu C, Bartram M, Muller RU, Kotsis F. 118.  et al. 2006. The von Hippel–Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J. Cell Biol. 175:4547–54 [Google Scholar]
  119. Blankenship C, Naglich JG, Whaley JM, Seizinger B, Kley N. 119.  1999. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 18:81529–35 [Google Scholar]
  120. Iliopoulos O, Ohh M, Kaelin WGJ. 120.  1998. PVHL19 is a biologically active product of the von Hippel–Lindau gene arising from internal translation initiation. PNAS 95:2011661–66 [Google Scholar]
  121. Frew IJ, Smole Z, Thoma CR, Krek W. 121.  2013. Genetic deletion of the long isoform of the von Hippel–Lindau tumour suppressor gene product alters microtubule dynamics. Eur. J. Cancer 49:102433–40 [Google Scholar]
  122. Berbari NF, O'Connor AK, Haycraft CJ, Yoder BK. 122.  2009. The primary cilium as a complex signaling center. Curr. Biol. 19:13R526–35 [Google Scholar]
  123. Davenport JR, Yoder BK. 123.  2005. An incredible decade for the primary cilium: a look at a once-forgotten organelle. Am. J. Physiol. Renal Physiol. 289:6F1159–69 [Google Scholar]
  124. Esteban MA, Harten SK, Tran MG, Maxwell PH. 124.  2006. Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein. J. Am. Soc. Nephrol. 17:71801–6 [Google Scholar]
  125. Lutz MS, Burk RD. 125.  2006. Primary cilium formation requires von Hippel–Lindau gene function in renal-derived cells. Cancer Res. 66:146903–7 [Google Scholar]
  126. Troilo A, Alexander I, Muehl S, Jaramillo D, Knobeloch K-P, Krek W. 126.  2013. HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia. EMBO Rep. 15:177–85 [Google Scholar]
  127. Stenmark H, Vitale G, Ullrich O, Zerial M. 127.  1995. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell 83:3423–32 [Google Scholar]
  128. Toyoshima F, Nishida E. 128.  2007. Integrin-mediated adhesion orients the spindle parallel to the substratum in an EB1- and myosin X-dependent manner. EMBO J. 26:61487–98 [Google Scholar]
  129. Toyoshima F, Matsumura S, Morimoto H, Mitsushima M, Nishida E. 129.  2007. PtdIns(3,4,5)P3 regulates spindle orientation in adherent cells. Dev. Cell 13:6796–811 [Google Scholar]
  130. Hell MP, Duda M, Weber TC, Moch H, Krek W. 130.  2013. Tumor suppressor VHL functions in the control of mitotic fidelity. Cancer Res. 74:92422–31 [Google Scholar]
  131. Hell MP, Thoma CR, Fankhauser N, Christinat Y, Weber TC, Krek W. 131.  2014. MiR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res. 74:92432–43 [Google Scholar]
  132. Holland AJ, Cleveland DW. 132.  2009. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10:7478–87 [Google Scholar]
  133. Metcalf JL, Bradshaw PS, Komosa M, Greer SN, Meyn MS, Ohh M. 133.  2014. K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene 33:81055–60 [Google Scholar]
  134. Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G. 134.  et al. 2010. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:7279360–63 [Google Scholar]
  135. Burrows AE, Smogorzewska A, Elledge SJ. 135.  2010. Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence. PNAS 107:3214280–85 [Google Scholar]
  136. Pawłowski R, Mühl SM, Sulser T, Krek W, Moch H, Schraml P. 136.  2013. Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int. J. Cancer 132:2E11–17 [Google Scholar]
  137. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B. 137.  et al. 1994. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. PNAS 91:219700–4 [Google Scholar]
  138. Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S. 138.  et al. 2001. Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma. Cancer Res. 61:197277–81 [Google Scholar]
  139. Dreijerink K, Braga E, Kuzmin I, Geil L, Duh FM. 139.  et al. 2001. The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. PNAS 98:137504–9 [Google Scholar]
  140. Herbers J, Schullerus D, Müller H, Kenck C, Chudek J. 140.  et al. 1997. Significance of chromosome arm 14q loss in nonpapillary renal cell carcinomas. Genes Chromosomes Cancer 19:129–35 [Google Scholar]
  141. Klatte T, Rao PN, de Martino M, LaRochelle J, Shuch B. 141.  et al. 2009. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J. Clin. Oncol. 27:5746–53 [Google Scholar]
  142. Schraml P, Struckmann K, Bednar R, Fu W, Gasser T. 142.  et al. 2001. CDKN2A mutation analysis, protein expression, and deletion mapping of chromosome 9p in conventional clear-cell renal carcinomas: evidence for a second tumor suppressor gene proximal to CDKN2A. Am. J. Pathol. 158:2593–601 [Google Scholar]
  143. Beroukhim R, Brunet JP, Di Napoli A, Mertz KD, Seeley A. 143.  et al. 2009. Patterns of gene expression and copy-number alterations in von-Hippel Lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69:114674–81 [Google Scholar]
  144. Maher ER. 144.  2012. Genomics and epigenomics of renal cell carcinoma. Semin. Cancer Biol. 23:110–17 [Google Scholar]
  145. Moch H, Artibani W, Delahunt B, Ficarra V, Knuechel R. 145.  et al. 2009. Reassessing the current UICC/AJCC TNM staging for renal cell carcinoma. Eur. Urol. 56:4636–43 [Google Scholar]
  146. Fuhrman SA, Lasky LC, Limas C. 146.  1982. Prognostic significance in morphologic parameters in renal cell carcinoma. Am. J. Surg. Pathol. 6:656–63 [Google Scholar]
  147. Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C. 147.  et al. 2013. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am. J. Surg. Pathol. 37:101490–504 [Google Scholar]
  148. Wyler L, Napoli CU, Ingold B, Sulser T, Heikenwälder M. 148.  et al. 2014. Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression. Br. J. Cancer 110:3686–94 [Google Scholar]
  149. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. 149.  2003. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425:6955307–11Found that the propensity to metastasize may be a very early event in ccRCC. [Google Scholar]
  150. Struckmann K, Mertz K, Steu S, Storz M, Staller P. 150.  et al. 2008. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma. J. Pathol. 214:4464–71 [Google Scholar]
  151. Luu VD, Boysen G, Struckmann K, Casagrande S, von Teichman A. 151.  et al. 2009. Loss of VHL and hypoxia provokes PAX2 up-regulation in clear cell renal cell carcinoma. Clin. Cancer Res. 15:103297–304 [Google Scholar]
  152. Boysen G, Bausch-Fluck D, Thoma CR, Nowicka AM, Stiehl DP. 152.  et al. 2012. Identification and functional characterization of pVHL-dependent cell surface proteins in renal cell carcinoma. Neoplasia 14:6535–46 [Google Scholar]
  153. Fisher R, Gore M, Larkin J. 153.  2013. Current and future systemic treatments for renal cell carcinoma. Semin. Cancer Biol. 23:138–45 [Google Scholar]
  154. Tan PH, Cheng L, Rioux-Leclercq N, Merino MJ, Netto G. 154.  et al. 2013. Renal tumors: diagnostic and prognostic biomarkers. Am. J. Surg. Pathol. 37:101518–31 [Google Scholar]
  155. Brugarolas J. 155.  2007. Renal-cell carcinoma—molecular pathways and therapies. N. Engl. J. Med. 356:2185–87 [Google Scholar]
  156. Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W. 156.  et al. 1998. Prevalence, morphology and biology of renal cell carcinoma in von Hippel–Lindau disease compared to sporadic renal cell carcinoma. J. Urol. 160:41248–54 [Google Scholar]
  157. Gossage L, Eisen T. 157.  2010. Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat. Rev. Clin. Oncol. 7:5277–88 [Google Scholar]
  158. Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP. 158.  et al. 2014. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46:3225–33Characterization of intratumoral genetic heterogeneity in ccRCC, implying the parallel evolution of tumor-cell clones. [Google Scholar]
  159. Bissig H, Richter J, Desper R, Meier V, Schraml P. 159.  et al. 1999. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am. J. Pathol. 155:1267–74 [Google Scholar]
  160. Xu X, Hou Y, Yin X, Bao L, Tang A. 160.  et al. 2012. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148:5886–95 [Google Scholar]
  161. Schraml P, Struckmann K, Hatz F, Sonnet S, Kully C. 161.  et al. 2002. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J. Pathol. 196:2186–93 [Google Scholar]
  162. Gerstung M, Beisel C, Rechsteiner M, Wild P, Schraml P. 162.  et al. 2012. Reliable detection of subclonal single-nucleotide variants in tumour cell populations. Nat. Commun. 3:811 [Google Scholar]
  163. Rechsteiner MP, von Teichman A, Nowicka A, Sulser T, Schraml P, Moch H. 163.  2011. VHL gene mutations and their effects on hypoxia inducible factor HIFα: identification of potential driver and passenger mutations. Cancer Res. 71:165500–11 [Google Scholar]
  164. Vanharanta S, Shu W, Brenet F, Hakimi AA, Heguy A. 164.  et al. 2012. Epigenetic expansion of VHL–HIF signal output drives multiorgan metastasis in renal cancer. Nat. Med. 19:150–56Identification of the contribution of epigenetic alterations to metastatic spread by expanding the HIF-α transcriptional program. [Google Scholar]
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