Abstract
Hemangioblastomas (HBs) are benign, highly vascular tumors, often characterized by loss of function of the von Hippel–Lindau (vHL) gene. They are the most common central nervous system tumor observed in vHL syndrome. Loss of function of the vHL gene creates a “pseudo-hypoxic” state, causing overactivation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-related pathways. In some cases, HBs can rapidly increase in size during pregnancy to then present acutely, which most frequently occurs after the 20th gestational week. These changes in size usually occur from enlargement of the cystic component of the HB. Due to their preferred location in the posterior fossa near critical structures as well as along the spinal cord, such cases can present with severe neurological deficits, requiring urgent surgical intervention in a multidisciplinary setting. However, the reasons for this acute flare-up during pregnancy remain poorly understood, as are the reasons why this occurs in only a subset of tumors. Unveiling the etiology for this clinical scenario can affect the treatment of HBs, as it will contribute to the understanding of the pathophysiology of such a transformation from a quiescent lesion to a symptomatic one, not only in the setting of pregnancy. Identifying the correct triggers and the conditions initiating and mediating this switch will enable us to develop preventive medications which should allow us to keep the tumor in its quiescent phase. In this pathophysiological review, we investigate the association between HB growth and pregnancy based on an analysis > 40 such published cases. We suggest that the proangiogenic state of pregnancy is the leading etiology for this striking association, and to support the argument, we discuss its potential impact on HIF overexpression in a non-hypoxic manner through activation of the PI3K/Akt/mTOR pathway by proangiogenic factors. Specifically, we discuss the involvement of placental growth factor (PlGF) and its receptor vascular endothelial growth factor receptor 1 (VEGFR-1) in various pathologic processes that can lead to the formation and growth of peritumoral edema and cysts, which are the primary causes for the development of any symptoms in HB. Both PlGF and VEGFR-1 are expressed at increased levels during pregnancy, and both have been reported as part of various pathological processes, including angiogenesis and tumorigenesis. The unique feature that both do essentially not show any significant negative impact on regular physiological processes makes them attractive therapeutic targets since very little side effects are expected. Further research into the effects of anti-PlGF or anti-VEGFR-1 therapy in HB is therefore recommended.
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Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, Walsh K, Aird WC (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24:294–300
Akrami H, Mahmoodi F, Havasi S, Sharifi A (2016) PlGF knockdown inhibited tumor survival and migration in gastric cancer cell via PI3K/Akt and p38MAPK pathways. Cell Biochem Funct 34:173–180. https://doi.org/10.1002/cbf.3176
Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464
Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ (2010) Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. Hypertension 56:1003–1008. https://doi.org/10.1161/HYPERTENSIONAHA.1110.158931
An J, Rettig MB (2005) Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol Cell Biol 25:7546–7556
Autiero M, Luttun A, Tjwa M, Carmeliet P (2003) Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1:1356–1370
Baggenstos MA, Butman JA, Oldfield EH, Lonser RR (2007) Role of edema in peritumoral cyst formation. Neurosurg Focus 22:E9
Baker PN, Krasnow J, Roberts JM, Yeo KT (1995) Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol 86:815–821
Bellik L, Vinci MC, Filippi S, Ledda F, Parenti A (2005) Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia. Br J Pharmacol 146:568–575
Binder NK, Evans J, Salamonsen LA, Gardner DK, Kaitu’u-Lino TJ, Hannan NJ (2016) Placental growth factor is secreted by the human endometrium and has potential important functions during embryo development and implantation. PLoS One 11:e0163096. https://doi.org/10.1371/journal.pone.0163096.eCollection2016
Blakeley JO, Ye X, Duda DG, Halpin CF, Bergner AL, Muzikansky A, Merker VL, Gerstner ER, Fayad LM, Ahlawat S, Jacobs MA, Jain RK, Zalewski C, Dombi E, Widemann BC, Plotkin SR (2016) Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol 34(14):1669–1675
Bobic S, Seys S, De Vooght V, Callebaut I, Hox V, Dooms C, Vinckier S, Jonckx B, Saint-Remy JM, Stassen JM, Bullens DM, Ceuppens JL, Carmeliet P, Hellings PW (2012) Placental growth factor contributes to bronchial neutrophilic inflammation and edema in allergic asthma. Am J Respir Cell Mol Biol 46:781–789. https://doi.org/10.1165/rcmb.2011-0152OC
Bohling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M (1996) Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol 55:522–527
Boker A, Ong BY (2001) Anesthesia for Cesarean section and posterior fossa craniotomy in a patient with von Hippel-Lindau disease. Can J Anaesth 48:387–390
Bourdillon PJ, Hickman RC (1967) Von Hippel-Lindau’s disease presenting at an early age. J Neurol Neurosurg Psychiatry 30:559–562
Broager B (1949) Multiple cerebellar angioreticulomas; discussion of high protein contents of the cysts and of enclosed parts of the subarachnoid space. Acta Psychiatr Neurol 24:317–332
Brown MA, Zammit VC, Lowe SA (1989) Capillary permeability and extracellular fluid volumes in pregnancy-induced hypertension. Clin Sci (Lond) 77:599–604
Cao Y, Linden P, Shima D, Browne F, Folkman J (1996) In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest 98:2507–2511
Capone F, Profice P, Pilato F, Zollino M, Colosimo C, Di Lazzaro V (2013) Spinal hemangioblastoma presenting with low back pain in pregnancy. Spine J 13:e27–e29. https://doi.org/10.1016/j.spinee.2013.1007.1428
Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, VandenDriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583
Carnevale D, Lembo G (2012) Placental growth factor and cardiac inflammation. Trends Cardiovasc Med 22:209–212. https://doi.org/10.1016/j.tcm.2012.1007.1022
Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, Goncalves L, Gomez R, Edwin S, Mazor M (2005) Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 17:3–18
Cianfarani F, Zambruno G, Brogelli L, Sera F, Lacal PM, Pesce M, Capogrossi MC, Failla CM, Napolitano M, Odorisio T (2006) Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential. Am J Pathol 169:1167–1182
Cipolla MJ (2007) Cerebrovascular function in pregnancy and eclampsia. Hypertension 50:14–24
Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127. https://doi.org/10.1111/joim.12019
Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478
Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D (2001) Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery 48:55–62 discussion 62-53
Criscuolo GR (1993) The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66:277–314
De Falco S (2012) The discovery of placenta growth factor and its biological activity. Exp Mol Med 44:1–9. https://doi.org/10.3858/emm.2012.3844.3851.3025
Delisle MF, Valimohamed F, Money D, Douglas MJ (2000) Central nervous system complications of von Hippel-Lindau disease and pregnancy; perinatal considerations: case report and literature review. J Matern Fetal Med 9:242–247
Dery MA, Michaud MD, Richard DE (2005) Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37:535–540
Donnini S, Machein MR, Plate KH, Weich HA (1999) Expression and localization of placenta growth factor and PlGF receptors in human meningiomas. J Pathol 189:66–71
Dupperat B (1945) Tumeurs cerebrales et grossesse. Pr Med 52:118
Erdogan B, Sen O, Aydin MV, Bagis T, Bavbek M (2002) Cerebellar hemangioblastoma in pregnancy. A case report. J Reprod Med 47:864–866
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111
Evans P, Wheeler T, Anthony F, Osmond C (1997) Maternal serum vascular endothelial growth factor during early pregnancy. Clin Sci (Lond) 92:567–571
Evans PW, Wheeler T, Anthony FW, Osmond C (1998) A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod 13:1057–1062
Feldman MJ, Sizdahkhani S, Edwards NA, Merrill MJ, Ray-Chaudhury A, Zhuang Z, Lonser RR, Oldfield EH, Chittiboina P (2016) Loss of quiescence in von Hippel-Lindau hemangioblastomas is associated with erythropoietin signaling. Sci Rep 6:35486
Ferrante L, Celli P, Fraioli B, Santoro A (1984) Haemangioblastomas of the posterior cranial fossa. Acta Neurochir 71:283–294
Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475
Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956. https://doi.org/10.1038/nrc2524
Frantzen C, Kruizinga RC, van Asselt SJ, Zonnenberg BA, Lenders JW, de Herder WW, Walenkamp AM, Giles RH, Hes FJ, Sluiter WJ, van Pampus MG, Links TP (2012) Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology 79:793–796
Ghosh S, Tergaonkar V, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T (2006) Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 10:215–226
Glasker S, Vortmeyer AO, Lonser RR, Lubensky IA, Okamoto H, Xia JB, Li J, Milne E, Kowalak JA, Oldfield EH, Zhuang Z (2006) Proteomic analysis of hemangioblastoma cyst fluid. Cancer Biol Ther 5:549–553
Green CJ, Lichtlen P, Huynh NT, Yanovsky M, Laderoute KR, Schaffner W, Murphy BJ (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61:2696–2703
Grimbert P, Chauveau D, Remy SR, Grunfeld JP (1999) Pregnancy in von Hippel-Lindau disease. Am J Obstet Gynecol 180:110–111
Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268. https://doi.org/10.1084/jem.20080108
Hallsworth D, Thompson J, Wilkinson D, Kerr RS, Russell R (2015) Intracranial pressure monitoring and caesarean section in a patient with von Hippel-Lindau disease and symptomatic cerebellar haemangioblastomas. Int J Obstet Anesth 24:73–77
Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849
Hatva E, Bohling T, Jaaskelainen J, Persico MG, Haltia M, Alitalo K (1996) Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 148:763–775
Hayashi S, Takeda N, Komura E (2010) Symptomatic cerebellar hemorrhage from recurrent hemangioblastoma during delivery. Case report. Neurol Med Chir (Tokyo) 50:1105–1107
Hayden MG, Gephart R, Kalanithi P, Chou D (2009) Von Hippel-Lindau disease in pregnancy: a brief review. J Clin Neurosci 16:611–613. https://doi.org/10.1016/j.jocn.2008.1005.1032
Hiratsuka S, Kataoka Y, Nakao K, Nakamura K, Morikawa S, Tanaka S, Katsuki M, Maru Y, Shibuya M (2005) Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos. Mol Cell Biol 25:355–363
Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213
Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95:9349–9354
Ho MC, Chen CN, Lee H, Hsieh FJ, Shun CT, Chang CL, Lai YT, Lee PH (2007) Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma. Cancer Lett 250:237–249
Hoeve JV (1923) Eye diseases in tuberous sclerosis of the brain and in Recklinghausen’s disease. Trans Ophthalmol Soc U K 43:534–541
Hrisomalos FN, Maturi RK, Pata V (2010) Long-term use of intravitreal bevacizumab (avastin) for the treatment of von hippel-lindau associated retinal hemangioblastomas. Open Ophthalmol J 4:66–69
Ilhan-Mutlu A, Wagner L, Widhalm G, Wohrer A, Bartsch S, Czech T, Heinzl H, Leutmezer F, Prayer D, Marosi C, Base W, Preusser M (2013) Exploratory investigation of eight circulating plasma markers in brain tumor patients. Neurosurg Rev 36:45–55; discussion 55-46. https://doi.org/10.1007/s10143-10012-10401-10146
Incio J, Tam J, Rahbari NN, Suboj P, McManus DT, Chin SM, Vardam TD, Batista A, Babykutty S, Jung K, Khachatryan A, Hato T, Ligibel JA, Krop IE, Puchner SB, Schlett CL, Hoffmman U, Ancukiewicz M, Shibuya M, Carmeliet P, Soares R, Duda DG, Jain RK, Fukumura D (2016) PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin Cancer Res 22:2993–3004. https://doi.org/10.1158/1078-0432.CCR-2915-1839
Inoue A, Kohno S, Kumon Y, Watanabe H, Ohnishi T, Hashimoto H, Matsubara K (2015) A case of cerebellar hemangioblastoma complicated by pregnancy and concerns about the surgical period. No Shinkei Geka 43:57–62
Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH (2008) Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 108:210–222. https://doi.org/10.3171/JNS/2008/3108/3172/0210
Jeffreys R (1975) Clinical and surgical aspects of posterior fossa haemangioblastomata. J Neurol Neurosurg Psychiatry 38:105–111
Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T, Yao M (1994) Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54:4845–4847
Kasarskis EJ, Tibbs PA, Lee C (1988) Cerebellar hemangioblastoma symptomatic during pregnancy. Neurosurgery 22:770–772
Kenyon AP, Haider S, Ashkan K, Nelson-Piercy C (2009) Cerebellar haemangioblastoma presenting with dizziness in pregnancy: case report and review of the literature. Obstet Med 2:164–167. https://doi.org/10.1258/om.2009.090018
Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049. https://doi.org/10.1056/NEJMra0706596
Kim KJ, Cho CS, Kim WU (2012) Role of placenta growth factor in cancer and inflammation. Exp Mol Med 44:10–19. https://doi.org/10.3858/emm.2012.3844.3851.3023
Korula G, Farling P (1998) Anesthetic management for a combined Cesarean section and posterior fossa craniectomy. J Neurosurg Anesthesiol 10:30–33
Krauss T, Pauer HU, Augustin HG (2004) Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 23:101–111
Kuhnigk H, Danhauser-Leistner I (1994) Cesarean section with subsequent craniotomy in the area of the posterior cranial fossa. Anasthesiol Intensivmed Notfallmed Schmerzther 29:184–187
Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, Gull I, Lessing JB (1997) Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 38:302–306
Kurne A, Bakar B, Arsava EM, Tan E (2003) Pregnancy associated quadriparesis in a patient with Von-Hippel Lindau disease. J Neurol 250:234–235
Landgren E, Schiller P, Cao Y, Claesson-Welsh L (1998) Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 16:359–367
Lassen U, Nielsen DL, Sorensen M, Winstedt L, Niskanen T, Stenberg Y, Pakola S, Stassen JM, Glazer S (2012) A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours. Br J Cancer 106:678–684. https://doi.org/10.1038/bjc.2011.1609
Laviv Y, Kasper BS, Kasper EM (2017) Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels, CSF clotting, and communicating hydrocephalus: a comprehensive review. Neurosurg Rev 7:017–0839
Lechowski S, Stypula J, Niespodzianski K, Domagala S (1992) Surgery of brain angioma (hemangioblastoma cerebelli) during the 31st week of pregnancy. Ginekol Pol 63:424–427
Lee JY, Dong SM, Park WS, Yoo NJ, Kim CS, Jang JJ, Chi JG, Zbar B, Lubensky IA, Linehan WM, Vortmeyer AO, Zhuang Z (1998) Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 58:504–508
Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683
Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, Blink AL, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2005) Urinary placental growth factor and risk of preeclampsia. JAMA 293:77–85
Lindau A (1931) Discussion on vascular tumours of the brain and spinal cord: Joint Discussion No. 1. Proc R Soc Med 24:363–388
List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bellamy W, Powis G (2004) Vascular endothelial growth factor receptor-1 and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid leukemia cells. Exp Hematol 32:526–535
Luttun A, Tjwa M, Carmeliet P (2002) Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. Ann N Y Acad Sci 979:80–93
Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840
Lyall F, Greer IA, Boswell F, Fleming R (1997) Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol 104:223–228
Mӧller H (1944) Ophthalmic symptoms and heredity in cerebellar angioreticuloma. Acta Psychiatr Neurol 19:275–292
Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 88:9267–9271
Matsumoto K, Suzuki K, Koike H, Okamura K, Tsuchiya K, Uchida T, Takezawa Y, Kobayashi M, Yamanaka H (2003) Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels. Anticancer Res 23:4953–4958
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658
Morii K, Tanaka R, Washiyama K, Kumanishi T, Kuwano R (1993) Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem Biophys Res Commun 194:749–755
Muramatsu M, Yamamoto S, Osawa T, Shibuya M (2010) Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res 70:8211–8221. https://doi.org/10.1158/0008-5472.CAN-8210-0202
Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109–119. https://doi.org/10.1007/s10456-10008-19099-z
Naidoo K, Bhigjee AI (1998) Multiple cerebellar haemangioblastomas symptomatic during pregnancy. Br J Neurosurg 12:281–284
Nathan L, Satin AJ, Twickler DM (1995) Cerebellar hemangioblastoma complicating pregnancy. A case report. J Reprod Med 40:662–664
Newell LF, Holtan SG (2017) Placental growth factor: what hematologists need to know. Blood Rev 31:57–62. https://doi.org/10.1016/j.blre.2016.1008.1004
Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H (1998) Placenta growth factor (PlGF) mRNA expression in brain tumors. J Neuro-Oncol 40:123–130
Odorisio T, Cianfarani F, Failla CM, Zambruno G (2006) The placenta growth factor in skin angiogenesis. J Dermatol Sci 41:11–19
Ogasawara KK, Ogasawara EM, Hirata G (1995) Pregnancy complicated by von Hippel-Lindau disease. Obstet Gynecol 85:829–831
Omar AI (2012) Bevacizumab for the treatment of surgically unresectable cervical cord hemangioblastoma: a case report. J Med Case Rep 6:1752–1947
Ortega-Martinez M, Cabezudo JM, Fernandez-Portales I, Pineda-Palomo M, Rodriguez-Sanchez JA, Bernal-Garcia LM (2007) Multiple filum terminale hemangioblastomas symptomatic during pregnancy. Case report. J Neurosurg Spine 7:254–258
Othmane IS, Shields C, Singh A, Shields J, Goldman W (1999) Postpartum cerebellar herniation in von Hippel-Lindau syndrome. Am J Ophthalmol 128:387–389
Palm M, Basu S, Larsson A, Wernroth L, Akerud H, Axelsson O (2011) A longitudinal study of plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), sFlt1: PlGF ratio and vascular endothelial growth factor (VEGF-A) in normal pregnancy. Acta Obstet Gynecol Scand 90:1244–1251. https://doi.org/10.1111/j.1600-0412.2011.01186.x
Palmer JJ (1972) Haemangioblastomas. A review of 81 cases. Acta Neurochir 27:125–148
Park DM, Zhuang Z, Chen L, Szerlip N, Maric I, Li J, Sohn T, Kim SH, Lubensky IA, Vortmeyer AO, Rodgers GP, Oldfield EH, Lonser RR (2007) von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med 4:e60
Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269:25646–25654
Pereda Rios A, Pintado Recarte P, De Leon-Luis J, Fernandez-Garcia P, Iza B, Salinero Paniagua E, Aguaron de la Cruz A, Ortiz Quintana L (2012) Cerebellar hemangioblastoma as the cause of maternal obstructive hydrocephalus during the third trimester. Eur J Obstet Gynecol Reprod Biol 165:370–372
Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, Kalra VK, Malik P (2003) Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 102:1506–1514
Persico MG, Vincenti V, DiPalma T (1999) Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr Top Microbiol Immunol 237:31–40
Pierscianek D, Wolf S, Keyvani K, El Hindy N, Stein KP, Sandalcioglu IE, Sure U, Mueller O, Zhu Y (2017) Study of angiogenic signaling pathways in hemangioblastoma. Neuropathology 37:3–11. https://doi.org/10.1111/neup.12316. Epub 12016 Jul 12317
Rafii S, Avecilla S, Shmelkov S, Shido K, Tejada R, Moore MA, Heissig B, Hattori K (2003) Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann N Y Acad Sci 996:49–60
Rehman T, Ali R, Yonas H (2009) Cerebellar haemangioblastoma: temporising treatment in a high risk pregnancy. BMJ Case Rep. https://doi.org/10.1136/bcr.01.2009.1413
Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674
Robinson RG (1966) Aspects of the natural history of cerebellar haemangioblastomas. Acta Neurol Scand 41:372–380
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44. https://doi.org/10.1016/j.ccr.2010.1011.1009. Epub 2011 Jan 1016
Romansky K, Arnaudova V, Nachev S (1992) Hemangioblastoma during pregnancy. Case report. Zentralbl Neurochir 53:37–39
Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karumanchi SA (2008) A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med 21:9–23. https://doi.org/10.1080/14767050701830480
Sabin FR (2002) Preliminary note on the differentiation of angioblasts and the method by which they produce blood-vessels, blood-plasma and red blood-cells as seen in the living chick. 1917. J Hematother Stem Cell Res 11:5–7
Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66:11432–11440
Satyarthee GD, Kumar S (2016) Cerebellar hemangioblastoma symptomatic during pregnancy: a short review. Am J Clin Neurol Neurosurg 2:25–28
Scarcella G, Allen MB Jr, Andy OJ (1961) Vascular lesions of the posterior fossa during pregnancy. Am J Obstet Gynecol 82:836–840
Schmidt T, Kharabi Masouleh B, Loges S, Cauwenberghs S, Fraisl P, Maes C, Jonckx B, De Keersmaecker K, Kleppe M, Tjwa M, Schenk T, Vinckier S, Fragoso R, De Mol M, Beel K, Dias S, Verfaillie C, Clark RE, Brummendorf TH, Vandenberghe P, Rafii S, Holyoake T, Hochhaus A, Cools J, Karin M, Carmeliet G, Dewerchin M, Carmeliet P (2011) Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia. Cancer Cell 19:740–753. https://doi.org/10.1016/j.ccr.2011.1005.1007
Schreurs MP, Houston EM, May V, Cipolla MJ (2012) The adaptation of the blood-brain barrier to vascular endothelial growth factor and placental growth factor during pregnancy. FASEB J 26:355–362. https://doi.org/10.1096/fj.1011-191916
Selvaraj SK, Giri RK, Perelman N, Johnson C, Malik P, Kalra VK (2003) Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood 102:1515–1524
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985
Shankar GM, Taylor-Weiner A, Lelic N, Jones RT, Kim JC, Francis JM, Abedalthagafi M, Borges LF, Coumans JV, Curry WT, Nahed BV, Shin JH, Paek SH, Park SH, Stewart C, Lawrence MS, Cibulskis K, Thorner AR, Van Hummelen P, Stemmer-Rachamimov AO, Batchelor TT, Carter SL, Hoang MP, Santagata S, Louis DN, Barker FG, Meyerson M, Getz G, Brastianos PK, Cahill DP (2014) Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun 2:014–0167
Sharkey AM, Cooper JC, Balmforth JR, McLaren J, Clark DE, Charnock-Jones DS, Morris NH, Smith SK (1996) Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Investig 26:1182–1185
Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076. https://doi.org/10.1016/j.cell.2013.1001.1036
Stein AA, Schilp AO, Whitfield RD (1960) The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–761
Takahashi A, Sasaki H, Kim SJ, Kakizoe T, Miyao N, Sugimura T, Terada M, Tsukamoto T (1999) Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. Biochem Biophys Res Commun 257:855–859
Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Terada M (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237
Tandon V, Hiwale S, Amle D, Nagaria T, Patra PK (2017) Assessment of serum vascular endothelial growth factor levels in pregnancy-induced hypertension patients. J Pregnancy 3179670:4
Tarallo V, Vesci L, Capasso O, Esposito MT, Riccioni T, Pastore L, Orlandi A, Pisano C, De Falco S (2010) A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization. Cancer Res 70:1804–1813. https://doi.org/10.1158/0008-5472.CAN-1809-2609
Terry AR, Merker VL, Barker FG 2nd, Leffert L, Bateman BT, Souter I, Plotkin SR (2015) Pregnancy complications in women with rare tumor suppressor syndromes affecting central and peripheral nervous system. Am J Obstet Gynecol 213:108–109. https://doi.org/10.1016/j.ajog.2015.1002.1013
Torry RJ, Rongish BJ (1992) Angiogenesis in the uterus: potential regulation and relation to tumor angiogenesis. Am J Reprod Immunol 27:171–179
Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, Loges S, Albrecht I, Jonckx B, Vinckier S, Van Steenkiste C, Tugues S, Rolny C, De Mol M, Dettori D, Hainaud P, Coenegrachts L, Contreres JO, Van Bergen T, Cuervo H, Xiao WH, Le Henaff C, Buysschaert I, Kharabi Masouleh B, Geerts A, Schomber T, Bonnin P, Lambert V, Haustraete J, Zacchigna S, Rakic JM, Jimenez W, Noel A, Giacca M, Colle I, Foidart JM, Tobelem G, Morales-Ruiz M, Vilar J, Maxwell P, Vinores SA, Carmeliet G, Dewerchin M, Claesson-Welsh L, Dupuy E, Van Vlierberghe H, Christofori G, Mazzone M, Detmar M, Collen D, Carmeliet P (2010) Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141:178–190. https://doi.org/10.1016/j.cell.2010.1002.1039
Vaquero J, Martinez R (1984) Progesterone receptor proteins in cerebellar hemangioblastoma. Surg Neurol 21:99
Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH (2004) Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol 55:721–728
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH (2003) The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 98:82–94
Weed S, Bastek JA, Anton L, Elovitz MA, Parry S, Srinivas SK (2012) Examining the correlation between placental and serum placenta growth factor in preeclampsia. Am J Obstet Gynecol 207:140.e141–140.e146. https://doi.org/10.1016/j.ajog.2012.1005.1003
Wei SC, Tsao PN, Yu SC, Shun CT, Tsai-Wu JJ, Wu CH, Su YN, Hsieh FJ, Wong JM (2005) Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 54:666–672
Wikstrom AK, Larsson A, Eriksson UJ, Nash P, Norden-Lindeberg S, Olovsson M (2007) Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol 109:1368–1374
Wizigmann-Voos S, Breier G, Risau W, Plate KH (1995) Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55:1358–1364
Wu Y, Hooper AT, Zhong Z, Witte L, Bohlen P, Rafii S, Hicklin DJ (2006) The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer 119:1519–1529
Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC (2008) Elevated levels of placental growth factor represent an adaptive host response in sepsis. J Exp Med 205:2623–2631. https://doi.org/10.1084/jem.20080398
Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V, Shibuya M, Ferrara N, Bais C (2011) Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci U S A 108:11590–11595. 10.11073/pnas.1109029108
Yao YG, Yang HS, Cao Z, Danielsson J, Duh EJ (2005) Upregulation of placental growth factor by vascular endothelial growth factor via a post-transcriptional mechanism. FEBS Lett 579:1227–1234
Ye DY, Bakhtian KD, Asthagiri AR, Lonser RR (2012) Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg 117:818–824
Yonekura H, Sakurai S, Liu X, Migita H, Wang H, Yamagishi S, Nomura M, Abedin MJ, Unoki H, Yamamoto Y, Yamamoto H (1999) Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis. J Biol Chem 274:35172–35178
Zhang L, Chen J, Ke Y, Mansel RE, Jiang WG (2005) Expression of Placenta growth factor (PlGF) in non-small cell lung cancer (NSCLC) and the clinical and prognostic significance. World J Surg Oncol 3:68
Zhou Y, Tu C, Zhao Y, Liu H, Zhang S (2016) Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease. Biochem Biophys Res Commun 470:967–974. https://doi.org/10.1016/j.bbrc.2016.1001.1073
Zhuang Z, Frerich JM, Huntoon K, Yang C, Merrill MJ, Abdullaev Z, Pack SD, Shively SB, Stamp G, Lonser RR (2014) Tumor derived vasculogenesis in von Hippel-Lindau disease-associated tumors. Sci Rep 4:4102
Ziche M, Maglione D, Ribatti D, Morbidelli L, Lago CT, Battisti M, Paoletti I, Barra A, Tucci M, Parise G, Vincenti V, Granger HJ, Viglietto G, Persico MG (1997) Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Lab Investig 76:517–531
Zilidis G, Cadoux-Hudson TA (2007) Recurrent dural based cystic cerebellar haemangioblastoma in a patient with von Hippel-Lindau disease. Acta Neurochir 149:433–436
Zygmunt M, Herr F, Munstedt K, Lang U, Liang OD (2003) Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 22:S10–S18
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Laviv, Y., Wang, J.L., Anderson, M.P. et al. Accelerated growth of hemangioblastoma in pregnancy: the role of proangiogenic factors and upregulation of hypoxia-inducible factor (HIF) in a non-oxygen-dependent pathway. Neurosurg Rev 42, 209–226 (2019). https://doi.org/10.1007/s10143-017-0910-4
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DOI: https://doi.org/10.1007/s10143-017-0910-4