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Accelerated growth of hemangioblastoma in pregnancy: the role of proangiogenic factors and upregulation of hypoxia-inducible factor (HIF) in a non-oxygen-dependent pathway

  • Yosef Laviv
  • Joshua L. Wang
  • Matthew P. Anderson
  • Ekkehard M. Kasper
Review

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.

Keywords

Hemangioblastoma Pregnancy Angiogenesis Vascular permeability Placental growth factor 

Notes

Funding information

This work was not funded or financially supported.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Beth Israel Deaconess Medical Center and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Division of Surgery, Department of Neurosurgery, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

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