Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation

Abstract

The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch+/− mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche.DOI: http://dx.doi.org/10.7554/eLife.16764.001

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

“…Additionally, norrin signaling through β-catenin and endothelin-2 can protect photoreceptors from light damage (73). In the brain, norrin protects the blood-brain barrier integrity in a rat model of subarachnoid hemorrhage (74), and by activating FZD4 signaling, it can reduce the pre-neoplasic lesions of medulloblastoma (75).…”

Identification of regulators of germ stem cell enwrapment by its niche in C. elegans

“…Niche dysregulation is implicated in diseases, including leukemia (Wiseman, 2011; Zambetti et al, 2016), myelodysplastic syndrome (Hoggatt et al, 2016), Alzheimer’s disease (Hamilton et al, 2015), medulloblastoma (Bassett et al, 2016), and testicular germ cell tumors (Silván et al, 2013). Thus, understanding mechanisms that regulate stem cell-niche interactions is important for our basic understanding of tissue maintenance, growth, regeneration, and numerous human diseases.…”

Endothelial Cell–Specific Inactivation of TSPAN12 (Tetraspanin 12) Reveals Pathological Consequences of Barrier Defects in an Otherwise Intact Vasculature

“…The role of canonical signaling in pathological vascular growth has been studied in models of retinopathies. 17 – 19 In addition, NDP has also been studied in neuroprotection, 20 regulation of tumor stroma, 21 and regulation of neural progenitors. 22 However, little is known about the role of NDP/FZD4 signaling in the mature vasculature.…”