Leptomeningeal dissemination: a sinister pattern of medulloblastoma growth

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Leptomeningeal dissemination (LMD) is the defining pattern of metastasis for medulloblastoma. Although LMD is responsible for virtually 100% of medulloblastoma deaths, it remains the least well-understood part of medulloblastoma pathogenesis. The fact that medulloblastomas rarely metastasize outside the CNS but rather spread almost exclusively to the spinal and intracranial leptomeninges has fostered the long-held belief that medulloblastoma cells spread directly through the CSF, not the bloodstream. In this paper the authors discuss selected molecules for which experimental evidence explains how the effects of each molecule on cell physiology contribute mechanistically to LMD. A model of medulloblastoma LMD is described, analogous to the invasion–metastasis cascade of hematogenous metastasis of carcinomas. The LMD cascade is based on the molecular themes that 1) transcription factors launch cell programs that mediate cell motility and invasiveness and maintain tumor cells in a stem-like state; 2) disseminating medulloblastoma cells escape multiple death threats by subverting apoptosis; and 3) inflammatory chemokine signaling promotes LMD by creating an oncogenic microenvironment. The authors also review recent experimental evidence that challenges the belief that CSF spread is the sole mechanism of LMD and reveal an alternative scheme in which medulloblastoma cells can enter the bloodstream and subsequently home to the leptomeninges.

ABBREVIATIONS EMT = epithelial-to-mesenchymal transition; HGF = hepatocyte growth factor; LMD = leptomeningeal dissemination; MT1-MMP = membrane type-1 matrix metalloproteinase; PI3K = phosphatidylinositol-3 kinase; Tsp-1 = thrombospondin-1; VEGF = vascular endothelial growth factor.

Article Information

Correspondence Daniel W. Fults: University of Utah School of Medicine, Salt Lake City, UT. daniel.fults@hsc.utah.edu.

INCLUDE WHEN CITING Published online February 15, 2019; DOI: 10.3171/2018.11.PEDS18506.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

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    Radiographic staging of metastatic medulloblastoma. A: Sagittal T1-weighted MR image showing primary medulloblastoma (black arrow) in the cerebellum and dissemination of tumor to the third ventricle (white arrow). Spinal MRI was normal. Metastasis stage for this patient is M2 (intracranial LMD). B: Gadolinium-enhanced, axial T1-weighted MRI showing tumor dissemination (arrow) to the subarachnoid spaces of the cerebellum remote from the primary tumor mass. Spinal MRI was normal. Metastasis stage for this patient is M2 (intracranial LMD). C: Gadolinium-enhanced, T1-weighted sagittal MRI showing dissemination of tumor to the leptomeningeal surfaces of the spinal cord (white arrows) and spinal nerves of the cauda equina (black arrow). Metastasis stage for this patient is M3 (spinal LMD). D: 18F-FDG-PET showing dissemination of medulloblastoma to multiple bone marrow sites. Metastasis stage for this patient is M4 (extraneural metastasis).

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    The invasion–metastasis cascade, a paradigm for hematogenous metastasis. Clinically detectable metastases are the end result of a series of cellular events collectively known as the invasion–metastasis cascade. Carcinoma cells undergo the epithelial-to-mesenchymal transition (EMT) to become more motile and invasive. They invade the extracellular matrix at the site of tumor origin and then enter local blood vessels by intravasation. Once inside the lumina of blood vessels, cancer cells course through the bloodstream where, in this dispersed state, they are vulnerable to destructive forces such as anoikis, an apoptotic cell death program triggered when epithelial cells detach from a supporting matrix. Whether circulating cancer cells arrest at a distant organ by physical trapping in the capillary bed or actively home to a specific organ via molecular interactions is the subject of ongoing research. Arrested cells traverse blood vessels of the target organ by extravasation. Having escaped the bloodstream and entered the parenchyma of a distant organ, metastasizing cancer cells must first survive and then proliferate in a tissue microenvironment to which they are at first poorly adapted. This final step in the invasion–metastasis cascade, metastatic colonization, results in macroscopic, clinically detectable metastases.

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    The LMD cascade, a molecular and cellular model of CSF dissemination of medulloblastomas. The 3-stage process begins when medulloblastoma cells escape from the primary tumor mass in the cerebellum and enter the CSF (initiation). Subsequently, surviving tumor cells transit through the CSF (dispersal) and ultimately implant on leptomeningeal surfaces of the spinal cord to establish a proliferating metastatic nidus (colonization). The cell-biological traits required for disseminating cells to complete each stage are shown below the anatomical images. Genes that confer metastatic traits to medulloblastoma cells are assigned to each stage (green represents oncogenes, red represents tumor suppressor genes). Genes encoding the many proteins of the PI3K signaling pathway are not shown individually. Initiation, dispersal, and colonization are partitioned into discrete stages only to build a simplified conceptual framework. Individual LMD-driving molecules and the cellular traits they induce can influence multiple stages.

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    Chemokine signaling creates an oncogenic microenvironment. Ccl2 chemokine molecules (blue circles) on the luminal surface of endothelial cells stop the movement of circulating monocytes by binding monocyte surface receptor Ccr2. Arrested monocytes exit the bloodstream, penetrate the endothelium, and enter abluminal sites of inflammation, where they differentiate into activated macrophages. Inflammatory macrophages create an oncogenic tissue environment, by: 1) generating reactive oxygen molecules, which cause DNA damage; 2) secreting proteolytic enzymes, which promote migration of cancer cells through the extracellular matrix; and 3) producing angiogenesis-inducing VEGF. A wide variety of cell types, including endothelial cells and macrophages, express Ccl2. When produced by macrophages, Ccl2 moves by transcytosis to the luminal surface of endothelial cells.

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