Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention

Cancer Cell. 2019 Sep 16;36(3):250-267.e9. doi: 10.1016/j.ccell.2019.08.001.

Abstract

How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.

Keywords: CCL19; CNSL; CXCL12; DLBCL; PCNSL; SCNSL; gliosis; lymphoma; metastasis; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aging / pathology*
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / pathology
  • Cell Line, Tumor / transplantation
  • Central Nervous System Neoplasms / diagnostic imaging
  • Central Nervous System Neoplasms / pathology*
  • Central Nervous System Neoplasms / surgery
  • Chemokine CCL19 / genetics
  • Chemokine CCL19 / metabolism*
  • Chemokine CXCL12
  • Disease Models, Animal
  • Female
  • Gliosis / diagnostic imaging
  • Gliosis / pathology*
  • Humans
  • Intravital Microscopy
  • Lymphoma / diagnostic imaging
  • Lymphoma / pathology*
  • Lymphoma / surgery
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence, Multiphoton
  • Middle Aged
  • NF-kappa B / metabolism
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / metabolism
  • Time-Lapse Imaging
  • Young Adult

Substances

  • CCL19 protein, human
  • Ccl19 protein, mouse
  • Ccr7 protein, mouse
  • Chemokine CCL19
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • NF-kappa B
  • Receptors, CCR7