Lymphoma cells were more likely to take hold in gliotic central nervous systems (CNS) in mice.
Major Finding: Lymphoma cells were more likely to take hold in gliotic central nervous systems (CNS) in mice.
Mechanism: Astrocytic CCL19 appeared responsible for retention of lymphoma cells in the CNS in mice and humans.
Impact: Age-related gliosis may partially explain the increased incidence of CNS lymphomas with age.
Lymphomas may arise in or disseminate to the central nervous system (CNS), but how this occurs is unclear. O'Connor and colleagues developed a mouse model with high expression of lymphotoxins α and β (LTα and LTβ) in the CNS, resulting in chronic gliosis without severe damage to neurons or breakdown of the blood–brain barrier. This chronic gliosis conferred increased susceptibility to developing CNS lymphoma following intravenous injection of either of two types of neoplastic B cells. Although the expression of several leukocyte-specific cell-adhesion molecules (CAM) was upregulated in mice with CNS overexpression of LTα and LTβ, CAM upregulation alone was not sufficient to cause CNS lymphoma. Following injection of lymphoma cells, chronic gliosis was associated with an increase in parenchymal lymphoma cells. Though lymphoma cells also entered wild-type brain parenchyma, wild-type mice rarely developed CNS lymphoma. A possible explanation for this phenomenon is that lymphoma cells were more prone to being retained in the brain parenchyma in mice with chronic gliosis. Astrocyte-generated CCL19 and lymphoma cell–expressed CCR7 were required for the retention of lymphoma cells in the gliotic mouse brains, and evidence of this mechanism was also observed in biopsies from patients with primary and secondary CNS lymphoma. In concordance with the facts that gliosis increases with age and that the average age of onset for primary CNS lymphoma is 65 years, larger B220+ lesions developed in the brains of aged mice with gliosis than in younger mice following lymphoma-cell injection. Collectively, this work provides mechanistic insight into the relationship between aging-related gliosis and the development of CNS lymphoma and provides clues about possible risk factors for the disease.
O'Connor T, Zhou X, Kosla J, Adili A, Garcia Beccaria M, Kotsiliti E, et al. Age-related gliosis promotes central nervous system lymphoma through CCL19-mediated tumor cell retention. Cancer Cell 2019:36;250–67.E9.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.