Complement Component 3 Promotes Leptomeningeal Metastasis

Leptomeningeal metastasis is the spread of cancer metastases to the leptomeninges, the two innermost layers of tissue covering the brain and spinal cord that contain cerebrospinal fluid (CSF), which results in the rapid dissemination of cancer cells in the CNS and, if not diagnosed early, results in irreversible neurologic deficits and death. However, current therapeutic strategies for the treatment of patients with leptomeningeal metastasis, which have focused on the combination of intrathecal chemotherapy and radiation therapy, have not significantly improved patient outcome. To elucidate the mechanisms that promote the growth of leptomeningeal metastases in the CSF, Boire and colleagues generated matched brain parenchyma–specific and leptomeningeal-specific metastatic derivative clones from metastatic breast and lung cancer cell lines. Each leptomeningeal-specific metastatic cell line was demonstrated to be phenotypically and transcriptionally distinct from its matching brain parenchyma–specific metastatic cell line, and expression profiling showed that complement component 3 (C3) was upregulated in leptomeningeal-specific metastatic cells. Similarly, C3 levels were elevated in the CSF of patients with leptomeningeal metastasis and in the primary lung or breast tumors of patients who developed leptomeningeal metastasis. Ablation of cancer cell–derived C3, but not host C3, decreased leptomeningeal metastatic cell growth in vivo; similarly, only CSF from patients with leptomeningeal metastasis promoted leptomeningeal metastatic cell growth in vitro. Choroid plexus epithelial cells, which form the blood–CSF barrier and control transport from blood into CSF, expressed the C3 receptor C3aR, and C3 diminished tight junction integrity of choroid plexus epithelial cells in vitro and in vivo. Further, C3-mediated disruption of the blood–CSF barrier resulted in the increase of growth-promoting mitogens, such as amphiregulin, in the CSF, and inhibition of C3aR resulted in decreased leptomeningeal metastasis and improved survival. These results describe the complement-dependent mechanism by which disseminated tumor cells promote the growth of leptomeningeal metastasis and suggest a potential therapeutic strategy for patients with leptomeningeal metastasis.

Boire A, Zou Y, Shieh J, Macalinao DG, Pentsova E, and Massagué J. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 2017;168:1101–13.