Cell. 2017 Mar 9;168(6):1101-1113.e13. doi: 10.1016/j.cell.2017.02.025.
Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis.
Boire A1, Zou Y2, Shieh J2, Macalinao DG2, Pentsova E3, Massagué J4.
Author information
1
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
j-massague@ski.mskcc.org.
Abstract
We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course. C3 expression in primary tumors was predictive of leptomeningeal relapse. Mechanistically, we found that cancer-cell-derived C3 activates the C3a receptor in the choroid plexus epithelium to disrupt the blood-CSF barrier. This effect allows plasma components, including amphiregulin, and other mitogens to enter the CSF and promote cancer cell growth. Pharmacologic interference with C3 signaling proved therapeutically beneficial in suppressing leptomeningeal metastasis in these preclinical models.
Copyright © 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
GDNF; PDGF; amphiregulin; brain metastasis; carcinomatous meningitis; cerebrospinal fluid breast cancer; choroid plexus; complement C3; leptomeningeal metastasis; lung cancer
PMID: 28283064 DOI: 10.1016/j.cell.2017.02.025