Cell
Volume 168, Issue 6, 9 March 2017, Pages 1101-1113.e13
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Article
Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis

https://doi.org/10.1016/j.cell.2017.02.025Get rights and content
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Highlights

  • Leptomeningeal metastatic cells upregulate complement component 3

  • Cancer cells from patients’ cerebrospinal fluid (CSF) produced C3

  • C3a receptor activation allows entry of plasma growth factors into CSF

  • Interruption of C3a receptor signaling blocks leptomeningeal metastasis in mice

Summary

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.

Keywords

leptomeningeal metastasis
carcinomatous meningitis
brain metastasis
complement C3
cerebrospinal fluid breast cancer
lung cancer
choroid plexus
amphiregulin
PDGF
GDNF

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