Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis

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, mitog...

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Bibliographic Details
Published in:Cell Vol. 168; no. 6; pp. 1101 - 1113.e13
Main Authors: Boire, Adrienne, Zou, Yilong, Shieh, Jason, Macalinao, Danilo G, Pentsova, Elena, Massagué, Joan
Format: Journal Article
Language:English
Published: United States 09.03.2017
Subjects:
Animals
Breast Neoplasms - pathology
Cerebrospinal Fluid
Choroid Plexus - blood supply
Complement C3 - genetics
Complement C3 - metabolism
Humans
Intercellular Signaling Peptides and Proteins - metabolism
Lung Neoplasms - pathology
Macrophage-1 Antigen - metabolism
Meningeal Neoplasms - secondary
Mice
Neoplasm Metastasis - pathology
Signal Transduction
Tumor Microenvironment
Up-Regulation
amphiregulin
lung cancer
leptomeningeal metastasis
GDNF
carcinomatous meningitis
PDGF
cerebrospinal fluid breast cancer
complement C3
brain metastasis
choroid plexus
ISSN:1097-4172
Online Access:Get more information
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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.
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ISSN:1097-4172
DOI:10.1016/j.cell.2017.02.025