Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis

Abstract

We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), 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 the 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 to suppress leptomeningeal metastasis in these preclinical models.

Novel mechanisms and functions of complement

“…C3aR signaling, for instance, is implicated in the dissemination of cancer to the nervous system by disrupting the blood-cerebrospinal fluid barrier 107 . Additionally, triggering of C3aR-, C5aR1- or MAC-mediated signaling activates PI3K-AKT pathways that culminate in cell proliferation 108,109 .…”

Complement in cancer: untangling an intricate relationship

“…Various models of tumorigenesis, including colon cancer, pancreatic cancer, squamous cell carcinoma, lung cancer and breast cancer models, support this contention by showing increased production of complement proteins in metastatic settings, followed by modulation of immune responses and establishment of an environment that suppresses effector T cells 23,58,89,90 . C3aR has been further implicated in the dissemination of cancer to the nervous system by disrupting the blood–cerebrospinal fluid (CSF) barrier and permitting the access of plasma components and other mitogens to the CSF 91 .…”

Leptomeningeal metastasis from systemic cancer: Review and update on management

“…Unfortunately, understanding of disease pathogenesis has not improved markedly since LM was initially described in the late 19th century . Recent studies have started to shed light on the pathogenesis, however, with 1 study demonstrating that cancer cells within the cerebrospinal fluid (CSF) upregulate the production of complement component 3 . This, in turn, leads to disruption of the BBB and entry of plasma growth factors into the CSF, promoting cancer cell growth.…”

“…2 Recent studies have started to shed light on the pathogenesis, however, with 1 study demonstrating that cancer cells within the cerebrospinal fluid (CSF) upregulate the production of complement component 3. 3 This, in turn, leads to disruption of the BBB and entry of plasma growth factors into the CSF, promoting cancer cell growth. Cancerous involvement of the leptomeninges is thought to occur by several mechanisms, including direct extension from brain parenchyma, dura, or bone; hematologic spread, particularly through venous plexi and/or perineural extension.…”