Abstract
The leptomeninges, the cerebrospinal-fluid-filled tissues surrounding the central nervous system, play host to various pathologies including infection, neuroinflammation and malignancy. Spread of systemic cancer into this space, termed leptomeningeal metastasis, occurs in 5–10% of patients with solid tumours and portends a bleak clinical prognosis. Previous, predominantly descriptive, clinical studies have provided few insights. Recent development of preclinical leptomeningeal metastasis models, alongside genomic, transcriptomic and proteomic sequencing efforts, has provided groundwork for mechanistic understanding and identification of long-needed therapeutic targets. Although previously understood as an anatomically isolated compartment, the leptomeninges are increasingly appreciated as a major conduit of communication between the systemic circulation and the central nervous system. Despite the unique nature of the leptomeningeal microenvironment, the general principles of metastasis hold true: cells metastasizing to the leptomeninges must gain access to the new environment, survive within the space and evade the immune system. The study of leptomeningeal metastasis has the potential to uncover novel site-specific metastatic principles and illuminate the physiology of the leptomeningeal space. In this Review, we provide a biology-focused overview of how metastatic cells reach the leptomeninges, thrive in this nutritionally sparse environment and evade the detection of the omnipresent immune system.
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Acknowledgements
The authors gratefully acknowledge their patients who inspire this work, their mentors who have provided the tools to carry out this research and the philanthropic and governmental sources that enable experimental work in their laboratories. This work was supported in part by the NIH/NCI Cancer Center Support Grant NCI P30 CA008748.
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J.R. and A.B. are inventors on the provisional US patent applications 63/449,817 and 63/449,823 and international patent application PCT/US24/18343. A.B. holds an unpaid position on the scientific advisory board for Evren Scientific and is an inventor on the US patents 62/258,044, 10/413,522 and 63/052,139.
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Glossary
- Acute phase reactants
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A group of proteins that are markedly elevated in the plasma during acute and chronic inflammation.
- Arachnoid mater
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The upper layer of leptomeninges composed of a fibroblastoid network of cells connected to the pia mater by a series of fibrous strands.
- Brain’s four ventricles
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A system of interconnected cerebrospinal fluid-filled cavities within the brain.
- Bridging vessels
-
Veins that extend from the brain parenchyma to the subdural space.
- Cauda equina
-
Spinal nerve roots that extend beyond the terminus of the spinal cord, transmitting motor and sensory information to the bowel, bladder and lower limbs.
- Cerebrospinal fluid
-
(CSF). A colourless, paucicellular fluid that surrounds the brain and the spinal cord.
- Choroid plexuses
-
Specialized, cerebrospinal fluid-secreting structures within the ventricular system, composed of a blood vessel network, surrounded by a fibroblast and extracellular matrix-rich stroma and encircled by specialized polarized, secretory epithelial cells.
- Ependyma
-
A layer of polarized, secretory neuroepithelial cells, lining the cerebral ventricles and spinal central canal, capable of cerebrospinal fluid production.
- Ferroptosis
-
A molecularly distinct type of cell death classically resulting from interactions between iron and lipids to generate reactive oxygen species.
- Liquid biopsy
-
Analysis of the tumour-derived material in easily accessed body fluids, including blood, urine or cerebrospinal fluid.
- Paraneoplastic syndromes
-
A rare complication of cancer whereby the immune system attacks normal neural tissues causing neurological symptoms such as seizures, dementia, loss of coordination and sensory disturbances.
- Pia mater
-
A fibroblastoid monolayer of cells that make up the innermost layer of the leptomeninges.
- Posterior fossa
-
The lower portion of the cranial cavity that houses the cerebellum, pons and medulla oblongata.
- Subarachnoid space
-
Cerebrospinal fluid-filled compartment between the arachnoid and pial membranes, surrounding the brain and the spinal cord.
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Remsik, J., Boire, A. The path to leptomeningeal metastasis. Nat Rev Cancer 24, 448–460 (2024). https://doi.org/10.1038/s41568-024-00700-y
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DOI: https://doi.org/10.1038/s41568-024-00700-y