Complement Component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis.
Open accessAbstract
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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Cancer cells are able to grow in the nutrient deficient CSF filled leptomeninges using several notable mechanisms, such as tumor cells secreting complement component 3 which disrupts the barrier functions of choroid plexus epithelial cells, allowing nutrients and macromolecules to enter the CSF.
“cancer cells are able to grow in the nutrient deficient CSF filled leptomeninges using several notable mechanisms”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Boire et al., 2017
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Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers
Klotz, R. V., Thomas, A., Teng, T., Han, S. M., Iriondo, O., Li, L., Restrepo-Vassalli, S., Wang, A., Izadian, N., MacKay, M. J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0384 · Cited by 137 · see citing works
“Previously, crucial information on mechanisms of brain metastasis was identified from triple-negative breast cancer cell lines (13, 32, 33).”
BackgroundLiving on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
Role of the complement system in the tumor microenvironment
Zhang, R., Liu, Q., Li, T., Liao, Q., & Zhao, Y. (2019) · Cancer Cell International · doi:10.1186/s12935-019-1027-3 · Cited by 127 · see citing works
Leptomeningeal Metastasis from Non–Small Cell Lung Cancer and Current Landscape of Treatments
Ozcan, G., Singh, M., & Vredenburgh, J. J. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-1585 · Cited by 127 · see citing works
Skull bone marrow channels as immune gateways to the central nervous system
Mazzitelli, J. A., Pulous, F. E., Smyth, L. C. D., Kaya, Z., Rustenhoven, J., Moskowitz, M. A., Kipnis, J., & Nahrendorf, M. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01487-1 · Cited by 116 · see citing works
“https://doi.org/10.1038/s41593-023-01487-1 using acute lymphoblastic leukemia, breast or lung cancer cells demonstrated that CSF contains chemoattractants that promote malignant cell migration 21,49 .”
MethodInfluentialBrain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines
Valiente, M., Swearingen, A. E. D. V., Anders, C. K., Bairoch, A., Boire, A. A., Bos, P. D., Cittelly, D. M., Erez, N., Ferraro, G. B., Fukumura, D., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0291 · Cited by 123 · see citing works
“LeptoM cell lines do not generate parenchymal metastases upon IC injection, and, in fact, differ from them transcriptomically (100).”
BackgroundReactive Astrocytes in Brain Metastasis
Wasilewski, D., Priego, N., Torre, C. F., & Valiente, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00298 · Cited by 121 · see citing works
“We will focus on metastatic cells invading the brain parenchyma in contrast to the less frequent invasion of the leptomeninges by cancer cells, which has a very different biology derived from its location (meningeal space filled with cerebrospinal fluid) and cellular components of the microenvironment (2).”
BackgroundMetformin Abrogates Age-Associated Ovarian Fibrosis
McCloskey, C. W., Cook, D. P., Kelly, B. S., Azzi, F., Allen, C. H., Forsyth, A., Upham, J., Rayner, K. J., Gray, D. A., Boyd, R. W., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0603 · Cited by 113 · see citing works
Macrophages on the margin: choroid plexus immune responses
Cui, J., Xu, H., & Lehtinen, M. K. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.07.002 · Cited by 110 · see citing works
Ajona, D., Zandueta, C., Corrales, L. P., Moreno, H., Pajares, M. J., Ortiz‐Espinosa, S., Martínez‐Terroba, E., Perurena, N., de Miguel, F. J., Lewintre, E. J., et al. (2018) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201703-0660oc · Cited by 108 · see citing works
“A recent report shows that other complement components critically contribute to metastasis to the brain (48).”
BackgroundZha, H., Wang, X., Zhu, Y. J., Chen, D., Han, X., Yang, F., Gao, J., Hu, C., Shu, C., Feng, Y., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0272 · Cited by 112 · see citing works
“Our result was consistent with reports (18, 24) that exogenous C3a does not promote the proliferation of LLC tumor cells, at least not in an anchorage-dependent manner.”
BackgroundResultInfluentialNew concepts on the therapeutic control of complement anaphylatoxin receptors
Hawksworth, O. A., Li, X. X., Coulthard, L. G., Wolvetang, E. J., & Woodruff, T. M. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.05.015 · Cited by 92 · see citing works
“Additionally, inhibition of C3a-C3aR signaling has been shown to maintain the blood-CSF barrier, preventing metastatic spread to the leptomeningeal space (Boire et al., 2017).”
BackgroundDrug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?
Kabraji, S. K., Ni, J., Lin, N., Xie, S., Winer, E. P., & Zhao, J. J. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3351 · Cited by 90 · see citing works
“A recent study using a brain-tropic breast cancer cell line, MDA-MB-231 (with corroborating data from patients with leptomeningeal metastases), found that cancer-cell expression of complement component 3a disrupts the blood–CSF barrier, facilitating the survival of breast cancer cells as leptomeningeal metastases (31).”
Oliva, I. C. G., Ferguson, S. D., Bassett, R. L., Foster, A. P., John, I., Hennegan, T. D., Rohlfs, M. L., Richard, J., Iqbal, M., Dett, T., et al. (2023) · Nature Medicine · doi:10.1038/s41591-022-02170-x · Cited by 90 · see citing works
“Percutaneous IT injection was performed with a 30-gauge Hamilton needle 27 .”
MethodLeptomeningeal metastasis from solid tumors
Thakkar, J. P., Kumthekar, P., Dixit, K., Stupp, R., & Lukas, R. V. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116706 · Cited by 87 · see citing works
Wilcox, J. A., Chukwueke, U. N., Ahn, M., Aizer, A. A., Bale, T., Brandsma, D., Brastianos, P. K., Chang, S., Daras, M., Forsyth, P. A., et al. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae103 · Cited by 90 · see citing works
“The leptomeninges, consisting of the pia and inner arachnoid, surround the CNS and contain circulating CSF. 14 Upon entry, leptomeningeal cancer cells freely circulate throughout the neuraxis driven by pulsatile CSF flow, where they exist either as adherent plaques to the surface of the brain,…”
BackgroundMethodInfluentialRiihilä, P., Viiklepp, K., Nissinen, L. M., Farshchian, M., Kallajoki, M. A., Kivisaari, A., Meri, S., Peltonen, J. T. K., Peltonen, S. A., & Kähäri, V. (2019) · British Journal of Dermatology · doi:10.1111/bjd.18095 · Cited by 87 · see citing works
Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis
Whiteley, A. E., Ma, D., Wang, L., Yu, S., Yin, C., Price, T. T., Simon, B. G., Xu, K. R., Marsh, K. A., Brockman, M. L., et al. (2024) · Science · doi:10.1126/science.adh5548 · Cited by 88 · see citing works
“Elegantexperimentshaveshownthat breast cancer cells (BCCs) can colonize the LM by compromising the blood-CSF barrier of the choroid plexus ( 8 ) — a CSF-producing secretory epithelium within the ventricles of the brain.”
BackgroundComplement activation contributes to perioperative neurocognitive disorders in mice
Xiong, C., Liu, J., Lin, D., Zhang, J., Terrando, N., & Wu, A. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1292-4 · Cited by 81 · see citing works
“C3/C3aR activation can induce impairments in bloodcerebrospinal fluid barrier (BCSFB) in the choroid plexus, which has been implicated in cognitive decline [21, 29].”
BackgroundLeptomeningeal metastases in glioma
Andersen, B. M., Miranda, C., Hatzoglou, V., DeAngelis, L. M., & Miller, A. M. (2019) · Neurology · doi:10.1212/wnl.0000000000007529 · Cited by 77 · see citing works
Magrini, E. I., Marco, S. D., Mapelli, S. N., Perucchini, C., Pasqualini, F., Donato, A., Lopez, M. D. L. L. G., Carriero, R., Ponzetta, A., Colombo, P., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00173-0 · Cited by 73 · see citing works
Shu, C., Zha, H., Long, H., Wang, X., Yang, F., Gao, J., Hu, C., Zhou, L. Q., Guo, B., & Zhu, B. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1515-2 · Cited by 74 · see citing works
Tyagi, A., Wu, S.-Y., Sharma, S., Wu, K., Zhao, D., Deshpande, R. P., Singh, R. N., Li, W., Topaloĝlu, Ü., Ruiz, J., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02322-w · Cited by 73 · see citing works
“0) [24] to estimate the immune cell infiltration based on gene expression in the previously published dataset (GSE83132, GSE115699) [25, 26] and found that both brain metastatic patients A.”
BackgroundInfluentialRetractedMetastasis as a systemic disease: molecular insights and clinical implications
Alečković, M., McAllister, S. S., & Polyák, K. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.06.002 · Cited by 73 · see citing works
Ruan, H., Zhou, Y., Shen, J., Zhai, Y., Xu, Y., Pi, L., Huang, R., Chen, K., Li, X., Ma, W., et al. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.246 · Cited by 70 · see citing works
“enter the CSF and promote cancer cell growth (27).”
BackgroundFlura-seq identifies organ-specific metabolic adaptations during early metastatic colonization
Basnet, H., Tian, L. H., Ganesh, K., Huang, Y.-H., Macalinao, D. G., Brogi, E., Finley, L. W. S., & Massagué, J. (2019) · eLife · doi:10.7554/elife.43627 · Cited by 68 · see citing works
“In recent years, analysis of these signatures in cells derived from human tumors and xenografts has uncovered numerous factors whose expression mediates organ-specific metastasis in animal models and is associated with organspecific metastasis in patients (Ell and Kang, 2013; Kang et al., 2003; Minn et al., 2005; Bos…”
BackgroundTargeting complement-mediated immunoregulation for cancer immunotherapy
Kolev, M. V., & Markiewski, M. M. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.02.003 · Cited by 70 · see citing works
“Boire and colleagues showed that leptomeningeal metastases synthesize and secrete C3 [86].”
BackgroundInfluentialNevel, K. S., DiStefano, N. M., Lin, X., Skakodub, A., Ogilvie, S. Q., Reiner, A. S., Pentsova, E. I., & Boire, A. A. (2019) · Neuro-Oncology · doi:10.1093/neuonc/noz208 · Cited by 63 · see citing works
Mao, X., Zhou, L., Tey, S. K., Ma, A. P. Y., Yeung, C. L. S., Ng, T. H., Wong, S. W. K., Liu, B. H. M., Fung, Y. M. E., Patz, E. F., et al. (2020) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12031 · Cited by 63 · see citing works
“Leptomeningeal metastatic cells secrete complement C3 which has been proven to promote cancer growth in cerebrospinal fluid (Boire et al., 2017).”
BackgroundThe microenvironment of brain metastases from solid tumors
Srinivasan, E. S., Deshpande, K., Neman, J., Winkler, F., & Khasraw, M. (2021) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdab121 · Cited by 60 · see citing works
Smalley, I., Law, V., Wyatt, C. J., Evernden, B. R., Fang, B., Koomen, J. M., Welsh, E. A., Macaulay, R. J. B., Forsyth, P. A., & Smalley, K. S. M. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2840 · Cited by 55 · see citing works
“…work in breast and lung cancer models of leptomeningeal metastasis has suggested that high C3 levels may contribute to LMM progression by disrupting the blood-choroid plexus barrier, allowing growth factors such as amphiregulin to leak into the CSF space leading to increased tumor growth (29).”
Glitza, I. C., Smalley, K. S. M., Brastianos, P. K., Davies, M. A., McCutcheon, I. E., Liu, J. K., Ahmed, K. A., Arrington, J. A., Evernden, B. R., Smalley, I., et al. (2020) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12861 · Cited by 55 · see citing works
“Modern, highly granular analytic approaches to CSF, or “liquid biopsies,” have the potential to greatly improve diagnostic sensitivity of LMD, guide treatment decisions, and drive discovery (Boire et al., 2019, 2017; Lin et al., 2017; Miller et al., 2019).”
BackgroundThe path to leptomeningeal metastasis
Remšík, J., & Boire, A. A. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00700-y · Cited by 58 · see citing works
“Observation of this phenomenon in a xenograft breast cancer mouse model further supports this 11 .”
InfluentialLorusso, G., Wyss, C. B., Kuonen, F., Vannini, N., Billottet, C., Duffey, N., Pineau, R., Lan, Q., Wirapati, P., Barras, D., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.aax8933 · Cited by 53 · see citing works
A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis
Hoj, J. P., Mayro, B., & Pendergast, A. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.018 · Cited by 54 · see citing works
Complement System: An Immunotherapy Target in Colorectal Cancer
Talaat, I. M., Elemam, N. M., & Saber-Ayad, M. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.810993 · Cited by 52 · see citing works
Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity
Chen, X., Momin, A., Wanggou, S., Wang, X., Min, H.-K., Dou, W., Gong, Z., Chan, J., Dong, W., Fan, J. J., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.007 · Cited by 53 · see citing works
The complement system in neurodegenerative and inflammatory diseases of the central nervous system
Negro‐Demontel, M. L., Maleki, A. F., Reich, D. S., & Kemper, C. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1396520 · Cited by 52 · see citing works
The molecular biology of medulloblastoma metastasis
Ommeren, R. V., Garzia, L., Holgado, B., Ramaswamy, V., & Taylor, M. D. (2019) · Brain Pathology · doi:10.1111/bpa.12811 · Cited by 52 · see citing works
Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity
Strickland, M. R., Alvarez-Breckenridge, C. A., Gainor, J. F., & Brastianos, P. K. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0976 · Cited by 51 · see citing works
Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment
Wang, Y., Yang, X., Li, N., & Xue, J. (2022) · Lung Cancer · doi:10.1016/j.lungcan.2022.09.013 · Cited by 51 · see citing works
Choroid plexus mast cells drive tumor-associated hydrocephalus
Li, Y., Di, C., Song, S., Zhang, Y., Lu, Y., Liao, J., Lei, B., Zhong, J., Guo, K., Zhang, N., et al. (2023) · Cell · doi:10.1016/j.cell.2023.11.001 · Cited by 53 · see citing works
Mechanisms of Organ-Specific Metastasis of Breast CancerPreprint
Nolan, E., Kang, Y., & Malanchi, I. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041326 · Cited by 51 · see citing works
Díaz, M., Singh, P., Kotchetkov, I. S., Skakodub, A., Meng, A., Tamer, C., Young, R. J., Reiner, A. S., Panageas, K. S., Ramanathan, L. V., et al. (2022) · Journal of Neuro-Oncology · doi:10.1007/s11060-022-03949-1 · Cited by 48 · see citing works
Leptomeningeal metastatic cells adopt two phenotypic states
Remšík, J., Chi, Y., Tong, X., Sener, U. T., Derderian, C., Park, A., Saadeh, F. S., Bale, T., & Boire, A. A. (2020) · Cancer Reports · doi:10.1002/cnr2.1236 · Cited by 48 · see citing works
“To functionally dissect these two distinct cancer cell subtypes, we took advantage of unique leptomeningeal (LeptoM) derivatives of human lung and breast cancer cell lines.(7) When injected intracisternally, PC9 LeptoM cells fully colonize the cranial cavity of immunodeficient mice within 4 weeks (Figure 2A).”
BackgroundMethodInfluentialLeptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches
Pellerino, A., Brastianos, P. K., Rudà, R., & Soffietti, R. (2021) · Cancers · doi:10.3390/cancers13122888 · Cited by 48 · see citing works
“When C3aR signaling is blocked using a specific antagonist, LM development is suppressed [39].”
BackgroundBreast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)
Elkholi, I. E., Lalonde, A., Park, M., & Côté, J. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1902 · Cited by 46 · see citing works
“Cells capable of growing in growth factor–free CSF are predicated to modulate this microenvironment to their benefit, as supported by two reports (110, 164).”
BackgroundResultGu, J., Hoj, J. P., Rouse, C., & Pendergast, A. M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0241423 · Cited by 46 · see citing works
Emerging Immunotherapies in the Treatment of Brain Metastases
Nieblas‐Bedolla, E., Nayyar, N., Singh, M., Sullivan, R. J., & Brastianos, P. K. (2020) · The Oncologist · doi:10.1002/onco.13575 · Cited by 46 · see citing works
“Besides evasion, components of the immune system may actively assist tumor growth and metastasis, such as in the disruption of the blood-CSF barrier [109].”
BackgroundComplement in Neurologic Disease
Propson, N. E., Gedam, M., & Zheng, H. (2020) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-031620-113409 · Cited by 43 · see citing works
Complement System in Cutaneous Squamous Cell Carcinoma
Riihilä, P., Nissinen, L. M., Knuutila, J. S., Nezhad, P. R., Viiklepp, K., & Kähäri, V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143550 · Cited by 44 · see citing works
The impact of inflammation and acute phase activation in cancer cachexia
Robinson, T. P., Hamidi, T., Counts, B. R., D, D. C. G., Ostrowski, M. C., Zimmers, T. A., & Koniaris, L. G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1207746 · Cited by 42 · see citing works
Complement in Metastasis: A Comp in the Camp
Ajona, D., Ortiz‐Espinosa, S., Pı́o, R., & Lecanda, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00669 · Cited by 42 · see citing works
“However, C3 did not mediate cancer cell entry into the cerebrospinal fluid but other determinants were required for full tumor cell colonization (109).”
BackgroundRosberg, R., Smoląg, K. I., Sjölund, J., Johansson, E., Bergelin, C., Wahldén, J., Pantazopoulou, V., Ceberg, C. P., Pietras, K., Blom, A. M., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.179854 · Cited by 41 · see citing works
Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade
Fu, M., Zhao, J., Zhang, L., Sheng, Z., Li, X., Qiu, F., Feng, Y., You, M., Xu, H., Zhang, J., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.09.012 · Cited by 41 · see citing works
Targeting Complement C3a Receptor to Improve Outcome After Ischemic Brain Injury
Pekna, M., Stokowska, A., & Pekny, M. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03419-6 · Cited by 41 · see citing works
Ruan, H., Wang, Z., Sun, Z., Wei, J., Zhang, L., Ju, H., Wang, T., Zhang, C., Guan, M., & Pan, S. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.885 · Cited by 39 · see citing works
Leptomeningeal Metastases: New Opportunities in the Modern Era
Wilcox, J. A., Li, M., & Boire, A. A. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01261-4 · Cited by 38 · see citing works
Breast leptomeningeal disease: a review of current practices and updates on management
Figura, N. B., Rizk, V. T., Armaghani, A. J., Arrington, J. A., Etame, A. B., Han, H. S., Czerniecki, B. J., Forsyth, P. A., & Ahmed, K. A. (2019) · Breast Cancer Research and Treatment · doi:10.1007/s10549-019-05317-6 · Cited by 38 · see citing works
Zhang, Y., Wang, X., Gu, Y., Liu, T., Zhao, X., Cheng, S., Duan, L., Huang, C., Wu, S., & Gao, S. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2420005122 · Cited by 37 · see citing works
“Recent studies highlighted the role of C3a–C3aR axis in disrupting epithelia tight junctions ( 15 ), activating of cancer - associated fibroblasts ( 16 ) and recruiting of neutrophils or PMN - MDSCs ( 17 , 18 ) during metastatic progression or relapse.”
Interferon-γ orchestrates leptomeningeal anti-tumour response
Remšík, J., Tong, X., Kunes, R., Li, M., Estrera, R., Snyder, J., Thomson, C., Osman, A. M., Chabot, K., Sener, U. T., et al. (2025) · Nature · doi:10.1038/s41586-025-09012-z · Cited by 40 · see citing works
The anatomic basis of leptomeningeal metastasis
Freret, M. E., & Boire, A. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20212121 · Cited by 38 · see citing works
“In these models, cancer cells reproducibly colonize the choroid plexuses a few days before they are detectable within the CSF (Boire et al., 2017).”
BackgroundInfluentialBhambhvani, H. P., Rodrigues, A. J., Umeh-Garcia, M. C., & Gephart, M. H. (2020) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2020.06.010 · Cited by 35 · see citing works
Transitional dynamics of cancer stem cells in invasion and metastasis
Richard, V., Kumar, T. R. S., & Pillai, R. M. (2020) · Translational Oncology · doi:10.1016/j.tranon.2020.100909 · Cited by 34 · see citing works
Leptomeningeal metastatic disease: new frontiers and future directions
Ozair, A., Wilding, H. E., Bhanja, D., Mikolajewicz, N., Glantz, M., Grossman, S. A., Sahgal, A., Rhun, É. L., Weller, M., Weiß, T., et al. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00970-3 · Cited by 35 · see citing works
“An elevated but probably misdirected inflammatory response has been described in CSF in preclinical models of LMD that is distinct from the immune exclusion seen in brain metastases 24,34 .”
Complementing Cancer Metastasis
Kochanek, D. M., Ghouse, S. M., Karbowniczek, M., & Markiewski, M. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01629 · Cited by 34 · see citing works
“Boire and colleagues recently demonstrated that C3 produced and secreted from tumor cells has prosurvival functions and facilitates leptomeningeal metastasis (95).”
BackgroundHeming, M., Börsch, A., Wiendl, H., & zu Hörste, G. M. (2022) · Genome Medicine · doi:10.1186/s13073-022-01097-9 · Cited by 33 · see citing works
Diagnostic and Therapeutic Updates in Leptomeningeal Disease
Roy-O’Reilly, M. A., Lanman, T. A., Ruiz, A. N., Rogawski, D. S., Stocksdale, B. R., & Nagpal, S. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01432-2 · Cited by 35 · see citing works
Breaking boundaries: role of the brain barriers in metastatic process
Izadi, N., Solar, P., Hašanová, K., Zamani, A., Akbar, M. B., Mrázová, K., Bartošík, M., Kazda, T., Hrstka, R., & Joukal, M. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00618-z · Cited by 36 · see citing works
“Alterations in the B-CSF barrier induced by C3a potentiate the entry of the EGFR ligand amphiregulin into the CSF, thus promoting the growth of leptomeningeal metastases [289].”
Wyss, C. B., Duffey, N., Peyvandi, S., Barras, D., Martínez-Usatorre, A., Coquoz, O., Romero, P. J., Delorenzi, M., Lorusso, G., & Rüegg, C. (2021) · Cancer Research · doi:10.1158/0008-5472.can-19-3560 · Cited by 33 · see citing works
“It has been reported that metastatic cells disseminating to the brain express PDGFs (7, 49).”
BackgroundAn overview of leptomeningeal disease
Nguyen, T. K., Nguyen, E. K., & Soliman, H. (2020) · Annals of Palliative Medicine · doi:10.21037/apm-20-973 · Cited by 32 · see citing works
“Previously, the mechanisms by which tumor cells penetrate the blood-brain and blood-CSF barrier were poorly understood; however, recent evidence suggests that cancer cells invading the CSF have upregulated production of complement component 3 (C3), which can affect the permeability of the epithelial barriers similar t…”
BackgroundDankner, M., Lam, S., Degenhard, T., Garzia, L., Guiot, M., Petrecca, K., & Siegel, P. M. (2021) · Cancers · doi:10.3390/cancers13040732 · Cited by 32 · see citing works
“Recent studies have clarified that LM is indeed a distinct biological entity from parenchymal brain metastases, indicating that significant pre-clinical and clinical research efforts must be undertaken to better understand and treat LM [13].”
BackgroundInfluentialLipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC
Li, Y.-S., Lai, W., Yin, K., Zheng, M.-M., Tu, H., Guo, W., Li, L., Lin, S., Wang, Z., Zeng, L., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114613 · Cited by 33 · see citing works
The complement system in clinical oncology: Applications, limitations and challenges
Ajona, D., Cragg, M. S., & Pı́o, R. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2024.101921 · Cited by 31 · see citing works
Liu, L., Zhang, X., Chai, Y., Zhang, J., Deng, Q., & Chen, X. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07336-2 · Cited by 32 · see citing works
“In vitro experiments on acute lymphoblastic leukemia, breast cancer, or lung cancer cells revealed that chemoattractants, which can promote the migration of malignant cells, were present in CSF [26, 149].”
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Liquid biopsy for brain metastases and leptomeningeal disease in patients with breast cancer
Morganti, S., Parsons, H. A., Lin, N., & Grinshpun, A. (2023) · npj Breast Cancer · doi:10.1038/s41523-023-00550-1 · Cited by 30 · see citing works
- Authors
- Boire, A., Zou, Y., Shieh, J., Macalinao, D. G., Pentsova, E., & Massagué, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Massagué, Joan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 168
- Issue
- 6
- Pages
- 1101-1113.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5405733
- OpenAlex
- W2591646072
- Cited by
- 366
- References
- 65
- Citations by year
- 2026: 38 · 2025: 50 · 2024: 45 · 2023: 52 · 2022: 41 · 2021: 39 · 2020: 38 · 2019: 36 · 2018: 17 · 2017: 10
- FWCI
- 22.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 373 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P01-CA129243, U54-163167, P30 CA008748)
- DOD (W81XWH-12-0074)
- Alan and Sandra Gerry Metastasis Research Initiative
- MSKCC Clinical Scholars Training Program
- Solomon R. and Rebecca D. Baker Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- complement C3, leptomeningeal metastasis, cerebrospinal fluid, choroid plexus epithelium, C3a receptor, blood-CSF barrier, amphiregulin, lung cancer, breast cancer, complement activation, tumor microenvironment
- MeSH terms
- Animals, Breast Neoplasms, Cerebrospinal Fluid, Choroid Plexus, Complement C3, Humans, Lung Neoplasms, Meningeal Neoplasms, Neoplasm Metastasis, Signal Transduction, Up-Regulation, Macrophage-1 Antigen, Intercellular Signaling Peptides and Proteins, Mice, Tumor Microenvironment
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