Abstract
Meningeal metastasis is a fatal complication of breast cancer which affects 8–15% of patients who experience severe neurological complications of cranial nerves, cerebrum, and spinal cord. Survival once diagnosed is less than 4 months. Currently there is no cure. Aggressive multimodal radiation, intra-CSF, or systemic chemotherapy is palliative. Investigation of urgently needed new treatment modalities is hindered by the lack of suitable animal models to effectively study tumor growth kinetics. We present a model of meningeal metastases where tumor growth and associated neurological symptoms have been characterized over 3 weeks by sequential molecular imaging, tumor growth kinetics, and histopathology. Meningeal metastases were induced by stereotaxic injection of human breast cancer cells (MDA-MB-231-Rluc) into the lateral ventricle. Tumor identified by Gd-MRI and Rluc-bioluminescence depict growth in 3 phases, namely lag, exponential, and plateau phase. Invasive tumor growth was highlighted by changes in contrast distribution in the meninges, ventricle and brain compartments over time where moderate contrast uptake in the early growth phase gave rise to a heavy tumor burden in the base of the brain in the latter phases. Tumor growth was accompanied with debilitating neurological symptoms and change in body mass. Tumor was confirmed by ex vivo histology. The reliability of the model to study novel therapeutics was confirmed by oncolytic virus delivered into the lateral ventricle showed potential for treatment. This effective and reliable model resembles human disease progression and is ideally suited to investigate novel treatments.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
19 February 2024
Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.
References
Alnajar H, Rosen L, Javidiparsijani S, Al-Ghamdi Y, Gattuso P Prognostic Markers and Histologic Subtypes in Patients with Meningeal Carcinomatosis in Breast Cancer. Acta Cytol. 2017;61:140–144.
Gauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, et al. Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol. 2010;21:2183–7.
Oechsle K, Lange-Brock V, Kruell A, Bokemeyer C, de Wit M. Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis. J Cancer Res Clin Oncol. 2010;136:1729–35.
Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H. Management of leptomeningeal metastases: Prognostic factors and associated outcomes. J Clin Neurosci. 2016;27:130–7.
Chamberlain MC. Neoplastic meningitis. Handb Clin Neurol. 2012;105:757–66.
Groves MD. Leptomeningeal disease. Neurosurg Clin N Am. 2011;22:67–78.
Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin. 2003;21:25–66.
Kokkoris CP. Leptomeningeal carcinomatosis. How does Cancer Reach pia-arachnoid?. Cancer. 1983;51:154–60.
Lamovec J, Zidar A. Association of leptomeningeal carcinomatosis in carcinoma of the breast with infiltrating lobular carcinoma. Autops Study Arch Pathol Lab Med. 1991;115:507–10.
Lee SS, Ahn JH, Kim MK, Sym SJ, Gong G, Ahn SD, et al. Brain metastases in breast cancer: prognostic factors and management. Breast Cancer Res Treat. 2008;111:523–30.
Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013;4:S265–88.
Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010;74:1449–54.
Le Rhun E, Galanis E. Leptomeningeal metastases of solid cancer. Curr Opin Neurol. 2016;29:797–805.
Watanabe M, Tanaka R, Takeda N. Correlation of MRI and clinical features in meningeal carcinomatosis. Neuroradiology. 1993;35:512–5.
Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics. 2007;27:525–51.
Chamberlain MC, Sandy AD, Press GA. Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology. 1990;40:435–8.
Sze G, Soletsky S, Bronen R, Krol G. MR imaging of the cranial meninges with emphasis on contrast enhancement & meningeal carcinomatosis. AJNR Am J Neuroradiol. 1989;10:965–75.
Van Horn A, Chamberlain MC. Neoplastic meningitis. J Support Oncol. 2012;10:45–53.
Chamberlain MC, Glantz M, Groves MD, Wilson WH. Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol. 2009;36:S35–45.
Brandsma D, Taphoorn MJ, Reijneveld JC, Nas TM, Voest EE, Nicolay K, et al. MR imaging of mouse leptomeningeal metastases. J Neurooncol. 2004;68:123–30.
Reijneveld JC, Taphoorn MJ, Voest EE. A simple mouse model for leptomeningeal metastases and repeated intrathecal therapy. J Neurooncol. 1999;42:137–42.
Ushio Y, Chernik NL, Posner JB, Shapiro WR. Meningeal carcinomatosis: development of an experimental model. J Neuropathol Exp Neurol. 1977;36:228–44.
Saito N, Hatori T, Murata N, Zhang ZA, Nonaka H, Aoki K, et al. Comparison of metastatic brain tumour models using three different methods: the morphological role of the pia mater. Int J Exp Pathol. 2008;8:38–44.
Siegal T, Sandbank U, Gabizon A, Mizrachi R, Ben-David E, Catane R. Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis. A morphologic and adriamycin-penetration study. J Neurooncol. 1987;4:233–42.
Kuruppu D, Brownell AL, Shah K, Mahmood U, Tanabe KK. Molecular imaging with bioluminescence and PET reveals viral oncolysis kinetics and tumor viability. Cancer Res. 2014;74:4111–21.
George Paxinos, Keith B.J. Franklin, MA, PhD (eds). The Mouse Brain in Stereotaxic Coordinates. 3rd Edition. Elsevier Science Publishing Co Inc, (2007).
Kuruppu D, Brownell AL, Zhu A, Yu M, Wang X, Kulu Y, et al. Positron emission tomography of herpes simplex virus 1 oncolysis. Cancer Res. 2007;67:3295–300.
Cruz-Munoz W, Man S, Xu P, Kerbel RS. Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res. 2008;68:4500–5.
Boskovitz A, McLendon RE, Okamura T, Sampson JH, Bigner DD, Zalutsky MR. Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab. Nucl Med Biol. 2009;36:659–69.
Conley FK. Development of a metastatic brain tumor model in mice. Cancer Res. 1979;39:1001–7.
Schabet M, Herrlinger U. Animal models of leptomeningeal metastasis. J Neurooncol. 1998;38:199–205.
Schackert G, Fidler IJ. Development of in vivo models for studies of brain metastasis. Int J Cancer. 1988;41:589–94.
Sagar SM, Price KJ. An experimental model of leptomeningeal metastases employing rat mammary carcinoma cells. J Neurooncol. 1995;23:15–21.
Engebraaten O, Fodstad O. Site-specific experimental metastasis patterns of two human breast cancer cell lines in nude rats. Int J Cancer. 1999;82:219–25.
Myklebust AT, Helseth A, Breistol K, Hall WA, Fodstad O. Nude rat models for human tumor metastasis to CNS. Procedures for intracarotid delivery of cancer cells and drugs. J Neurooncol. 1994;21:215–24.
Brastianos PK, Brastianos HC, Hsu W, Sciubba DM, Kosztowski T, Tyler BM, et al. The toxicity of intrathecal bevacizumab in a rabbit model of leptomeningeal carcinomatosis. J Neurooncol. 2012;106:81–8.
Grisold W, Grisold A. Cancer around the brain. Neurooncol Pract. 2014;1:13–21.
Fink KR, Fink JR. Imaging of brain metastases. Surg Neurol Int. 2013;4:S209–19.
Chamberlain M, Soffietti R, Raizer J, Ruda R, Brandsma D, Boogerd W, et al. Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro Oncol. 2014;16:1176–85.
Acknowledgements
This work was funded by the following grants: 1. Department of Defense Idea Award (DK). Award No: W81XWH-11-1-0388. 2. NIH R21 NCI Omnibus Award. Award No: 1R21CA186054-01 (DK). 3. MGH-ESSCO Breast Cancer Research Award. Award No: 2015A052076 (DK)
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Kuruppu, D., Bhere, D., Farrar, C. et al. A model of breast cancer meningeal metastases: characterization with in vivo molecular imaging. Cancer Gene Ther 26, 145–156 (2019). https://doi.org/10.1038/s41417-018-0060-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41417-018-0060-z
This article is cited by
-
Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases
Cancer Gene Therapy (2023)
-
Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer
Journal of Translational Medicine (2022)
-
A common goal to CARE: Cancer Advocates, Researchers, and Clinicians Explore current treatments and clinical trials for breast cancer brain metastases
npj Breast Cancer (2021)