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A model of breast cancer meningeal metastases: characterization with in vivo molecular imaging

Cancer Gene Therapy volume 26, pages 145–156 (2019)Cite this article

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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.

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.

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  • 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

  1. 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.

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. Chamberlain MC. Neoplastic meningitis. Handb Clin Neurol. 2012;105:757–66.

    Article  PubMed  Google Scholar 

  6. Groves MD. Leptomeningeal disease. Neurosurg Clin N Am. 2011;22:67–78.

    Article  PubMed  Google Scholar 

  7. Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin. 2003;21:25–66.

    Article  PubMed  Google Scholar 

  8. Kokkoris CP. Leptomeningeal carcinomatosis. How does Cancer Reach pia-arachnoid?. Cancer. 1983;51:154–60.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  11. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013;4:S265–88.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010;74:1449–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Le Rhun E, Galanis E. Leptomeningeal metastases of solid cancer. Curr Opin Neurol. 2016;29:797–805.

    Article  PubMed  Google Scholar 

  14. Watanabe M, Tanaka R, Takeda N. Correlation of MRI and clinical features in meningeal carcinomatosis. Neuroradiology. 1993;35:512–5.

    Article  CAS  PubMed  Google Scholar 

  15. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics. 2007;27:525–51.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Van Horn A, Chamberlain MC. Neoplastic meningitis. J Support Oncol. 2012;10:45–53.

    Article  PubMed  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Reijneveld JC, Taphoorn MJ, Voest EE. A simple mouse model for leptomeningeal metastases and repeated intrathecal therapy. J Neurooncol. 1999;42:137–42.

    Article  CAS  PubMed  Google Scholar 

  22. Ushio Y, Chernik NL, Posner JB, Shapiro WR. Meningeal carcinomatosis: development of an experimental model. J Neuropathol Exp Neurol. 1977;36:228–44.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. George Paxinos, Keith B.J. Franklin, MA, PhD (eds). The Mouse Brain in Stereotaxic Coordinates. 3rd Edition. Elsevier Science Publishing Co Inc, (2007).

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Conley FK. Development of a metastatic brain tumor model in mice. Cancer Res. 1979;39:1001–7.

    CAS  PubMed  Google Scholar 

  31. Schabet M, Herrlinger U. Animal models of leptomeningeal metastasis. J Neurooncol. 1998;38:199–205.

    Article  CAS  PubMed  Google Scholar 

  32. Schackert G, Fidler IJ. Development of in vivo models for studies of brain metastasis. Int J Cancer. 1988;41:589–94.

    Article  CAS  PubMed  Google Scholar 

  33. Sagar SM, Price KJ. An experimental model of leptomeningeal metastases employing rat mammary carcinoma cells. J Neurooncol. 1995;23:15–21.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. Grisold W, Grisold A. Cancer around the brain. Neurooncol Pract. 2014;1:13–21.

    PubMed  PubMed Central  Google Scholar 

  38. Fink KR, Fink JR. Imaging of brain metastases. Surg Neurol Int. 2013;4:S209–19.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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)

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Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Darshini Kuruppu & Kenneth K. Tanabe

  2. Department of Neurosurgery, Brigham & Women’s Hospital, Boston, MA, USA

    Deepak Bhere & Khalid Shah

  3. Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

    Christian T. Farrar & Anna-Liisa Brownell

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  1. Darshini Kuruppu
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  4. Khalid Shah
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Correspondence to Kenneth K. Tanabe.

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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

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