Skip to main content

Advertisement

SpringerLink
Log in

Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sun YS, Zhao Z, Yang ZN et al (2017) Risk factors and preventions of breast cancer. Int J Biol Sci 13(11):1387–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kondziolka D, Kalkanis SN, Mehta MP, Ahluwalia M, Loeffler JS (2014) It is time to reevaluate the management of patients with brain metastases. Neurosurgery 75(1):1–8

    PubMed  Google Scholar 

  3. Zhang J, Spath SS, Marjani SL, Zhang W, Pan X (2018) Characterization of cancer genomic heterogeneity by next-generation sequencing advances precision medicine in cancer treatment. Precis Clin Med 1(1):29–48

    PubMed  PubMed Central  Google Scholar 

  4. Piccirilli M, Sassun TE, Brogna C, Giangaspero F, Salvati M (2007) Late brain metastases from breast cancer: clinical remarks on 11 patients and review of the literature. Tumori 93(2):150–154

    PubMed  Google Scholar 

  5. Termini J, Neman J, Jandial R (2014) Role of the neural niche in brain metastatic cancer (vol 74, pg 4011, 2014). Can Res 74(19):5680–5680

    CAS  Google Scholar 

  6. Jandial R, Anderson A, Choy C, Levy ML (2012) Bidirectional microevnironmental cues between neoplastic and stromal cells drive metastasis formation and efficiency. Neurosurgery 70(4):N12–N13

    PubMed  Google Scholar 

  7. Honda Y, Goto R, Idera N et al (2014) Prognostic significance of subtypes and gpa (graded prognostic assessment) in brain metastases from breast cancer. Ann Oncol 25:v103

    Google Scholar 

  8. Pestalozzi BC (2009) Brain metastases and subtypes of breast cancer. Ann Oncol 20(5):803–805

    CAS  PubMed  Google Scholar 

  9. Chen W, Hoffmann AD, Liu H, Liu X (2018) Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis Oncology 2(1):4

    Google Scholar 

  10. Lu X, Kang Y (2007) Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12(2–3):153–162

    PubMed  Google Scholar 

  11. Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited–the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128(11):2527–2535

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jandial R, Choy C, Levy DM, Chen MY, Ansari KI (2017) Astrocyte-induced Reelin expression drives the proliferation of Her2(+) breast cancer metastases. Clin Exp Metas 34(2):185–196

    CAS  Google Scholar 

  13. Choy C, Ansari KI, Neman J et al (2017) Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. Breast Cancer Res BCR 19(1):51

    PubMed  Google Scholar 

  14. Ansari SR, Jandial Z, Wu X, Liu X, Chen MY, Ansari KI (2019) Synergistic inhibition of SCR1- and ERBB2-driven brain metastatic breast cancer cells. J Cancer Metastasis Treat 5:20

    CAS  Google Scholar 

  15. Ozdemir BC, Sflomos G, Brisken C (2018) The challenges of modeling hormone receptor-positive breast cancer in mice. Endocr Relat Cancer 25(5):R319–R330

    CAS  PubMed  Google Scholar 

  16. Wu Q, Li J, Zhu S et al (2017) Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study. Oncotarget 8(17):27990–27996

    PubMed  PubMed Central  Google Scholar 

  17. De Mattos-Arruda L (2017) Liquid biopsy for HER2-positive breast cancer brain metastasis: the role of the cerebrospinal fluid. ESMO Open 2(4):e000270

    PubMed  PubMed Central  Google Scholar 

  18. Wang WC, Zhang XF, Peng J et al (2018) Survival mechanisms and influence factors of circulating tumor cells. Biomed Res Int 2018:6304701

    PubMed  PubMed Central  Google Scholar 

  19. Pachmayr E, Treese C, Stein U (2017) Underlying mechanisms for distant metastasis—molecular biology. Visc Med 33(1):11–20

    PubMed  PubMed Central  Google Scholar 

  20. Neman J, Choy C, Kowolik CM et al (2013) Co-evolution of breast-to-brain metastasis and neural progenitor cells. Clin Exp Metas 30(6):753–768

    CAS  Google Scholar 

  21. Saunus JM, Momeny M, Simpson PT, Lakhani SR, Da Silva L (2011) Molecular aspects of breast cancer metastasis to the brain. Genet Res Int 2011:219189

    PubMed  PubMed Central  Google Scholar 

  22. Zhu MX, Feng Y, Dangelmajer S et al (2015) Human cerebrospinal fluid regulates proliferation and migration of stem cells through insulin-like growth factor-1. Stem Cells Dev 24(2):160–171

    CAS  PubMed  Google Scholar 

  23. Lehtinen MK, Zappaterra MW, Chen X et al (2011) The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69(5):893–905

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakazawa E, Ishikawa H (1998) Ultrastructural observations of astrocyte end-feet in the rat central nervous system. J Neurocytol 27(6):431–440

    CAS  PubMed  Google Scholar 

  25. Gato A, Alonso MI, Martin C et al (2014) Embryonic cerebrospinal fluid in brain development: neural progenitor control. Croat Med J 55(4):299–305

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ghersi-Egea JF, Strazielle N, Catala M, Silva-Vargas V, Doetsch F, Engelhardt B (2018) Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol 135(3):337–361

    CAS  PubMed  Google Scholar 

  27. Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20(2):160–172

    CAS  PubMed  Google Scholar 

  28. Choi SS, Lee HJ, Lim I, Satoh J, Kim SU (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS ONE 9(4):e92325

    PubMed  PubMed Central  Google Scholar 

  29. Batchelor DC, Hutchins AM, Klempt M, Skinner SJ (1995) Developmental changes in the expression patterns of IGFs, type 1 IGF receptor and IGF-binding proteins-2 and -4 in perinatal rat lung. J Mol Endocrinol 15(2):105–115

    CAS  PubMed  Google Scholar 

  30. Rajaram S, Baylink DJ, Mohan S (1997) Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18(6):801–831

    CAS  PubMed  Google Scholar 

  31. Russo VC, Azar WJ, Yau SW, Sabin MA, Werther GA (2015) IGFBP-2: The dark horse in metabolism and cancer. Cytokine Growth F R 26(3):329–346

    CAS  Google Scholar 

  32. Chua CY, Liu Y, Granberg KJ et al (2016) IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene 35(6):738–747

    CAS  PubMed  Google Scholar 

  33. Libreros S, Garcia-Areas R, Iragavarapu-Charyulu V (2013) CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/protumorigenic and angiogenic factors. Immunol Res 57(0):99–105. https://doi.org/10.1007/s12026-013-8459-y

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We tender our heartfelt gratitude to Kerin Higa for critically evaluating and proofreading the manuscript. Experimental design; data collection, analysis, and interpretation; and manuscript preparation were supported by the Department of Defense Breast Cancer Research Program (BCRP; BC142323) and the Margaret E. Early Medical Research Trust.

Author information

Authors and Affiliations

  1. Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA

    Khairul I. Ansari, Arunoday Bhan, Mike Y. Chen & Rahul Jandial

  2. Division of Biostatistics, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Xueli Liu

  3. Celcuity, 16305 36th Ave N, Suite 100, Minneapolis, MN, 55446, USA

    Khairul I. Ansari

Authors
  1. Khairul I. Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arunoday Bhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueli Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mike Y. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rahul Jandial
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Khairul I. Ansari or Rahul Jandial.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Electronic supplementary material 1 (PDF 513 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ansari, K.I., Bhan, A., Liu, X. et al. Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer. Clin Exp Metastasis 37, 401–412 (2020). https://doi.org/10.1007/s10585-020-10032-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-020-10032-4

Keywords

Search

Navigation