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Co-evolution of breast-to-brain metastasis and neural progenitor cells

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Abstract

Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-β superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain metastatic) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.

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Acknowledgments

We thank Dr. Margaret Morgan for her comments and careful editing of this manuscript. Rahul Jandial is supported by National Institutes of Health (NIH) Grant 2K12CA001727-16A1. Josh Neman is supported by California Institute for Regenerative Medicine (CIRM) Grant TG2-01150. Additional project support was provided by National Cancer Institute Grant (NCI) P30 CA033572.

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The authors declare no competing interests exist.

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Authors and Affiliations

  1. Division of Neurosurgery, City of Hope and Beckman Research Institute, 1500 East Duarte RD, MOB 2001, Duarte-Los Angeles, CA, 91010, USA

    Josh Neman, Cecilia Choy, Athena Anderson, Vincent J. Duenas, Sarah Waliany, Mike Y. Chen & Rahul Jandial

  2. Division of Molecular Medicine, City of Hope and Beckman Research Institute, Duarte-Los Angeles, CA, 91010, USA

    Claudia M. Kowolik

  3. Department of Diagnostic Radiology, City of Hope and Beckman Research Institute, Duarte-Los Angeles, CA, 91010, USA

    Bihong T. Chen

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10585_2013_9576_MOESM1_ESM.tiff

Supplementary material 1: Figure 1. (A, B) Immunocytochemistry and Real-time RT PCR of the lineage progression of human NPCs into astrocytes following exogenous BMP-2 treatment over 15 days in vitro. Data are represented as mean values ± standard error of the mean (n = 3) (TIFF 20745 kb)

10585_2013_9576_MOESM2_ESM.tiff

Supplementary material 2: Figure 2. Validation of BMP-2 knockdown (231BrKD), overexpression (231 KI), and shRNA control (231Br NT) in breast cancer cells. (A) Real time RT-PCR for BMP-2 mRNA expression. (B) Western blot analysis of BMP-2, BMP-4, TGF-β3, and SMAD1/5/8. (C) BMP-2 and BMP-4 ELISA. (D) Immunofluorescence of ZsGreen+ 231Br NT, 231BrKD, and 231KI stained for BMP-2 (red), BMP-4 (white), nuclear DAPI (blue). (E) 231BrNT have similar NPC differentiation capacity and (F) corresponding proliferative advantage as 231Br. Data are represented as mean values ± standard error of the mean (n = 3). Statistical significance was assessed using Student’s t test or 1-way ANOVA with Bonferroni’s multiple comparison test (p value: *p < 0.05, **p < 0.01, and ***p < 0.001; 95 % Confidence interval of difference) (TIFF 24465 kb)

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Neman, J., Choy, C., Kowolik, C.M. et al. Co-evolution of breast-to-brain metastasis and neural progenitor cells. Clin Exp Metastasis 30, 753–768 (2013). https://doi.org/10.1007/s10585-013-9576-7

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