title: Co-evolution of breast-to-brain metastasis and neural progenitor cells.
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.
authors: Division of Neurosurgery, City of Hope and Beckman Research Institute, 1500 East Duarte RD, MOB 2001, Duarte-Los Angeles, CA, 91010, USA.
authors: Josh
authors: J
authors: Neman
authors: Cecilia
authors: C
authors: Choy
authors: Claudia M
authors: CM
authors: Kowolik
authors: Athena
authors: A
authors: Anderson
authors: Vincent J
authors: VJ
authors: Duenas
authors: Sarah
authors: S
authors: Waliany
authors: Bihong T
authors: BT
authors: Chen
authors: Mike Y
authors: MY
authors: Chen
authors: Rahul
authors: R
authors: Jandial
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis; D058953:Neural Stem Cells / Q000166:cytology*; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse