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 meta-static) 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.

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

“…Consequently, the invading breast cancer cells exhibit specific neural characteristics which enable them to penetrate into the brain tissue; thereby, highly activated GABA expression increases their proliferative capacity, particularly within the pre-metastatic niches as the preferable microenvironment. In this context, an active communication between invading cancer cells, astrocytes and microglia in the Bhosting^brain parenchyma has been identified representing an essential part of the successful cancer cell nesting and metastatic process [49][50][51][52].…”

The Role of Astrocytes in Tumor Growth and Progression

“…The variable PTEN expression in metastatic tumor cells in response to different organ environments suggests a genetic component that drives co-evolution adaptive behavior between metastatic cells and their microenvironment [176]. Brain homing MDA-MB-231 cells secrete bone morphogenic protein-2 (BMP-2), which mediates the differentiation of NSCs into astrocytes; subsequently, downregulation of BMP-2 in the brain homing tumor cells diminished their engraftment and colonization abilities [176].…”

“…The variable PTEN expression in metastatic tumor cells in response to different organ environments suggests a genetic component that drives co-evolution adaptive behavior between metastatic cells and their microenvironment [176]. Brain homing MDA-MB-231 cells secrete bone morphogenic protein-2 (BMP-2), which mediates the differentiation of NSCs into astrocytes; subsequently, downregulation of BMP-2 in the brain homing tumor cells diminished their engraftment and colonization abilities [176]. Further, when cocultured with NSCs, primary (non-brain homing) MDA-MB-231 cells fail to proliferate over 15 days, but brain homing MDA-MB-231 cells escaped this growth inhibition, and proliferation occurred in parallel with NSCs' differentiation into astrocytes [176].…”

“…Brain homing MDA-MB-231 cells secrete bone morphogenic protein-2 (BMP-2), which mediates the differentiation of NSCs into astrocytes; subsequently, downregulation of BMP-2 in the brain homing tumor cells diminished their engraftment and colonization abilities [176]. Further, when cocultured with NSCs, primary (non-brain homing) MDA-MB-231 cells fail to proliferate over 15 days, but brain homing MDA-MB-231 cells escaped this growth inhibition, and proliferation occurred in parallel with NSCs' differentiation into astrocytes [176]. This suggests that both the brain homing MDA-MB-231 cells' adaptive phenotype and the NSCs' differentiation into astrocytes are codependent, meaning the brain homing MDA-MB-231 cells require astrocytic signals to survive.…”

Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context

“…Mediators of this process include specific adhesion molecules and proteases (e.g., integrins α5, β1, β3, cathepsin-S, matrix metalloproteinases (MMPs), and E-selectin [47,[49][50][51][52][53]). The perivascular niche (PVN) is another critical point of tumour cell attrition-most are unable to tolerate the neuroinflammatory reaction that is rapidly instigated by microglia and astrocytes [28,45,48,[54][55][56][57][58][59][60][61]. Cross-talk with resident pericytes and endothelia in the PVN seems to be key for tumour cell survival, quiescence, and therapeutic resistance-capabilities that underpin dormancy [62].…”