ABSTRACT
Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.
Subject(s)
Brain Neoplasms/secondary , Brain/pathology , Breast Neoplasms/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neoplastic Cells, Circulating/metabolism , Animals , Brain Neoplasms/blood , Brain Neoplasms/mortality , Breast Neoplasms/blood , Breast Neoplasms/mortality , Cell Hypoxia , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mammary Glands, Animal/pathology , Metabolomics , Mice , RNA, Small Interfering/metabolism , RNA-Seq , Signal Transduction/drug effects , Signal Transduction/genetics , Spheroids, Cellular , Stereotaxic Techniques , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: This paper describes the use of real-time magnetic resonance imaging to simultaneously obtain magnetic resonance imaging (MRI) videos in both a sagittal and coronal plane during the performance of a musical exercise in five advanced trombone players. METHODS: Dual-slice recordings were implemented in a frame-interleaved manner with 20 ms acquisitions per frame to achieve two interleaved videos at a rate of 25 frames per second. A customized MATLAB toolkit was used for the extraction of line profiles from MRI videos to quantify tongue movements associated with exercise performance from both perspectives. RESULTS: Across all subjects, the analyses revealed precise coupling of vertical movements of the dorsal tongue surface (DTS), viewed from a sagittal perspective, with reduction in the vertical and horizontal dimensions of the air channel formed between the DTS and the hard palate, viewed from a coronal perspective. The cross-correlation between these movements was very strong (mean R=0.967). CONCLUSIONS: These results demonstrate the unique utility of this dual-slice technology in describing the coordination of complex tongue movements occurring in two planes (i.e., three directions) simultaneously, lending a deeper understanding of lingual motor control during trombone performance.
