Activation of NOTCH Signaling by Tenascin-C Promotes Growth of Human Brain Tumor-Initiating Cells
Autor: | Stephen M. Robbins, Reza Mirzaei, Susobhan Sarkar, Franz J. Zemp, V. Wee Yong, Wu Wei, Donna L. Senger |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research JAG1 Blotting Western Notch signaling pathway Mice SCID Real-Time Polymerase Chain Reaction Extracellular matrix 03 medical and health sciences Mice Glioma Cell Line Tumor medicine Gene silencing Animals Humans Immunoprecipitation Autocrine signalling Oligonucleotide Array Sequence Analysis biology Receptors Notch Brain Neoplasms Tenascin C Tenascin musculoskeletal system medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Cell culture Gene Knockdown Techniques Cancer research biology.protein Neoplastic Stem Cells Heterografts Signal Transduction |
Zdroj: | Cancer research. 77(12) |
ISSN: | 1538-7445 |
Popis: | Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) in malignant glioma, but the mechanism of its activation is unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTIC to promote their growth. We demonstrate the proximal localization of TNC and BTIC in human glioblastoma specimens and in orthotopic murine xenografts of human BTIC implanted intracranially. In tissue culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTIC. Exogenously applied or autocrine TNC increased BTIC growth through an α2β1 integrin-mediated mechanism that elevated NOTCH ligand Jagged1 (JAG1). Microarray analyses and confirmatory PCR and Western analyses in BTIC determined that NOTCH signaling components including JAG1, ADAMTS15, and NICD1/2 were elevated in BITC after TNC exposure. Inhibition of γ-secretase and metalloproteinase proteolysis in the NOTCH pathway, or silencing of α2β1 integrin or JAG1, reduced the proliferative effect of TNC on BTIC. Collectively, our findings identified TNC as a pivotal initiator of elevated NOTCH signaling in BTIC and define the establishment of a TN-α2β1-JAG1-NOTCH signaling axis as a candidate therapeutic target in glioma patients. Cancer Res; 77(12); 3231–43. ©2017 AACR. |
Databáze: | OpenAIRE |
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