Abstract
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.
Highlights
Malignant gliomas are thought to be maintained by a rare population of transformed stem-like cells referred to as glioma stem cells or brain tumor-initiating cells (BTIC; refs. 1, 2)
TNC has been documented to be markedly elevated in malignant glioma compared with surrounding normal brain tissue [22], and we have demonstrated by Western blot analyses the substantial increase in TNC content in glioblastoma compared with nontransformed human brain specimens [37]
For most tumor types, including gliomas, the availability of extracellular matrix (ECM) proteins is considered a critical step in cell invasion and tumor growth as they activate integrins on the cell surface to trigger signaling and because the ECM is a rich source of growth factors
Summary
Malignant gliomas are thought to be maintained by a rare population of transformed stem-like cells referred to as glioma stem cells or brain tumor-initiating cells (BTIC; refs. 1, 2). Malignant gliomas are thought to be maintained by a rare population of transformed stem-like cells referred to as glioma stem cells or brain tumor-initiating cells BTICs exhibit increased resistance to radiation [3, 4] and chemotherapy [5, 6] as compared with their more differentiated transformed progeny ( referred to as differentiated glioma cells), and they account for glioma recurrence following efficient chemotherapy in mice [7]. The identification of mechanisms that maintain the growth of BTICs will be important for therapeutic purposes. NOTCH proteins (NOTCH 1-4 in mammals) are transmembrane proteins activated by ligands such as delta 1-4 and serrate/jagged 1 (JAG1) and JAG2. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). R. Mirzaei and F.J. Zemp share second authorship of this article
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