Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells

Abstract

Histology of malignant glioma depicts dense proliferative areas rich in angiogenesis as well as dissemination of neoplastic cells into adjacent brain tissue. Although the mechanisms that trigger transition from proliferative to invasive phenotypes are complex, the dichotomy of cell proliferation and migration, the “Go or Grow” hypothesis, argues for specific and coordinated regulation of these phenotypes. We investigated transcriptional elements that accompany the phenotypes of migration and proliferation, and consider the therapeutic significance of the “Go or Grow” hypothesis. Interrogation of matched core and rim regions from human glioblastoma biopsy specimens in situ (n = 44) revealed higher proliferation (Ki67 labeling index) in cells residing at the core compared to the rim. Profiling activated transcription factors in a panel of migration-activated versus migration-restricted GBM cells portrayed strong NF-κB activity in the migratory cell population. In contrast, increased c-Myc activity was found in migration-restricted proliferative cells. Validation of transcriptional activity by NF-κB- or c-Myc-driven GFP or RFP, respectively, showed an increased NF-κB activity in the active migrating cells, whereas the proliferative, migration restricted cells displayed increased c-Myc activity. Immunohistochemistry on clinical specimens validated a robust phosphorylated c-Myc staining in tumor cells at the core, whereas increased phosphorylated NF-κB staining was detected in the invasive tumor cells at the rim. Functional genomics revealed that depletion of c-Myc expression by siRNA oligonucleotides reduced cell proliferation in vitro, but surprisingly, cell migration was enhanced significantly. Conversely, inhibition of NF-κB by pharmacological inhibitors, SN50 or BAY-11, decreased both cell migration in vitro and invasion ex vivo. Notably, inhibition of NF-κB was found to have no effect on the proliferation rate of glioma cells. These findings suggest that the reciprocal and coordinated suppression/activation of transcription factors, such as c-Myc and NF-κB may underlie the shift of glioma cells from a “growing-to-going” phenotype.

Overexpression of MYC binding protein promotes invasion and migration in gastric cancer

“…Overexpression of MYC has been suggested to serve key roles in cell migration and invasion by promoting the expression of target genes (26). Previous studies have been performed to inhibit the expression of MYCBP, and thus the MYC pathway, and observe the resultant inhibition of cancer cell migration and invasion (20,27).…”

Intravenous delivery of camptothecin-loaded PLGA nanoparticles for the treatment of intracranial glioma

“…Formalin fixed brains were sliced into thick sections and embedded in paraffin. H&E staining and IHC staining were performed as described previously (Dhruv et al, 2013). Briefly, 5 mM thick sections from the tissue blocks were baked at 65 C for 1 h, deparaffinized in three xylene washes, dehydrated in series graded ethanol, and rehydrated in water.…”

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

“…In previous investigations of this phenotypic axis, signaling molecules such as miRNAs and proteins have been characteristically revealed as monotonic regulators of growth or invasion [1,12,22,65]. Here, we identify miR-9 as a molecule with the capacity to drive either invasion or growth, dependent upon local cell density.…”

“…Glioma cell migration and proliferation are stochastically mutually exclusive processes, and the tumor cells defer cell division in order to migrate and vice versa [1,2]. Due to the phenotypic switch between motility and growth, invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, which may contribute to chemotherapy and radiation resistance [3].…”