Development of hypoxic regions is an indicator of poor prognosis in many tumors. Here, we demonstrate that HIF1alpha, the direct effector of hypoxia, partly through increases in SDF1alpha, induces recruitment of bone marrow-derived CD45+ myeloid cells containing Tie2+, VEGFR1+, CD11b+, and F4/80+ subpopulations, as well as endothelial and pericyte progenitor cells to promote neovascularization in glioblastoma. MMP-9 activity of bone marrow-derived CD45+ cells is essential and sufficient to initiate angiogenesis by increasing VEGF bioavailability. In the absence of HIF1alpha, SDF1alpha levels decrease, and fewer BM-derived cells are recruited to the tumors, decreasing MMP-9 and mobilization of VEGF. VEGF also directly regulates tumor cell invasiveness. When VEGF activity is impaired, tumor cells invade deep into the brain in the perivascular compartment.

Background: Glioblastoma multiforme (GBM) is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells.

Intra-tumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used EXPANDS and PyClone to detect clones >10% frequency within 1,165 exome sequences from TCGA tumors. 86% of tumors across 12 cancer types had at least two clones. ITH in nuclei morphology was associated with genetic ITH (Spearman ρ: 0.24–0.41, P<0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (HR=2.15, 95% CI: 1.71–2.69). The risk of mortality also increased when >2 clones coexisted (HR=1.49, 95% CI: 1.20–1.87). In two independent datasets, copy number alterations affecting either <25% or >75% of a tumor’s genome predicted reduced risk (HR=0.15, 95% CI: 0.08–0.29). Mortality risk also declined when more than four clones coexisted in the sample, suggesting a tradeoff between costs and benefits of genomic instability. ITH and genomic instability have the potential to be useful measures universally applicable across cancers.