The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Retinoic-Acid-Induced Downregulation of the 67 KDa Laminin Receptor Correlates with Reduced Biological Aggressiveness of Human Neuroblastoma Cells

“…Recently it has been reported that 67LR is a hypoxia-inducible factor target gene in gastric cancer (Liu et al, 2010). In neuroblastoma the hypoxia-inducible factors play an important role in maintaining an undifferentiated stem cell-like phenotype, that correlates with poor outcome (HolmquistMengelbier et al, 2006;Noguera et al, 2009;Pietras et al, 2009;Pietras et al, 2010). Finally, we show that more than 71% of the high-grade primary neuroblastoma samples expressed 67LR as revealed by immunocytochemical analysis.…”

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

“…S4 E-H). In CHP-212 tumors where treatment was terminated at D22 and the tumors were retrieved when they had reached 1000 mm 2 , there was no enrichment for Hallmark HYPOXIA in any of the treatment groups.…”

“…High-risk tumors are characterized by MYCN amplification (MYCN amp ) and chromosomal aberrations, such as hemizygous loss of the distal part of chromosome 1p (1p36) (1). Several studies have also reported that high levels of the hypoxia-induced protein HIF2α is a hallmark of aggressive NB (2)(3)(4)(5), implying that it acts as an oncogene in NB. An additional feature of high-risk NB is high levels of DNA methylation of promoters of putative tumor suppressors (6).…”

Cancer Stem Cells in Tumor Heterogeneity

“…Accumulating evidence additionally support a direct and crucial role for cancer stem cells in the recruitment, expansion and differentiation of normal host-derived tumor vasculature, thereby contributing to another well-documented intratumoral heterogeneity ( (Pietras et al, 2008;Kim et al, 2009;Li et al, 2009;Bar et al, 2010;Mendez et al, 2010;Pietras et al, 2010;Pistollato et al, 2010a;Seidel et al, 2010). The mechanisms underlying this pseudo-hypoxic phenotype of cancer stem cells remain poorly understood, but it is increasingly clear that both metabolic and angiogenic heterogeneity within tumors are affected by aberrant expression of key players of the hypoxic response.…”

“…In this review, I will discuss the potential implications of the cancer stem cell hypothesis for the emergence of intratumoral tumor cell heterogeneity. Even though intratumoral heterogeneity is likely evident in virtually all measurable properties of tumor cells, like proliferation rate, invasiveness, migratory potential or therapeutic responses (Heppner, 1984), a lot of recent attention has been given heterogeneity with respect to tumor cell differentiation status (Shipitsin et al, 2007;Pietras et al, 2008;Pietras et al, 2010;Pistollato et al 2010a). …”