Key words: EGFR; NF-B; AP-1; IL-8; VEGF; PI3K; MEK; HNSCCIncreased angiogenesis is critical to tumor progression and metastasis, and we and others have shown that expression of members of the C-X-C cytokine and vascular endothelial growth factor families such as IL-8, growth regulated oncogene-1 (Gro 1) and VEGF can promote angiogenesis, tumorigenesis and metastatic tumor progression. 1-3 The expression of multiple factors with proangiogenic activity by cancer cells poses a significant obstacle to effective therapy with agents targeted toward individual factors and receptors. Identification of common mechanism(s) underlying expression of such a diversity of factors could guide the development of therapy using fewer selective agents. We previously observed that IL-8, VEGF and other cytokines are coexpressed and often vary concurrently in serum and supernatants from cell lines from different patients with head and neck squamous cell carcinoma (HNSCC), 4,5 suggesting that these factors could be regulated by common signal pathways or transcription factors.Examination of the regulatory region of many proinflammatory cytokines and proangiogenic factors reveals that they share common promoter sites for transcription factors such as nuclear factor-B (NF-B) and/or activator protein-1 (AP-1), which can be activated by injury, cytokines and growth factors. 6 We found that differences in expression of these cytokines in different cancers was often related to differences in constitutive activation of both NF-B and AP-1. 6 Inhibition of NF-B activation by expression of a dominant negative inhibitor-B or pharmacologic agents was found to inhibit expression of IL-8 and other proinflammatory and proangiogenic cytokines, 7-10 as well as tumorigenesis and angiogenesis in vivo. 7,9 Inhibition of activation of extracellular signalregulated kinase (ERK) and AP-1 with antagonists of mitogenactivated/extracellular signal-regulated kinase (MEK) partially inhibited expression of both IL-8 and VEGF. 10 These results provided evidence that at least 2 signal pathways upstream of NF-B and AP-1 make important contributions to expression of these angiogenesis factors.We have recently examined the contribution of several factors that may contribute to upstream signal activation of NF-B and AP-1 and expression of IL-8 and VEGF. We found that IL-1␣ expressed by HNSCC promotes autocrine activation of NF-B and AP-1, expression of IL-8 and cell survival. 11 Expression of IL-1 receptor antagonist inhibited NF-B reporter activity and IL-8 expression by 60 -80%, indicating that IL-1␣ is a major contributor to constitutive activation of NF-B and IL-8. HNSCC were also found to express c-MET, a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). 12 Increased expression of HGF/SF was detected together with IL-8 and VEGF in serum of patients with HNSCC, and recombinant HGF and HGF from stromal fibroblasts was found to further induce IL-8 and VEGF expression by human HNSCC lines. Inhibitors of MEK and Abbreviations: AP-1, activator...

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The WNT signaling pathway has been of great interest to developmental biologists for decades and has more recently become a central topic for study in cancer biology. It is vital for cell growth and regulation of embryogenesis in many organ systems, particularly the CNS and its associated vasculature. We summarize the role of WNT in CNS development and describe how WNT signaling makes key contributions to malignant glioma stemness, invasiveness, therapeutic resistance, and angiogenesis. The role of WNT in these mechanisms, along with creation and maintainance of the blood-brain barrier (BBB), points to the potential of WNT as a multi-faceted target in malignant glioma therapy.