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This is the first description of an extensive immunohistochemical analysis of interferon (IFN)-inducible gene IFI16 expression in normal tissues. Immunohistochemical detection of IFI16 in paraffin-embedded tissues is achieved by using a polyclonal antibody raised against its C-terminal fragment that recognizes its three closely migrating isoforms in Western blotting. The results clearly indicate that IFI16 expression is not restricted to the hematopoietic compartment. In normal adult human tissues, it is prominent in stratified squamous epithelia and particularly intense in parabasal cells in the proliferating compartments, but it gradually decreases in the more differentiated suprabasal layers. Understanding of IFI16 expression in vivo is essential for interpretation of the results obtained from in vitro studies and elucidation of its physiologic role. The constitutive expression and wider distribution of IFI16 in normal human tissues, not restricted to the hematopoietic compartment, strongly support the possibility of an important role in cell differentiation that can be further modulated by other stimuli, such as IFN. 815

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Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a multifunctional cytokine. It is overexpressed in several conditions, which are characterized by vascular hyperpermeability and angiogenesis. In this investigation, we have evaluated the possibility that VEGF/VPF could be expressed in periapical lesions. We studied 17 periapical granulomas and 6 periapical cysts by immunohistochemistry. An immunopositive reaction for VEGF/VPF was observed in all 23 periapical lesions; however, the intensity of immunostaining by anti-VEGF antibody varied according to histopathological findings. In periapical granulomas without epithelium, almost all of the inflammatory cells were immunoreactive to anti-VEGF/VIP antibody. In periapical granulomas, which had rests of Malassez in them, some inflammatory cells were stained. On the other hand, epithelial cells always were stained by VEGF/VPF antibody, both in periapical lesions with epithelium and in radicular cysts. This study demonstrated that periapical lesions express VEGF/VPF, although with some differences in cell immunolabeling, which correlated to the lesions' stages of development. Initially, VEGF/VPF would assure angiogenesis and vascular hyperpermeability, resulting in accumulation of inflammatory cells, later it could be involved in cyst fluid accumulation. We hypothesize, therefore, that VEGF/VPF expression plays an important role in the pathogenesis of periapical granulomas and enlargement of radicular cysts by several mechanisms.

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HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.

Recent evidence suggesting vascular endothelial growth factor-C (VEGF-C), which is a regulator of lymphatic and vascular endothelial development, raised the question whether this molecule could be involved in Kaposi's sarcoma (KS), a strongly angiogenic and inflammatory tumor often associated with infection by human immunodeficiency virus-1. This disease is characterized by the presence of a core constituted of three main populations of "spindle" cells, having the features of lymphatic/vascular endothelial cells, macrophagic/ dendritic cells, and of a mixed macrophage-endothelial phenotype.In this study we evaluated the biological response of KS cells to VEGF-C, using an immortal cell line derived from a KS lesion (KS IMM), which retains most features of the parental tumor and can induce KS-like sarcomas when injected subcutaneously in nude mice. We show that VEGFR-3, the specific receptor for VEGF-C, is expressed by KS IMM cells grown in vitro and in vivo. In vitro, VEGF-C induces the tyrosine phosphorylation of VEGFR-2, a receptor also for VEGF-A, as well as that of VEGFR-3. The activation of these two receptors in KS IMM cells is followed by a dose-responsive mitogenic and motogenic response. The stimulation of KS IMM cells with a mutant VEGF-C unable to bind and activate VEFGR-2 resulted in no proliferative response and in a weak motogenic stimulation, suggesting that VEGFR-2 is essential in transducing a proliferative signal and cooperates with VEGFR-3 in inducing cell migration.Our data add new insights on the pathogenesis of KS, suggesting that the involvement of endothelial growth factors may not only determine KS-associated angiogenesis, but also play a critical role in controlling KS cell growth and/or migration and invasion.

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