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Studies concerning the expression of the receptor CD95 (Fas) by tumor cells and the role of this protein in apoptosis induced by the effector host cells that bear Fas-ligand are mainly focused on the membrane-bound form of Fas. There are only a few data about the production of the soluble form of Fas by the tumor cells, its role in the interaction with the effector host cells, and the possible changes in the synthesis of this protein during tumor progression. In the present work, three in vivo transformed parental cell lines of different origin and 24 of their variants isolated after a short cycle of natural selection in vivo were studied. It was demonstrated for the first time that: 1) production of the soluble Fas by all selected in vivo variant tumor cell lines increased significantly (2-10-fold) in comparison to the initial (parental) cell lines and did not depend on the origin of the parental lines. At the same time, the expression of the membrane bound form of Fas decreased considerably; 2) variations of the balance between membrane-bound and soluble forms of Fas in selected in vivo variant cells and the expression of the [H2O2 CA + PGES]-phenotype by these cells (this phenotype determines one of the essential mechanisms of the protection of a tumor cell in vivo) possibly represent independent secondary changes acquired during tumor progression in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Intratumoral hypoxia is a hallmark of solid tumor formation and a negative predictor of patient survival. Adaptation to hypoxia is mainly achieved by the transcription factor HIF-1α, which is upregulated in a diverse range of human and experimental tumors and their metastases. HIF-1α target genes have been implicated in the induction of invasion and metastasis. However, HIF-1α's tumor-supporting action depends on cell type and microenvironment and the precise role of HIF-1α for the pathogenesis ofneuroendocrine tumors (NET) is largely unknown. Aim(s): Molecular analysis of HIF-1α's role in the pathobiology of gastroenteropancreatic neuroendocrine tumors (GEP-NET). Materials and methods: Functional inactivation of HIF-1α was achieved by lentiviral-mediated siRNA transduction. Substrate-independent growth was analyzed by colony formation assay. Migration capacity was examined via wound healing assays. Results: Loss of HIF-1α in the GEP-NET cell line BON-1 resulted in a robust growth defect under normoxic and substrate-dependent conditions. Furthermore, HIF-1α knock-down cells displayed a 67% reduction of colonies when grown substrate-independently. In addition, inactivation of HIF-1α diminished the migratory potential of GEP-NET cells significantly. Conclusion: Substrate-independent growth and migration are hallmarks of malignant cells and a central prerequisite for metastatic spread. Our results therefore argue for a central role of HIF-1α in mediating systemic dissemination in GEP-NET. [ABSTRACT FROM AUTHOR]