leukotriene-b4 and Neoplasm-Metastasis

Fibroblast are responsible for the synthesis of the structural proteins of the connective tissue. A further property of these cells, their migratory ability, could be analyzed in the last years. A special form of migration is chemotaxis, which can be quantitatively measured in a modified Boyden chamber in-vitro. Using this method chemoattractive substances could be characterized, which are able to stimulate fibroblasts and tumorcells to chemotactic migration. Furthermore it could be proved, that benign and transformed cell lines react in a different manner towards these chemoattractive substances. The in-vitro results allow some hypotheses about both fibroblast migration in wound healing or chronic inflammation, and the mechanisms of tumor cell evasion in the tumor surrounding tissue or the metastasizing process in other organs.

Topics: Animals; Chemotaxis; Fibroblasts; Fibronectins; Humans; In Vitro Techniques; Leukotriene B4; Lymphokines; Macrophage Activation; Neoplasm Metastasis; Neoplasms; Wound Healing

5-lipoxygenase (5-LOX), a member of the lipoxygenase gene family, is a key enzyme assisting in the conversion of arachidonic acid to 5-HETE and leukotrienes. Tumor-associated macrophages (TAMs) have a critical role in the progression and metastasis of many tumors, including ovarian tumors. Moreover, TAMs are often found in a high density in the hypoxic areas of tumors. However, the relevant mechanisms have not been studied explicitly until now. In this study, we found that the expression of 5-LOX strongly correlated with the density of TAMs in hypoxic areas of human ovarian tumor tissues. In cultured ovarian cancer cells, 5-LOX metabolites were increased under hypoxic conditons. Increased 5-LOX metabolites from hypoxic ovarian cancer cells promoted migration and invasion of macrophages, which was further demonstrated to be mediated by the upregulation of matrix metalloproteinase (MMP)-7 expression through the p38 pathway. Besides, we also showed that 5-LOX metabolites enhanced the release of tumor necrosis factor (TNF-α) and heparin-binding epidermal growth factor-like growth factor through upregulation of MMP-7. Furthermore, in animal models, Zileuton (a selective and specific 5-LOX inhibitor) reduced the MMP-7 expression and the number of macrophages infiltrating in the xenograft. Our findings suggest for the first time that increased metabolites of 5-LOX from hypoxic ovarian cancer cells promote TAM infiltration. These results of this study have immediate translational implications for the therapeutic exploitation of TAMs.

Topics: Animals; Arachidonate 5-Lipoxygenase; Cell Line; Cell Line, Tumor; Chemotaxis, Leukocyte; Disease Models, Animal; Female; Heparin-binding EGF-like Growth Factor; Heterografts; Humans; Hydroxyeicosatetraenoic Acids; Hydroxyurea; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leukotriene B4; Macrophages; MAP Kinase Signaling System; Matrix Metalloproteinase 7; Mice; Neoplasm Metastasis; Ovarian Neoplasms; Tumor Necrosis Factor-alpha

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B(4) receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappaB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.

Topics: Animals; Cell Transformation, Neoplastic; Genes, ras; Humans; Leukotriene B4; Matrix Metalloproteinase 9; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; ras Proteins; Rats; Reactive Oxygen Species; Receptors, Leukotriene B4; Tumor Cells, Cultured; Up-Regulation

Topics: Animals; Humans; Infections; Inflammation; Leukotriene B4; Magnetic Resonance Imaging; Neoplasm Metastasis; Neoplasms; Positron-Emission Tomography; Receptor, Adenosine A1