Karoly Szekeres

Eicosanoid Regulation of Angiogenesis in Human Prostate Carcinoma and Its Therapeutic Implications

Abstract: Cancer of the prostate is the most commonly diagnosed cancer in America. There are several lines of evidence implicating the involvement of arachidonate 12‐lipoxygenase, an enzyme metabolizing arachidonic acid to form 12(S)‐hydroxyeicosatetraenoic acid (HETE), in prostate cancer progression. First, as prostate cancer reaches a more advanced stage, the level of 12‐lipoxygenase expression is increased. Second, overexpression of 12‐lipoxygenase in human prostate cancer cells stimulates angiogenesis and tumor growth. Third, an inhibitor of 12‐lipoxygenase has been found effective against metastatic prostate tumor growth, and the inhibition of 12‐lipoxygenase is related with the reduction of tumor angiogenesis. Collectively, these studies suggest that 12‐lipoxygenase regulates tumor angiogenesis in prostate cancer and that inhibition of 12‐lipoxygenase is a novel therapeutic approach for the treatment of prostate cancers.

Expression and function of the high affinity αIibβ3 integrin in murine melanoma cells

In resting platelets integrin αIibβ3 is constitutively expressed in an inactive state and it does not recognize soluble proteins. Platelet activation results in a conformational change of the low-affinity αIibβ3 to a high-affinity state which then recognizes plasma fibrinogen. The ectopic expression of αIibβ3 integrin in rodent and human cells derived from solid tumors is well documented, although little is known about its affinity state in these tumor cells. In this study we analysed expression and function of high-affinity αIibβ3 in murine metastatic melanoma B16a cells by using a mAb that specifically recognizes high-affinity αIibβ3 (PAC-1). These tumor cells while in suspension bound PAC-1 and fibrinogen. Immunofluorescent studies of B16a cells indicated that high-affinity αIibβ3 is associated with the Golgi complex and the cell surface. Stimulation of B16a cells with a PKC-activator, 12(S)-HETE, induced translocation of the high-affinity integrin from an intracellular pool to the plasma membrane, which resulted in increased tumor cell adhesion to fibronectin. In addition to participating in 12(S)-HETE-stimulated adhesion of B16a cells, the high-affinity aIIbb3 inte-grin is also involved in tumor cell invasion through a reconstituted basement membrane. In conclusion, results from this study suggest that in non-megakaryocytic lineage B16a cells αIibβ3 is constitutively expressed in a high-affinity state, and that this conformation participates in tumor cell adhesion and invasion.

The Role of Eicosanoids in Tumor Growth and Metastasis

Mobilization of esterified arachidonic acid (AA) from membrane glycerolipid pools represents the key regulatory step in cellular responses to various stimuli, such as growth factors, cytokines, chemokines and circulating hormones. Released AA is metabolized via the cyclo-oxygenase (COX 1 and COX 2), lipoxygenase (LOX) or P450-dependent epoxygenase pathways to generate eicosanoids. In addition to their normal biological activities, such as stimulation of mitogenesis and cellular motility, eicosanoids have also been postulated to contribute to tumorigenesis and to the progression of certain tumor cells. Various AA metabolites have been implicated in a variety of growth-related signaling pathways involving ras (Han et al. 1991), interferon-α, epithelial growth factor (EGF), cyclic adenosine monophosphate, protein kinase C (PKC; Hannigan and Williams 1991; Peppelenbosch et al. 1993; Tang et al. 1995a), mitogen-activated kinases (Rao et al. 1988) and fos (Danesch et al. 1994). Numerous studies have demonstrated a strong correlation between growth-factor-promoted cell proliferation and generation of various COX products, primarily prostaglandins (Nolan et al. 1988).

Key Determinants of the Invasion Mechanism of Melanoma

Dissemination of malignant tumors (metastasis) is a cascade consisting of detachment of cells from the primary tumor, invasion of the surrounding extracellular matrix (ECM), intravasation, dissemination in the circulatory system, adhesion to the vessel wall, extravasation and growth at secondary sites. It is clear that tumor cell-ECM interactions are extremely important during these steps (1). Tumor cell-ECM interactions are mediated by adhesion receptors; integrins (2), non-integrins (3) and proteoglycans (4), motility-receptors and enzymes responsible for digestion (1).The two major aspects of tumor progression are; cell proliferation and cell-cell/cell-matrix interactions (l). During tumor cell dissemination, adhesive processes become more significant than the proliferation. The integrin receptors on tumor cells have been shown to be involved in different steps of the metastatic cascade: adhesion to and spreading on matrices, in cellular migration as well as in vivo metastasis (5). Among the different integrin receptors P3-s have been implicated in melanoma-ECM interactions thereby influencing the metastatic phenotype (5). Accumulating data indicate that integrins serve as two-ways signaling components: outside-in as well as inside-out devices (6). Certain tyrosine kinases (PTK) such as F AK and src (6) and PKC (7) were found to be localized to focal adhesions which suggests that PTK and PKC activation/translocation both serves as effector elements during matrix-receptor activation. Experimental data suggest, that outside-in signaling through integrins might involves PTK while inside-out signaling might involves PKC signaling (6). How-