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Growth factors and cytokines control and coordinate a broad spectrum of fundamental cellular functions, and are evolutionarily conserved both in vertebrates and invertebrates. In this review, we focus our attention on the functional phylogenetic aspects of growth factors/cytokines like the Transforming Growth Factor- (TGF-), the Connective Tissue Growth Factor (CTGF), and the Vascular Endothelial Growth Factor (VEGF). We will also delve into the activites of two chemokine families, interleukin (IL)-8 (or CXCL8) and CC chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2). These molecules have been selected for their involvement in immune responses and wound healing processes, where they mediate and finely regulate various regeneration processes like angiogenesis or fibroplasia, not only in vertebrates, but also in invertebrates.

The intricate interplay between the endothelium and immune cells has been well recognized in the context of immune responses. However, the fact that this inter-relation extends well beyond immune regulation is becoming increasingly recognized, with particular regards to the influence of the immune system on the essential endothelial process of angiogenesis, where the contribution of cytokines drives the angiogenic process. As angiogenesis is an important component of numerous pathological states, among these chronic inflammatory conditions and cancer, understanding the role of cytokines and chemokines in guiding new vessel formation provides key insight into novel therapeutic modalities. Here we review the actions of principal cytokines and chemokines on the angiogenic process and discuss how both can be considered potential pharmaceutical targets or pharmaceuticals themselves for modulation of angiogenesis in chronic inflammation associated with cancer, rheumatoid arthritis and other inflammatory diseases.

Tumors growing within the host form dynamic aberrant tissue that consists of host components, including the stroma, an expanding vasculature and often chronic inflammation, in addition to the tumor cells themselves. These host components can contribute to, rather than limit, tumor expansion, whereas deprivation of vessel formation has the potential to confine tumors in small, clinically silent foci. Therapeutic inhibition of vessel formation could be best suited to preventive strategies aimed at the suppression of angiogenesis in primary tumors in subjects at risk, or of micrometastases after surgical removal of a primary tumor. Our analysis of potential cancer chemopreventive molecules including N-acetylcysteine, green tea flavonoids and 4-hydroxyphenyl-retinamide has identified antiangiogenic activities that could account -at least in part - for the tumor prevention effects observed with these compounds. These drugs appear to target common mechanisms of tumor angiogenesis that may permit identification of critical targets for antiangiogenic therapy and antiangiogenic chemoprevention.

Tumor-induced angiogenesis is a key event for neoplastic progression. In vitro assays are important for identification of potential angiogenic agents and rapid sceening for pharmacological inhibitors. The increased interest in this field of study has generated several in vitro assays that recapitulate the steps of endothelial cell activation and differentiation. In this short report we emphasize the utility of Matrigel, a reconstituted basement membrane, to define two different steps in the angiogenic process: invasion in response to growth factors and organization of microvessels into a network with branching morphology on a Matrigel substrate.

Kaposi's Sarcoma (KS) is a pathology which occurs with increased frequency and in a particularly aggressive form in AIDS patients. The HIV-1 Tat protein appears to be an important co-factor in the induction of the extensive neo-vascularization associated with AIDS-KS. Tat acts as a chemoattractant for endothelial cells in vitro, inducing both chemotactic and invasive responses. Several clinical trials have been performed testing the effectiveness of diverse biological agents in therapy of KS, among these the type I interferons. Type I IFNs have diverse biological functions besides their anti-viral activity, including anti-angiogenic properties. We have shown that IFNα and IFNβ are potent inhibitors of both primary and immortalized endothelial cell migration and morphogenesis in vitro as well as neo-angiogenesis induced by HIV-1 Tat in vivo. The inhibitory effect of IFN class I on HIV-Tat associated angiogenesis further supports its use as a therapy for epidemic Kaposi's sarcoma. The use of recombinant IFNs at the levels required to obtain a therapeutic effect are associated with side effects and toxicity, therefore we are now developing a gene therapy approach for constant and local delivery type I IFNs.

Kaposi’s sarcoma (KS) is a highly angiogenic lesion which frequently presents as an aggressive form in HIV-infected male patients. We have previously shown that the HIV-1 Tat protein induces endothelial cell migration and invasion in vitroand a rapid angiogenic response in vivo, suggesting that it acts as a cofactor in epidemic KS. In this study we tested beta interferon (IFNβ) and retinoic acid (RA) for the inhibition of Tat-induced angiogenesis using in vivoand in vitromodels. IFNβ, at a concentration above 2500U/ml, was an effective inhibitor of Tat-stimulated growth, migration and morphogenesis of an endothelial cell line in vitroand of angiogenesis in vivo. A strong reduction of properties associated with neovascularisation was induced by 10000U/ml. In vivo, RA alone was on ineffective inhibitor of angiogenesis, and in vitrogave only a limited inhibition of endothelial cell growth. However, 13-cisRA used in combination with IFNβ impressively potentiated its effects. A combination of lower doses of IFNβ (2500U/ml) and 13-cisRA induced a virtually complete inhibition of the Tat-related angiogenic phenotype both in vivoand in vitro. The potentiation of the anti-angiogenic activity of IFNβ by 13-cisRA suggests that this combination could be a useful approach for the therapy of epidemic KS.

Human immunodeficiency virus (HIV) Tat is chemotactic for monocytes and dendritic cells, an activity that could play a key role in the expansion of HIV infection of accessory cells. To date, domains of Tat previously found to interact with cell surface molecules have shown only partial chemotactic activity toward monocytes. Using overlapping Tat peptides, we identify a novel region of Tat with a potent chemotactic activity for monocytes, reaching levels equal to Tat itself. This peptide also provokes monocyte polarization similar to Tat and is able to compete with Tat for induction of monocyte migration. Specific high affinity (kd = 3 x 10(-9) M) cell surface binding sites on monocyte cell surfaces for this region of Tat are demonstrated. These data indicate that the majority of Tat effects on monocytes are mediated by a novel region in the cysteine-rich and core domains. These domains are highly conserved among different HIV isolates, suggesting an important role in the establishment of HIV infection.

Extracellular human immunodeficiency virus type 1 (HIV-1) Tat protein promotes growth of spindle cells derived from AIDS-associated Kaposi sarcoma (AIDS-KS), an angioproliferative disease very frequent in HIV-1-infected individuals. Normal vascular cells, progenitors of AIDS-KS cells, proliferate in response to Tat after exposure to inflammatory cytokines, whose levels are augmented in HIV-1-infected individuals and in KS lesions. Here we show that Tat also promotes AIDS-KS and normal vascular cells to migrate and to degrade the basement membrane and stimulates endothelial cell morphogenesis on a matrix substrate. These effects are obtained at picomolar concentrations of exogenous Tat and are promoted by the treatment of the cells with the same inflammatory cytokines stimulating expression of the receptors for Tat, the integrins alpha 5 beta 1 and alpha v beta 3. Thus, under specific circumstances, Tat has angiogenic properties. As Tat and its receptors are present in AIDS-KS lesions, these data may explain some of the mechanisms by which Tat can induce angiogenesis and cooperate in the development of AIDS-KS.

Epidermoid cysts are about 1 % of all testicular tumours. The Authors report a case observed at their Urological Department and justify the choice of radical surgical treatment due to the possible malignancy of the lesion, which could not be ascertained through the diagnostic means available; overall the Authors analyse critically the rationale for conservative surgical management.

During the last 10 years, 18 patients affected by kidney neoplasia have been operated on conservatively (2 patients with bilateral carcinoma, 1 patient with damaged controlateral kidney, and 15 patients with controlateral healthy kidney). All the tumors were smaller than 5 cm. In 14 cases the histological examination showed the tumor as being renal cell carcinoma, in 3 cases oncocytoma and in 1 case angiomyolipoma. All the patients had a normal post operative course and are alive with a mean follow up of 21.1 months.

Reports on the establishment and characterization of two Kaposi's sarcoma (KS) cells from cultures obtained from patients with AIDS and in a non-AIDS patient. KS as an opportunistic lesion in HIV-positive patients; KS description; Relationship between KS and immune deficiency virus infection; Characteristics of KS lesions; Testing of angiogenic response from KS-cell supernatants.

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Neoangiogenesis, the formation of new capillary vessels, is essential for tumor growth and the formation of metastases. This process requires that the activated endothelial cells invade their own basement membrane. We have used the reconstituted basement membrane Matrigel model (Albini et al., Cancer Res. 47: 3239, 1987) to study endothelial cell (EC) invasion in vitro. Supernatants (CM) of cells from Kaposi's sarcoma (KS), a highly angiogenic neoplasm strongly induce EC invasiveness. The activity of gelatinase-A, an enzyme closely linked with the invasive phenotype of metastatic cells, is enhanced in endothelial cells treated with KS-CM. Exogenous TIMP-2 is capable of suppressing endothelial cell invasion stimulated by KS products. Inhibition is also induced by a synthetic peptide from the propeptide region of gelatinase A, containing a conserved unpaired cysteine residue. bFGF (a product of KS cells) as well as KS-CM are strongly angiogenic in the matrigel sponge model in vivo. TIMP-2 can suppress bFGF induced neovascularization of the sponges and inhibits KS products associated angiogenesis. Histological examination shows that no endothelial cells were present in the TIMP-2 treated bFGF sponges, confirming that endothelial cell invasiveness is necessary for tumor angiogenesis. We are now attempting to use N-acetyl-cysteine, a chemopreventive agent which also interferes with metalloprotease activity, as potential antiangiogenic drug (AIDS & CNR grants)

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