Sarcoma De Kaposo

Somatostatin controls Kaposi’s sarcoma tumor growth through inhibition of angiogenesis
A. ALBINI,*,1 T. FLORIO,†,‡ D. GIUNCIUGLIO,*,‡ L. MASIELLO,* S. CARLONE,*,‡ A. CORSARO,†,‡ S. THELLUNG,†,‡ T. CAI,* D. M. NOONAN,* AND G. SCHETTINI§,†,‡ *Modulo Progressione Neoplastica, the §Servizio di Farmacologia e Neuroscienze, Istituto Nazionale per la Ricerca sul Cancro, the †Sezione di Farmacologia,Dept of Oncologia, Univ. of Genova, and the ‡Centro di Biotecnologie Avanzate, 16132 Genova, Italy
ABSTRACT Somatostatin and its analogs are active in the inhibition of SST receptor-positive endocrine neoplasms, but their activity and mechanism in nonendocrine tumors is not clear. Somatostatin potently inhibited growth of a Kaposi’s sarcoma xenograft in nude mice, yet in vitro the tumor cells didnot express any known somatostatin receptors and were not growth inhibited by somatostatin. Histological examination revealed limited vascularization in the somatostatin-treated tumors as compared with the controls. Somatostatin was a potent inhibitor of angiogenesis in an in vivo assay. In vitro, somatostatin inhibited endothelial cell growth and invasion. Migration of monocytes, importantmediators of the angiogenic cascade, was also inhibited by somatostatin. Both cells types expressed somatostatin receptor mRNAs. These data demonstrate that somatostatin is a potent antitumor angiogenesis compound directly affecting both endothelial and monocytic cells. The debated function of somatostatin in tumor treatment and the design of therapeutic protocols should be reexamined considering thesedata.—Albini, A., Florio, T., Giunciuglio, D., Masiello, L., Carlone, S., Corsaro, A., Thellung, S., Cai, T., Noonan, D. M., Schettini, G. Somatostatin controls Kaposi’s sarcoma tumor growth through inhibition of angiogenesis. FASEB J. 13, 647– 655 (1999)

Key Words: endothelial cells monocytes macrophages invasion neovascularization somatostatin receptors

It is well established that tumorneovascularization is necessary for tumor growth and metastatic dissemination (1). A critical step in the process of neovascularization is local stimulation of endothelial cells by cytokines produced by inflammatory and tumor cells. The endothelial cells then lose their contact inhibition, migrate and breach the basement membrane, proliferate, and differentiate to organize new vessels (2). Stimulationof endothelial cells by tumor cells is due to an alteration in the balance of angiogenic and antiangiogenic factors (1, 2). It has become evident that certain drugs with reported
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antitumor activity have angiogenesis as one of their major targets. Several such factors are effective in maintaining tumor dormancy or even inducing tumor regression (1, 3–5).Somatostatin, a regulatory peptide originally described as an inhibitor of somatotropin release, has a wide range of activities (see ref 6 for review). Somatostatin and its analogs seem to be active in the inhibition of certain tumors (7, 8). This cyclic peptide binds to seven transmembrane domain, G-protein-coupled receptors that transduce a variety of signals. At least five somatostatin receptorsubtypes have been cloned and characterized (9). All five of these receptor subtypes bind somatostatin 14 and somatostatin 28 (9). The somatostatin receptors have been reported to affect many different intracellular pathways. For instance, somatostatin has been reported to inhibit cAMP formation, L-type calcium channel activity, and to activate K channels (6). In the past few years it has beendemonstrated that different somatostatin receptor subtypes are able to induce a phosphotyrosine phosphatase activity that has been proposed to be responsible for the direct antiproliferative activity of this peptide (10, 11). Inhibitory effects of somatostatin on the growth of various normal and transformed cells have been reported (12–14). Tumors of endocrine origin respond to both the direct...