Vascular cell adhesion molecules, P-and L-selectins, facilitate metastasis of cancer cells in mice by mediating interactions with platelets, endothelium, and leukocytes. Heparanase is an endoglycosidase that degrades heparan sulfate of extracellular matrix, thereby promoting tumor invasion and metastasis. Heparin is known to efficiently attenuate metastasis in different tumor models. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanase-specific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P-and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanasespecific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P-and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase.-Hostettler, N., Naggi, A., Torri, G., IshaiMichaeli, R., Casu, B., Vlodavsky, I., Borsig, L. Pselectin-and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FA...
Background: G lucoco rti coids (GC) a re pote nt a nti -inflam matory a nd immunosuppress ive stero id ho rm ones, mainl y produced by the adrena l gla nd s. H o wever, increas ing evidence suppo rts th e id ea o f additi ona l ex tra-a drenal so urces o f bi oacli ve G c. The lung epithelium is co nsta ntly exposed to a pl eth ora of a ntigenic stimuli , and local GC sy nthesis co uld co ntribu te to limit unco ntrolled immune rea cti o ns a nd ti ss ue da mage. Methods: Expression o f steroid ogeni c enzymes a nd GC synthesis in ex vivo o rga n cultures was studied in mo use lun g tiss ue after in vivo stimul a ti o n o f immune cells. Results: M o use lung ti ss ue was fo und to express steroid ogenic enzymes required fo r the sy nthesis of co rticostero ne from cholesterol a nd to sy nthesize co rti cos tero ne in la rge qu a ntities a fter immune cell activa tion by a nti-C D3 antibody, lipo pol ysaccharide, o r TNFa. In ma rk ed co ntras t, ova lbumin-ind uced all ergic a irway infla mm a ti o n failed to promo te lung G C sy nthes is. Altho ugh the lung ex presses all steroid ogenic enzymes necessa ry fo r de no vo synthesis o f co rti cos terone from ch o les tero l, functio nal da ta indi ca ted th a t ina cti ve se rum -deri ved dehyd roco rti costerone is converted to ac tive co rti coste rone by II p-hydroxystero id dehydroge na se I. Conclusion: Our res ults suppo rt the no tion tha t loca l GC synthesis represe nts a novel immunoreg ul a tory mechani sm to limit unco ntroll ed immune respo nses in the lung a nd indi ca te th a t defecti ve local stero idoge nesis may co ntribute to the p a th ogenes is of a llergic airway infl a mm ation.
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