Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo

Abstract

IntroductionThe formation of new capillaries from pre-existing vessels (angiogenesis) appears to be essential for tumor growth and survival. [1][2][3][4][5][6] Whereas hypoxic conditions in expanding tumors often initiate a cascade of endothelial cell sprouting and formation of new vessels, tumor growth can be arrested by inadequate blood supply and a lack of metabolic exchange, often leading to tumor necrosis and regression. 7 Several tumor-derived, circulating angiogenesis inhibitors generated in vivo by proteolytic degradation have been recently identified (reviewed in Cao 8 and Marneros and Olsen 9 ). In particular, a 20-kDa C-terminal proteolytic fragment of collagen XVIII, termed endostatin, inhibits tumor growth in several animal models. [10][11][12][13][14][15] Although the mechanisms of action are incompletely understood, endostatin reportedly interacts with several endothelial cell-surface receptors that are critically involved in angiogenesis. Endostatin binds directly to the fibronectin receptor ␣ 5 ␤ 1 16,17 and also interacts with ␣ v ␤ 3 and ␣ v ␤ 5 integrins. 17 In keeping with these interactions, endostatin inhibits endothelial cell binding to the ␣ v ␤ 3 -ligand gelatin 17 and also their binding to collagen type I in a dose-dependent manner. 18 Moreover, endostatin binds to heparan sulfate, [19][20][21][22] tropomyosin, 23 caveolin-1, 16 VEGFR-1 (vascular endothelial growth factor receptor-1; Flt-1), and VEGFR-2 (Flk-1) 24 and was recently shown to depend on E-selectin expression to be effective in vivo. 25 Interaction of endostatin with endothelial cells leads to a variety of downstream effects, [26][27][28] including inhibition of the Wnt/␤-catenin pathway, 29 and actin reorganization in endothelial cells. 16,[30][31][32][33] In fact, this wide variety of effects elicited by 1 endogenous inhibitor of angiogenesis was recently supported by 2 studies of global gene expression in endostatin-treated endothelial cells. 27,34 There is general agreement that the in vitro action of endostatin involves inhibition of endothelial cell migration, but less clear whether endostatin also affects endothelial cell apoptosis and proliferation. 6,12,26,[35][36][37][38][39] Furthermore, even less is known about how endostatin affects endothelial cell function in vivo, as readouts have been restricted to analysis of vascular density or blood flow in tumors, [12][13][14]35,40 or neovascularization of the chick allantoic membrane. 10,12,39 Moreover, studies that focused in more detail on endothelial cell behavior in vivo either failed to detect substantial effects of endostatin 41 or found subtle signs of impaired blood vessel maturation. 42 Finally, several studies failed to observe an antitumor effect of endostatin (reviewed in Marshall 43 ). Thus, there is an obvious need to more carefully analyze the effect of endostatin at the level of single endothelial cells during angiogenesis.Here, we describe the effect of endostatin in an in vivo model of human endothelial cell behavior in which the final stages of angio...

Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer

“…This aspect gains support by an observation that breast cancer patients with elevated endostatin levels following surgery showed a lower risk of relapse (Zhao et al, 2004). Further, a recent publication showed that endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis and perivascular cell recruitment in vivo (Skovseth et al, 2005). These findings underscore the impact of endostatin on endothelial cells in vivo and sustain the hypothesis of a direct relationship between lowered CEC levels and elevated serum endostatin.…”

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

“…As an endogenous antiangiogenic protein, ES inhibits endothelial cell proliferation and tube formation (8,9). Since Judah Folkman's laboratory first identified ES (10,11), anticancer effects of ES have been extensively studied in both tumors and tumor-associated endothelia (8,(12)(13)(14).…”

Enhanced antiangiogenic therapy with antibody‐collagen XVIII NC1 domain fusion proteins engineered to exploit matrix remodeling events

“…12 The complexity of the ES action mechanism is supported by genome-wide expression profiling studies 13,14 and a recently published work in a surrogate model of human angiogenesis, where ES inhibited EC migration, capillary morphogenesis and perivascular cell recruitment. 15 Given that the combination of antiangiogenic agents with distinct modes of action may result in synergistic effects, 2 we reasoned that a combined therapy with L36 and ES could exhibit greater tumor inhibitory effects than do antibody and ES individually. In this study, we have explored new approaches to combine both activities in one active compound.…”