1. Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth.
- Author
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Pike SE, Yao L, Setsuda J, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Atreya CD, Teruya-Feldstein J, Wirth P, Gupta G, and Tosato G
- Subjects
- Animals, Antineoplastic Agents pharmacology, Burkitt Lymphoma drug therapy, Calcium-Binding Proteins chemistry, Calcium-Binding Proteins therapeutic use, Calreticulin, Cattle, Cell Division drug effects, Cells, Cultured, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Female, Heart, Humans, Mice, Mice, Nude, Neovascularization, Pathologic pathology, Neovascularization, Pathologic prevention & control, Peptide Fragments therapeutic use, Recombinant Proteins pharmacology, Ribonucleoproteins chemistry, Ribonucleoproteins therapeutic use, Transplantation, Heterologous, Tumor Cells, Cultured, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents therapeutic use, Burkitt Lymphoma pathology, Calcium-Binding Proteins pharmacology, Calcium-Binding Proteins toxicity, Endothelium, Vascular physiology, Neovascularization, Physiologic drug effects, Peptide Fragments pharmacology, Peptide Fragments toxicity, Ribonucleoproteins pharmacology, Ribonucleoproteins toxicity
- Abstract
Several angiogenesis inhibitors are fragments of larger proteins that are themselves not active as angiogenesis inhibitors. Vasostatin, the N-terminal domain of calreticulin inclusive of amino acids 1-180, is an angiogenesis inhibitor that exerts antitumor effects in vivo. In the present study, we examined whether the full-length calreticulin molecule shares the antiangiogenic and antitumor activities of vasostatin. Similar to vasostatin, calreticulin selectively inhibited endothelial cell proliferation in vitro, but not cells of other lineages, and suppressed angiogenesis in vivo. When inoculated into athymic mice, calreticulin inhibited Burkitt tumor growth comparably with vasostatin. Calreticulin lacking the N-terminal 1-120 amino acids inhibited endothelial cell proliferation in vitro and Burkitt tumor growth in vivo comparably with vasostatin. An internal calreticulin fragment encompassing amino acids 120-180 also inhibited endothelial cell proliferation in vitro and angiogenesis in vivo comparably with calreticulin and vasostatin. These results suggest that the antiangiogenic activities of vasostatin reside in a domain that is accessible from the full-length calreticulin molecule and localize to calreticulin N-terminal amino acids 120-180. Thus, calreticulin and calreticulin fragments are inhibitors of angiogenesis that directly target endothelial cells, inhibit angiogenesis, and suppress tumor growth. This information may be critical in designing targeted inhibitors of pathological angiogenesis that underlies cancer and other diseases.
- Published
- 1999