Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells

• Published in: Annals of surgical oncology 2006-01, Vol.13 (1), p.125-133
• Main Authors: Feldman, Elizabeth D, Weinreich, David M, Carroll, Nancy M, Burness, Monika L, Feldman, Andrew L, Turner, Ewa, Xu, Hui, Alexander, Jr, H Richard
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Alternative splicing; Angiogenesis Inhibitors - pharmacology; Animal models; Animals; Antitumor activity; Apoptosis; Cell Proliferation; Chemokine CXCL10; Chemokines, CXC - pharmacology; Endothelial cells; Female; Fibroblasts; Fibroblasts - drug effects; Gene expression; Growth rate; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; IP-10 protein; Lymphocytes T; Melanoma; Melanoma - drug therapy; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Polymerase chain reaction; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA-directed DNA polymerase; Tumor cell lines; Tumor Cells, Cultured; Umbilical vein; Umbilical Veins - cytology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - physiology; Xenografts; γ-Interferon
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/ASO.2006.03.038

Interferon gamma-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was >40 in HUVECs, compared with