AIDS‐related Kaposi's sarcoma cells rapidly internalize endostatin, which co‐localizes to tropomysin microfilaments and inhibits cytokine‐mediated migration and invasion

Abstract

AIDS-related Kaposi's sarcoma (KS) is the most common HIV-related malignancy. In some respects, KS is analogous to other angioproliferative diseases, in that KS lesions are highly vascularized and promoted by inflammatory cytokines. However, unlike other cancers or inflammatory mediated vascular diseases, KS is unique in that the KS lesional cells both express and respond to the complete angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Therefore, the angiogenic phenotype, which is crucial for cancer progression, is inherent to KS tumor cells. Due to the recognized importance of angiogenesis in cancer progression, numerous angiostatic agents are being investigated as potential therapeutic agents. One such agent is endostatin, which is a 20-kDa carboxyl-terminal fragment of collagen XVIII that has demonstrated potent angiostatic activities at both the in vivo and in vitro levels. Since endostatin is recognized as a potent angiostatic agent, the majority of in vitro endostatin studies have evaluated its effects on endothelial cells. Although KS cells are speculated to arise from endothelial cell precursors and KS lesions are highly vascularized, no previous studies have investigated endostatin-KS cell interactions. This present study evaluated endostatin's effects on KS tumor cell: (i) signal transduction (endostatin internalization and transcription factor activation), and (ii) migration and invasion (functional activity assays and tropomysin co-localization). Our results show that KS cells rapidly internalize endostatin and that endostatin initiates activation of the transcription activating factors nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1). Our data also show that internalized endostatin co-localizes to tropomysin microfilaments and acts to inhibit KS cell migration and invasion in response to the clinically relevant angiogenic cytokines VEGF and bFGF. As a consequence of its combined angiostatic and antitumorigenic activities, endostatin could provide dual therapeutic benefits for patients with mucocutaneous KS.