ABSTRACT
Head and neck cancers are significant due to their high morbidity and associated complications. We report, for the first time, that endostatin directly affects epithelial lineage human cells derived from tumors of patients with head and neck squamous cell carcinoma (HNSCC). This study investigated endostatin's effects on several HNSCC cellular functions that are essential for tumor progression. We determined that exposure of HNSCC cells to endostatin activated the transcription-activating factors, NF-xB and AP-1 in a cell-line-dependent fashion. Endostatin also down-regulated the gene expression of several pro-migratory molecules. Migration and invasion assays showed that endostatin significantly inhibited these functions that are essential for tumor progression. Fluorescent labeling studies showed endostatin co-localized to tropomysin-binding HNSCC the microfilaments, suggesting endostatin's suppression of HNSCC cell migration and invasion may reflect perturbation of the microfilament function. Our data imply that endostatin's clinical efficacy extends beyond angiostatic properties to encompass a direct anti-tumorigenic effect against HNSCC cells.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Squamous Cell/pathology , Collagen/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Peptide Fragments/pharmacology , Tongue Neoplasms/pathology , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Adult , Aged , Antineoplastic Agents/metabolism , Cell Movement/drug effects , Collagen/metabolism , Depression, Chemical , Endostatins , Epidermal Growth Factor/pharmacology , Humans , Integrins/biosynthesis , Integrins/genetics , Male , Matrix Metalloproteinase 10 , Metalloendopeptidases/biosynthesis , Metalloendopeptidases/genetics , Middle Aged , NF-kappa B/metabolism , Neoplasm Invasiveness , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Peptide Fragments/metabolism , Tissue Inhibitor of Metalloproteinase-2/biosynthesis , Tissue Inhibitor of Metalloproteinase-2/genetics , Transcription Factor AP-1/metabolism , Transcription, Genetic/drug effects , Tropomyosin/metabolism , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effectsABSTRACT
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.
