Abstract
BackgroundThe importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity.MethodsThe in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse.ResultsHB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice.ConclusionsAlthough HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma.
Highlights
The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis
HB-19 delays significantly development of spontaneous melanoma in RET mice To evaluate the in vivo anti-tumor effect of HB-19 on the natural course of melanoma progression, RET mice were treated in a prophylactic setting that extended 300 days as described in Methods
Angiogenesis quantified by image analysis of CD34-labeled endothelial cells showed that HB-19 induced a reduction of 51% in microvessel density compared to control tumors
Summary
The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. Nucleolin is an abundant DNA-, RNA- and protein-binding protein ubiquitously expressed in exponentially growing eukaryotic cells. It is found at several locations in cells: in the nucleolus it controls many aspects of DNA and RNA metabolism; in the cytoplasm it shuttles pro-. Emerging evidences highlight the importance of the cell-surface expressed nucleolin in cell proliferation, tumor cell growth and angiogenesis [3,10,11,12,13,14]. Other surface nucleolin binding proteins such as laminin-1, factor J, L- and P-selectins, and hepatocyte growth factor are involved in tumor development, induce cell differentiation, regulate cell adhesion, leukocyte trafficking, inflammation and angiogenesis [19,20,21,22,23]. Ligand binding results in clustering of cell-surface nucleolin in lipid raft membrane microdomains before endocytosis of the ligand-nucleolin complex by an active process [5,24,25]
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