Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice.
BACKGROUND
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. 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.


METHODS
The 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.


RESULTS
HB-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-alpha in the TIII cells and in melanoma tumors of RET mice.


CONCLUSIONS
Although 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.
El Khoury
Diala
D
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 27 rue du Faubourg Saint-Jacques, 75014 Paris, France.
Destouches
Damien
D
Lengagne
Renée
R
Krust
Bernard
B
Hamma-Kourbali
Yamina
Y
Garcette
Marylène
M
Niro
Sandra
S
Kato
Masashi
M
Briand
Jean-Paul
JP
Courty
José
J
Hovanessian
Ara G
AG
Prévost-Blondel
Armelle
A
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D000097796:Nucleolin
D010446:Peptide Fragments; D010750:Phosphoproteins; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin