NM23 deficiency promotes metastasis in a UV radiation-induced mouse model of human melanoma.
Cutaneous malignant melanoma is the most lethal form of skin cancer, with 5-year survival rates of <5 % for patients presenting with metastatic disease. Mechanisms underlying metastatic spread of UVR-induced melanoma are not well understood, in part due to a paucity of animal models that accurately recapitulate the disease in its advanced forms. We have employed a transgenic mouse strain harboring a tandem deletion of the nm23-m1 and nm23-m2 genes to assess the combined contribution of these genes to suppression of melanoma metastasis. Crossing of the nm23-h1/nm23-h2 knockout in hemizygous-null form ([m1m2](+/-)) to a transgenic mouse strain (hepatocyte growth factor/scatter factor-overexpressing, or HGF(+) strain) vulnerable to poorly-metastatic, UVR-induced melanomas resulted in UVR-induced melanomas with high metastatic potential. Metastasis to draining lymph nodes was seen in almost all cases of back skin melanomas, while aggressive metastasis to lung, thoracic cavity, liver and bone also occurred. Interestingly, no differences were observed in the invasive characteristics of primary melanomas of HGF(+) and HGF(+) × [m1m2](+/-) strains, with both exhibiting invasion into the dermis and subcutis, indicating factors other than simple invasive activity were responsible for metastasis of HGF(+) × [m1m2](+/-) melanomas. Stable cell lines were established from the primary and metastatic melanoma lesions from these mice, with HGF(+) × [m1m2](+/-) lines exhibiting increased single cell migration and genomic instability. These studies demonstrate for the first time in vivo a potent metastasis suppressor activity of NM23 in UVR-induced melanoma, and have provided new tools for identifying molecular mechanisms that underlie melanoma metastasis.
Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
Stuart G
SG
Jarrett
Marian
M
Novak
Nathan
N
Harris
Glenn
G
Merlino
Andrezj
A
Slominski
David M
DM
Kaetzel
D000818:Animals; D002465:Cell Movement; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D042822:Genomic Instability; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology* / Q000556:secondary; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014945:Wound Healing
D054778:NM23 Nucleoside Diphosphate Kinases; D017228:Hepatocyte Growth Factor; D007041:Hypoxanthine Phosphoribosyltransferase; C517939:Nme1 protein, mouse